comparative analysis of montelukast, levocetirizine

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Mansoor et al. World Journal of Pharmacy and Pharmaceutical Sciences

COMPARATIVE ANALYSIS OF MONTELUKAST,

LEVOCETIRIZINE, CETIRIZINE & FEXOFENADINE

Namia Mansoor*, Ramya Nadig, Rohan Munoth, Vasavi Reddy and Yadini Kamdi

Manipal Institute of Technology, Vishnu Institute of Pharmaceutical Education, Priyadarshini

Institute of Engineering and Technology.

ABSTRACTS

This article is an examination of the Comparative Analysis of

Fexofenadine, Levocetirizine, Cetirizine and Montelukast. The

scientific development and subsequent continues to influence

researchers all over the globe today. This article examines the research

done and published by researchers and scientists. Consideration of

current trends and data in scientific queries and demonstrates further

aspects of Comparative Analysis of Fexofenadine, Levocetirizine,

Cetirizine and Montelukast. Additionally, this article explores options

for therapeutic functions of the antihistamines while diving into

allergenic issues as well.

KEYWORDS: Montelukast, Cetirizine, Levocetirizine, Fexofenadine,

Allergy.

INTRODUCTION

Antihistamines are a class of drugs that are generally used to combat allergic reactions and

subsequent symptoms. These medications are used to treat conditions resulting in an

increased incidence of histamine, a chemical produced by the immune system. People who

are allergic to pollen and other allergens are the most active members of antihistamines.

They're also used to treat a host of other issues, including digestive issues, colds, and anxiety.

Antihistamine medications are among the most widely used drugs in pediatric medicine.

According to the International Medical Statistics (IMS), approximately 2 million

antihistamine units were sold in Spain (2006) for paediatric use. Of this first-generation or

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 10, Issue 4, 1305-1335 Research Article ISSN 2278 – 4357

*Corresponding Author

Namia Mansoor

Manipal Institute of

Technology, Vishnu

Institute of Pharmaceutical

Education, Priyadarshini

Institute of Engineering and

Technology.

Article Received on

11 Feb. 2021,

Revised on 03 March 2021,

Accepted on 23 March 2021

DOI: 10.20959/wjpps20214-18729


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sedating antihistamines accounted for 34% of the total. When it comes to drug development

testing, the challenges are multiplied significantly when children are involved. Any drug used

in this age group must maintain the strictest safety regulations and provide the highest degree

of efficacy satisfaction. As a consequence, thorough knowledge of the best scientific

evidence available concerning these aspects is required. The first-generation antihistamines

have never been extensively tested in infants, even though they are still commonly used in

paediatric patients.

The paper provides a comparative investigation of four commonly used antihistamines such

as montelukast, levocetirizine, cetirizine and fexofenadine while weighing in factors such as

cardiological safety and pulmonary function.

METHODS

The study was conducted using four databases Gosogle Scholars SAGE, DOAJ and PubMed.

Selection of papers were done based on keywords and themes relevant to this review. Further

the published papers from these databases were arranged in systematic order with respect to

the year of publication.

RESULTS AND DISCUSSION

Montelukast

The efficiency of montelukast as a beta antagonist

Compared to the placebo, montelukast significantly improved asthma control during a 12-

week treatment period. With a sample size of 300 patients for the montelukast group and 200

patient’s placebo group, the study was designed to have 95% power to detect a mean

difference between treatment groups of 5.4 percentage points in forced expiratory flow in 1

second (FEV1) and 9.1% in daytime symptom score. Patient-reported endpoints, e.g.,

daytime asthma symptoms and as-needed β-agonist, were significantly compared with

placebo) improved by montelukast (Figure 1). Each asthma-specific quality-of-life domain

had notably higher scores for patients treated with montelukast during the 12week treatment

period (Figure 2). This clinical trial demonstrated that montelukast provides clinical benefits

during the 12-week treatment period as it had consistent and significant improvement of all

asthma control variables compared with placebo.

