Fig.No.1 :Alopecia Aereta in Male and Female
Fabtech College of Pharmacy Sangola, Solapur, Maharashtra-413307
[authorID1] => [authorID2] => [authorID3] => [authorID4] => [authorID5] => [authorID6] => [authorID7] => [authorID8] => [authorID9] => [authorID10] => [createdDate] => 2025-12-26 00:00:00 [createdByUserID] => 1 [updatedDate] => 2025-12-26 18:00:40 [updatedByUserID] => 0 [isActive] => 1 [titleOfPaperOne] => The Review on Alopecia Areata A Comprehensive Review of Pathogenesis Diagnosis Clinical Pattern and Remedies [txtBody] =>Alopecia areata (AA) is a prevalent, immunological-mediated, Non-scarring alopecia with a clinically varying range. Alopecia totalis or alopecia universalis can influence the entire head or body, or it may just impact one or more prominent, identifiable round or oval regions of loss of hair on your head or skin.[1] Additionally, the course of the condition is unexpected; renewed episodes can occur at any time, and 80% people suffer spontaneously development of hair in the initial year. [2, 3] The subgroups of total hair loss and universalized alopecia have a poor prognosis because,well as aspects such related nail lesions, hair loss that has lasted longer than ten years, and a positive family history. In addition to making it a mental difficulty, AA sufferers are more likely than the general population to experience anxiety and depression. (4)" Research on immune system and genetic factor, specifically in area of dentritics units, is advised for AA because there is poof that DC may be used to treat other autoimmune disorders like cancer and multiple sclerosis. Promising therapies for AA therapy include PRP and JAK-STAT inhibitors. The disorder unclear pathologic mechanisms and variable remission rates make it difficult to implement and assess treatment procedures for AA. [5] Although dermatologic application medications been utilised for Alopecia areate, the effectiveness of these therapies varies greatly, and the therapy should also address the client psychosocial necessary which makes care extra challenging[6 ]
The recommended course of treatment includes corticosteroid therapy. For patients with mild to moderate AA, topical and intralesional corticosteroids are both suitable and efficacious. [7,8]
It is more difficult to treat severe AA conditions such as alopecia universalis, totalis, and ophiasis.[9] In these patients, systemic corticosteroids are typically beneficial and can be given intravenously, orally, or intramuscularly. [10].
Fig.No.1 :Alopecia Aereta in Male and Female
HISTORICAL BACKGROUND :
Alopecia Areata's Historical Context One of the earliest known dermatological conditions is alopecia areata (AA), which has been described for several millennia. There are allusions to AA-like patchy, non-scarring hair loss in ancient Egyptian, Greek, and Roman medical texts. Inspired by the patchy hair loss observed in fox mange, the word alopecia is derived from the Greek word "alopex" (fox). Early Accounts (Ancient to Medieval Period) Hippocrates (5th century BCE) and Galen (2nd century CE) recorded instances of abrupt, confined hair loss that closely resemble contemporary accounts of alopecia areata. Due to similar clinical features, the illness was frequently mistaken for infectious causes in the Middle Ages, particularly tinea capitis.[11]
CLINICLE PRESENTATION :
Alopecia areata can appear clinically in a variety of ways both within and between individuals. Clinically, the illness is divided into multiple variations according on the outer skin layer affected, pattern, and the level of hair loss. Table 1
Table 1. Alopecia areata clinical variations and their distinctive symptoms
|
Clinical variations of alopecia areata |
Feature |
|
Patchy alopecia areata |
Most common type; well-defined,Circular or elliptical areas ,Reduced hair density or other hair-bearing areas. |
|
Alopecia totalis |
Entire scalp hair fall , progression from patchy alopecia. |
|
Alopecia universalis |
Complete Total loss of all body including scalp, eyebrows, eyelashes, beard, and body hair. |
|
Ophiasis alopecia areata |
Linear pattern hair loss along temporal sides and occipital base of the scalp margins (“snake-like” pattern); often resistant to treatment. |
|
Inverse-ophiasis (or sisaipho) alopecia areata |
Opposite of ophiasis; sparing temporal and occipital margins, with hair loss in central/scalp vertex areas. |
|
Diffuse alopecia areata/ Alopecia areata incognita |
Sudden, widespread thinning of scalp hair resembling telogen effluvium; difficult to diagnose without biopsy. |
|
Reticular Alopecia areata |
Net-like or patchy, interconnecting pattern of hair loss. |
|
Marie-Antoinette Syndrome |
Abrupt whitening of hair due to preferential loss of pigmented hair shafts (sparing white hairs). |
A number of localized regions of head hair loss are the hallmark of patchy AA, which is the most prevalent kind of AA (Fig.2a). These irregular regions could be distinct, stand alone, or merge with neighboring lesions to form a larger, hairless area. The skin inside the lesions is smooth, healthy-looking, and intact, despite the rare little edema that is palpable but doesn’t show up as redness or other signs of infection. Based on the activity of the condition, an area may grow in width or stay the same shape. Additionally, it could naturally cure and either entirely or in part regrow. Baldness or alopecia universalis , a form of which is the complete absence of scalp scalp hair, can result from patchy alopecia Areata. May lead to a condition called alopecia totalis , characterized by an overall reduction in head hair, or alopecia universalis , or is a total lack of all body hair (Fig. 2b). These are more clinically types of alopecia areata of the head because it can manifest in various manners.[12]
Fig.No:2
The opposite disorder, known as sisaipho or inverse-ophiasis type, is characterised by central hair loss that resembles androgenetic alopecia. One uncommon, Non-localized variant of Alopecia Areata that is frequently Incorrectly diagnosed or has a noticeably delayed diagnosis is diffuse alopecia areata (DAA), also known as alopecia areata incognita (AAI). Women aged 20 to 40 are more likely to suffer from diffuse AA, which is typified by diffuse hair loss [13,14]
EPIDEMIOLOGY :
The second most common reason of hair loss after androgenetic A is AA [15] , affecting 2% of people worldwide, and its frequency is rising. [16] Ophiasis type, alopecia totalis , and alopecia universalis are less common than severe Alopecia Areta symptoms and specific Medical subtypes, with respective prevalences of 0.02%, 0.08 percent, and 0.03%. Both sexes seem to be equally affected by alopecia areata, which can happen to anyone of any age or origin. Compared to adults, young people are more likely to have AA. Additionally, AA is more prevalent among African or African American communities than in Asian and Asian groups, according to recent studies.(17)
Epidemiology : based on sex
The two population studies did not find any discernible variation the occurrence of alopecia areata in both genders [18,19] According to reports, male patients had been identified with AA earlier than female patients.[20] 4 Certain research indicates that there are not statistically reliable variations in duration, or years of AA onset by sex or race.[21]
Epidemiology : based on age
Generally younger age groups have been more likely to be members of AA. The age group that presented for care the most frequently was twenty one–fourty years old, followed by one–twenty years old, fourty one–sixty years old, and 61–80years old.Similarly, the age groups of 31–35 and 30–59 have been found to have the highest rates of AA visits. In 82.6% to 88% of cases, AA patients initially develop the disease by the age of 40, and in 40.2% of cases, it occurs by the age of 20. Table No. shows that the average age at which onset occurs has been found between twenty five. five and thirty six. Three years .Different reports have indicated that the age of onset for females is lower (24.2 vs 26.7 years),the same for males (20),and higher(36.2 vs 31.5 years ).It has been found that the mean year of onset in youngsters is between the years of 5 &10 .[22]
EPIDEMIOLOGY :based on body part
The head is the mainly affected area, either alone or in conjunction with other body parts (such the beard, eyelashes, and eyebrows).[23] In particular, the occipital area was the most frequently affected site, occurring in 33.4% of females and 38.4% of males.[24] 58% of adult patients reported patchy hair loss on initial presentation, affecting less than half of the scalp.[25]
PROGNOSIS :
The illness has an uncertain prognosis. Thirty four% to fifty % of patients recoverd in a year, according to current data, while 14% to 25% of patients advance to AT or AU, where they hardly ever totally recover. Twelve of the seventy patients with AT/AU (17.1%) who had their charts reviewed retrospectively over a ten-year period showed full hair regrowth. Out of seventy patients with alopecia areata, 17 (24.2%) recorded getting at least ninety percent of their hair back. Five patients with AT (20.8%) and thirty with AU (65.2%) did not exhibit any improvement in their hair growth. Patients may experience multiple Period of hair fall followed by regrowth over the activity of their lifetimes. The following factors are linked to bad prognosis: a history of atopy, early year at onset, Nail disorder ,significant hair fall, Occipital–temporal alopecia pattern or the presence of other autoimmune illnesses. [26]
DIAGNOSIS :
The disorder is generally recognized by clinically, and findings like a +ve trichoscopy or Performing a pull test could aid. Active illness is identified on trichoscopy by breaked hairs, "exclamation mark" or thinning hair, dark spots, and yellow spots. Another sign of AA is vellus hair in lesions, which could be an indication of inactive or late illness. A biopsy may be performed in circumstances that are unclear.[27]
HISTOPATHOPHYSIOLOGY :
The disease's histology will change depending on its stage. A peribulbar lymphocytic infiltration in the acute and subacute phases is characterised by a "swarm of bees" pattern of CD4+ and CD8+ T-cells surrounding a growing hair follicle Furthermore, follicle miniaturisation occurs as the hair development stage transitions from the catagen to the telogen (resting) phase. The hair follicles may be surrounded by macrophases, foreign body giant cells, oedema, microvesiculation and apoptosis. In the chronic stage, pigmentary incontinence occurs, the amount of catagen or telogen hair grows, and the inflammation may or may not go away .[28]
PATHOPHYSIOLOGY :
At this time, the precise diseases condition of the illness is unspecified. But there is evidence that Alopecia Areta is brought on by autoimmune response to hair follicles that results from a combination of environmental and hereditary causes.[29]
A unique type of microorgan, the hair follicular (HF) undergoes a continuous, lifelong process of reproduction. The lower part of the good analog HF (the bulk and column) protects the follicle that produces hair from infection and promotes immunity due to its relative immune privilege (IP).[30]
Fig. No.3 : a. Healthy Hair Follicle
b. Alopecia Areata Hair Follicle
REMIDIES
Hair development is promoted by coconut oil, which improves the health of the scalp and hair. There are other nutrients that can help in growth. The oil that is derived from dried coconuts is called coconut oil. It has a white butter-like appearance at room temperature and melts when heated. Hair care, cosmetics, cooking, and food preparation all make great use of this natural oil. Several medical studies have shown the profit of coconut oil for the skin, hair, & body. Some people apply coconut oil to their scalp and hair because they believe it accelerates hair growth. We'll see whether we can accomplish this.
Research on the connection between hair growth and coconut oil is nonexistent. However, coconut oil is beneficial the hair & scalp. As a result, the hair will grow faster.[31,32]
Fig. No. 4: Coconut oil
Hair loss is a major problem among numerous younger girls and women. The hair problem is not brand-new, but it has evolved over the past few years. Fast-paced lifestyles, increased stress levels, and pollution have made hair loss more of a problem. Every day, we hear women and girls talking about hair difficulties in casual conversations and on social media. Thanks to natural medicine, we can be saved! Do you remember your grandmother talking about how her mother used herbs to heal a range of illnesses? Or did your parent tell you about the hair remedies and treatments she tride when she was younger ? Natural hair treatments are always dependable because they have been proven to be easy , efficient , and successful .when use it with the appropriate hair treatment product , you won’t be concerned about hair loss anymore ! Over the year ,individuals have tride , tested , and verified the efficacy of numerous cures , such as dairy products, aloe vera ,and lemon. Because of its benefits and uses ,fenugreek stands out from other hair care products. [33]
Fig. No. 5: Fenugreek seed (Methi)
baldness is a major issue, and practically all women grow weary of keeping track of how much hair they lose each day. Dandruff, balding, thinning hair, and grey hair are just a few of the issues that accompany hair. Naturally, pollution is to blame for this, and regardless of our actions, we are constantly in contact with it. Use heat-resistant cosmetics or wrap our hair in a scarf to protect it. Hair loss is a major issue, and nearly all women grow weary of keeping track of how much hair they lose each day. Dandruff, balding, thinning hair, and grey hair are just a few of the issues that accompany hair.
Naturally, pollution is to fault for this, because we are constantly exposed to it regardless of our actions. Wrap our hair with a headscarf or use heat-resistant cosmetics to protect it.[34,35]
Fig.No. 6 :Onion Oil
4.Amla (Indian Gross Berry)
Five uses for amla in hair treatment :
Reducing Hair Loss with Amla: Consuming amla on a daily basis can make your hair seem amazing. Amla juice is also delicious.
Drinking is recommended for people who experience significant hair loss.
One glass of amla juice on without food each day.[36]
Amlicanemblica Juice Promotes Hair Growth: The straightforward yet potent amla tonic is for you if you're looking for thicker, stronger hair. Gently massage the scalp after applying freshly extracted amla juice. Rinse your hair well with a gentle shampoo after 50 to 60 minutes.[37]
Nourish with Lemon and Amla: It is thought that amla and lemon restore hair from its insides out. A mixture of freshly cut fruit juice and lemon juice makes a pleasant tonic. Put this remedy on your scalp. Let it sit for 30 minutes. To rinse your hair, use warm water.[38]
Use Alma water to wash your hair. Add a couple of freshly crushed amla in a water dish. Let the water come to a boil. Give the water at least thirty to forty minutes to cool and drain. Dried gooseberry slices can be soaked in water for a whole night.
For optimum results, clean your hair with such water every day.[39]
Use Shiitake and Amla for Strong Hair: It's well known that shiitake and amla mushrooms support healthy hair. Make a hair mask with powdered shiitake mushrooms and amla. Add water and carefully stir. Use the mask and keep it on for 30 minutes if you have lengthy hair. Rinse your hair well with cold water. Use this combination to help control hair loss .[40]
Fig . No.7: Indian Gross Berry (Amla)
5. Aloevera Hair Mask
Aloe Vera Hair Mask Benefits: Aloe Vera's anti-inflammatory properties reduce skin inflammation. The fatty acids and enzymes in aloe vera help to reduce inflammation. Its moisturising qualities are beneficial to dull, dry hair. In addition, aloe vera contains vitamin C, folate, and choline to support good hair. It is known as an organic hair cleanser since it eliminates dead tissue, excess filth, sebum, and dirt from the scalp and hair. Aloe vera keeps the scalp clear and helps prevent dandruff. Aloe vera hair mask's many antibacterial, antifungal, and antiviral properties help to eliminate microbial illnesses in the hair.
It also protects the hair by fortifying the hair roots. Additionally, aloe vera has components that encourage hair development. Your scalp's pH balance is restored by using an aloe vera hair mask. Your mane will appear glossy if you use an aloevera hair mask for curly hair.
Aloe vera hair masks and shampoos have a variety of uses. Among the possibilities that can be prepared at home are egg and aloe hair masks and coconut and aloe hair treatments.[41,42]
Fig.No.8; Aloevera Hair Mask
Fig .NO.9: Aloevera Hair Mask
CONCLUSION:
The immune-mediated, multifactorial condition known as alopecia areata still poses serious therapeutic and psychological difficulties. Its unpredictable course, fluctuating diagnosis, and frequent relapses necessitate a personalised and all-encompassing management approach, even though it is non-scarring and frequently reversible. Results and standards of life can be enhanced by timely diagnosis and suitable intervention. New treatments like as JAK inhibition, PRP medications, and immune-modulating agents have had encouraging outcomes in resistant cases, but corticosteroids continue to be the cornerstone of care. By enhancing scalp health and fortifying hair follicles, natural therapies like oil of coconut, fenugreek seed, onions oil, amla, and aloe vera may offer additional benefits in addition to medical care. However, additional clinical verification through controlled trials is needed to confirm their effectiveness.
REFERENCE
Valmik Naik College of Pharmacy, Telwadi, Kannad Chh. Sambhaji Nagar.
[authorID1] => [authorID2] => [authorID3] => [authorID4] => [authorID5] => [authorID6] => [authorID7] => [authorID8] => [authorID9] => [authorID10] => [createdDate] => 2025-12-08 00:00:00 [createdByUserID] => 1 [updatedDate] => 2025-12-08 06:50:17 [updatedByUserID] => 0 [isActive] => 1 [titleOfPaperOne] => Diagnosis Prevention and Treatment of Scabies [txtBody] =>Aristotle and the Old Testament were the first to describe scabies.Sarcoptes scabiei gets its name from the Latin word “scabere,” which means to scratch, and the Greek words “sarx,” which means flesh, and “koptein,” which means to cut. The mite that causes scabies is an ectoparasite infection; it was isolated from human skin and identified by Bonomo in 1687. Renucci in Paris in 1814 demonstrated the disease in vivo and using light microscopy that same year (1–3).
Grouping The mite S. scabiei var hominis is the cause of the illness (2). S. scabiei is a 300–400 mm arthropod that is an obli-gate human parasite (4). It belongs to the order Astigmata, family Sarcoptidae, class Arachnids, and subclass Acari. These are ovoid creatures with a little anterior head and a caudal thoraco-abdominal section. The primitive legs have hair-like projections on them.
The presence of a unique head with mouthparts known as gnatosoma and the absence of a separation between the abdomen and cephalothorax allow them to be clearly identified from other arachnids (2,5). The male mite is half the size of the female, which is 0.3–0.4 mm in size (FIG. 2) (6). The mating of an adult male mite with a female mite initiates the life cycle of S. scabiei. The adult male dies after mating, and the female mite spends four to six weeks in the skin burrow laying her eggs. The female may live for 24 to 36 hours at room temperature (8) and crawls at a speed of 2.5 cm/minute on warm skin, not going beyond the stratum granulosum (7).
[FIG.1] Scabie Mites, Ova Feces.
The female lays one to three eggs every day, which hatch after three to four days to generate adult larvae. Before molting into either males or females, the larvae go through two more developmental stages: protonymphs and tritonymphs. Eventually, these larvae pierce the burrow’s roof and emerge at the skin’s surface. The life cycle lasts anywhere from 30 to 60 days (8). All phases of life can enter through the intact epidermis by secreting enzymes that break down the skin, which is then consumed. In less than half an hour, the mites can penetrate the skin. The mite population can reach up to 500 mites after 50 days and up to 25 adult females during the first month of infection.100 days (9). Nonetheless, 10–12 mites are often present on a typical host (7). In general, mite populations drop down quickly after three months. The human immunological response and mechanical elimination of the mites by scratching are likely answers. One month following the first infestation, for instance, sensitivity to mite antigens can be seen (9).
The human-specific mite Sarcoptes scabiei var. hominis is the cause of scabies, a parasitic skin ailment. Since adult mites are only about 0.4 mm in size, imaging tools are needed to see them [10,11]. When a pregnant female mite burrows on the human epidermis and produces two to three eggs per day, the life cycle of a scabies infection begins. After 48 to 72 hours, the majority of eggs laid in the burrows develop into larvae. In 10–14 days, larvae dig more burrows and mature into adults. The life cycle is’then repeated by adult mites through reproduction. After the first infection, the incubation period is thought to last four to six weeks. Mostly by direct skin-to-skin contact [11-13], but infrequently through indirect contaminated fomites, especially in individuals with crusted scabies [5,6,8]. Not living.
[FIG.2] Sarcoptes Scabiei.
Scabies mites can survive in thehuman host for 24 to 36 hours at room temperature, which allows for additional infection [12,13]
The study of epidemiology Scabies ”reverence fluctuates. Prevalence among the general population has been found to range from 4 to 27% in certain underdeveloped nations. [14] While the frequency of scabies is similar across all age groups in industrialized countries, it tends to be higher in preschoolers and adolescents in undeveloped countries. [15, 16] The idea that scabies outbreaks happen in 30-year cycles because of shifts in the host population’s immunological status is no longer recognized. [17, 18] Andrews [19] has charted the available data and found that the two World Wars were accompanied by two pandemics. As observed in New Zealand and Germany in the 1930s, isolated and unconnected epidemics do occasionally occur in addition to these two pandemics. There is no discernible regular cycle in the incidence.
The human scabies mite, Sarcoptes scabiei varietas hominis, is the pathogen responsible for causing scabies. The female adult measures approx. About twice as large as the male mite, measuring 0.3×0.4 mm. On the heated surface of the body, these parasites can travel at a speed of about 2.5 cm per minute. In the stratum corneum, pregnant females excavate superficial passages known as burrows (about 0.5–5 mm every day) and typically remain there for the next four to six weeks of their lives, depositing two to three eggs every day (20,21). Non-ovicidal antiscabies medications must therefore stay in the epidermis for at least this long since the larvae that hatch from them two to three days later swarm out onto the cutaneous surface and mature into in hair follicles and skin folds into nymphs, which develop into sexually mature mites within 9–17 days and copulate (22,23) The cycle restarts when the pregnant female mites burrow back into the skin and the male mites die soon after.
