INTRODUCTION:

Allergy:

Allergies, also known as allergic diseases, refer to a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, allergic asthma, and anaphylaxis. Symptoms may include red eyes, an itchy rash, sneezing, coughing, a runny nose, shortness of breath, or swelling. Note: food intolerances and food poisoning are separate conditions.

Common allergens include pollen and certain foods. Metals and other substances may also cause such problems. Food, insect stings, and medications are common causes of severe reactions. Their development is due to both genetic and environmental factors.

The underlying mechanism involves immunoglobuline antibodies (Ige), part of the body's immune system, binding to an allergen and then to a receptor on mast cells or basophils where it triggers the release of inflammatory chemicals such as histamine. Diagnosis is typically based on a person's medical history. Further testing of the skin or blood may be useful in certain cases. Positive tests, however, may not necessarily mean there is a significant allergy to the substance in question.

Early exposure of children to potential allergens may be protective. Treatments for allergies include avoidance of known allergens and the use of medications such as steroids and antihistamines. In severe reactions, injectable adrenalin (epinephrine) is recommended. Allergen immunotherapy, which gradually exposes people to larger and larger amounts of allergen, is useful for some types of allergies such as hay fever and reactions to insect bites. Its use in food allergies is unclear.

Allergies are common. In the developed world, about 20% of people are affected by allergic rhinitis, about 6% of people have at least one food allergy, and about 20% have or have had atopic dermatitis at some point in time. Depending on the country, about 1–18% of people have asthma. Anaphylaxis occurs in between 0.05–2% of people. Rates of many allergic diseases appear to be increasing. The word "allergy" was first used by clemens von pirquet in 1906¹.

Signs and symptoms:

Many allergens such as dust or pollen are airborne particles. In these cases, symptoms arise in areas in contact with air, such as the eyes, nose, and lungs. For instance, allergic rhinitis, also known as hay fever, causes irritation of the nose, sneezing, itching, and redness of the eyes. Inhaled allergens can also lead to increased production of mucus in the lungs, shortness of breath, coughing, and wheezing.

Aside from these ambient allergens, allergic reactions can result from foods, insect stings, and reactions to medications like aspirin and antibiotics such as penicillin. Symptoms of food allergy include abdominal pain, bloating, vomiting, diarrhea, itchy skin, and hives. Food allergies rarely cause respiratory (asthmatic) reactions, or rhinitis. Insect stings, food, antibiotics, and certain medicines may produce a systemic allergic response that is also called anaphylaxis; multiple organ systems can be affected, including the digestive system, the respiratory system, and the circulatory system. Depending on the severity, anaphylaxis can include skin reactions, bronchoconstriction, swelling, low blood pressure, coma, and death. This type of reaction can be triggered suddenly, or the onset can be delayed. The nature of anaphylaxis is such that the reaction can seem to be subsiding but may recur throughout a period of time².

Skin:

Substances that come into contact with the skin, such as latex, are also common causes of allergic reactions, known as contact dermatitis or eczema. Skin allergies frequently cause rashes, or swelling and inflammation within the skin, in what is known as a "weal and flare" reaction characteristic of hives and angioedema. With insect stings, a large local reaction may occur in the form of an area of skin redness greater than 10 cm in size that can last one to two days. This reaction may also occur after immunotherapy.

CAUSES OF ALLERGY:

Risk factors for allergies can be placed in two broad categories, namely host and environmental factors. Host factors include heredity, sex, race, and age, with heredity being by far the most significant. However, there have been recent increases in the incidence of allergic disorders that cannot be explained by genetic factors alone. Four major environmental candidates are alterations in exposure to infectious diseases during early childhood, environmental pollution, allergen levels, and dietary changes³.

Dust mites:

Dust mite allergy, also known as house dust allergy, is a sensitization and allergic reaction to the droppings of house dust mites. The allergy is common and can trigger allergic reactions such as asthma, eczema, or itching. It is the manifestation of a parasitosis. The mite's gut contains potent digestive enzymes (notably peptidase 1) that persist in their feces and are major inducers of allergic reactions such as wheezing. The mite's exoskeleton can also contribute to allergic reactions. Unlike scabies mites or skin follicle mites, house dust mites do not burrow under the skin and are not parasitic.