Tolerance can sometimes be a clinical problem with some therapies, including receptor

antagonists. Following the 12 weeks of treatment, montelukast removal did not cause


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rebound worsening of asthma at any endpoint. Across patient pre-randomization

characteristics, the effect of montelukast was generally consistent. These characteristics

include demographic variables and baseline values for the endpoints (forced expiratory flow

in 1 second and daytime symptom score), indicating a similar clinical response to

montelukast across subgroups of the asthmatic population studied.

The 10 mg dosage given orally once daily at bedtime during a 12-week treatment period,

montelukast sodium, provided significant clinical benefit to patients with chronic asthma.

Effective, well-tolerated oral therapies may have a substantial impact on the management of

asthma.

Adverse skin effects due to montelukast

Asthma is a widely present long-term disease affecting nearly 300 million people, with 100

million more patients by 2025. Allergic rhinitis is a common disease; it affects 10 – 40% of

the United States population. In epidemiologic studies, evidence for the association between

allergic rhinitis and asthma has been reported frequently. Montelukast is a potent and specific

cysteinyl leukotriene receptor antagonist that possesses broncho-dilating and anti-

inflammatory properties and effectively treats both asthma and allergic rhinitis. Developed as

a treatment for asthma, montelukast treats allergic rhinitis. Adverse effects of asthma

treatment using montelukast includes headache, gastrointestinal disturbance, fatigue,

pharyngitis, upper-respiratory-tract infection, rash, worsening of asthma, cough, sore throat,

hallucinations, depression, suicidal ideation, and tremors. During studies with montelukast

treatment, a few sporadic cases of mild to moderate acute hepatitis were reported. Skin

reactions associated with montelukast include unspecified rash, with or without blistering,

hives, inflammation in blood vessels, swelling of the area beneath the skin, erythema

nodosum, ecchymosis, skin ulcers, and, rarely, skin nodules. The most severe complication is

Churg- Strauss syndrome, a vasculitis reported in people with asthma treated with leukotriene

receptor antagonists. Frequent skin problems of Churg-Strauss syndrome are palpable

purpura, hemorrhagic lesions, cutaneous and subcutaneous nodules, erythematous

maculopapular rarely, ulcers, infarcts, livedo-like eruption and facial oedema. It was thought

that the decreased corticosteroid dosage needed to control asthma symptoms in patients

receiving leukotriene receptor antagonists unmasked an underlying vasculitis that had been

controlled previously by the corticosteroids. The authors' patient was not receiving oral

corticosteroid. The beginning leukotriene receptor antagonists in asthmatic patients were not


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treated with steroids. The American College of Rheumatology has proposed six criteria for

diagnosing Churg-Strauss syndrome: asthma, eosinophilia of greater than 10% in peripheral

blood, paranasal sinusitis, pulmonary infiltrates, histologic proof of vasculitis with

extravascular eosinophils, and mononeuritis multiplex or polyneuropathy.

Inhibition of cysteinyl leukotrienes by montelukast for whooping cough

Postinfectious cough is a commonly found symptom in primary care but has no guaranteed

treatments. Raised concentrations are observed in children with RSV bronchiolitis and virus-

induced wheeze. Cysteinyl leukotrienes are involved in developing a postinfectious cough

and whooping cough and potentiating the effects of inflammatory neuropeptides. Respiratory

viruses can sensitize airways to leukotrienes by increasing the production of interferon-γ,

eight, thereby increasing cysteinyl leukotriene type 1 receptor expression. The authors

investigated montelukast's effectiveness, a cysteinyl leukotriene receptor antagonist, to treat

postinfectious cough. For this randomized and placebo-controlled trial, health-care specialists

at 25 clinics in southwest England and Thames Valley recruited patients aged 16–49 years

with a postinfectious cough.

Between April 13, 2011, and September 21, 2012, the authors screened 339 patients, of

whom 276 were randomly allocated to receive placebo (n=139) or montelukast (n=137).