Only around 11 adult female mites are identified on the skin surface after the Immune response starts, as opposed to the otherwise anticipated exponential rise, which is explained by the fact that many defensive systems kill scabies mites by mechanical and immunological ways( 22):
leukemia, lymphoma, HIV or HTLV-1 infection, graft-versus-host disease, congenital immune deficiencies, drug-induced (systemic and topical corticosteroids, immunosuppressants, cytostatic agents, biological agents), and Down syndrome.
Extreme autoimmune disease, diabetes, liver disease, end-stage renal failure, drug and alcohol abuse, and undernutrition and malnourishment.
Leprosy, syringomyelia, spinal cord damage, sensory neuropathy, tabes dorsalis, and senile dementia.
Outside of the human body, the mites can live for 24 to 36 hours at room temperature. (21° C) and in relatively humid (40–80%) air (25,26). Higher humidity and lower temperatures allow them to live much longer (e 4). It only takes one pregnant mite or multiple larvae to infect another human host. This necessitates intense skin-to-skin contact lasting at least five to ten minutes in cases of common scabies, such as when nursing or snuggling a baby, engaging in sexual activity, or tending to nursing-dependent individuals (22, 25, 27).
All stages of mites can be wiped or washed away until they successfully penetrate the skin, which takes a little less than half an hour (26). Although there aren’t many scientific investigations on the quantity of mites or how they spread (22, 25, 26), the following hypotheses are tenable:
The number of mites—and, consequently, the transmissibility of infestation—is quite high until the specific immune response manifests and for a while following, after which the number of female mites significantly decreases (22). Medical examinations, handshakes, and hugs are insufficiently intensive types of contact to spread common scabies. Members of the same family or communal living group, as well as nursing-dependent individuals and those who care for them, are typically the contacts of individuals with common scabies who become infected (25). In common scabies, indirect transmission of the infection through clothing, furniture, or everyday use is uncommon but not completely insignificant (22). Even brief physical contact with the patient, exposure to the patient’s items, or dandruff can result in infestation in forms of scabies with numerous mites, especially crusted scabies (21, 29). In conclusion, the quantity of mites on the skin and the length and frequency of direct physical contact determine the likelihood of infestation transmission (21, 22, 28, 29).
After penetrating the skin, S. scabiei releases chemicals in reaction to kerati-nocytes and Langerhans cells (30), starting an immunological inflammatory response involving several cell types (31).
Both type I and type IV hypersensitivity reactions are present in the reaction. The type I reaction occurs when an antigen on the mite comes into contact with certain immunoglobulin-E (IgE) on mast cells in the epidermis. This causes the mast cells to degranulate, which results in wheal-and-flare reactions. The fact that IgE antibody levels are elevated in scabies patients and then fall following effective treatment lends credence to this (32).Furthermore, it has been reported that the scabies mite and the home dust mite are cross-reactive (33). Patients who have not come into touch with the mite will experience the rash in the type IV hypersensitivity reaction 10 to 30 days before it becomes apparent (32). A hypersensitivity reaction may appear within a day of a patient contracting the infection for the second time.
Scabies will eventually have increased antibody titers specific for parasite antigens and show significant superficial and deep dermal and perivascular inflammatory infiltrates made up of lymphocytes, histiocytes, and eosinophils. Interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) secretion are significantly elevated, while granulocyte colony stimulating factor (G-CSF) secretion is slightly elevated from normal human epidermal keratinocytes. While IL-8 and G-CSF encourage monocytes to develop into dendritic cells and neutrophils to proliferate, IL-6 is known to enhance the proliferation of kerati-nocytes (34). Additionally, IL-6 is known to stimulate Th1 CD4+ cells to release IL-2, which promotes their growth and differentiation, and to stimulate Th2 CD4+ cells to release IL-4, which stimulates the production of antibodies known to raise vascular permeability and start inflammation, which accounts for the edema seen in scabies lesions (31).
The hyperkeratosis observed in chronic and crusted scabies is clinically correlated with earlier research that demonstrated enhanced mitosis in keratinocytes in the basal layer of the epidermis (30, 35)
[FIG 3- Hot Immune Response
Types of scabies
The host immunological response to borrowed mites and their byproducts causes the most prevalent symptoms. The usual description of classic scabies is a severe, uncontrollable, widespread pruritus that is worse at night, while some patients may not have any symptoms at all (36).
The clinical manifestation is a small, erythematous papulovesicular rash that is usually symmetrical and preferentially affects the anterior axillary folds, the female nipple area, the periumbilical skin, the elbows, the volar surface of the wrists, the interdigital web spaces, the belt line, thighs, buttocks, penis, scrotum, and ankles. In adults, it typically spares the head, face, and neck, but it can also affect newborns and people with compromised immune systems.
[FIG.4] Burrows and excoriations in an infant with scabies.
Scabietic nodules and skin burrows are the pathognomonic lesions. The female mite’s tunnel is represented by the burrow, a narrow, serpiginous gray line that measures 1 to 10 mm (37). It is located on the hands and feet, namely on the finger web gaps, thenar, and hypothenar eminences. Distinct on the wrists (FIG. 4) Figure 2. Excoriations and burrows in a scabies infant. Scabies Lesions are frequently written off as excoriated or impetiginized skin, and burrows are rarely apparent to the unaided eye (38).
[FIG.5] Acral pustules in scabies.
A high index of suspicion is required in order to make the diagnosis. In addition, the clinical distribution and history of itching in other family members are almost pathognomonic.
Scabies in newborns and young children affects the neck, face, and scalp; however, infantile scabies is specific to the palms and ssoles (39). Very young infants may appear unhappy, feed poorly, and not scratch. Clinically, vesicles and brownish to pinkish nodules are frequently observed with plaques, pustules, or nodules. Common are acral pustules (FIG. 5). The use of topical steroids or a bacterial superinfection frequently results in changes to the rash’s appearance. Genital or groin nodules may be more common in adulthood (FIG. 4 and 5).
The Most patients will report having a severe itching sensation, particularly at night and after taking a hot shower. A hypersensitivity reaction to the excreta that the mite deposits inside the burrow has been linked to this (40).
2 Nodular scabies:
The glans, scrotum, thighs, and axilla are the most common locations for these violaceous, itchy nodules, which can last for several months and from which mites cannot be extracted (41). This is thought to be a type of hypersensitivity reaction to mite antigens that results in nodules. It can be misdiagnosed as urticaria pigmen-tosa (43), B-cell lymphoma or lymphomatoid papulosis (42), or chronic lymphocytic leukemia. Intralesional corticosteroids (44) or topical pimecrolimus twice daily (45), are two possible treatments.
3 Vesicular – bullous scabies:
t is an uncommon clinical manifestation that typically occurs in the elderly. Clinically, histologically, and in immunofluorescent results, it resembles bullous pemphigoid (46–47). According to theories, superinfection with Staphylococcus aureus could explain the mechanism, which would resemble how blisters form in bullous impetigo (48). Additionally, some believe that the mite’s penetration of the dermo-epidermal junction, cross-reaction with bullous pemphigoid antigen, or lytic secretions generated at the dermoepidermal connection may promote the synthesis of autoantibodies, which in turn trigger complement activation (49). Pemphigoid, pemphigus, bullous impetigo, epidermolysis bullosa, arthropod bite reaction, and acute contact dermatitis are among the differential diagnoses (46).
4 Special forms of scabies:
Due to their unusual presentation, these varieties are frequently misdiagnosed.
Incognito. This alters the clinical aspect of lesions and is caused by the administration of topical corticosteroids (44). There exists a correlation between mildly reduced immunity and hypereosophilia (50).
Infants and young children. Frequently, they are misdiagnosed. Lesions in clinical practice are primarily found on the hands, feet, and body folds and consist of more vesicles, pustules, and nodules. Patients may exhibit poor feeding and irritability (51). Histologically, there may be a thick infiltrate of Langerhans cells, which could lead to a misdiagnosis as Langerhans cell histocytosis.
Elderly. Often misdiagnosed as senile pruritus, they are treated with strong corticosteroid medications for extended periods of time, which might result in crusted scabies. Bullous scabies is another clinical manifestation that might resemble bullous pemphigoid (42,52).
Scabies of the scalp. Dermatomyositis and seborrheic dermatitis may be related or similar. More prevalent in patients with crusted scabies, children, newborns, the elderly, and immunocompromised people (41).
Crusted. Previously referred to as Norwegian scabies, it was initially identified in leprosy patients in Norway in 1848. Immunosuppression (topical or systemic glucocorticoid medication, HIV, human T lymphotropic virus 1 (HTLV-1) infection, organ transplant recipients), psychologically retarded, physically disabled, and indigenous Australians without a recognized immune deficiency are the causes of this (42,53,54).
Clinically, the hands, feet, knees, elbows, trunk, scalp, nail beds, and occasionally the entire body are affected by thick, gray, scaly, hyperkeratotic, or crusted plaques (55). Patients with crusted scabies frequently have mites under their nails, which can lead to thickenednails with dystrophies. Larger mite populations in crusted scabies may result in longitudinal nail splitting and subungual hyperkeratosis, although in normal scabies, the distal ends of nails may house scabies mites, where they are shielded from topical treatment (56). Untreated nails may serve as an infection reservoir, leading to treatment failure and symptom recurrence months later (57).
In certain instances, there is eosinophilia and generalized adenopathy (51). These patients have a high mite infestation and exhibit physical limitations, lack of control, or ignorance of the defensive scratching movements, such as in neuropsychiatric disorders, osteoarticular deformities, muscular atrophy, or other neuromuscular problems occasionally associated with loss of sensation, hypoesthesia, or anesthesia. Additionally, due to altered immune response in immunocompromised subjects, itching is less severe or absent in thesedisorders of patients(58).
Mites are abundant in the crusts, which flake off and contaminate clothes, linens, curtains, walls, floors, furniture, and the surrounding area. The mites stay infectious for two to three days after this. High fatality rates from secondary sepsis are associated with crusted scabmites( 59). After receiving inflix-imab treatment for juvenile rheumatoid arthritis, a case of crusted scabies was recorded. This was believed to be secondary to the patient’s susceptibility to a severe infection due to its immunomodulatory effects on cellular immunity (60). Psoriasis is a differential diagnosis (61).
Subungual scabies. Despite being well-known, this condition is frequently misdiagnosed. Even after effective treatment, it still shows up as nail plate dystrophy (62). Numerous fingernails and/or toe nails may be affected; they appear thicker and whiter, with or without subungual horny debris and/or nail plate deformity. This can possibly be the first sign of scabies (63).
Because scabies causes continual itching, the scratching may capture live mites that can live beneath the nails and subsequently spread across the skin, beginning proximally around the nail. When patients are treated, this will aid in reinfestation. For this reason, in addition to the usual therapy, it is advised to cut the nails extremely short and then brush the tips of the fingers with scabicidal for a few days in a row (64).
Canine. The prevalence of canine scabies infection in humans is unknown, and it is frequently misdiagnosed as papular urticaria or insect bites. Additionally, it is a severe rash that appears on parts of the body that come into contact with the pet, such as the chest, belly, thighs, and forearms. It appears 24 to 96 hours after the encounter and lasts for 5 to 13 weeks on average. Patients may exhibit fever, lymphadenopathy, and a subsequent bacterial infection in more complex cases. Patches of hair loss and/or scratching make it easy to identify the pet. According to some reports, var hominis may develop some protective immunity as a result of repeated exposure to S. scabiei var canis. All that has to be done is treat the dog (65).
dermatitis are examples of differential diagnosis. Scabies infestation can be mistaken for immunobullous illness, Langerhans cell histiocytosis, and severe medication reactions (66, 67–68). All individuals experiencing widespread impetigo in hot, humid climates should have their scabies status checked.
The Scabies is mostly diagnosed based on the patient’s medical history, physical examination, and family and close contact history. Scabies’ classic symptoms include acute, widespread itching that typically spares the head and face. At night, pruritus is more severe. The majority of the lesions are found in the finger webs , the flexor surfaces of the wrists, the elbows, the axillae, the buttocks and genitaliafingel, and the female breasts . Most sites have inflammatory, itchy papules. Scabies-specific nodules (usually in the axillae and vaginal areas) and burrows may be absent. Excoriations, eczematization and impetiginization are examples of nonspecific secondary lesions that can appear anywhere.
According to a report from a sub-Saharan area with a high (13%) prevalence of Scabies, the diagnosis had 100% sensitivity and 97% specificity when diffuse itching and visible lesions were linked to either at least two typical scabies locations or a household member who was itching. (69) There is a dearth of such data from regions where scabies is less common. Scabies
Occasionally, scabies manifests in atypical forms (70) that are more challenging to detect than the classic forms, perhaps increasing the likelihood of outbreaks. The face, scalp, palms, and soles are frequently affected by atypical presentations in babies. Elderly people have atypical papular scabies, immunocompromised individuals have localized or generalized crusted scabies, and patients with superinfected scabies have impetigo
Diagnostic Test:
The detection of mites, eggs, eggshell pieces, or mite pellets is necessary for a definitive diagnosis. In order to collect multiple superficial skin samples from distinctive lesions, such as burrows or papules and vesicles in the burrow site, a blade should be scraped laterally across the skin, being careful not to cause bleeding. A light microscope operating at low power can be used to examine the specimens Since potassium hydroxide dissolves mite pellets, it should not be utilized. This method is very operator dependant becausee there are few mites in cases of typical scabies. Scabies is not always ruled out when mites are not found.
A skin biopsy may be used to confirm the diagnosis In unusual circumstances or when direct examination is impossible. However, mites or other diagnostic findings are frequently absent, and histologic examination typically reveals a nonspecific, delayed hypersensitivity reaction.(71) Despite the relatively low sensitivity of diagnostic testing, empirical treatment is not recommended for patients with generalized itching and should be reserved for patients with a history of exposure, a typical eruption, or both.
(FIG.6) Dermoscopic image of a scabies burrow
Regardless of the presence of symptoms, infected individuals and their close physical contacts should receive treatment concurrently. Although there aren’t many thorough trials to support their use, topical or oral medications may be employed. The dosages and adverse effects of typical scabies treatments are compiled
Topical
The two topical scabies therapies that have been explored the most are lindane and permethrin. Permethrin, administered as a single nighttime application, was shown to be more successful than lindane in a Cochrane meta-analysis of four randomized trials comparing these treatments (odds ratio for clinical failure, 0.66; 95 percent confidence interval, 0.46 to 0.95).(72, 73 )Nonetheless, the meta-analysis revealed significant variation in the results across the trials. Clinical cure rates did not differ in the largest experiment; at an average of 28 days following therapy, 181 out of 199 patients treated with permethrin (91 percent) and 176 out of 205 patients treated with lindane (86 percent) had achieved complete resolution.(74)
However, lindane’s use has been restricted because to its potential neurotoxicity, particularly with repeated applications (75); the product is no longer available in Australia or the United Kingdom. The likelihood of negative effects from using 5 percent permethrin cream was shown to be at least 40 times lower than that of using 1 percent lindane lotion in an in vitro model evaluating systemic exposure under overuse setpatient (76) In a 1996 study, doctors noted a modest rate of central nervous system side effects in patients (1 per 500,000 U of disseminated permethrin), with no significant events. (77) The Centers for Disease Control and Prevention (CDC) recommend 5 percent permethrin as a first-line topical treatment for scabies, even though it is more expensive than litreatme (78) In areas where scabies is endemic, mass treatment with permethrin has also been successful in reducing the disease.
Crotamiton and benzyl benzoate, which are not accessible in the US, are further topical therapies. The cure rate at three weeks was 51% (19 of 37 patients) with 10% benzyl benzoate in a randomized trial conducted in Vanuatu, in the South Pacific, where scabies is a significant public health issue. This is comparable to the cure rate of 56% with a single oral dose of ivermectin of 200 µg per kilogram of body weight.(79) However, compared to 7% of patients treated with oral ivermectin, a third of patients treated with benzyl benzoate felt burning or stinging. Based mostly on professional experience, benzyl benzoate is regardedas the first-line local treatment in France, where permethrin is unavailable. The Cochrane Review came to the conclusion that there was not enough information to compare the efficacy of lindane or permethrin with either benzyl benzoate or crotamiton.(8) Crotamiton appears to be substantially less effective than permethrin at four weeks, according to scant data from a randomized trial (61 percent vs. 89 percent).(80)
Scabies has also been treated with pyrethrin as an aerosol spray, such as allethrin. However, two asthmatic girls with head lice experienced acute bronchospasm as a result of this treatment, and one of them died. People with a history of asthma should never be provided such a formulation of pyrethrin.(81) There is insufficient evidence to support the use of sulfur, topical ivermectin, and tea tree oil (82) as therapies.
Oral
Some individuals may not tolerate topical treatments well (e.g., they are messy, may be difficult to apply, and may cause burning or stinging, especially when the skin is excoriated or eczematous, and potential percutaneous absorption may offer a concern). Oral ivermectin (83) is a different strategy that has been widely utilized to treat a number of parasitic illnesses, such as lymphatic filariasis, onchocerciasis, and other nematode-related infestations. It is believed that ivermectin paralyzes and kills parasites by blocking glutamate-induced and {gamma}-aminobutyric acid-induced neurotransmission.Twenty Ivermectin does not pass across the intact blood-brain barrier (84) in humans, but it has been shown to cause central nervous system toxicity and abrupt death in collies.(85)
The effectiveness of a single dose of Ivermectin (200 µg per kilogram) for the treatment of scabies has been evaluated in a number of controlled trials. 37 out of 50 patients treated with ivermectin (74%) were cured in one placebo-controlled experiment, compared to 4 out of 26 patients in the placebo group (15%).(86) Ivermectin and 10% benzyl benzoate (15) or ivermectin and lindane did not significantly differ in clinical cure rates in short investigations.(87) A single ivermectin dose cured 70% of patients in a randomized trial comparing oral ivermectin with an overnight application of 5% perivermect (88), compared to a 98% cure rate with permethrin (P<0.003). However, a second ivermectin dose administered two weeks later increased the cure rate to 95%. Ivermectin’s lack of ovicidal activity may be the cause of its reduced efficacy when taken in a single dose.
Clinical experience and randomized trials have indicated that ivermectin is safe. Patients treated with this medication who had onchocerciasis and a high Loa loa microfilariae infection have been documented to experience encephalopathy. (89) A widespread ivermectin treatment program for children with scabies in the Solomon Islands showed no significant side effects. (90) Elderly patients who got ivermectin for scabies (91) were shown to have an increased risk of death in one study, but selection bias and confounding factors could be the cause. Other investigations, particularly those including nursing home residents, have not supported this finding.(92)
Although ivermectin may be used as first-line treatment, topical treatments may be a better option due to its greater cost in some nations. Ivermectin should be the first line of treatment for patients who do not respond to topical scabicides. It may also be the best option for older patients, those with generalized eczema, and other patients who might not be able to tolerate or adhere to topical medication.
Assessing the response
Patients should be informed that following the conclusion of properly administered scabicide medication, itching may continue for up to four weeks. The reason for the itching should then be looked into again.
Control of Infectivity
The most typical way that classic scabies is spread is through prolonged skin-to-skin contact with an infected individual. Treatment should be given to people who have this kind of contact but not to those who have more casual touch. All members of the home and any sexual encounters should have prescriptions, even if they don’t exhibit any symptoms. There is considerable worry that patients treated with ivermectin may stay contagious longer than those treated with topical treatments, however the time course for the eradication of parasites following therapy for classic scabies has not been thoroughly investigated.
Crusted scabies is very contagious, and treatment of anyone who has been even slightly exposed is advised. Patient care professionals and support staff (e.g., cleaning and laundry employees) in institutional settings should be regarded to have been exposed to infected individuals.