Foods:

A wide variety of foods can cause allergic reactions, but 90% of allergic responses to foods are caused by cow's milk, soy, eggs, wheat, peanuts, tree nuts, fish, and shellfish. Other food allergies, affecting less than 1 person per 10,000 population, may be considered "rare". The use of hydrolyzed milk baby formula versus standard milk baby formula does not appear to affect the risk.

The most common food allergy in the us population is sensitivity to crustacea. Although peanut allergies are notorious for their severity, peanut allergies are not the most common food allergy in adults or children. Severe or life-threatening reactions may be triggered by other allergens and are more common when combined with asthma.

Rates of allergies differ between adults and children. Children can sometimes outgrow peanut allergies. Egg allergies affect one to two percent of children but are outgrown by about two- thirds of children by the age of 5. The sensitivity is usually to proteins in the white, rather than the yolk.

Milk-protein allergies are most common in children. Approximately 60% of milk-protein reactions are immunoglobulin e-mediated, with the remaining usually attributable to inflammation of the colon. Some people are unable to tolerate milk from goats or sheep as well as from cows, and many are also unable to tolerate dairy products such as cheese. Roughly 10% of children with a milk allergy will have a reaction to beef. Beef contains small amounts of proteins that are present in greater abundance in cow's milk. Lactose intolerance, a common reaction to milk, is not a form of allergy at all, but due to the absence of an enzyme in the digestive tract.

Those with tree nut allergies may be allergic to one or to many tree nuts, including pecans, pistachios, pine nuts, and walnuts. In addition, seeds, including sesame seeds and poppy seeds, contain oils in which protein is present, which may elicit an allergic reaction. Allergens can be transferred from one food to another through genetic engineering; however genetic modification can also remove allergens. Little research has been done on the natural variation of allergen concentrations in unmodified crops.

Latex:

Latex can trigger an ige-mediated cutaneous, respiratory, and systemic reaction. The prevalence of latex allergy in the general population is believed to be less than one percent. In a hospital study, 1 in 800 surgical patients (0.125percent) reported latex sensitivity, although the sensitivity among healthcare workers is higher, between seven and ten percent. Researchers attribute this higher level to the exposure of healthcare workers to areas with significant airborne latex allergens, such as operating rooms, intensive-care units, and dental suites. These latex-rich environments may sensitize healthcare workers who regularly inhale allergenic proteins.

The most prevalent response to latex is an allergic contact dermatitis, a delayed hypersensitive reaction appearing as dry, crusted lesions. This reaction usually lasts 48–96hours. Sweating or rubbing the area under the glove aggravates the lesions, possibly leading to ulcerations. Anaphylactic reactions occur most often in sensitive patients who have been exposed to a surgeon's latex gloves during abdominal surgery, but other mucosal exposures, such as dental procedures, can also produce systemic reactions.

Latex and banana sensitivity may cross-react. Furthermore, those with latex allergy may also have sensitivities to avocado, kiwifruit, and chestnut. These people often have perioral itching and local urticaria. Only occasionally have these food-induced allergies induced systemic responses. Researchers suspect that the cross-reactivity of latex with banana, avocado, kiwifruit, and chestnut occurs because latex proteins are structurally homologous with some other plant proteins.

Medications:

About 10% of people report that they are allergic to penicillin; however, 90% turn out not to be. Serious allergies only occur in about 0.03%.

Insect stings:

Typically, insects which generate allergic responses are either stinging insects (wasps, bees, hornets and ants) or biting insects (mosquitoes, ticks). Stinging insects inject venom into their victims, whilst biting insects normally introduce anti-coagulants.

Toxins interacting with proteins:

Another non-food protein reaction, urushiol-induced contact dermatitis, originates after contact with poison ivy, eastern poison oak, western poison oak, or poison sumac. Urushiol, which is not itself a protein, acts as a hapten and chemically reacts with, binds to, and changes the shape of integral membrane proteins on exposed skin cells. The immune system does not recognize the affected cells as normal parts of the body, causing a t-cell-mediated immune response. Of these poisonous plants, sumac is the most virulent. The resulting dermatological response to the reaction between urushiol and membrane proteins includes redness, swelling, papules, vesicles, blisters, and streaking.

Estimates vary on the percentage of the population that will have an immune system response. Approximately 25percent of the population will have a strong allergic response to urushiol. In general, approximately 80 percent to 90percent of adults will develop a rash if they are exposed to .0050 milligrams (7.7×10-5gr) of purified urushiol, but some people are so sensitive that it takes only a molecular trace on the skin to initiate an allergic reaction.