Classic scabies seldom spreads without direct person-to-person contact. However, the recovery of live mites from chairs and couches in scabies patients’ homes supports the adoption of environmental measures,(93 )despite a lack of data to prove their usefulness in preventing transmission. Ideally, garments and bed linens should be machine washed at 60°C and machine dried the day after the initial treatment (94); insecticide powder or aerosolized insecticide is typically kept for things that cannot be laundered. Items can also be kept in a sealed plastic bag for at least 48-72 hours. Only clothes and linens that came into contact with the patient during the last 48 to 72 hours should be cleaned, based on mite survival rate
Aloe barbadensis mill
Barbadensis Mill, a member of the Liliaceae family, is native to Eastern and Southern Africa but has spread to China, North Africa, the Mediterranean, the West Indies, and the Middle East. Hamdard Laboratories Waqf Pakistan manufactures Aloe barbadensis Mill under the brand name Baarasil. The chemical ingredient is Aloe barbadensis mill. Aloe vera gel can treat a variety of medical issues, including insect stings, eczema, bites, wound healing, acne, skin care, bruising, pruritus, and allergies. The drug is provided in syrup form, with a recommended dosage of 5 tsp thrice daily (Mantle, Gok, & Lennard, 2001).(95)
Rosmarinus officinalis
R. officinalis is utilized as a therapeutic herb around the world. This plant includes active compounds including 8-cineole and camphor. It possesses anti-inflammatory, antibacterial, and astringent properties that aid in treating scabies condition. Rosemary oil kills mites and quickly heals wounds and bruises. However, it is not recommended for internal usage (Chen et al., 2006; Issabeagloo et al., 2012).(96)
Cinnamomum camphor
This tree has been used for years to treat scabies effectively. C. camphor is a fragrant shrub that also has analgesic properties. This tree has insecticidal properties, which may have therapeutic benefits. It is beneficial in the treatment of muscle discomfort. Using the oil of this tree for 10 days will completely cure scabies illness.(97)
CONCLUSION:
Scabies remains a major global health concern, especially among overcrowded, resource-limited, and immunocompromised communities. Understanding the biology, transmission, and clinical variants of Sarcoptes scabiei is critical for accurate diagnosis and treatment. Although classic scabies is distinguished by distinctive itching and burrows, various atypical variants can delay diagnosis and raise the risk of outbreaks.
Accurate diagnosis is based on a thorough clinical examination accompanied by dermoscopy or microscopic identification of mites. Effective care necessitates the simultaneous treatment of infected persons and close contacts with both topical treatments such as 5% permethrin and systemic therapy such as oral ivermectin in appropriate instances. Prevention techniques, such as maintaining good personal hygiene, decreasing overcrowding, and properly cleaning linens and clothing, are essential for interrupting the transmission cycle. Early detection, adequate treatment, and community-level control strategies remain the cornerstones of decreasing morbidity and preventing recurrent or crusted scabies, which pose a significant risk of consequences. Continued awareness and education are critical to limiting the spread of this extremely contagious but totally treatable disease.
REFERENCES
Rashtriya College of Pharmacy Hatnoor, Kannad, Chh. Sambhajinagar 431103
[authorID1] => [authorID2] => [authorID3] => [authorID4] => [authorID5] => [authorID6] => [authorID7] => [authorID8] => [authorID9] => [authorID10] => [createdDate] => 2025-12-02 00:00:00 [createdByUserID] => 1 [updatedDate] => 2025-12-02 17:20:04 [updatedByUserID] => 0 [isActive] => 1 [titleOfPaperOne] => A Review by Paediatric Epilepsy A Comprehensive Overview of Diagnosis Treatment and Management [txtBody] =>Pediatric epilepsy is one of the most common chronic neurological disorders affecting children worldwide. It estimated that around 50 million people globally live with epilepsy, and nearly 10 million of them are children under the age of 15. Every year, approximately 4 to 6 out of every 1,000 children are diagnosed with epilepsy. It is characterized by recurrent, unprovoked seizures caused by abnormal electrical activity in the developing brain. In this not only affect brain but the overall life of a child and family.
Research shows that around 80% of children with epilepsy live in low- and middle- income countries, where early diagnosis and treatment are still a challenge. India has the highest number of affected children, mainly because of its huge population and small towns. China also has close to a million children living with epilepsy, in African countries like Nigeria, Ethiopia and other Sub-Saharan regions, the situation is even more challenging. It estimated that over two million children there suffer from epilepsy, often due to infection like malaria, meningitis or birth complications, which damage the brain in early life. On other hand, developed counties such as the United States have around 470,000 children diagnosed with epilepsy, but most of them receive early treatment, regular follow-up and support systems that help them lead a better quality of life.
RISK FACTORS
Risk factor of epilepsy is higher in preterm populations due to white matter gliosis, hypoxic-ischemic brain damage, hippocampal sclerosis, decreased brain structure development, and increased infection risk in preterm populations. Eclampsia is a significant condition that can progress to epilepsy in young people via a variety of paths. In reality women may suffer hypoxia, which can increase the incidence of epilepsy and interfere with the unborn brain’s normal growth[2]. Other major factor is a positive family history are linked to genetic mutations and inherited syndromes such as Dravet syndrome. Even children whose birth weight falls within the normal range are at heightened risk for epilepsy due to intrauterine growth restriction[3].
The following are some of the risk factors that might increase the risk of epilepsy[4].
Figure 1: Epilepsy risk factors.
People with epilepsy are unable to lead normal lives because of the stigma associated with the condition. The economic burden of epilepsy is very high. The dual burden of learning disability, cognitive impairment, and subpar academic achievement is common in children with epilepsy. Perinatal insults such as metabolic derangement, and central nervous system [CNS] infections are important modifiable risk factors of epilepsy. Regretfully, there is a dearth of information from India regarding the risk factors for childhood epilepsy. There are several methodological limitations for epidemiological studies on epilepsy in developing countries[5]. Childhood epilepsy may be predisposed by perinatal causes. But the observations in epidemiological studies had been rather negative or conflicting[6]. There was no correlation found between prenatal insult and childhood epilepsy in a door-to-door survey conducted in West Bengal, however another comparable study in Kerala state supported an association between the two. The first step towards preventing epilepsy in children would be to identify such risk factors, according to a population-based survey conducted in Kerala's Northern district.
EPIDEMIOLOGY
In epidemiological research on childhood epilepsy, the exclusion of children aged<6 years, because febrile seizures are common in this age-group and would confound estimates. In studies presenting sub analyses by age-group, as expected, prevalence of epilepsy increased with age, while incidence decreased with age and the highest incidence was in the 0- to 5-year age-group[7,8].
Active prevalence of epilepsy is a measure of the proportion of patient currently suffering from active epilepsy or experiencing the consequences of epilepsy as measured by taking anticonvulsant medication[9].
TABLE 1: AGE SPECIFIC INCIDENCE RATES [ROCHESTER, MINNESOTA, 1935-1979]
|
Age group [years] |
No. patients |
Rate/ 100,000 Person-years |
Proportion |
|
Male/ female [%] |
|
Idiopathic[%] |
Partial [%] |
||||
|
<1 |
41 |
121 |
54 |
17 |
120 |
|
1-4 |
85 |
63 |
81 |
28 |
97 |
|
5-14 |
129 |
44 |
84 |
47 |
123 |
Since one need only to identify existing cases of the illness, prevalence studies are considerably easier to conduct that incidence studies. Prevalence studies have been performed across numerous populations varying by geographic area, race, and socioeconomic status. From an epidemiology standpoint, prevalence is of value chiefly as it is a reflection of cumulative incidence. Since prevalence represents the complex interaction, as a rule, is of limited value for the generation of hypotheses concerning etiology.
The estimated prevalence of epilepsy varies widely in reported studies by a factor of 20, and ranges from a low of 2/1,000 in the Marianas Islands to a high of 37/1,0000 in Nigeria[10]. Unfortunately, the variation seems more related to study methodology and to definition of epilepsy in individual studies based upon incidence cohorts, prevalence tends to increase with advancing age through early childhood, only to stabilize in the teenage and young adult years.
CLASSIFICATION
Classification of seizure type-expanded version[11]:
Fig 2: classification of seizures.
CLINICAL PRESENTATION
Definition:
A seizure (ictus) represents transient neurological manifestation because of abnormal, excessive neuronal discharges originating from the cerebral cortex. This discharge can result in many different neurological manifestations according to the seizure origin and spread (for example sensory, motor, somatosensory, psychic).
A convulsion refers to a seizure with motor manifestations, usually generalized tonic clonic. A “fit” is a term that should not be used as it may imply a psychogenic etiology. Epilepsy (to be attacked in Greek) is recurrent (2 or more) unprovoked seizures. Transient provoked seizures caused by fever, illness, electrolyte imbalance, toxic exposure, or head injury, are not classified as epilepsy[12].
Seizure is a paroxysmal involuntary disturbance of brain function that may manifest as:
Fig 3: Seizure symptoms.
Convulsion is generalized seizure with increased tone and tonic–clonic movements of the body.
Fig 4: Stages of a seizure.
GTCS – [Generalized Tonic – Clonic Seizures]
Duration- seconds to hours.
Etiology
Fig 5: Causes of epilepsy.
DIAGNOSIS
The most challenging condition, which happens to be treated during an emergency, is the status epilepticus. Because of this, diagnosis and treatment section are focused on the clinical state.
Clinical presentation in status epilepticus varies. It depends on the type of seizures, stage, and previous state conditions of the pediatric patient. Diagnosis is based on the identification of continuous or recurrent seizures, and it is easy to recognize during the clinical manifestation[14].
After persisting status epilepticus, despite disappearance of motor manifestation, it is difficult to exclude non-epilepticus continuous status.
A complete instrumental evaluation can be requested in case of first clinical presentation of SE, or in case of complicated SE, comorbidity, and in infants.
Laboratory test, neurological exams, and EEG imaging methods are all necessary for epilepsy and seizures[15].
Fig 6: Diagnostic Procedure of epilepsy [16]
A healthcare provider will diagnose epilepsy in children after examination and testing that may include:
Tests help your healthcare provider understand what caused your child’s seizures and rule out conditions that cause them. An epilepsy diagnosis may take time and it usually doesn’t happen overnight[17].
TREATMENT:
Non pharmacological treatment
First Aid
Helping the patient manage the situation an epileptic seizure is known as first aid treatment. Because of the common misconception, people appear afraid when they witness someone having an epileptic seizure. Since studies have shown that patients and their families can easily control or manage epileptic seizures with the correct guidance and training, it is more important that’s ever to stay calm and help the sufferer. Since epileptic seizures are not emergencies, there is no need to call for ambulance. Consequently, the best way to help patients manage their seizures on their own and boost their confidence is through self-management training[18].
Ketogenic Diet
Throughout history, diets have been used to manage seizures. However, it was the first documented in the early 1920s, the nutritional diet was used as a therapeutic treatment for epilepsy. Dietary treatments for DRE include Low Glycemic Index Therapy (LGIT), Modified Atkins diet (MAD), and the traditional Ketogenic Diet (KD).[19] KD and MAD diets are high in fat, but LGIT focuses mostly on consuming low- glycemic foods that are low in carbohydrates. These diets compositions are explained below. A diet consisting of 90% fat, 7%protein, and 3% carbohydrates is the traditional ketogenic diet, that produces metabolic changes associated with the starvation state. A ketogenic diet, sometimes known as the keto diet, may be an option for certain kids to manage their seizures if medicine isn’t enough[20].
Diet vs MAD Ketogenic
Both RCTs compared KD with MAD. One RCT found higher rates of seizures freedom with KD than with MAD at 3 months (53% vs 25%). For seizure frequency reduction, the same RCT [21] reported an advantage of KD over MAD at both 3 months (58% vs7%) and 6 months (71%vs 28%), and the other RCT reported statistically nonsignificant results in the same direction (81% vs 54% at 3 months and 100%vs 60% at 6 moths)[22].
Neurostimulation
This treatment involves the nervous system receiving tiny electric currents via a gadget. Three forms of neurostimulation are now used to treat epilepsy they are; vagus nerve stimulation, Responsive neurostimulation, Deep brain stimulation[23].
Pharmacological Treatment
There are already more than 20 antiepileptic drugs (AEDs) on the market, and choosing the appropriate medication mostly depends on the type of seizure and the patient's age. The first-line accepted treatment is AED therapy[24], both for symptomatic myoclonic seizures and generalized tonic-clonic seizures were best administrated with sodium valproate. Primary first-line therapies for complex partial seizures were carbamazepine and oxcarbazepine, with valproate also being recommended[25]. Although using AEDs alone or in combination, approximately 20% of children with epilepsy will still have seizures[26].
The main pharmacological agents, often used first, are carbamazepine, valproic acid, oxcarbazepine and phenytoin. Other drugs used in the treatment of epilepsy are vigabatrin, lamotrigine, felbamate, gabapentin levetiracetam, ethosuximide[27,28]. The mechanisms of action of these drugs are summarized in Table 2.
Table 2. Mechanisms of action of antiepileptic drugs[29,30].
|
Drug |
Mechanism of action |
|
Phenytoin |
Inhibition of intracellular sodium currents. Reduces the influx of calcium ions into the cell. Inhibition of motor cortex and subcortical centres responsible for the tonic phase of convulsion. |
|
Carbamazepine |
Blocks potential-dependent sodium channels and secondary reduction of glutamate release and catecholamine metabolism in the central nervous system. Stabilization of the membrane of over-excite nerve fibers. |
|
Lamotrigine |
Inhibits sodium channels and blocks release of excitatory amino acids [glutamic acid]. |
|
Oxcarbazepine |
Blocks potential-dependent sodium channels. Stabilizes over-excited nerve fiber membranes. Inhibits repetitive neuronal discharges. Reduces synaptic transmission of excitatory stimuli. |
|
Topiramate |
Blocks membrane voltage-dependent sodium channels, increases gamma-aminobutyric acid activity, and shows antagonism to the receptor for glutamic acid. |
|
Gabapentin |
Inhibits voltage-gated calcium channels. |
|
Pregabalin |
Binds to an auxiliary subunit [ of the membrane voltage-shifted calcium channel in the central nervous system. |
|
Levetiracetam |
Affects protein concentrations in neurons by partially inhibiting N-type calcium currents and reducing the release of calcium ions stored inside neurons. |
|
Vigabatrin |
Selective, irreversible inhibitors of y-aminobutyric acid aminotransferase [GABA-T]. |
|
Felbamate |
Demonstrates GABA inhibitory activity and benzodiazepine receptor binding. |
|
Lacosamide |
Attenuation of low-threshold T-type calcium currents in thalamic nerve cells. |
|
Ethosuximide |
Bloking of T-type calcium channel, inhibitory effect on thalamic neurons. |
|
Eptoin |
Eptoin tablet contain the active ingredient is phenytoin, which works primarily by blocking voltage-gated sodium channels in nerve cells. This action helps to control and prevent seizures. |
Fig 6: Eptoin tablet.
Surgical treatment of epilepsy
If drug-resistant epilepsy (DRE) is diagnosed, surgery is diagnosed, surgery is an alternative to pharmacotherapy. Studies have shown the positive impact of early surgical intervention on cognitive function and thus, further intellectual development in pediatric patients[31]. Depending on the etiology of the seizures, resection, separation, or neurostimulation procedures are used.
Pediatric Epilepsy Surgeries:
Fig 7: laser interstation thermal therapy (LITT) is a minimally invasive surgical option for pediatric epilepsy where a laser is used to destroy the specific brain tissue causing seizures.
Gene Therapy:
One of the most rapidly developing methods of pharmacological therapy for treating diseases; drugs currently in the laboratory phase. Gene therapy involves placing foreign genetic material into a patient cell, resulting in one of 3 options: inhibiting production, of the gene, increasing production of the gene, or modifying the site of the gene[33].
One of the newer possible therapeutic options now is the treatment of loco-resistant epilepsy with cannabinoids (CBD), derived from the cannabis plant[34].
In 2018, CBD was approved for use by the united-states food and drug administration for treating Dravet syndrome and Lennox-Gastaut syndrome in patients aged two years and over[35].
Management Of Drug -Resistant Epilepsy
The prevalence of DRE among epilepsy patients was 30% in a recent study and the pooled incidence was 15%. Numerous research have clarified the risk factors for developing drug-resistant epilepsy. Age at onset, symptomatic epilepsy, abnormal neuroimaging findings, abnormal electroencephalography results, history of mental retardation, neuropsychiatric disorders, febrile seizures, and status epilepticus increased risk for DRE[36].
Risk Factors
DRE has already been associated with the occurrence of neuropsychiatric disorders cerebral impairment, a history of protracted febrile seizures, and particular electroencephalogram (EEG) abnormalities. DRE has been associated with the age at the epilepsy start (one year), the etiology, abnormal neuroimaging, the presence of these abnormalities, and the coexistence of these conditions[37].
Pathogenesis
Drug resistance etiology is likely diverse and complicated[38]. The hypothesized drug resistance pathways, which also include genetic and disease-related ones, may be interrelated.
The transporter hypothesis states that independent of the site of such an ASMs action increased multi drug efflux protein expression or function decreases the efficacy of ASMs in human epileptic brain tissue and DRE animal studies[39].
According to the pharmacokinetic theory, efflux transporter over expression is concentrated in decreasing the dose of ASM that is capable of permeating the BBB most likely in peripheral organs like the liver, colon, and kidneys[40].
MANAGEMENT OF EPILEPSY
Data on childhood-epilepsy management in Kenya is limited. The low rate of epilepsy diagnosis and the treatment gap are both influenced by culturally motivated health-seeking behaviours. In Kenya, the proportion of individuals with active epilepsy who lack access to appropriate medical care is known as the "treatment gap," and it is quite high. The selection of the first antiepileptic medication is affected by a combination of patient- specific and AED-Specific factors[41].
Long term AED treatment should be started after second seizure[42]. Complete seizure control without serious side effects is the goal of treatment. Complete seizure control without serious side effects is the goal of treatment. AED is based on the predominant seizer type or syndrome type with possible adverse effect and co-morbidities taken into account[42,43]. All drugs are started in low doses and increased gradually up to a maximum does till seizure control is achieved or side effects appears. Dosage needs to be adjusted to the child’s daily activity. Extended releases formulations in twice a day dosing are preferable[44].
Fig 7: Management approaches for epilepsy[45].
AED choice may be influenced by seizure frequency and severity in addition to seizure type. For example, between two equally affective AEDs, a patient with daily, prolonged generalized tonic-clonic seizures may be started on the AED than can be titrated more swiftly to a therapeutic dose. Lastly, while some AED efficacy results in children parallel those in adults[46], this comparison may not apply to all pediatric epilepsy patients[47], and individualized medication selection is vital to success.
Objective self-management challenge facing adults with epilepsy include limited understanding of the condition and treatment, associated psychosocial issues, and lack of community integration. Self-management interventions improve patients medical, life role, and emotional management[48]. Epilepsy has a significant and well-researched psychosocial impact on the affected individual and their family. Interventions such as educational programs and lifestyle management education to improve self-mastery and quality of life in people with epilepsy are not necessarily integrated in standard care practices[49].
Acute and emergency management
Chronic management
FUTURE DIRECTION
The percentage of childhood-onset epilepsies that are resistant to therapy has essentially stayed constant despite significant recent advancements in our understanding of the aetiology of epilepsy and the introduction of several novel AEDs. To address this issue, there is a clear need for a more stratified approach to treatment. Traditionally, stratification has been by broad seizure type (focal or generalized), and only occasionally by epilepsy syndrome[50].
The challenges for the future will be to use this information not only for diagnosis he development of rational treatments. Gene therapy is clearly an important long-term approach, but in the meantime an understanding of epileptogenic mechanisms arising from gene mutations could provide “downstream” targets for therapy developmentIn order to screen new treatments, mouse models will be crucial. For acquired epilepsies, many potential mechanisms have also been found. Understanding which of these are necessary and sufficient to produce epilepsy should lead to intervention that will stop the development and progression of these seizure disorders[51].
Some manufactures, such as Medtronic, have newer technology that can apply electricity to the brain, but also record it, a process Dr. conner described as similar to a thermostat."It senses the situation and modifies the delivery of electricity."I think that the technology is still in its infancy, but we’re getting there,” he said. “this’s brain sensing” will help improve how effective DBS is at treating epilepsy and make it easier for physicians to program[52].
New techniques target neural networks
Thalamic responsive neurostimulation (RNS) is one of the most recent surgical techniques for treating paediatric epilepsy. This robotic-assisted procedure involves implanting a small RNS device in the thalamus-a major control center for the brain. The device continually monitors a patient’s brain waves and delivers a tiny electrical impulse to stop seizures in their tracks. The goal is to modulate a whole network of different parts of the brain that are communicating in an abnormal way to ignite a seizure[53].
Thalamic RNA offers a much-needed treatment option for children with multifocal seizures who do not respond to medication or diet therapy. Then the many patients see more that a 90% reduction in seizures[54].
CONCLUSION
Seizure in children are a serious medical issue that has to be diagnosed and treated quickly. Finding the underlying cause of the seizures requires an understanding of the several etiologies, which range from neurological problems to metabolic issues. Children’s risk of seizures is further influenced by risk variables such age, genetic predisposition, and prior neurological history. Treatment choices depend on an accurate diagnosis, which frequently requires imaging, laboratory testing, and clinical examination. The main goal of treatment to manage seizures and stop them from happening again by using medicine, changing one’s lifestyle, and occasionally having surgery.
REFERENCES
MET Institute of Pharmacy, Nashik, Maharashtra, India.
[authorID1] => [authorID2] => [authorID3] => [authorID4] => [authorID5] => [authorID6] => [authorID7] => [authorID8] => [authorID9] => [authorID10] => [createdDate] => 2025-11-22 00:00:00 [createdByUserID] => 1 [updatedDate] => 2025-11-22 05:46:51 [updatedByUserID] => 0 [isActive] => 1 [titleOfPaperOne] => Varicose Veins A Comprehensive Review on Epidemiology Pathophysiology Clinical Features Risk Factors Diagnosis Management Prevention and Future [txtBody] =>Understanding Varicose Veins
Definition
Varicose veins are dilated, twisted, and tortuous superficial veins caused by venous valve incompetence
Location
Most commonly occur in lower extremities due to increased venous pressure and gravitational effect
Classification
Varicosities represent a spectrum of chronic venous disorders including reticular veins (1–3 mm), spider veins (<1 mm), and large varicose veins (>3 mm)
Problem Statement
Despite high prevalence, varicose veins are often considered cosmetic rather than a medical issue, leading to delayed diagnosis and management
ANATOMY OF VENOUS SYSTEM
The lower limb venous system comprises:
1. Superficial veins
2. Deep veins
3. Perforator veins
Function of venous valves
Venous valves prevent blood backflow. Their failure leads to reflux, venous pooling, and varicosities
EPIDEMIOLOGY
Global Impact
High-Risk Populations
ETIOLOGY (CAUSES)
Varicose veins develop due to increased venous pressure and valve incompetence.
Hereditary Factors
Genetic weakness of vein walls plays a significant role.
Venous Valve Issues
Degeneration of venous valves leads to blood reflux.
Obesity
Increased abdominal pressure contributes to vein strain.
Pregnancy
Hormonal changes and increased pressure impact veins.
Occupational Hazards
Jobs involving prolonged standing increase risk.
Aging
Age-related connective tissue weakness in vein walls.
Deep Vein Thrombosis (DVT)
Previous DVT can damage veins and valves.
Trauma
Injury to veins can lead to varicosity development.
PATHOPHYSIOLOGY
The pathophysiology includes:
Venous Valve Incompetence
Valves fail to close, blood flows backward, pooling, dilation
Venous Hypertension
Inflammation
Remodeling of Vein Wall
CLASSIFICATION (CEAP)
The CEAP clinical classification includes:
CLINICAL FEATURES (SYMPTOMS)
RISK FACTORS
Primary Risk Factors
Lifestyle Factors
Medical Factors
COMPLICATIONS
If not treated, varicose veins may lead to:
DIAGNOSIS
Clinical Examination
Doppler Ultrasound
Gold standard for:
Venography
MANAGEMENT
Treatment includes both conservative and interventional methods.
Conservative Management
Medical Treatment
Surgical / Interventional Treatment
PREVENTION
FUTURE SCOPE
Future research focuses on:
CONCLUSION
Varicose veins are a common but neglected venous disorder affecting millions worldwide. Early diagnosis, lifestyle changes, and modern minimally invasive treatments can significantly improve quality of life. Awareness, preventive strategies, and advanced research can reduce the rising burden of chronic venous disease.
REFERENCE
JKKMMRF’S- Annai JKK Sampoorani Ammal College of Pharmacy, B. Komarapalayam Affiliated by the Tamil Nadu Dr. MGR Medical University, Chennai.
[authorID1] => [authorID2] => [authorID3] => [authorID4] => [authorID5] => [authorID6] => [authorID7] => [authorID8] => [authorID9] => [authorID10] => [createdDate] => 2025-11-03 00:00:00 [createdByUserID] => 3 [updatedDate] => 2025-11-03 08:02:11 [updatedByUserID] => 0 [isActive] => 1 [titleOfPaperOne] => Polycystic Ovary Syndrome A Comprehensive Review of Pathophysiology Diagnosis And Emerging Therapeutic Strategies [txtBody] =>This endocrine condition is more common in women of reproductive age. It affects 5% to 15% depending on the diagnostic criteria used. PCOS is among the most common endocrine and metabolic disorders that afflict humans globally [1]. PCOS presentation is diverse hyperandrogenism, menstrual irregularities, hirsutism, acne and alopecia [2]. PCOS displays significant individual variances, but hyperandrogenism, abnormal menstruation, and multiple ovarian cysts are characteristic signs. The first to develop this complex disease are high-risk adolescents who are likely to have other complications such as obesity, type II diabetes, infertility, endometrial dysplasia cardiovascular problems and mental health issues.[3]
Since Stein and Leventhal first characterized the syndrome characteristics more than 80 years ago, its classification has been based on Rotterdam criteria with four phenotypes, raising questions over whether women who normally ovulate or do not have hyperandrogenism should be classified as having PCOS [4].
The American gynaecologist Irving F. Stein, SR, and Michael L. Leventhal called this disorder Stein Leventhal Syndrome, which is also known as multi-cystic ovaries or schlerocystic ovaries This hormonal condition impacts women between the ages of 18 and 44 [6]. It is frequently linked to metabolic abnormalities, namely insulin resistance and compensatory hyperinsulinemia, which are acknowledged as a significant contributing factor, as well as psychological issues, such as depression and other mood disorders is charge of changing the synthesis and metabolism of androgens.[7] Obese adults and Individuals who eat fast food more frequently are more likely to develop PCOS. Consequently, exercise therapy is the mainstay of PCOS treatment. The greatest strategies to attain good control would be to limit fast food consumption and use weight-loss methods in addition to calorie-restricted meals and exercise Regarding PCOS [8]
Epidemiology:
The prevalence of eating disorders in 2000 amounted to 3.5% worldwide. For 2007 through 2012, this figure stood at 4.9%. Moreover, for the 2013-2018 period, rough ground between 7.8%. Eating disorders typically reflect distortions in aspirations, thoughts and actions in relation to food, eating and body weight [9]. PCOS can seriously damage ovaries and therefore affects metabolism in general as well as fertility, The prevalence of PCOS in the world's population is estimated at between 4 and 20%. According to figures from the World Health Organization, which were released in 2012, 116 million women worldwide–or 3.4% of all women–are on earth challenges PCOS in one form and another. The prevalence of polycystic ovarian syndrome (PCOS) is 3.7% - 22.5% in India, compared to that in other developing countries [10].
Etiology:
Polycystic Ovary Syndrome is a multi- factorial hormonal, metabolic and reproductive endocrine derangement disorder. Its etiology is not known, though some of the pathogenesis factors have been proposed by recent research work.
Genetic Factors:
PCOS is genetically and familywise positive and is linked to insulin signaling, steroidogenesis and gonadotropin regulation. DNA methylation and histone modification may be epigenetic mechanisms underlying the hereditary features of PCOS [11].
Insulin Resistance and Hyper-Insulinemia:
Most women with PCOS have Insulin resistance, elevating the level of insulin. It may cause the cells in the ovaries to secrete too much androgen, leading to hirsutism and anovulation and vulnerability to type 2 diabetes and cardiovascular disease [12].
Hormonal Imbalances:
PCOS pathophysiology a further characterised by hypothalamic- pituitary- ovarian axis dysregulation with high level of luteinizing hormone (LH) compared to follicle stimulating hormone (FSH) suppressing follicular growth and anovulation. Suppressed development of the follicles can be caused by high level of anti- Mullerian hormone (AMH) [13].
Low-Grade Inflammation:
Chronic low- grade inflammation in PCOS patients is typically linked with high pro- inflammatory cytokines that worsen insulin resistance and hyperandrogenism, impairing reproductive and metabolic well-being [14].
Environmental and Lifestyle Determinants:
Diet lifestyle and exposure to environmental toxins can influence the severity of PCOS. Obesity increases insulin resistance and androgen further more severely whereas an unhealthy diet can alter gut microbiota and hence influence endocrine equilibrium [15].
Psychosocial Determinants:
PCOS is also linked with psychiatric morbidity, i.e., depression and anxiety, otherwise exacerbated by infertility, obesity and hirsutism and hence must be addressed holistically [16].
Sign And Symptoms:
Polycystic Ovary Syndrome (PCOS) is a multi-factorial etiology endocrinopathy of female disease caused primarily by secondary hormonal imbalance with elevated androgens. The presenting symptoms initially are irregular menstruation, cysts in the ovary, hirsutism, acne, and dark skin folds (acanthosis nigricans), and headache are also common. The subsequent complications of PCOS are weight gain, metabolic syndrome, insulin resistance, and risk of type 2 diabetes development. Moreover, endocrine imbalances predispose to certain cancers, e.g., endometrial cancer, and infertility, as a result of abnormal or absence of ovulation. PCOS is also linked with sleep apnea, and chronic inflammation gives rise to most systemic and metabolic complications. PCOS should be treated for overall well-being. [17].
Athophysiology:
Figure.1: Pathophysiology
PCOS is an endocrine condition with multifactorial reproductive, Hormonal and Metabolic abnormalities. PCOS is defined by dysregulation of GnRH secretion leading to increased pulsatility. Low levels of progesterone may lead to a defective pattern in which the anterior pituitary overproduces LH compared to follicle-stimulating hormone.
This results in the overproduction of androgens by the cells in the ovaries. Androgens either directly or indirectly due to the peripheral conversion of androgens to dihydrotestosterone (DHT) by 5α- reductases is key factor in causation of skin features of PCOS, including Acne, Hirsutism and Androgenic alopecia [18].
Hyperandrogenism in PCOS primarily affects the pilosebaceous unit (PSU) which include the hair follicles and Sebaceous glands. Higher androgen levels stimulate the PSU. Increasing sebum production and promoting hyper keratinization. Elevated DHT levels in the PSU due to increased 5αreductase activity can worsen the effects. The hormonal environment favors acne vulgaris by causing follicular plugging and inflammation Androgen- induced follicular dynamics can lead to shortening of the hair follicle anagen phase which results in androgenic alopecia.
Hyperandrogenism in PCOS may be heightened by insulin resistance Hyperinsulinemia stimulates androgen production by exciting the ovarian theca cells and suppressing the secretion of sex hormone- binding globulin (SHBG) the liver. This increase concentration of free androgens which exert more pronounced effect on the skin Insulin resistance may lead to acanthosis nigricans a hyperpigmented velvety plaque condition seen in PCOS [19].
Diagnosis Of Polycystic Ovary Syndromes (PCOS):
The diagnosis of PCOS is largely clinical and depends upon fulfillment of some or all of the criteria. The best accepted criteria are the Rotterdam criteria which demand two or more of the following three features:
1. Clinical or biochemical hyperandrogenism: These are signs such as hirsutism, acne and alopecia or raised levels of androgens as reported by laboratory investigations.
2. Oligo-ovulation or anovulation: Irregular or missed menstrual cycles reflecting infrequent or non-ovulation.
3. Polycystic ovarian morphology (PCOM): Ultrasound scan diagnosed by the occurrence of 12 or more follicles 2–9 mm in diameter in one or more ovaries or elevated ovarian volume (>10 cm³) [20].
In teenagers, the diagnostic strategy is cautious because of pubertal physiological changes. Hyperandrogenism either clinical or biochemical and menstrual disturbance need to happen in a case of PCOS in this group [21].
Modern guidelines place a high priority on a reflective evaluation with a complete medical history, general physical examination and reflective laboratory and imaging studies. Exclusion of other conditions with a similar presentation is thyroid disease, hyperprolactinemia and non-classic congenital adrenal hyperplasia.
Metabolic Complication:
PCOS has linked in several metabolic comorbidities such as Insulin Resistance (IR), Hyperinsulinemia, Impairment of Glucose Tolerance, Type 2 Diabetes Mellitus (T2DM), Gestational Diabetes, Hypertension, Endometrial Carcinoma, Non Alcoholic Fatty Liver Disease (NAFLD), Ovarian Dysfunction, Dyslipidemias, Metabolic syndromes and cardiovascular risk enhancements [22].
Mood disorders
PCOS patients frequently have mood issues. The condition may arise as a result of numerous events, both connected and unrelated to it. The two most prevalent psychological comorbidities seen in young PCOS patients are anxiety and depression. There is also often a negative body image, psycho-sexual dysfunction, eating problems, and a lower quality of life. Since young PCOS patients are more likely to have depression at baseline and to develop depressive symptoms later on, tests such as the OGTT, fasting plasma glucose, or HbA1c should be conducted every one to three years and adjusted for other diabetic risk factors [23].
Management & Treatment:
According to the 2018 PCOS guideline, there is not enough data to conclude that any one dietary strategy has a greater positive impact on health outcomes. In accordance with general population recommendations, recommendations may adopt a range of balanced dietary strategies based on the lifestyle needs and preferences of the individual. Weight loss improves the presentation of PCOS regardless of dietary composition, according to a systematic review that compared various dietary compositions (such as low carbohydrate, low glycaemic index (GI) and glycaemic load (GL), high protein, monounsaturated fatty acid (MUFA) enriched, and fat counting diets) to best manage PCOS [24].
Aerobic workout
This is essential to cardiovascular functioning and to the increase in energy expenditure during the course of a weight-loss program. It is important to realize that an obese, unfit patient will not necessarily be able to accomplish a great deal of aerobic exercise that enhance suppleness and flexibility. Although they will not necessarily increase caloric expenditure much, they can improve morale for an exercise program, minimize risk of injury and overall enhance well-being.
Exercise for endurance
Long-term lower-intensity exercise is a suitable method for patients who are unable to handle high-intensity exercise to improve their fitness and raise their energy expenditure. Using a pedometer while walking can be a very helpful way to start increasing energy expenditure.
Training with resistance
Weight training has been overlooked as a way to improve function and body composition by increasing muscle mass and strength up until recently. Resistance training is currently thought to be a very acceptable method of influencing weight, body composition, and insulin sensitivity because of the high metabolic rate of muscle, which makes muscle mass a significant determinant of resting energy expenditure [25].
B. Pharmacological Therapy:
|
Condition |
Treatment |
Dosage |
Possible ADRS |
|
Insulin Resistance |
Metformin |
A total of 500 mg (initial dose) with increases of 500 mg within 1–2 weeks, and employing extended-release formulations may reduce side effects and improve adherence |
Nausea, flatulence, and vitamin B12 deficiency |
|
Irregular Menstrual Cycle |
Oral Contraceptives (OCPs) |
20–35 µg Low-estrogen dose OCPs (eg,Ethinylestradiol 20 µg) |
Weight gain, Venous thromboembolism, spotting and breast tenderness |
|
Hirsutism |
Cyproterone acetate (monotherapy) Ethinylestradiol (in combination) |
10 mg 20–50 µg |
Headache, breast tenderness |
|
Infertility |
Clomiphene citrate, Letrozol |
Clomiphene citrate: 50–150 mg for 5 days; Letrozole: 2.5–5 mg/day (days 3–7 of menstrual cycle) |
Nausea and mood changes Multiple pregnancies; hot flashes |
|
Hyperandrogenism |
Spironolactone, Flutamide, Finasteride |
Spironolactone: 25–100 mg Flutamide: 500 mg + OCP |
Spironolactone: fatigue, irregular cycle (at high doses), hyperkalemia Finasteride: hepatotoxicity Flutamide: hepatotoxicity |
|
Obesity |
Pioglitazone, GLP-1-agonists, Orlistat |
Pioglitazone: 15–30 mg/daily; GLP-1-agonists: Semaglutide 0.25−1 mg once weekly; Liraglutide 0.6–1.8 mg once daily, Orlistat 120 mg twice a day |
Pioglitazone: mild peripheral edema and muscle cramping; GLP-1-agonists: gastrointestinal symptoms (nausea, diarrhea, vomiting, constipation, abdominal pain, or dyspepsia); Orlistat: increased bowel movement, oily stool, oily spotting, stomach pain and some cases of liver injury [26] |
Metformin
Because it enhances ovulation, insulin sensitivity, and potentially hyperandrogenism, metformin has gained popularity as a therapy [23].
It is frequently used, either by itself or in conjunction with clomiphene-citrate, to treat infertility. Since it causes some women to ovulate more frequently, it can also raise the, frequency of endometrial shedding and could aid in the regulation of the cycle. The long-term effects of treating insulin resistance in women with normal glucose levels with metformin are unknown. Metformin reduces the progression of poor glucose tolerance to type 2 diabetes in different groups. Therefore, women with polycystic ovarian syndrome and hyperglycemia may benefit from taking metformin. Whether or not administer this medication should be decided individually. Contraception should be recommended to those who do not want to get pregnant [27].
Infertility Management:
Menstrual irregularities (such as oligomenorrhea, amenorrhea, and anovulatory cycles) can result from hormonal abnormalities in women with PCOS (such as high androgen levels), which can induce dysfunctional uterine hemorrhage and inability to conceive. The ovulatory disruption in PCOS women may result in infertility and unfavorable pregnancy outcomes. PCOS-related infertility is treated with dietary, behavioral, and exercise modifications.
Letrozole should be regarded as a first-line pharmaceutical treatment for ovulation induction in PCOS women, as should pharmaceutical therapies (oral agents like rosiglitazone, clomiphene citrate either alone or in combination, letrozole, or metformin, or injectable agents like gonadotrophins), surgical therapies (laparoscopic ovarian surgery), or in vitro fertilization (IVF) [28].
C. Non-Pharmacological/ Procedural:
HIRSUTISM:
Management in hirsute PCOS females is identical to non-PCOS hirsute females. Non-pharmacological management is removal of hair by bleaching, plucking, waxing, depilatory creams, electrolysis, thermolysis and laser.
Drug therapy involves:
First-line: Spironolactone, metformin and eflornithine topical in facial hirsutism.
Oral contraceptives: Especially low-androgenic progestins (norgestimate, desogestrel, drospirenone) with inhibition of hair growth.
Other drugs: Flutamide and finasteride are potent but to be administered during pregnancy with caution.
Combinations: Oral contraceptives and spironolactone will be effective but raise potassium. Spironolactone is more potent than finasteride, and spironolactone and rosiglitazone will be more potent than metformin. Evidence for metformin is mixed—some trials show benefit; others show little effect. Facial hair is managed with topical eflornithine cream, which is FDA-approved, and perhaps with sibutramine (an anti-obesity drug). [29]
Treatments for Hirsutism
In PCOS-afflicted women are akin to those for patients of idiopathic hirsutism, who are not PCOS victims. There are numerous nonpharmacologic treatment alternatives, such as electrolysis, waxing, bleaching, plucking, depilatory creams (whereby one dissolves the hair), thermolysis (use of heat) as well as laser therapy. Various medications have been investigated for management of hirsutism in PCOS-affected women. The medications spironolactone and contraceptive oral drugs may be combined, but with drospirenone there must be a care since the two medications can lead to the hyperkalemia. Metformin, rosiglitazone (Avandia) and acarbose (Precose) are all insulin- sensitizing drugs for the treatment of hirsutism in PCOS women. Ferriman-Gallwey scores of hirsutism have shown that rosiglitazone and spirolactone are superior to metformin. Even though flutamide (formerly Eulexin) and finasteride (Propecia) are FDA pregnancy categories X and D, respectively and work, both are off-label when prescribed for hirsutism. Spironolactone is better than finasteride according to a Cochrane review.
The drugs oral contraceptives and spironolactone can be combined together, but in the patients on drospirenone one needs to be a cautious because both of these are medications can cause hyperkalemia. Metformin, rosiglitazone (Avandia) and acarbose (Precose) are the insulin- sensitising medication used to treat hirsutism in PCOS women are metformin, rosiglitazone (Avandia) and acarbose (Precose). Ferriman-Gallwey scores for hirsutism have revealed that rosiglitazone and spirolactone are superior to metformin. According to a Cochrane review, that for treatment of hirsutism in PCOS women, metformin is as effective as oral contraceptives; however, in a recent systematic review, it was observed that metformin is ineffective. One Topical eflornithine cream has been approved by the FDA for the treatment of unwanted facial hair, particularly in PCOS patients. Sibutramine (Meridia), a prescription antiobesity medication, also decreases hirsutism.
Surgical Treatments In PCOS:
The principal surgical treatment available is laparoscopic ovarian drilling (LOD) which is intended to correct ovulation by lowering ovarian androgen production.
1. Laparoscopic Ovarian Drilling (LOD)
LOD entails the movement of a laser or electrosurgical needle through the ovarian capsule, decreasing cyst numbers and reducing androgen concentrations. Systematic review and meta-analysis in 2025 contrasted unilateral LOD (ULOD) and bilateral LOD (BLOD) in terms of improving fertility outcomes. The research outcome showed that ULOD had fewer chances of complications such as scarring of the ovaries and premature ovarian failure but had satisfactory fertility outcomes [30].