Genetics:

Allergic diseases are strongly familial:

Identical twins are likely to have the same allergic diseases about 70% of the time; the same allergy occurs about 40% of the time in non-identical twins. Allergic parents are more likely to have allergic children, and those children's allergies are likely to be more severe than those in children of non-allergic parents. Some allergies, however, are not consistent along genealogies; parents who are allergic to peanuts may have children who are allergic to ragweed. The likelihood of developing allergies is inherited and related to an irregularity in the immune system, but the specific allergen is not.

The risk of allergic sensitization and the development of allergies varies with age, with young children most at risk. Several studies have shown that ige levels are highest in childhood and fall rapidly between the ages of 10 and 30 years. The peak prevalence of hay fever is highest in children and young adults and the incidence of asthma is highest in children under 10. Ethnicity may play a role in some allergies; however, racial factors have been difficult to separate from environmental influences and changes due to migration. It has been suggested that different Genetic loci are responsible for asthma, to be specific, in people of european, hispanic, asian, and african origins.

Stress:

Chronic stress can aggravate allergic conditions. This has been attributed to a t helper 2 (th2)- predominant response driven by suppression of interleukin 12 by both the autonomic nervous system and the hypothalamic–pituitary–adrenal axis. Stress management in highly susceptible individuals may improve symptoms.

Other environmental factors:

Allergic diseases are more common in industrialized countries than in countries that are more traditional or agricultural, and there is a higher rate of allergic disease in urban populations versus rural populations, although these differences are becoming less defined. Historically, the trees planted in urban areas were predominantly male to prevent litter from seeds and fruits, but the high ratio of male trees causes high pollen counts, a phenomenon that horticulturist tom ogren has called "botanical sexism".

Alterations in exposure to microorganisms is another plausible explanation, at present, for the increase in atopic allergy. Endotoxin exposure reduces release of inflammatory cytokines such as tnf-a, ifn?, interleukin-10, and interleukin-12 from white blood cells (leukocytes) that circulate in the blood. Certain microbe-sensing proteins, known as toll-like receptors, found on the surface of cells in the body are also thought to be involved in these processes.

Gutworms and similar parasites are present in untreated drinking water in developing countries, and were present in the water of developed countries until the routine chlorination and purification of drinking water supplies. Recent research has shown that some common parasites, such as intestinal worms (e.g., hookworms), secrete chemicals into the gut wall (and, hence, the bloodstream) that suppress the immune system and prevent the body from attacking the parasite. This gives rise to a new slant on the hygiene hypothesis theory—that co-evolution of humans and parasites has led to an immune system that functions correctly only in the presence of the parasites. Without them, the immune system becomes unbalanced and oversensitive. In particular, research suggests that allergies may coincide with the delayed establishment of gut flora in infants. However, the research to support this theory is conflicting, with some studies Performed in china and ethiopia showing an increase in allergy in people infected with intestinal worms. Clinical trials have been initiated to test the effectiveness of certain worms in treating some allergies. It may be that the term 'parasite' could turn out to be inappropriate, and in fact a hitherto unsuspected symbiosis is at work^4,5.

Chlorpheniramine is a histamine-h1 receptor antagonist indicated for the management of symptoms associated with upper respiratory allergies. A histamine h1 antagonist used in allergic reactions, hay fever, rhinitis, urticaria, and asthma. It has also been used in veterinary applications. One of the most widely used of the classical antihistaminics, it generally causes less drowsiness and sedation than promethazine.

Russom et al., 2017 stated stevens - johnson syndrome (sjs), toxic epidermal necrolysis (ten) and erythema multiform (em) are very rare but potentially fatal cutaneous reactions. As of the publication of this case report, the association of chlorpheniramine and the serious cutaneous reactions em, sjs and ten is not documented in literature. However, inthe international adverse drug reaction database (vigibase) we found a total of 53 cases of em, sjs, and ten submitted from different parts of the world including eritrea. This case study, based on data retrieved from vigibase, was therefore aimed at assessing the causal association of ten, sjs and em with the use of chlorpheniramine. Search was made in the vigibase, using vigilyze with ‘chlorpheniramine’, ‘chlorpheniramine maleate’ and ‘chlorphenamine’ as drug substance and ‘eryhthemamutiforme’, ‘stevens-johnson syndrome’ and ‘toxic epidermal necrolysis’ as reactionmeddra terms. Possible duplicates were eliminated using vigimatch. Retrieved cases were then subjected to causality assessment using austin bradford-hill criteria. From 1973 to april 2017, a total of 53 serious cutaneous reactions including sjs (26), em (14), ten (8) and epidermal necrolysis (5) were reported to the global database. Chlorpheniramine was the only suspected drug in 15 of the cases with no concomitants except for one case. The median time to onset was found to be three days and in four of the cases, reaction outcome was marked as ‘fatal’ and in 13 as ‘not yet recovered’. This case series assessment found a suggestive causal association between chlorpheniramine and the serious cutaneous reactions under discussion.