2. Ovarian Wedge Resection
Once a common operation, wedge resection of the ovary is now performed fairly infrequently due to its tendency to cause postoperative adhesions and the availability of less dangerous alternatives.
3. Bariatric Surgery
In overweight or obese women with PCOS, bariatric surgery has been demonstrated to enhance insulin sensitivity, reduce testosterone, and normalize ovulation. It is generally reserved for patients, however, in whom lifestyle modifications and pharmacologic treatments have failed [31].
4. Emerging Research
A 2023 review pointed out that surgery could be a safe and efficient method of treatment for drug-resistant PCOS, especially in women intending to conceive. The review added decreased levels of LH and AMH after surgery, reflecting an improved balance of hormones [32].
Recent Advances & Future Direction:
1. Inositols
Myo-Inositol (MI) and D-Chiro-inositol (DCI) is insulin sensitisers and have ovarian physiology effects. Meta-analyses indicate MI ± DCI enhances insulin resistance, menstrual cyclicity, and certain ovarian outcomes in PCOS women. Myo-inositol pretreatment in IVF augmented mature oocyte rates but live birth outcomes are unclear. Dosage is typically 2–4 g/day; side effects are minimal GI symptoms. Overall, inositols are safe addition therapy, but evidence is heterogenous [33].
2. Vitamin D Supplementation
Vitamin D deficiency is common in PCOS. Supplementation lowers inflammatory biomarkers (e.g., hs-CRP) can improve glucose and lipid metabolism. Modest benefits are reported by meta-analyses but inconsistent dosing regimens and heterogeneity between trials moderate the conclusion [34][35]. Correcting deficiency is acceptable, but clinical endpoints such as fertility are in doubt.
3. GLP-1 Receptor Agonists
GLP-1 RAs (liraglutide, semaglutide) lead to weight loss and enhanced insulin sensitivity, addressing specifically PCOS metabolic derangement. Clinical trials report significant weight loss and increased menstrual cyclicity and androgen, although big RCTs by fertility indications are awaited [36]. GI-associated adverse effects frequent; pregnancy is a contraindication. Possibly valuable in obese PCOS but off-label in most indications present at the moment.
4. Genetics & Molecular Biomarkers
GWAS and molecular research find several loci associated with PCOS, namely genes controlling insulin and gonadotropin pathways. Predictive ability is still moderate. Reviews invoke promise for personalized treatment through multi-omic integration (hormones, microRNAs, metabolites) but no common biomarkers yet progressed to clinical practice [37].
5. Gut Microbiome Modulation
PCOS is linked with gut dysbiosis — decreased diversity and changing taxa (e.g., ↓Akkermansia, ↑Bacteroides/Escherichia). Small RCTs and animal models indicate that probiotics, prebiotics, or synbiotics correct insulin resistance and inflammation [38]. Mechanisms are robust but microbiome-directed interventions are experimental and need larger human trials.
CONCLUSION:
PCOS is complex endocrine- metabolic disease that affects the Female Reproductive Tract, Metabolic system and Moods. Its etiology is a multifactorial, Involving genetic, Hormonal, Metabolic, Inflammatory and Environmental factors, Rendering diagnosis according to the Rotterdam criteria problematic. Successful treatment demands tailored, Multi- Disciplinary strategies with primacy of lifestyle therapy— diet, physical exercise and weight reduction and drug treatment with metformin and oral contraceptives. New treatments such as inositol therapy and genetic assessment augment personalized care. Current studies strive to optimize diagnostic precision and comprehensive treatment for improved outcomes in women with PCOS.
ACKNOWLEDGEMENT:
The authors are thankful to Department of Pharmacy Practice, JKKMMRF’s Annai JKK Sampoorani Ammal College of Pharmacy, Affiliated to Tamil Nadu Dr.M.G.R. Medical University, Chennai, Tamil Nadu, India.
REFERENCES
Samarth College of Pharmacy, Belhe, Pune, Maharashtra, India, 412410
[authorID1] => [authorID2] => [authorID3] => [authorID4] => [authorID5] => [authorID6] => [authorID7] => [authorID8] => [authorID9] => [authorID10] => [createdDate] => 2025-10-24 00:00:00 [createdByUserID] => 1 [updatedDate] => 2025-10-24 09:41:18 [updatedByUserID] => 0 [isActive] => 1 [titleOfPaperOne] => Cervical Cancer Current Perspectives on Pathophysiology Diagnosis Prevention and Therapeutic Advances [txtBody] =>One of the most common gynaecologic diseases in the world is still cervical cancer. Based on available statistics, it is the fourth most prevalent cancer in women globally and ranks 14th overall. Cervical cells are where cervical cancer begins. The lower, narrow end of the uterus, or womb, is called the cervix. The uterus and vagina (birth canal) are connected by the cervix. Typically, cervical cancer progresses gradually over time. Cervical cells undergo a process called dysplasia, in which aberrant cells start to show up in the cervical tissue, prior to cancer developing in the cervix. The aberrant cells may eventually develop into cancer cells and begin to proliferate and spread farther into the cervix and surrounding regions if they are not eliminated or eliminated. Primary and secondary prevention are the main goals of cervical cancer intervention. The most effective ways to reduce the incidence and mortality of cervical cancer are through primary prevention and screening.[1] With racial, ethnic, and age differences, screening rates are lower in low-socioeconomic and low-resource locations. According to studies, women who are obese and suffer from chronic illnesses may be less likely to get screened for breast and cervical cancer. Cervical cancer is avoidable because it is a STI, and by focusing on education, screening, and prevention, the incidence of cervical cancer can be decreased worldwide. Cervical cancer preventative vaccinations have been available since 2006. When the World Health Organization (WHO) called for the universal eradication of cervical cancer in May 2018, almost 70 nations and international academic bodies responded right once. Subsequently, on November 17, 2020, the World Health Organization unveiled the global strategy to expedite the eradication of cervical cancer as a public health issue in order to illuminate the path for future cervical cancer prevention and control. This means that 194 nations have committed to working together to eradicate cervical cancer for the first time.[2]
2. BIOLOGY OF CERVICAL CANCER
The mucus-secreting columnar epithelium and stratified squamous epithelium that envelop the cervix are especially susceptible to viral neoplastic transformation at the squamocolumnar junction. Adenocarcinomas are more prevalent in endocervix tumors, but squamous cell carcinomas are the most prevalent kind. The majority of cervical cancer cases are caused by HPV infection, which is responsible for 95% of malignant lesions. It may take years or decades for dysplasia to develop into aggressive cancer.
Over 99 percent of cervical malignancies are caused by a persistent HPV infection. Worldwide, there are over 250,000 cervical cancer-related fatalities and over 500,000 new cases of the disease each year. Developing nations account for 80% of instances. About 4,000 women in the US lose their lives to cervical cancer each year. Low-resource communities have a far higher death rate and more disparities in evidence-based care for women, Black people, and Hispanic people. Women who have not been screened in the previous five years and those who do not have regular follow-up when a precancerous cervical lesion is discovered have a higher mortality rate. According to trends, women who are most at risk for mortality might be less likely to get vaccinated against HPV.[3]
Symptoms of Cervical Cancer: Early cervical cancer commonly has no symptoms, which is why screening is necessary to detect it. The most common actual symptoms are:
Vaginal bleeding: Because of the cervix's extremely delicate surface, tumours leak readily. In reality, a woman's overall risk of developing cervical cancer is around 30% if she experiences fresh vaginal bleeding after menopause. Women with premenstrual syndrome are frequently at risk for bleeding throughout their periods, strong menstrual flow, spotting bleeding during periods, or after sexual activity.
Vaginal discharge: White or often yellowish foul-smelling discharge that may occur with particularly advanced or necrotic cancer.
Cervical pain: When inserting a tampon or finger rather than the vagina, cervical pain is felt. This cervical motion pain raises the possibility of an infection or malignancy upon physical examination. Pelvic pain may be widespread in cases of more severe disease.
Urinary symptoms: As the tumour spreads into the vagina and eventually blocks the kidneys' ability to drain urine, urinary symptoms appear as the disease progresses. The most frequent cause of cervical cancer-related deaths is uraemia.
Signs of spread to other areas of the body include: lymph gland enlargement in the groin or collar bone are or the left armpit. Advanced spread may give bone, liver, lung, bowel or brain abnormalities.
The late symptoms: can be weight loss, anaemia and body lethargy.
Human Papillomavirus (HPV) infection: 99% of cervical cancer cases Most cervical cancer cases are caused by the sexually transmitted human papillomavirus (HPV). This is the same virus that causes genital warts. There are about 100 different strains of HPV. Only certain types cause cervical cancer. The two types that most commonly cause cancer are HPV-16 and HPV-18.[5]
10. STAGES OF CERVICAL CANCER [14]
A cancer?stage describes the extent of cancer in the body, especially whether the cancer has spread from where it first formed to other parts of the body. It is important to know the stage of cervical cancer in order to plan the best treatment.
Stage I: cervical cancer?has formed and is found in the?cervix?only. It is divided into stages IA and IB, based on the size of the tumor?and the deepest point of tumor invasion.
Stage II cervical cancer:
In stage II, cervical cancer?has spread to the upper two-thirds of the?vagina?or to the tissue?around the?uterus.
Stage II is subdivided based on how far the cancer has spread.
Stage III cervical cancer:
In stage III, cervical?cancer?has spread to the lower third of the?vagina and/ or to the pelvic wall, and/ or has caused kidney problems, and/ or involves lymph nodes.
Stage III is subdivided based on how far the cancer has spread.
Stage IV cervical cancer:
In stage IV, cervical cancer?has spread beyond the?pelvis, or has spread to the lining of the bladder or rectum, or has spread to other parts of the body.
Stage IV is subdivided into stages IVA and IVB, based on where the cancer has spread.
11. RECURRENT CERVICAL CANCER
Recurrent cervical cancer is cancer that has recurred (come back) after it has been treated. The cancer may come back in the cervix or as metastatic tumors in other parts of the body.?Tests will be done to help determine where the cancer has returned in your body, if it has spread, and how far.?The type of treatment that you have for recurrent?cervical?cancer will depend on how far it has spread.
Fig.2 Staging of Cervix Cancer
12. PATHOPHYSIOLOGY OF CERVICAL CANCER
Step 1: HPV Infection
Step 2: Viral Replication
Step 3: Integration and Oncogenesis
Step 4: Immune Evasion
Step 5: Angiogenesis and Metastasis
Fig.1 Key Molecular Alteration
13.TYPES OF CERVICAL CANCER
1. Squamous Cell Carcinoma (SCC): 70-80% of cervical cancer cases
2. Adenocarcinoma (AC): 10-20% of cervical cancer cases
3. Adenosquamous Carcinoma (ASC): 3-5% of cervical cancer cases
4. Small Cell Carcinoma (SCC): 1-2% of cervical cancer cases
5. Large Cell Carcinoma (LCC): rare
6. Glassy Cell Carcinoma (GCC): rare
7. Mucoepidermoid Carcinoma (MEC): rare
8. Serous Carcinoma (SC): rare
Rare and Unusual Types
14. MECHANISM OF HPV 16 INDUCED CANCER
Step 1: Viral Entry
Step 2: Viral Replication
Step 3: Expression of Oncoproteins
Step 4: Inhibition of Tumor Suppressor Proteins [19,20,7]
Step 5: Disruption of Cell Cycle Regulation[24]
Step 6: Epigenetic Changes [25,26]
Step 7: Cervical Cancer Development [6]
Step 8: Progression to Invasive Cancer [23]
15. TREATMENT
The treatment of cervical cancer depends on several factors, including the stage of cancer, the patient’s overall health, and whether the cancer has spread to other areas. Treatment options are typically grouped into the following categories:
Surgery is often the primary treatment for early-stage cervical cancer and can also be used in combination with other therapies for more advanced stages. Surgical options include:
Radiation therapy uses high-energy radiation to kill cancer cells or shrink tumors. It is often used for patients with more advanced stages of cervical cancer or as part of adjuvant therapy (after surgery). There are two types of radiation used in cervical cancer treatment:
Chemotherapy involves the use of drugs that kill cancer cells or prevent their growth. It is commonly used for more advanced cervical cancers, cancers that have spread (metastasized), or recurrent cancer. Chemotherapy is often given in combination with radiation therapy (chemoradiation) to enhance treatment efficacy.
Immunotherapy is a newer treatment approach that enhances the body's immune system to recognize and fight cancer cells. It is often used for advanced or recurrent cervical cancer.
Targeted therapies are drugs that specifically target molecules involved in the growth and spread of cancer. These therapies are designed to affect cancer cells more precisely while sparing healthy cells. Some examples include:
Hormone therapy is not typically used for cervical cancer since it is not hormone-driven like other cancers (e.g., breast or prostate cancer). However, in some rare cases where cervical cancer has spread or recurred, hormonal therapy might be considered if there are estrogen receptors on the cancer cells.
For young women diagnosed with early-stage cervical cancer who wish to preserve their fertility, there are fertility-sparing options, including:
For patients with advanced or metastatic cervical cancer, palliative care focuses on alleviating symptoms and improving quality of life. It may include:
16. RECENTLY APPROVED VACCINE
for the prevention of cervical cancer. If given before sexual maturity, these vaccines can provide up to 90% protection against cervical cancer. These vaccines are:
a. Gardasil [32]
In December 2014, the FDA approved Gardasil 9, which protects against nine strains of HPV.
Gardasil is available as Gardasil which protects against 4 types of HPV (6, 11, 16, 18) and Gardasil 9 which protects against an additional 5 types (31, 33, 45, 52, 58).
Gardasil™ is given at 0, 2, and 6 months. This means after you take the first dose, the next dose needs to be taken after two months and thereafter 6 months.
GARDASIL 9 should be administered intramuscularly in the deltoid region of the upper arm or in the higher anterolateral area of the thigh.
The safety of GARDASIL 9 was evaluated in six clinical studies that included more than 13,000 individuals & it is used in both males and females.
Cervarix™ is given at 0, 1, and 6 months. This means after you take the first dose, the next dose needs to be taken after a month and thereafter 6 months.
Immunization with Cervarix consists of 3 doses of 0.5-mL each, by intramuscular injection according to the following schedule: 0, 1, and 6 months. The preferred site of administration is the deltoid region of the upper arm. Cervarix is available in 0.5-mL single-dose vials and prefilled TIP-LOK syringes. Cervarix is used only in female.
The most common local adverse reactions in patients were pain, redness, fatigue, headache, muscle pain, gastrointestinal symptoms, and joint pain and swelling at the injection site.
Cervarix was voluntarily taken off of the market in the US in 2016 due to low demand.
India's first indigenously developed vaccine to prevent cervical cancer, CERVAVAC, is all set to be available later this year, costing between ?200-400 a shot. CERVAVAC will be effective against at least four variants of Human Papilloma Virus (HPV). While the vaccines must be given to both young boys and girls, chances of getting this cancer are more among women.
Several brands of HPV vaccines are available in India, including Gardasil 9, a nonavalent vaccine priced at approximately Rs 10,000 per dose, Gardasil 4 (quadrivalent) at around Rs 4,000 per dose, and Cervavac, an indigenous quadrivalent vaccine by the Serum Institute of India, priced at about Rs 2,000 per dose. All of these vaccines are safe, with no major side effects reported so far.
The FDA has approved several treatments for cervical cancer in recent years, particularly focusing on immune checkpoint inhibitors and targeted therapies. These treatments are typically used for advanced or recurrent cervical cancer, especially after chemotherapy has failed.
B. Atezolizumab (Tecentriq) [35]
C. Niraparib (Zejula) [36]
18. CURRENT RESEARCH AREAS FOR THE TREATMENT OF CERVICAL CANCER [37]
a. Immunotherapy
Immunotherapy continues to be a promising area of research for cervical cancer treatment, especially for advanced or recurrent cases. Several immune checkpoint inhibitors, such as pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), are already in use for treating advanced cervical cancer. Current research is focused on:
b. Targeted Therapy
Research in targeted therapies is focused on drugs that block specific molecules or pathways driving cervical cancer. Key areas include:
c. Personalised and Precision Medicine
Advances in genomic profiling are helping to develop more personalized treatment plans. By analyzing the genetic makeup of cervical cancer cells, researchers hope to identify specific mutations that can be targeted with drugs or other therapies. Liquid biopsy technologies, which analyze tumor DNA from blood samples, are also being studied to monitor disease progression and tailor treatments to individual patients.
d. Therapeutic Vaccines
While HPV vaccines are primarily used for prevention, therapeutic vaccines are in development to treat existing cervical cancer. These vaccines aim to stimulate the immune system to recognize and attack HPV-infected cells that have progressed to cancer. Some of these therapeutic vaccines are designed to target specific viral proteins (like E6 and E7) that are present in HPV-driven cancers.
e. Adoptive Cell Therapy (ACT)
Adoptive T-cell therapy, including CAR-T cell therapy, is being explored for cervical cancer. This involves extracting and modifying a patient's immune cells to enhance their ability to target and destroy cancer cells. Although CAR-T therapy has shown success in blood cancers, research is ongoing to adapt this approach for solid tumors like cervical cancer.
Advances in radiation techniques are providing more targeted and effective treatments with fewer side effects. Proton therapy and stereotactic body radiation therapy (SBRT) are being researched for cervical cancer, offering the possibility of delivering higher doses of radiation to tumors while minimizing damage to surrounding healthy tissue.
g. HPV Vaccine Development
Researchers are working on new HPV vaccines that target additional strains of the virus, further improving protection against cervical cancer. These vaccines could help reduce the incidence of cervical cancer globally by preventing HPV infection, especially in populations where vaccine uptake is lower.
h. Combination Therapy Approaches
Combinations of chemotherapy, radiotherapy, immunotherapy, and targeted therapies are being explored to improve efficacy. Research is focused on finding the best combinations to treat cervical cancer while minimizing side effects and resistance.[38-42]
CONCLUSION
Cervical cancer remains a significant global health concern, with human papillomavirus (HPV) as the primary cause. While prevention through vaccination has substantially reduced the incidence of cervical cancer, early detection and effective treatment remain crucial for managing the disease, particularly in advanced stages. Recent advancements in cervical cancer treatment, including the approval of novel drugs and vaccines, alongside ongoing research, offer renewed hope for patients and clinicians alike.
In recent years, the approval of immunotherapies such as cemiplimab (Libtayo) and atezolizumab (Tecentriq) marks a significant shift toward immune checkpoint inhibitors as a cornerstone of treatment for advanced, recurrent, or metastatic cervical cancer. These therapies enhance the immune system's ability to target and eliminate cancer cells, especially in tumors expressing PD-L1. Such therapies, either alone or in combination with chemotherapy, have shown promising results, extending survival and improving quality of life for many patients.
The HPV vaccine has revolutionized prevention, significantly reducing the incidence of cervical cancer by targeting the HPV types responsible for the majority of cases. Newer HPV vaccine formulations and expanded coverage to additional strains continue to evolve, offering greater protection and potentially lowering cervical cancer rates globally. Therapeutic vaccines are also under investigation, aiming to treat existing HPV-related cancers by stimulating the immune system to target infected cells, further advancing the promise of personalized cancer immunotherapy.
Ongoing research into targeted therapies, including PARP inhibitors and angiogenesis inhibitors, is providing hope for patients with specific genetic mutations or metastatic disease. These therapies are being explored in combination with other treatments to overcome resistance and increase efficacy. Additionally, the use of genomic profiling and liquid biopsy technologies to personalize treatment is likely to further improve outcomes by identifying patients most likely to respond to particular therapies.
REFERENCES
1,2 National Research Institute of Unani Medicine for Skin Disorders, Hyderabad, Telangana
3,4 Deoband Unani Medical Collage Hospital and Research Centre, Deoband, Saharanpur, Uttar Pradesh
Unani system of medicine which is also known as Greco-Arab medicine, is based on the ideas and philosophies of different scholars like Buqrat (Hippocrates, 460–370 BCE) and Jalinoos (Galen, 129–200 CE). In later period it was significantly influenced by the Persian and Arab scholars and physicians like Ibn Sina (Avicenna) and Abu Bakr al-Razi (Rhazes).[1]
It was introduced to Indian subcontinent around the 8th century, here it adopted the local drugs and medicinal practices which helped it to grow and change over time according to cultural and practical changes.[2]
The basic principle of Unani system of medicine is the Humoral theory proposed by Buqrat (Hippocrates), according to which human health is achieved by the maintenance of the equilibrium of four humors in human body i.e. Dam (blood), Balgham (phlegm), Safra (yellow bile), and Sauda (black bile). The balance of these humours is influenced by the temperament and the external factors like climate, diet, lifestyle, emotional state, and seasonal variations.[1]
The treatment in the Unani system of medicine is personalized and changes according to the temperament, lifestyle, and environmental exposure of the individual and also with seasonal variation. There is the concept of Asbab-e-Sitta Zaruriyya, that means the six essential factors for preserving health, these are Air (hawa), Food and Drink (Makool wa Mashroob), Sleep and Wakefulness (Naum wa Yaqza), Retention and Evacuation (Ehtibas wa Istifragh), Physical activity and Rest (Harakat wa sukoon-e-badni), and Mental activity and Rest (Harkat wa sukoon-e-nafsani). This falls under the preventive aspect of the healthcare.
The Unani system of medicine provides healthcare through a combination of lifestyle modification, dietary changes, medications, regimenal therapy and in some cases the surgery. Therefore the treatment is classified into four main categories i.e. Diet therapy (Ilaj bil Ghiza), Drug therapy (Ilaj bil Dawa), Regimenal therapy (Ilaj bil Tadbeer), and surgical interventions (Ilaj bil Yad).[1]
Unani system of medicine is an integral part of healthcare especially in India and other South Asian countries. But this lacks the standardized treatment protocol and has minimum integration with modern day biomedical research. Patients often takes multiple healthcare systems simultaneously, so there is a need for evidence-based validation of traditional medicine and also how these medicines interacts with other systems of medicine, specially Modern medicine. Here, Artificial Intelligence (AI) can be used as a tool to bridge this gap.
Machine learning, natural language processing, predictive analytics, image recognition, and deep learning all these are included in the working of AI. These techniques are already being used in allopathic medicine in different departments from imaging and pathology to drug discovery and patient tracking. So, it is essential to integrate AI with the Unani system of medicine to improve our medication research process, diagnosis, therapy, and drug standardisation.[3,4]
This paper aims to explore opportunities of AI in Unani Medicine and suggests a roadmap for integrating it to make Unani System of Medicine more acceptable according to the current healthcare system.
2. Overview of Artificial Intelligence in Healthcare [5,6]
When machine thinks and acts like humans, it is called Artificial Intelligence. In healthcare it works by collecting large amount of patient data then processing it using algorithms, identifying patterns and then using the already available knowledge to help make decisions.
Typical AI techniques consist of:
Globally, AI has been integrated into modern systems of medicine with significant success. Radiologists use AI to detect early tumours in imaging scans. Pharmacologists apply AI in drug discovery. Public health researchers use predictive models to monitor epidemics. These global successes encourages us for the application of AI in Unani medicine.[7,8]
3. AI in Diagnosis for Unani Medicine
Mizaj (temperament), Akhlat (humoral balance), and Asbab-e-Sitta Zarooriya (six essential causes) are the basics for the diagnosis in Unani system of medicine along with other diagnostic techniques including pulse testing (Nabz Shanasi), urine analysis (Baul Shanasi), and stool examination. However, diagnosis remains subjective and depends on practitioner's wisdom.
AI can contribute in this by:
By digitising diagnostic methods, artificial intelligence (AI) can help in making Unani system of medicine an evidence-based practice and increasing its dependability and acceptance around the world.
4. AI in Treatment Planning [11,12]
In Unani system of medicine there is concept holistic approach of treatment, which considers physical, psychological, dietary, and environmental aspects for the treatment regime. AI can enhance this individualized approach through:
This integration will ensure that Unani treatments are not only traditional but also technologically optimized for modern day patient needs.
5. AI in Drug Development, Standardization, Preclinical and Clinical Research
Unani system of Medicine has hundreds of drugs from three main sources i.e. plant, mineral, and animal-based drugs. However, the scientific data of these drugs are limited. It is a major challenge for Unani system of Medicine to standardize, validate and provide scientific data of the drugs based on modern day parameters.
AI can help in achieving this at multiple levels:
5.1 Preclinical Research and Standardization [13,14,15]
In preclinical research the drugs are tested on animals to check their safety, effectivity and metabolism. These processes now can be done in-silico using AI based models which can predict metabolism of a drug and identify its harmful effects. Thus, it can help to simplify trials, minimise use of animal and ethical limitations by offering these insights prior to animal study.
5.2 Clinical Research [16,17]
6. AI in Patient Monitoring and Tele-Unani Healthcare [18,19,20,21]
Continuous patient monitoring is essential for chronic diseases beyond the clinical visits. It is difficult for researcher to monitor the patients on his own. AI can help in continuous follow-up by:
7. Working process of AI [22,23,24]
AI functions in a cyclical process:
9. Challenges and Ethical Considerations
Despite the growing potential of AI there are several important challenges in front of Unani system of Medicine. One of the major limitation is the lack of digitization of the literature of Unani medicine as well as patient records. Most of the institutions are still using handwritten registers to keep patients data, which makes it difficult to build large and structured datasets essential to train AI models. Without this data, predictive tools for diagnosis, drug response or treatment outcomes remain limited.
Many traditional physicians are hesitant about using technology because they fear it might take away the natural and holistic approach of their practice.
Ethical concerns are also an aspect to consider, because the use of AI in healthcare needs lot of data and we must ensure patient privacy, proper informed consent, and strict data security to prevent misuse of sensitive medical information.
AI-based automated results cannot replace human research results, thus it cannot be trusted blindly at least as of now. So they must be tested and validated by a human.
These challenges highlight the importance of careful planning and regulatory frameworks,
Future Prospects and recommendation
CONCLUSION
Artificial Intelligence provides an opportunity to integrate Unani System of Medicine with the modern science. AI can be helpful in solving critical challenges of Unani medicine from improving diagnostic accuracy to supporting personalized treatment, accelerating drug discovery, standardizing formulations and monitoring patients. AI complements the philosophy of Unani system of medicine with evidence, precision, and efficiency. Thus, AI can help Unani medicine to be recognized globally, as evidence-based healthcare system that continues to serve humanity.
ADDITIONAL INFORMATION
Author Contributions: All authors have reviewed the final version to be published and agreed to be accountable for all aspects of the work.
Financial support and sponsorship: Nil.
Conflicts of interest: No conflict of interest
REFERENCES
St. Wilfred’s Institute of Pharmacy, Panvel 410206
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The liver is the largest internal organ and gland in the human body, weighing approximately 1.4 to 1.8 kilograms in adults and accounting for about 2–3% of total body weight[1]. It is located in the right upper quadrant of the abdomen, beneath the diaphragm, and extends across the midline into the left hypochondrium[2]. The liver has a wedge-shaped structure, with a smooth convex diaphragmatic surface and a concave visceral surface that rests upon adjacent abdominal organs such as the stomach, duodenum, and right kidney. It is divided anatomically into four lobes—right, left, caudate, and quadrate—by the attachment of ligaments and fissures. The falciform ligament separates the right and left lobes on the anterior surface and contains the round ligament, a remnant of the foetal umbilical vein. The liver is attached to the diaphragm and anterior abdominal wall by peritoneal folds, including the falciform, coronary, and triangular ligaments. The inferior surface bears the porta hepatis, which serves as the hilum of the liver and allows passage of the hepatic artery, portal vein, and bile ducts[4].
Functionally, the liver is divided into eight segments according to the Couinaud classification, each with its own vascular inflow, outflow, and biliary drainage[3]. This segmental anatomy is based on the branching pattern of the portal vein and hepatic artery and is of great clinical importance in hepatic surgery and transplantation. The structural framework of the liver is enclosed in a thin connective tissue layer known as Glisson’s capsule, which extends into the parenchyma to form sheaths around the portal triads. The liver parenchyma is composed of hepatocytes—polygonal epithelial cells arranged in plates or cords radiating from a central vein. Between these plates lie hepatic sinusoids, specialised vascular channels lined by fenestrated endothelial cells and Kupffer cells that act as macrophages to remove pathogens and debris from the blood[5]. Blood from the hepatic artery and portal vein mixes in the sinusoids, allowing for metabolic exchange before draining into the central vein and subsequently into the hepatic veins, which empty into the inferior vena cava.
Fig. 1: Structure of Liver
Several models can describe the functional unit of the liver, the most clinically relevant being the hepatic acinus model, which divides the parenchyma into three zones based on proximity to the blood supply. Zone I (periportal) receives oxygen-rich blood and is active in oxidative metabolism and gluconeogenesis, while Zone III (pericentral) is more hypoxic and primarily involved in glycolysis, drug metabolism, and detoxification processes. This zonal organisation explains the varying susceptibility of hepatocytes to toxins and ischemic injury[6]. The space of Disse, located between the sinusoidal endothelium and hepatocytes, facilitates nutrient and waste exchange and contains hepatic stellate (Ito) cells that store vitamin A and contribute to fibrosis during chronic injury.
In addition to its vascular organisation, the liver possesses a complex biliary system that begins with bile canaliculi formed between adjacent hepatocytes. These canaliculi drain bile into the canals of Hering, then into intrahepatic bile ducts lined by cholangiocytes, which progressively unite to form the right and left hepatic ducts. These merge to form the common hepatic duct, which joins the cystic duct from the gallbladder to form the common bile duct that empties into the duodenum. The liver’s lymphatic system, consisting of superficial and deep networks, drains interstitial fluid toward hepatic and celiac lymph nodes and eventually into the thoracic duct.
FUNCTION OF LIVER
Functionally, the liver plays a central role in maintaining metabolic homeostasis. It is responsible for carbohydrate metabolism, including glycogen synthesis and gluconeogenesis, lipid metabolism, such as cholesterol and triglyceride synthesis, and protein metabolism involving the production of albumin, clotting factors, and transport proteins[7,8]. The liver also detoxifies endogenous and exogenous substances through enzymatic modification and conjugation, making them suitable for excretion via bile or urine. Furthermore, it serves as a major storage site for glycogen, vitamins (A, D, B12), and minerals (iron and copper)[9]. The bile produced by hepatocytes aids in emulsifying dietary fats and facilitates the absorption of fat-soluble vitamins in the intestine.
Overall, the liver’s intricate anatomy and microscopic structure are closely integrated with its diverse physiological functions. Its dual blood supply, segmental organisation, and specialised cellular architecture enable efficient processing of nutrients, detoxification of harmful substances, synthesis of vital biomolecules, and excretion of metabolic waste. Understanding this structure–function relationship is essential for comprehending both normal hepatic physiology and the mechanisms underlying liver diseases.
NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
Non-alcoholic fatty liver disease (NAFLD) is recognised as the liver disease epidemic of the 21st century, with a global prevalence ranging from 23–32% depending on geographical region[2,3]. In India and other developing nations, the rising incidence of obesity, sedentary lifestyles, and type 2 diabetes has contributed to a growing NAFLD burden[4]. The disease represents a broad clinicopathological spectrum, beginning with non-alcoholic fatty liver (NAFL), characterised by simple hepatic steatosis without significant inflammation, and progressing to non-alcoholic steatohepatitis (NASH), in which steatosis is accompanied by hepatocyte ballooning, inflammation, and variable fibrosis. Over time, these changes can progress to cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver disease, making NAFLD a leading cause of liver transplantation[1].
Fig. 2: Healthy Liver vs Fatty Liver
Unlike viral hepatitis, NAFLD is tightly interlinked with metabolic syndrome, with insulin resistance playing a central role in its pathogenesis[7]. Current evidence highlights the imbalance between lipid acquisition and disposal in the liver as a fundamental mechanism. Increased lipid uptake via fatty acid transporters, enhanced de novo lipogenesis driven by transcription factors such as SREBP1c, impaired mitochondrial fatty acid oxidation, and reduced very low-density lipoprotein (VLDL) export collectively contribute to hepatic lipid accumulation[5,6]. These changes trigger lipotoxic oxidative stress and pro-inflammatory signalling, promoting hepatocyte injury and fibrosis[8].
Clinically, NAFLD is often silent, and many patients remain undiagnosed until advanced stages. While liver biopsy remains the gold standard for diagnosing NASH and staging fibrosis, non-invasive methods such as elastography and serum fibrosis scores are increasingly applied in clinical practice. Importantly, fibrosis stage rather than steatosis per se is the strongest predictor of long-term outcomes. Currently, there are no FDA-approved pharmacological agents for NAFLD[9]. Lifestyle modification with dietary intervention, weight reduction, and regular physical activity remains the cornerstone of therapy. Pioglitazone and vitamin E are considered in selected patients with biopsy-proven NASH, while emerging therapies such as farnesoid X receptor (FXR) agonists, peroxisome proliferator-activated receptor (PPAR) ligands, and glucagon-like peptide-1 (GLP-1) receptor agonists show promise in clinical trials[10,11].
This review aims to provide a comprehensive overview of the molecular mechanisms underlying NAFLD, current diagnostic approaches, therapeutic strategies, and future directions in disease management.
PATHOPHYSIOLOGY OF NAFLD
The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is multifactorial, involving a complex interplay between genetic, metabolic, and environmental factors. Central to the disease process is an imbalance between hepatic lipid acquisition and disposal, leading to intrahepatic lipid accumulation and subsequent lipotoxic injury[1].
1. Substrate Overload and Lipotoxicity
The “substrate overload lipotoxic injury (SOLLI) model” explains NAFLD pathogenesis as a result of excessive delivery of glucose, fructose, and fatty acids to the liver[2].
While triglyceride accumulation (steatosis) may initially serve as a protective mechanism, the diversion of fatty acids into toxic lipid species such as diacylglycerols, ceramides, and lysophosphatidylcholines triggers endoplasmic reticulum (ER) stress, mitochondrial dysfunction, oxidative stress, and hepatocyte apoptosis[3].
These processes activate Kupffer cells and hepatic stellate cells, resulting in inflammation and fibrogenesis.
2. Molecular Mechanisms of Hepatic Lipid Accumulation
Hepatic steatosis develops when lipid acquisition exceeds disposal. Four main pathways are implicated:
(a) Increased fatty acid uptake:
Mediated by CD36, fatty acid transport proteins (FATP2, FATP5), and caveolins. Overexpression of these transporters in NAFLD enhances hepatic lipid influx[4].
(b) Enhanced de novo lipogenesis (DNL):
Excess carbohydrates are converted into fatty acids through insulin- and carbohydrate-mediated transcription factors.
SREBP1c (stimulated by insulin) and ChREBP (stimulated by glucose/fructose) upregulate lipogenic enzymes such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN).
In NAFLD, selective insulin resistance preserves the lipogenic action of insulin, sustaining high rates of DNL even during fasting[4].
(c) Impaired fatty acid oxidation:
Normally regulated by PPARα, mitochondrial β-oxidation is insufficient in NAFLD[5,6].
Lipid overload shifts oxidation to peroxisomes and cytochrome P450 isoforms, generating excessive reactive oxygen species (ROS). ROS amplify hepatocyte injury, inflammation, and fibrogenesis[5].
(d) Defective lipid export:
The liver exports triglycerides as very-low-density lipoprotein (VLDL) particles.
In NAFLD, microsomal triglyceride transfer protein (MTTP) and ApoB100 activity are impaired, limiting VLDL secretion and worsening lipid retention.
3. Genetic and Epigenetic Factors
Variants in PNPLA3 (I148M) and TM6SF2 (E167K) are strongly associated with increased risk of steatosis, NASH, and fibrosis progression.
Epigenetic changes (DNA methylation, microRNAs) also influence lipid metabolism and inflammatory signalling[6,7].
4. Gut-Liver Axis
Altered gut microbiota, increased intestinal permeability, and translocation of bacterial endotoxins promote systemic inflammation and hepatic injury. Short-chain fatty acids and bile acid metabolism also modulate NAFLD progression via FXR and TGR5 signalling[8].
5. Inflammation and Fibrosis
Damaged hepatocytes release danger signals (DAMPs), activating Kupffer cells. Activated hepatic stellate cells (HSCs) produce extracellular matrix proteins, leading to fibrosis[9,10]. The fibrosis stage has been identified as the strongest predictor of long-term outcomes, surpassing steatosis severity[11,12].
DIAGNOSIS OF NAFLD
Diagnosis of non-alcoholic fatty liver disease (NAFLD) involves determining (1) the presence of hepatic steatosis, (2) whether inflammation/ ballooning is present (i.e. NASH), and (3) the fibrosis stage[1]. Because liver biopsy is invasive and not always practical, the focus is shifting toward non-invasive biomarkers and imaging methods.
1. Liver Biopsy (Gold Standard)[2]
2. Serum / Circulating Biomarkers & Diagnostic Panels [3,4]
Routine Clinical Biochemistry
Novel Biomarkers / Omics / Molecular Markers
3. Non-Invasive Imaging and Elastography[5,6]
Imaging plays a central role in diagnosing and quantifying hepatic fat content, inflammation, and fibrosis.
Conventional Imaging Modalities
Elastography & Quantitative Imaging
4. Hybrid / Combined Approaches[7,8]
CURRENT MANAGEMENT / THERAPEUTIC APPROACHES IN NAFLD
Because there is no single approved “magic bullet” treatment for NAFLD/NASH, current management comprises a combination of lifestyle interventions, off-label pharmacotherapies, surgical approaches in selected cases, and investigational/emerging therapies.
1. Lifestyle Modification (Foundational Therapy)
Lifestyle changes remain the backbone of NAFLD management according to most guidelines and reviews[1].
a. Weight Loss
b. Dietary Interventions
c. Physical Activity / Exercise
d. Behavioural Support & Long-Term Adherence
The absence of a pharmacologic remedy underscores why lifestyle remains first-line, and many trials use weight loss as a comparator or adjunct.
RECENT ADVANCES & EMERGING THERAPIES IN NAFLD
In the last decade, there has been significant progress in the development of pharmacological agents targeting various pathogenic mechanisms of NAFLD/NASH. Although no drug has yet received full FDA approval for NAFLD, several agents in phase 2 and phase 3 clinical trials have shown promising results.
1. Thyroid Hormone Receptor-β (THR-β) Agonists
2. FXR (Farnesoid X Receptor) Agonists
3. PPAR (Peroxisome Proliferator-Activated Receptor) Agonists
4. GLP-1 Receptor Agonists & Incretin-Based Therapies
5. FGF (Fibroblast Growth Factor) Analogues
6. Anti-Fibrotic and Anti-Inflammatory Agents
7. Combination Therapies
Table. 1: Drugs and their mechanism and trial data
|
Drug/Class |
Target Mechanism |
Trial Outcomes |
Current Status |
|
Resmetirom (THR-β agonist) |
↑ Lipid metabolism, ↓ steatosis |
Reduced liver fat, improved fibrosis (MAESTRO-NASH) |
Phase 3 (FDA Fast Track) |
|
Obeticholic Acid (FXR agonist) |
Modulates bile acid, anti-fibrotic |
Fibrosis improvement, pruritus side effect (REGENERATE) |
Phase 3 |
|
Lanifibranor (pan-PPAR) |
Improves insulin sensitivity, ↓ inflammation |
Improved NASH histology (NATIVE trial) |
Phase 2 |
|
Semaglutide (GLP-1 RA) |
Weight loss, insulin sensitization |
NASH resolution, improved histology |
Phase 2/3 |
|
Tirzepatide (GLP-1/GIP dual) |
Incretin pathway modulation |
Significant weight loss, liver fat reduction |
Phase 3 |
|
Efruxifermin (FGF21 analogue) |
Fat oxidation, insulin sensitization |
Fibrosis regression in trials |
Phase 2 |
|
Belapectin (Galectin-3 inhibitor) |
Anti-fibrotic, prevents varices |
Mixed results, ongoing studies |
Phase 2 |
|
Cenicriviroc (CCR2/CCR5 antagonist) |
Blocks inflammatory signalling |
Limited benefit in fibrosis |
Development paused |
CHALLENGES AND LIMITATIONS IN NAFLD MANAGEMENT
Despite remarkable advances in understanding the molecular basis of NAFLD and numerous clinical trials, the translation into effective therapies has been slow. Several key challenges contribute to this gap:
1. Absence of FDA-Approved Drugs
2. Disease Heterogeneity
3. Diagnostic Limitations
4. Slow Disease Progression
5. Adherence to Lifestyle Interventions
6. Safety Concerns of Emerging Therapies
7. Comorbidities and Extrahepatic Outcomes
8. Economic and Healthcare Burden
FUTURE PERSPECTIVES IN NAFLD MANAGEMENT
With the global prevalence of NAFLD increasing and no approved pharmacotherapy yet available, research is shifting toward novel strategies and precision medicine. Future management will likely combine lifestyle, pharmacological, and technological interventions tailored to individual patient profiles.