Tas et al., 2003 evaluate the in vitro and ex vivo percutaneous absorption of chlorpheniramine maleate (cpm) from different hydrogel formulations. Various concentrations of polymers, including hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC) and methyl cellulose (MC) were used in the hydrogel formulations. All experiments were conducted using cellulose dialysis membrane. The passive permeation of cpm was affected by the polymer concentrations. The effect of each polymer on the release rate of cpm was found to be statistically different. The formulation which exhibited maximum drug release through cellulose membrane was then used with other membranes namely polyurethane membrane, rat skin and human skin. The release rate of cpm from different membranes was found to be statistically different. Within the different diffusional barriers rat skin was found to be best alternative to human skin. It seems suitable the use of cellulose derivatives for topical application of cpm to obtain high therapeutic concentration at the application site. The synthetic membranes can be used to assess product performance in quality assurance but give little indication of its performance.

Bleehen et al., 1987 one hundred and twenty patients with chronic idiopathic urticaria, who entered a study at five centres (sheffield, london, bristol, cardiff and leeds) were treated with therapeutic doses of the h1 antagonist chlorpheniramine for 6 weeks. Histamine 1 non- responders (40 patients) were entered into a double-blind study and received chlorpheniramine plus cimetidine 400 mg q.d.s. (21 patients) or chlorpheniramine plus placebo (19 patients) for a further 8 weeks. The most important response measure was the change from baseline of the total symptom score: an assessment of the number and duration of new wheals and degree of itching. There was a statistically significant difference between the average response in the two treatment groups in favour of chlorpheniramine plus cimetidine after 4- and 8-weeks’ treatment. No significant side-effects related to treatment were noted.

Rumore, 1984 reviewed the clinical pharmacokinetics of chlorpheniramine. Recent studies have established that the half-life of chlorpheniramine is longer than previously reported. Chlorpheniramine has a serum half-life of ~20 hours in adults, and elimination from the body is primarily by metabolism to monodesmethyl and didesmethyl compounds. The half-life is increased in the presence of renal dysfunction and decreased in children. The exact mechanism of the presystemic first-pass elimination and the effects of dose levels on the process presently are unclear. Biopharmaceutical and pharmacokinetic studies after single or multiple doses in humans reveal wide interindividual variations in pharmacokinetics. Age, dialysis, urinary ph and flow influence the elimination kinetics of chlorpheniramine. Attention is brought to major issues that need further clarification to optimize drug therapy with this antihistamine.

Peets et al., 1972 studied in man, the pharmacokinetics and metabolism of 3h-chlorpheniramine maleate. After a p.o. Dose (12mg), 3h appeared rapidly in plasma and at two hours was equivalent to 32.48mµg of chlorpheniramine per ml; radioactivity persisted in plasma through 48 hours. At five minutes after an i.v. Dose (4mg), 3h in plasma was equivalent to 20.88mµg of drug per ml and 3h again persisted in plasma. This persistence of plasma 3h was most probably due to tissue deposition of 3h-drug (or metabolites), directly indicated by its large volume of distribution, 250% of body weight. The drug was 72% bound to plasma protein. A review of the existing literature will illustrate significant recent advancements of new versions of chlorpheniramine lotion and also publication of literature review in reputable international journal. A thorough analysis of chlorpheniramine formulation will aid in determining the crucial factors that influence the final product's qualities and stability which will have great impact in reducing the allergy.

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Received on 02.08.2023 Modified on 11.09.2023

Res. J. Pharma. Dosage Forms and Tech.2024; 16(1):76-80.

DOI: 10.52711/0975-4377.2024.00013