1. Personalized and Precision Medicine
2. Gut–Liver Axis Modulation
3. Nanomedicine and Targeted Drug Delivery
4. Combination Therapies
5. Digital Health and Lifestyle Support
6. Early Detection and Preventive Strategies
MARKETED PREPARATION FOR NAFLD
Here are some of the marketed or recently approved preparations for non-alcoholic fatty liver disease (NAFLD) / non-alcoholic steatohepatitis (NASH), along with mechanism, status, and limitations. Note that many treatments are off-label or approved only in certain countries; always check local regulatory status.
Resmetirom (brand name Rezdiffra) is one of the newest agents approved by the U.S. FDA (in March 2024) for treatment of noncirrhotic NASH (now also called metabolic dysfunction-associated steatohepatitis, or MASH) with moderate to advanced fibrosis (F2–F3). It is a thyroid hormone receptor-β agonist, which acts by increasing hepatic fat oxidation and reducing inflammation and fibrosis.
In India, saroglitazar (dual PPAR α / γ agonist) has been approved by the Drug Controller General of India (DCGI) for the treatment of NAFLD/NASH in non-cirrhotic patients. Saroglitazar improves lipid parameters (via PPAR-α) and insulin sensitivity (via PPAR-γ), thereby impacting steatosis, inflammation, and metabolic comorbidities.
Very recently, in India, nor-ursodeoxycholic acid (NorUDCA) 500 mg tablets have also been approved by CDSCO for the treatment of NAFLD. NorUDCA is claimed to have choleretic and anti-inflammatory properties, enhancing bile flow, reducing hepatic inflammation and potentially slowing disease progression.
Besides these, other pharmacologic agents are often used off-label or in clinical trials. For example, vitamin E and pioglitazone have been used in selected non-diabetic NASH patients for inflammation improvement, though effects on fibrosis are less consistent.
CONCLUSION
Non-alcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disorder worldwide, closely linked with obesity, type 2 diabetes, and metabolic syndrome[1]. Its spectrum, ranging from simple steatosis to cirrhosis and hepatocellular carcinoma, underscores the importance of early recognition and intervention. Advances in understanding disease pathogenesis highlight the central roles of lipotoxicity, insulin resistance, inflammation, and fibrogenesis, with genetic and gut microbiota factors further modulating disease progression[2,3].
Diagnosis has shifted from invasive liver biopsy toward non-invasive biomarkers and imaging modalities, although limitations remain in identifying patients with “at-risk NASH”[4]. Lifestyle modification remains the cornerstone of therapy, but long-term adherence is a major challenge. Pharmacological therapies such as pioglitazone, vitamin E, and GLP-1 receptor agonists show promise, while newer agents resmetirom, obeticholic acid, lanifibranor, and FGF analogues are advancing through late-stage clinical trials[5,6].
Despite these developments, the absence of FDA-approved therapies, patient heterogeneity, and safety concerns remain major hurdles[7]. The future of NAFLD management will likely rely on precision medicine approaches, gut–liver axis modulation, nanotechnology-based drug delivery, and rational combination therapies[8,9,10]. Furthermore, integration of digital health solutions and population-level preventive strategies will be essential to curb the rising global burden.
In conclusion, NAFLD represents both a clinical challenge and an opportunity for innovative research. Continued multidisciplinary collaboration between clinicians, researchers, and policymakers is crucial to translate scientific advances into effective, accessible therapies that improve long-term patient outcomes[11,12].
REFERENCES
SET’s College of Pharmacy, Dharwad, Karnataka 580002
[authorID1] => [authorID2] => [authorID3] => [authorID4] => [authorID5] => [authorID6] => [authorID7] => [authorID8] => [authorID9] => [authorID10] => [createdDate] => 2025-10-06 00:00:00 [createdByUserID] => 1 [updatedDate] => 2025-10-06 11:35:16 [updatedByUserID] => 0 [isActive] => 1 [titleOfPaperOne] => Diabetes Mellitus Decoded Classification Diagnosis Therapeutics and Emerging Drug Frontiers [txtBody] =>Diabetes is characterized by elevated blood glucose levels, either in the fasting state or after meals. Persistent hyperglycaemia in diabetes mellitus (DM) contributes to progressive damage, dysfunction, and eventual failure of various organs and tissues, notably the retina, kidneys, peripheral nerves, heart, and vascular system1.
The pathogenesis of diabetes mellitus primarily involves two key mechanisms: autoimmune-mediated destruction of pancreatic β-cells, resulting in inadequate insulin production, and intrinsic cellular resistance to insulin action. These processes collectively contribute to the persistent hyperglycaemia characteristic of the disease2.
Diabetes mellitus (DM) is among the most prevalent metabolic disorders globally, with its incidence rising at an alarming pace. Between 1980 and 2014, the number of individuals diagnosed with DM surged from 108 million to 422 million. During the same period, the global prevalence of diabetes among adults aged 18 years and older increased from 4.7% to 8.5%. According to the World Health Organization (WHO), diabetes is projected to become the seventh leading cause of mortality by 2030.
Type 1 diabetes mellitus (T1DM), typically diagnosed during childhood or adolescence, accounts for approximately 5–10% of all diabetes cases and is primarily characterized by autoimmune destruction of pancreatic β-cells. In contrast, Type 2 diabetes mellitus (T2DM) represents the predominant form, comprising 90–95% of cases, and is commonly associated with insulin resistance and relative insulin deficiency.
Gestational diabetes mellitus (GDM) is a distinct subtype that manifests exclusively during pregnancy, affecting approximately 5–15% of pregnant women, with prevalence varying across ethnic groups and geographic regions. Notably, 40–60% of women diagnosed with GDM are at risk of developing overt diabetes within 5–10 years postpartum3.
TYPES OF DIABETES MELLITUS AND THEIR PATHOPHYSIOLOGY
Type 1 diabetes mellitus
Type 1 Diabetes Mellitus (T1DM), also known as autoimmune diabetes, insulin-dependent diabetes mellitus (IDDM), juvenile-onset, or ketosis-prone diabetes, is a chronic condition primarily affecting children and young adults. It is characterized by the autoimmune destruction of pancreatic β-cells, leading to an absolute deficiency of insulin. This destruction is mediated by CD4+ and CD8+ T cells and macrophages infiltrating the islets, and is often accompanied by the presence of autoantibodies such as anti-glutamic acid decarboxylase (GAD), islet cell antibodies, and insulin autoantibodies, which are detectable in 85–90% of individuals at the onset of fasting hyperglycaemia. The exact cause remains unknown, but strong evidence supports an autoimmune mechanism. Individuals with T1DM may also present with other autoimmune disorders like Graves’ disease, Hashimoto’s thyroiditis, and Addison’s disease. The disease disrupts normal glucose regulation not only due to insulin deficiency but also because of α-cell dysfunction, resulting in excessive glucagon secretion that exacerbates hyperglycaemia and contributes to metabolic imbalances. This dysregulation often leads to diabetic ketoacidosis in the absence of insulin therapy. Furthermore, insulin deficiency impairs peripheral glucose utilization by promoting uncontrolled lipolysis and elevating plasma free fatty acids, which inhibit glucose metabolism in tissues such as skeletal muscle. It also downregulates key insulin-responsive genes like glucokinase in the liver and GLUT4 transporters in adipose tissue, further compromising glucose uptake. Lifelong insulin administration remains the cornerstone of treatment to manage this life-threatening condition4-5.
Figure 1. Pathophysiology of T1DM
Type 2 diabetes mellitus
Type 2 Diabetes Mellitus (T2DM) is a prevalent metabolic disorder caused by defective insulin secretion from pancreatic β-cells and impaired insulin response in target tissues. Proper insulin synthesis, release, and action are essential for metabolic balance; disruptions in these mechanisms lead to T2DM.
According to the WHO, diabetes is a chronic condition marked by elevated blood glucose, which over time damages the heart, blood vessels, eyes, kidneys, and nerves. Over 90% of cases are T2DM, characterized by insulin resistance (IR), β-cell dysfunction, and inadequate compensatory insulin secretion, resulting in hyperglycaemia.
T2DM is commonly associated with obesity, especially abdominal fat, which contributes to IR via inflammatory pathways, increased free fatty acids, and adipokine imbalance. Key drivers of the global T2DM epidemic include rising obesity, sedentary behaviour, high-calorie diets, and aging populations.
Pathogenesis centres on two mechanisms:
Figure 2. Pathophysiology of T2DM
Gestational Diabetes Mellitus
Gestational diabetes mellitus (GDM) is a metabolic disorder affecting 14% of pregnancies worldwide, or 18–20 million births annually. It arises from insufficient insulin secretion during pregnancy, leading to hyperglycaemia. Risk factors include obesity, poor diet, sedentary lifestyle, and family history of diabetes. In obese women, GDM results from amplified insulin resistance due to pre-existing metabolic dysfunction. In lean women, impaired first-phase insulin response plays a larger role. Maternal hyperglycaemia causes excess glucose transfer to the foetus, triggering foetal hyperinsulinemia and resulting in macrosomia (birth weight >4000 g)7-8.
Figure 3. Pathophysiology of GDM
SYMPTOMS OF DM
Diabetes symptoms are caused by rising blood sugar.
Symptoms of type 1 diabetes can include
Symptoms of type 2 diabetes can include
Figure 4. Main symptoms of Diabetes Mellitus
COMPLICATIONS OF DM
As diabetes progresses, tissue and vascular damage become more pronounced, leading to severe complications such as diabetic retinopathy, neuropathy, cardiovascular disorders, and ulceration. Patients with long-standing Type 1 diabetes mellitus (T1DM) are particularly vulnerable to microvascular complications, including damage to the retina, kidneys, and peripheral nerves. They may also develop macrovascular diseases affecting the coronary arteries, heart, and peripheral vasculature.
Type 2 diabetes mellitus (T2DM), on the other hand, carries a significantly higher risk of large vessel disease. It is commonly associated with comorbid conditions such as hypertension and dyslipidaemia. Consequently, most patients with T2DM are predisposed to cardiovascular complications, which remain the leading cause of morbidity and mortality in this population10.
Figure 5. Complications of DM
DIAGNOSIS OF DM
A1C test. This blood test, which doesn't require not eating for a period of time (fasting), shows your average blood sugar level for the past 2 to 3 months. It measures the percentage of blood sugar attached to hemoglobin, the oxygen-carrying protein in red blood cells. It's also called a glycated hemoglobin test. The higher your blood sugar levels, the more hemoglobin you'll have with sugar attached. An A1C level of 6.5% or higher on two separate tests means that you have diabetes. An A1C between 5.7% and 6.4% means that you have prediabetes. Below 5.7% is considered normal.
Random blood sugar test. A blood sample will be taken at a random time. No matter when you last ate, a blood sugar level of 200 milligrams per deciliter (mg/dL), 11.1 millimoles per liter (mmol/L) or higher suggests diabetes.
Fasting blood sugar test. A blood sample will be taken after you haven't eaten anything the night before (fast). A fasting blood sugar level less than 100 mg/dL (5.6 mmol/L) is normal. A fasting blood sugar level from 100 to 125 mg/dL (5.6 to 6.9 mmol/L) is considered prediabetes. If it's 126 mg/dL (7 mmol/L) or higher on two separate tests, you have diabetes.
Glucose tolerance test. For this test, you fast overnight. Then, the fasting blood sugar level is measured. Then you drink a sugary liquid, and blood sugar levels are tested regularly for the next two hours. A blood sugar level less than 140 mg/dL (7.8 mmol/L) is normal. A reading of more than 200 mg/dL (11.1 mmol/L) after two hours means you have diabetes. A reading between 140 and 199 mg/dL (7.8 mmol/L and 11.0 mmol/L) means you have prediabetes11.
Figure 6. WHO Diabetes information chart of DM
TREATMENT OF DIABETES MELLITUS
Self-monitoring of blood glucose (SMBG) is a critical component in the management of type 1 diabetes mellitus (DM) and insulin-dependent type 2 DM. It enables patients to adjust insulin doses effectively, thereby minimizing the risk of both hypoglycaemia and hyperglycaemia.
According to the American Diabetes Association (ADA) guidelines, individuals with type 1 DM should monitor their blood glucose levels at the following times:
Patients must be educated on interpreting real-time glucose readings to make informed decisions about dietary intake and medication adjustments.
While SMBG is commonly advised for patients with type 2 DM, especially those on insulin therapy, its standalone effectiveness remains uncertain. Although early studies indicated improvements in HbA1c levels, confounding factors such as concurrent lifestyle modifications (e.g., diet and exercise) complicate the evaluation of SMBG’s direct impact.
The ADA recommends the following glycaemic targets:
Table 1. Oral Agents with Mechanism of Action and Side Effects13
|
Oral Antidiabetics |
Mechanism of Action |
Side Effects |
|
Sulfonylureas Glimiperide(Amaryl) Glipizide (Glucotrol) Glipizide-gits (GlucotrolXL) Glibenclamide Glyburide (Diabeta,Micronase) Glyburide-micronized (Glynase) Tolbutamide (Orinase) Chlorpropamide (Diabinese) Tolazamide (Tolinase) Acetoheximide (Dymelor) |
Stimulate first-phase insulin secretion by blocking K+ channel in ß- cells. |
Late hyperinsulinemia and hypoglycemia Weight gain. |
|
Meglitinides Repaglinide (Prandin) Nateglinide (Starlix) |
Stimulate first- phase insulin secretion by blocking K+ channel in ß-cells |
Hypoglycemia Weight gain. |
|
Biguanides Metformin (Glucophage,Riomet) Metformin-XR(Glucophage-XR) |
Decrease hepatic glucose production Increase muscle glucose uptake and utilization |
Nausea, Diarrhea Anorexia, Lactic acidosis. |
|
Thiazolidinedinediones Rosiglitazone (Avandia) Pioglitazone (Actos) |
Increase insulin sensitivity via Activation of PPAR-g receptors |
Fluid retention and weight gain. |
|
α-Glucoside Inhibitors Acarbose (Precose) Miglitol (Glyset) |
Decrease hepatic glucose production Delays glucose absorption |
Flatulence Abdominal bloating |
RECENT THERAPIES FOR TREATMENT OF DIABETES MELLITUS14
Here are several modern approaches involved in the management of diabetes. However, early diagnosis is central to achieving any targets set in DM management:
Lifestyle modification is a cornerstone of diabetes management, recommended for both pre-diabetic and diabetic individuals. Key changes include increasing physical activity, and adopting a healthy diet rich in vegetables, fruits, whole grains, lean meats, and non-fat dairy, while limiting sugary and fatty foods. Patients are also encouraged to quit smoking and reduce alcohol consumption.
Nanotechnology involves the use of nanoparticles (<100 nm). This has opened new frontiers in diabetes care. In medicine, this approach—known as nanomedicine—enhances the delivery and targeting of drugs and diagnostic agents. In diabetes, nanotechnology has enabled the development of advanced glucose monitoring systems and non-invasive insulin delivery methods. It also supports innovative therapies like cell-based and gene-based treatments for type 1 diabetes. Importantly, nanotech tools can detect immune cell activity, monitor beta-cell mass, and improve early diagnosis, which is crucial for preventing disease progression. Alternative non-invasive delivery routes, including oral, transdermal, and inhalation methods, are also under exploration to improve patient compliance and therapeutic outcomes.
Traditional glucose monitoring methods, involving frequent finger pricks, often suffer from poor compliance and limited temporal coverage (e.g., during sleep or driving). This can lead to dangerous glycaemic fluctuations and increased risk of complications. CGM systems, especially those using subcutaneous biosensors like amperometric sensors, offer a more consistent monitoring approach.
Medical Nutrition Therapy (MNT), delivered by registered dietitian nutritionists, is a cornerstone of diabetes management. It involves personalized nutrition diagnosis and counselling aimed at achieving glycaemic control and preventing complications. MNT is especially vital in gestational diabetes mellitus (GDM), where carbohydrate intake plays a central role. While low-carbohydrate diets have traditionally been used, emerging evidence supports the efficacy of low-glycaemic index diets in managing GDM.
Gene therapy is an innovative technique aimed at correcting disease symptoms caused by defective genes through the introduction or manipulation of functional genetic material.
Types of gene therapy:
In diabetes mellitus (DM), particularly type 1 diabetes mellitus (T1DM), gene therapy is emerging as a promising alternative to conventional treatments. T1DM is an autoimmune condition characterized by T-cell-mediated destruction of insulin-producing beta cells. Its multifactorial etiology involves both genetic and environmental factors. Recent research has identified several genes implicated in T1DM pathogenesis, making them potential targets for gene-based interventions.
In type 2 diabetes mellitus (T2DM) One notable target is NLRP3, a gene whose inhibition reduces inflammation and protects beta cells from apoptosis, thereby preventing T2DM onset in animal models.
Conventional diabetes treatments often fail to address the root causes and may carry adverse effects. Stem cell therapy offers a regenerative alternative by aiming to restore insulin-producing beta cells. While pancreas or islet-cell transplantation has shown promise, it’s limited by donor organ scarcity. Stem cells, with their unique ability to differentiate and regenerate, present a viable solution to this challenge.
Table 2. Stem cells drugs in the Pipeline
|
Drug Candidate |
Developer |
Mechanism Of Action |
Target Condition |
|
LY3502970 |
Eli Lilly |
Partial GLP-1R agonist (G-protein biased) |
Type 2 Diabetes (T2DM) |
|
SCO-094 |
SCOHIA |
Dual GIP and GLP-1receptor agonist |
Type 2 diabetes (T2DM) |
|
Ladarixin (LD) |
Dompé Farmacei |
CXCR1/ CXCR2 inhibitor |
New-onset Type 1 Diabetes (T1DM) |
CONCLUSION
Diabetes mellitus continues to pose a significant global health challenge, driven by lifestyle transitions, genetic susceptibility, and environmental factors. Despite advances in diagnosis and treatment, the burden of complications such as cardiovascular disease, neuropathy, nephropathy, and retinopathy remains high, highlighting the importance of early detection and effective management strategies. Conventional therapies, including lifestyle modification, insulin, and oral hypoglycaemics, form the cornerstone of treatment, yet emerging approaches—such as nanotechnology, continuous glucose monitoring, gene therapy, and stem cell-based interventions—offer promising avenues for more precise and personalized care. A multidisciplinary strategy integrating prevention, patient education, pharmacological innovations, and cutting-edge biomedical technologies is essential to reduce morbidity and mortality associated with diabetes. Ultimately, ongoing research and innovation hold the key to transforming diabetes management and mitigating its impact on individuals and healthcare systems worldwide.
ACKNOWLEDGEMENT
I would like to express my sincere gratitude to SET’s College of Pharmacy, Dharwad for providing the necessary infrastructure and academic support throughout the course. I am deeply thankful to my guide—her expertise and mentorship have been instrumental in shaping the direction and quality of this work. I also extend my appreciation to the faculty and staff for offering excellent facilities and fostering a stimulating academic environment. Finally, I am immensely grateful to my family, friends and Amrut Khavi for their constant encouragement and patience, which kept me motivated during the most challenging phases of this journey.
REFERENCES
1,2,3 Dr. Shivajirao Kadam College of Pharmacy, Kasabe Digraj, Miraj, Sangli, Maharashtra, 416305.
4 Shri Gajanan Arts Commerce and Science College, Jadra Boblad
The particularly prevalent type of dementia, Alzheimer's disease (AD), affects people globally
and a gradually developing neurological illness. Memory loss, cognitive decline, and neuropathological features such external amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau, neuroinflammation, and oxidative stress are its defining characteristics [1]. Timely intervention depends on early diagnosis, but traditional diagnostic approaches include Magnetic resonance imaging (MRI), Positron emission tomography (PET), and cerebrospinal fluid (CSF) Evaluation of biomarkers, are frequently intrusive, costly, or insensitive in the preclinical stages [2].
Because of the large proportion of surface to volume, capacity to cross blood-brain barrier (BBB) and potential for functionalization with ligands for targeted delivery, nanoparticles (NPs) have become innovative methodology in AD. In areas of diagnostics, nanoparticles (NPs) such Superparamagnetic Iron oxide nanoparticles (SPIONs), Quantum dots, and gold nanoparticles have been developed to improve imaging techniques and facilitate early detection by identifying biomarkers [3,4].
In a therapeutic context, NPs decrease systemic toxicity while enhancing drug solubility, stability, and targeted delivery. In order to deliver anti-amyloid medicines, antioxidants, siRNA, and gene treatments directly to the affected brain regions, advanced nanotechnologies are being developed, including polymeric nanoparticles, liposomes, dendrimers, and lipid-based carriers [5,6]. Targeting ligands, such as aptamers, peptides, or antibodies, improve NP selectivity for tau or Aβ aggregates, providing site-specific treatment [7]. Additionally, real-time monitoring and individualized therapy of AD are made possible by multifunctional "theranostic" nanoparticles that combine diagnostics and treatments [8].
With these properties, nanoparticles offer an innovative approach to Alzheimer's disease diagnosis, treatment, and targeted delivery, resolving significant issues in contemporary clinical practice and providing a route to more efficient and customized therapies.
For therapeutic and/or diagnostic reasons, it has been proposed to target the Aβ1–42 peptide in every form of agglomeration [9–14]. The Blood and central nervous system (CNS) are separated by BBB, a dynamic biological and physical barrier. The capillary endothelial cells in the brain, which limit transcellular transit, and firm and tight connections between the cells, which limit paracellular flux, are primarily responsible for functional complexity of blood-brain barrier [15].
Nanomedicines (NMs), which aim to engage in molecular interactions with BBB cells, that are currently the most sought-after approaches. In order to transfer NM for therapeutic purposes, these NMs take advantage of the physiological processes already present in the BBB. The transportation of NM is accomplished by a variety of transport techniques. The most significant processes that enable transcellular transfer of NM from Blood to the brain are receptor- and adsorptive-mediated transcytosis [16). Specific inhibition can be achieved by taking advantage of the NPs' differential binding to Aβ monomers and oligomers once they have entered the brain. Furthermore, blocking the oligomers by NPs would be crucial from the biological point of since it is thought that they are a type of Aβ agglomerates that are most neurotoxic.[17]. Due to the fact that they influence their toxicity, targeting capacity, and in vivo distribution, Particle size and charge, core and surface characteristics, shape and flexibility, multivalency, and controlled synthesis are the most significant characteristics of NP formulations. The uses of Polymeric nanoparticles loaded with AD drugs shown in fig. 1. As a result, these characteristics significantly affect the stability of nanoparticles as well as their ability to load and release drugs (18).
Fig 1 Polymeric nanoparticles containing drugs to treat AD.
Nanotechnology Could assist in early identification of Alzheimer's disease through very effective signal transduction techniques. The process of transforming and amplifying a biological signal for recording is known as signal transduction. Target-based treatment (TBT) advancement is currently of interest because the traditional medications used to treat AD can only slow its progression and not cure it [19,20]. Nanocarriers or nano-formulations offer many benefits over traditional treatment for AD, including avoiding hepatic metabolism, lowering dosage, improving medication stability, bioavailability, and targeted administration at area of the action. The most difficult aspect of treating neurological illnesses is getting medications into the brain. The physical barrier known as the blood–brain barrier (BBB) divides circulation in the periphery from CNS., prevents molecules from moving freely within the brain parenchyma [21]. Among the most difficult physiological hurdles is this one. The BBB can be penetrated by lipophilic molecules that are less than 400 Da. The mobility of larger hydrophilic molecules or lipid-insoluble molecules is restricted [22, 23]. Some methods to improve medication transport across BBB such as Liposomes, polymeric nanoparticles (PNPs), Solid lipid nanoparticles (SNPs), along with gold nanoparticles [24,25,26]. These potential alternatives, such as drug-loaded PNPs, can enhance the drug's distribution throughout brain. A broad spectrum of ligands can be effectively incorporated into surface of PNPs to enhance their stability, high loading capacity, regulated kinetics of drug release, and drug encapsulation. (27,28) Through targeted medication administration, metallic nanoparticles have been shown to be a helpful therapeutic method in Alzheimer’s disease therapy. These elements, which include iron, cerium, selenium, gold, & silver, are recognized to have strong anti-AD characteristics [29]. Because gold nanoparticles travel by transcytosis movement through the brain's endothelial cells without altering their surface, they are designated for AD.
These positively charged nanoparticles have the ability to transport bioactive substances and aid in the targeted delivery of brain regions [30]. Gold nanoparticles (Au-NPs) show both neuroprotective and excellent BBB penetration capabilities [30]. Because it prevents Aβ aggregation, Au-NPs conjugated utilizing glutathione has been found to have an anti-Alzheimer's action [31].
The steps involved in creating nanoparticles:
Nanoparticles (NPs) can be created chemically, physically, or biologically. The different components of NPs and its functions are listed in table 1 and methods involved are mentioned in fig 2. The uses, surface properties, and desired size all influence the process selection. The following are typical methods:
Mostly used for nanoparticles of polymers. A surfactant is used to emulsify a polymer in an aqueous phase after it has been dissolved in an organic solvent. After then, the solvent evaporates, producing NPs.
Applicable to drug carriers based on PLA, PLGA, and PCL.
A polymer dissolves in water when it is solubilized in a solvent that is organic and is introduced to water phase while being stirred, solvent diffusion causes the production of nanoparticles (33).
Benefit: Easy to use, quick, and prevents excessive heat.
Used for chitosan nanoparticles, in which a polyanion (such as tripolyphosphate) combines with cationic chitosan. (44)
Utilized to produce magnetic and metallic nanoparticles. Agents such as NaBH? convert metal salts to form nanoparticles. (35)
To produce homogeneous nanoparticles, a surfactant-stabilized emulsion is employed as a nanoreactor. (36)
Suitable for: oxide and metallic nanoparticles.
Fig 2 Some methods for production of Nanoparticle
Table No. 1 Ingredients Used in Nanoparticles and Their Significance
|
Ingredient |
Function |
Examples |
Significance |
|
Polymers |
Matrix or carrier material |
PLGA, PLA, PCL, chitosan |
Biodegradable, biocompatible; controls drug release [37] |
|
Lipids |
Form lipid nanoparticles or liposomes |
Phospholipids, cholesterol |
Good for encapsulating hydrophobic drugs [38] |
|
Surfactants/ Stabilizers |
Prevent aggregation, stabilize particles |
PVA, Tween 80, Poloxamer 188 |
Improve stability and dispersion [39] |
|
Crosslinking agents |
Solidify polymer or protein structure |
Glutaraldehyde, TPP |
Essential in ionic gelation or protein NPs [34] |
|
Solvents |
Dissolve polymers/ drugs |
Acetone, ethanol, dichloromethane |
Aid in nanoparticle formation; must be removed completely [33] |
|
Drugs/ Active Agents |
Therapeutic function |
Donepezil, curcumin, siRNA |
Incorporated for targeted delivery [37] |
|
Targeting Ligands |
Enable specific cell binding |
Antibodies, peptides, aptamers |
Enhance cellular uptake and selectivity [40] |
|
Metal Precursors |
For metallic nanoparticles |
FeCl? (iron), HAuCl? (gold) |
Provide core material for inorganic NPs [35] |
Alzheimer's Disease Causes:
A mixture of genetic, biochemical, and environmental factors that contributes to etiology of AD, a complex neurodegenerative disorder shown in fig 3
1. Accumulation of Amyloid-β (Aβ) Plaque
Aβ peptides build up extracellularly to form plaques, which impair synaptic function, induce neuroinflammation, and neuronal death [41].
2. Hyperphosphorylation of Tau Protein
Tau proteins that are abnormally phosphorylated produce neurofibrillary tangles, which disrupt microtubule activity and cause cell death [42].
3. Neuroinflammation
Pro-inflammatory cytokines released by activated microglia and astrocytes enhance neuronal damage and aid in the development of illness [43].
4. Oxidative Stress and Dysfunction of the Mitochondrion
While mitochondrial malfunction affects how neurons use energy, excessive reactive oxygen species (ROS) damages cellular components [44].
5. Genetic Variables
AD that begins early: brought on by changes in the genes PSEN1, PSEN2, APP as well.
Late-onset AD: Associated with APOE ε4 allele, one of main genetic hazardous factors, [45].
6. Lifestyle and Environmental Aspects
Cardiovascular illness, poor diet, smoking, low cognitive stimulation, social isolation, and physical inactivity are risk factors [46].
Fig 3 Causes of Alzheimer's disease
Prevention of Alzheimer's Disease:
Although at moment, there is no solution to completely avoid AD, changes in lifestyle can reduce the risk:
1. Nutritional Therapy
Slower cognitive decline is linked to Omega-3 fatty acids and antioxidants are abundant in Mediterranean or MIND diet. [47].
2. Exercise
Frequent exercise lowers Aβ levels, increases cerebral blood flow, and promotes neurogenesis [48].
3. Stimulation of the Cognition
Mentally demanding activities can postpone the development of symptoms and improve cognitive reserve [49].
4. Management of Cardiovascular Risk
Vascular contributions to cognitive impairment are decreased by managing blood pressure, cholesterol, diabetes, and obesity [50].
5. Hygiene of Sleep
Aβ elimination through the glymphatic system is facilitated by getting enough good sleep [51].
Alzheimer's Disease Treatment:
1. Pharmaceutical Interventions
Cholinergic function is enhanced by Cholinesterase inhibitors, including rivastigmine and donepezil.
Neurons are shielded from glutamate-induced toxicity by NMDA receptor antagonists, like memantine [52].
Aβ plaques are targeted and decreased by anti-amyloid monoclonal antibodies, for example lecanemab and aducanumab [53].
2. Alternative Medicine Methods
Quality of life is enhanced and functional deterioration is postponed through behavioral therapy, cognitive training, physical exercise, and caregiver support [54].
3. Emerging Nanotechnology-Based Therapies
In order to reduce Aβ buildup, oxidative stress, and neuroinflammation, nanoparticles are being investigated for the passage of specific medications via BBB.
Importance of nanoparticles in diagnosis of Alzheimer's Disease:
Early diagnosis of AD is essential to avoiding dementia and irreversible neural damage. Developing techniques to identify AD in its early stages is essential because investigating a real human brain is challenging and takes a long time.
Magnetic Nanoparticles as MRI (Magnetic Resonance Imaging) contrast agents:
Most efforts are focused on employing contrast-agent-doped nanoparticles in MRI to detect & identify amyloid plaques, as it is generally acknowledged in the field of science that development of senile plaques results in degeneration of the neurofibrilla (56). A contrast agent containing Nanoparticles that are magnetic and Aβ peptide was created using co-deposition and surface modification approaches. An MRI machine was used to image the brains of AD transgenic mice in order to investigate in vivo imaging. The findings showed that the contrast agent has good MRI enhancement of senile plaque and is about 5 nm in size (57).
It has been revealed that amyloid oligomers (AOs) are the only ones that have a sensitive contrast probe for molecular MRI. Antibodies that are unique to magnetic nanostructures with AOs showed that complex is stable; they attach to AOs on brain tissues as well as cells to generate an MRI signal. The probe immediately arrived in hippocampus of AOs in an AD mouse model after being administered intranasally. To differentiate AD from controls in separate samples of human brain tissue, an MRI signal was present. in isolated human brain tissue samples. These neurotoxic AO-targeting nanostructures should be helpful for assessing effectiveness of new medications and, potentially, for early diagnosis plus in addition to AD therapy (58). Furthermore, according to reports, development of Nanoparticles of monocrystalline iron oxide (MIONs) has advanced for coupled targeting and imaging of senile plaques and that these particles form a covalent link with amide linking to the A1-40 peptide's N-terminus.
Nanogels
Drug delivery treatments for AD have used nanogels, an efficient method for delivering pharmaceuticals that provides improved cellular absorption, decreased toxicity, enhanced medication loading and controlled release at the intended location. A recent study showed that chitosan and tripolyphosphate nanogels are effective in delivering deferoxamine in order to treat AD. By stopping formation of Aβ amyloid, Cholesterol-modified pullulan backbones serve as synthetic chaperones that decrease the pathophysiology of AD. Nanogels, which have non-toxic, stable, hydrophilic, and biodegradable qualities, improved the distribution of insulin, a possible AD medication, to the brain in preclinical animal studies, particularly when mixed with polysaccharides (60).
To overcome the drawbacks of existing AD treatments that are lacking ability to cross the BBB, researchers are investigating nanomaterials for precision medicine.
Nanotechnology in AD therapy:
Innovative drug development techniques are now essential to overcoming the restriction or obstacle that CNS medications experience in attempting to cross BBB. This need is satisfied by several methods based on nanotechnology that increase entrapped drug's effectiveness and prolonged release. Examples of techniques based on nanotechnology comprises polymers, solid lipid carriers, Nanoparticles made of lipoprotein & curcumin, optical imaging, metal-based carriers, magnetic, inorganic and antibody-tethered nanoparticles, as well as nanocomposites, dendrimers, and emulsion.
Polymeric nanoparticles:
The purpose of Nanoparticles of polymers are to improve bioavailability of hydrophobic medications while protecting them through deactivation of the environment & destruction.
Use of chitosan NPs in conjunction with rivastigmine for AD was investigated by Wilson et al. (2011). By emulsifying rivastigmine, the researchers synthesized chitosan nanoparticles (NPs) with mean size of 47 ± 4 nm. According to a zeta potential investigation, coating chitosan nanoparticles with polysorbate 80 reduced their positive charge. Drug release from NPs was shown to follow a biphasic, Fickian diffusion release pattern. Additionally, it was shown that covering NPs with 1% polysorbate 80 changed how the various organs absorbed the NPs. (61)
Liposomes:
Using a mediator of BBB transport with an anti-transferrin antibody (TrF) and a metabolite of curcumin, Mourtas et al. (2014) developed multifunctional liposomes. According to study of Liposomes containing either a curcumin derivative and anti-TrF shown significant attraction for amyloid plaques in post-mortem brain tissues from AD patients. Additionally, the authors found that liposomes containing curcumin derivatives did not stop Aβ aggregation or block Aβ deposit staining. However, brain-targeting ability was unaffected by the existence of a lipid-curcumin-PEG conjugate, indicating that these multifunctional NLs may be effective AD theranostics. (62)
Nanoparticles based on lipids or lipoproteins:
It is well known that lipid-based nanoparticles have a significant attraction for Aβ., which facilitates their breakdown and this enables them to be applied to diagnostic and therapeutic purposes. The system of apolipoprotein E3–reconstituted high-density lipoprotein (ApoE3–rHDL) nanoparticles was created by Song et al. (2014). in order to remove Aβ. Over four weeks of treatment every day, the amount of Aβ deposits, microgliosis, neurological changes, and memory issues diminished., indicating potential therapeutic application of ApoE3–rHDL in AD. Approximately 0.4% ID/g of ApoE3–rHDL was found in brain of a mouse one hour after intravenous delivery. Its toxicity is still unknown, though. (63)
According to Loureiro et al. (2017), extracts from skin of grape and grape seeds prevented AD patients' Aβ from aggregating. because resveratrol, which is found in grapes, is known to have neuroprotective characteristics., it was selected for the study. The authors found that bioactive extract was transported to an in vitro model of human BBB, An antibody that is monoclonal to the transferrin receptor was employed to functionalize solid lipid nanoparticles (SLNs).(OX26 mAb). OX26 SLN cellular absorption was considerably greater than that of SLNs that were not functionalized and SLNs that were functionalized using an unspecific antibody, according to experiments conducted on human brain-like endothelial cells. (64)
NPs loaded with curcumin:
Researchers have studied curcumin in recent decades and found that it has a variety of biological activities, including neuroprotective potential. Curcumin's effectiveness does not reach the biological system despite this potential. It has a limited bioavailability and is known to be sensitive to biodegradation and oxidation. Therefore, by encapsulating it in nanocapsules, this limitation can be removed., which will make the BBB easier to traverse. (65)
Metal-based carriers:
Recently generated Gold-based Magnetically sensitive carriers or metal-based nanoparticles, For instance Yb-doped or Ce-doped maghemite NPs (MNPs), have been employed as vehicles for drugs that have photosensitizing properties. These nanoparticles exhibit stability and increased ability to enter tissues, even ones that are cancerous.
Conjugates of nanoparticles:
Even very small concentrations of Up to 10–18 moles of protein biomarkers per liter, can be detected using DNA–nanoparticle complexes. The bio-barcode technique, another name for this detection method, use an antibody that is specific to a protein and has been tagged with gold nanoparticles. (65).
A dual-purpose, spherical delivery of A medication that contains β-sheet breaker peptides H102 (TQNP/H102) was designed by Zhang et al. (2014). To facilitate Aβ42 targeting and BBB transit, respectively, two targeting peptides—QSH & TGN—were attached to surfaces of nanoparticles. A unique dual-functional material was presented by Zhang and colleagues, and it was discovered to be a promising nanocarrier for proteins and peptides as well as for the selective administration of drugs into CNS and, later, brain AD lesions.
A very specialized form of AD therapy may be possible with this kind of technology. (67)
Delivery of nanoparticles intranasally:
In order to treat AD, Elnaggar et al. (2015) explored selective intranasal administration of NPs of chitosan laden with piperine (PIP). These chitosan NPs substantially decreased piperine-induced nasal trouble in a rat study without negatively affecting the brain. This work was first to show that PIP's benefits in AD were caused by its anti-apoptotic and anti-inflammatory effects. Additionally, the authors produced mucoadhesive chitosan nanoparticles (NPs) with success, which offered a way to circumvent PIP's negative effects by delivering PIP to the brains at 5% of the oral dosage, but at the same concentrations as oral delivery.
Alzheimer's Disease (AD) Nanoparticle Applications (69,70)
By overcoming the drawbacks of traditional therapeutics, such as inadequate BBB permeability, non-specific targeting, & limited drug bioavailability, nanoparticles (NPs) offer revolutionary potential in diagnosis, treatment, monitoring of AD as well. An extensive summary of uses of NPs in Alzheimer's Disease is provided below, along with relevant citations:
1. Systems for Drug Delivery
Transporting therapeutic medications crossing the BBB is a significant obstacle to AD treatment which NPs can help with.
Biodegradable polymeric nanoparticles (like chitosan and PLGA):
These can be altered with ligands to improve brain targeting.
For instance, in AD mice models, PLGA nanoparticles loaded with donepezil demonstrated enhanced memory.
Solid lipid nanoparticles and other lipid-based nanoparticles and liposomes:
Improve stability and solubility of medications.
As an illustration, liposomes laden with curcumin have demonstrated promise in lowering amyloid-beta (Aβ) plaques in AD mice.
Gold nanoparticles (AuNPs):
Photothermal treatment and targeting can be accomplished by functionalizing their surface.
Example: AuNPs conjugated employing antibodies against Aβ were able to bind Aβ and reduce toxicity.
2. Imaging and Diagnosis:
The early diagnosis of AD's sensitivity and specificity are enhanced by nanoparticles.
In order to identify Aβ plaques, magnetic nanoparticles, such as SPIONs, are employed as MRI contrast agents.
For instance, in transgenic mice with AD, imaging of amyloid plaques was improved by SPIONs coupled with an Aβ antibody.
Fluorescent nanoparticles known as quantum dots (QDs) are utilized to image Aβ aggregates in real time. Aβ peptide-tagged QDs, for instance, assisted in tracking the development of plaque.
3. Removal of Aβ Plaque
Aβ plaques, a defining feature of AD, can be broken down or removed with the help of NPs.
Immunotherapy with nanoparticles:
Provide peptides or antibodies that specifically target Aβ.
For instance, polymeric nanoparticles that delivered anti-Aβ antibodies enhanced cognition and decreased Aβ load.
Metal chelation:
Metal ions (such as Cu and Zn) linked to Aβ aggregation can be bound by chelators carried by NPs.
4. Gene Therapy:
To control genes linked to AD, genetic material (such as siRNA and miRNA) can be delivered by nanoparticles.
siRNA delivery: NPs facilitate effective siRNA transport to neurons while shielding it from degradation.
For instance, chitosan NPs loaded with siRNA decreased expression of the BACE1 gene, which decreased the generation of Aβ.
5. Anti-inflammatory and Antioxidant Effects:
Antioxidant substances carried by NPs can lessen AD's neuroinflammation and oxidative stress.
For example, CeO? NPs, or cerium oxide nanoparticles, mimic antioxidants.
CONCLUSION
In the fight to prevent Alzheimer's, nanoparticles have proven to be an incredibly adaptable platform, providing cutting-edge approaches to combination therapy, tailored medication administration, and early diagnostics. They are very appealing for both therapeutic and diagnostic applications because of their capacity to get beyond conventional obstacles including inadequate drug bioavailability and poor BBB permeability. Every type of nanoparticle, from metallic and hybrid nanostructures to polymeric and lipid-based carriers, offers distinct advantages for AD research. Even if there are still issues with long-term safety, targeted delivery, and clinical translation, continuous developments in molecular biology, materials science, and nanomedicine are opening up possibilities for Alzheimer's treatments of the future. In the nearer future., nanoparticles could completely change how we identify, treat, and eventually prevent Alzheimer's disease should interdisciplinary cooperation and translational research continue.
ACKNOWLEDGEMENTS
The authors wish to acknowledge the support and contributions that facilitated the completion of this work
Conflict of Interest Statement: The authors declared no conflict of interest.
REFERENCES