Seventy (25%) patients had positive lab tests for pertussis. In both groups, improvements in

cough-specific quality of life occurred after two weeks, but the difference between groups did

not match the minimum clinically significant difference of 1·3. After four weeks, significant

differences were not present between-group in cough-specific quality of life improvement or

adverse effect rates. However, 21 (15%) of 137 patients on montelukast reported one or more

adverse events: 31 (22%) of 139 on placebo.

Montelukast drug monitoring to ensure drug safety for asthma patients

The reporting odds ratio compares the rate of reporting a specific adverse effect in a drug

with reporting the same adverse effect in all other drugs. The division calculation for ROR is

as follows. The numerator is the number of patients who used montelukast. A specific ADR

was reported divided by the number of cases using montelukast in which the side effects were

not reported. The denominator is the number of adult and pediatric cases using other drugs,

reporting a specific adverse drug reaction divided by the number of cases using other drugs

without reporting that specific adverse drug reaction. For the global database VigiBase, the

study obtained numbers of reports and disproportionality per reported association, both in


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adults and children, through VigiLyze, a search and analysis tool. Conclusion: The study

covers a detailed overview of the safety of montelukast in clinical practice. Results Of the

331 reports on adverse drug reactions after montelukast were present, of which 124 were

reported in men, and 203 in women were present in the Dutch spontaneous reporting

database, in almost a third, the reports concerned individuals aged between 0 and 18 years

and in 214 cases, adults aged 19 years and older. This is the first study at the time of

publication, highlighting both adverse drug reactions in adults and children extracted from

two large databases.

Table 1: Adverse drug reactions (ADRs) after montelukast reported to the Netherlands

Pharmacovigilance Center Lareb and deemed serious, for example, leading to death,

hospitalization, or life threatening condition.

Adverse drug reaction Comments Relation with montelukast

according to the Naranjo

score (Naranjo et al. 1981)

Death 20‐year‐old woman with

pulmonary embolism

Woman of unknown age with

renal failure.

Allergic granulomatous

angiitis

Angioedema 4‐year‐old girl with

concomitant use of pulmicort

and foradil. Patient was

treated with tavergil and

prednisone. Montelukast was

discontinued. Angioedema

disappeared.

Possible

Malaise 45‐year‐old woman with

concomitant use of 8 other

medicines. Montelukast was

discontinued and she

recovered.

Possible

Epilepsy 9‐year‐old boy with no

concomitant use of other


discontinued and he

recovered.

Possible

Chest pain Man of unknown age with

concomitant use of seretide.

Montelukast was

discontinued and he

recovered.

Possible

Hallucination 13‐year‐old boy with no Possible

https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1002/prp2.341#prp2341-bib-0017


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concomitant use of


discontinued and he

recovered.

Myalgia 47‐year‐old man with



discontinued and he

recovered.

Possible

Eosinophilia 66‐year‐old woman with

concomitant use of seretide.

Montelukast was


recovered slowly.

Possible

Nightmare/somnambulism 72‐year‐old woman with




recovered.

Possible

Chest discomfort Woman of unknown age with


medicines. Further

information unknown

Woman of unknown age with


medicines. Further

information unknown.

Possible

Anaphylactic reaction 13‐year‐old boy with



discontinued and he

recovered.

Possible

Table 2: Characteristics of six patients hospitalized with allergic granulomatous angiitis

reported to the Netherlands Pharmacovigilance Center Lareb.

Description Latency Concomitant medicine

use

Action and

outcome

Relation with

Montelukast

33‐year‐old

woman with a

history of

asthma

6 months Doxycycline, prednisone,

flixonase

Patient was

treated with

high dose oral

prednisone;

not yet

recovered at

the time of

reporting.

Possible

53‐year‐old

man with an

unknown

history

5 years Flixonase, seretide Montelukast

has been

Withdrawn;

patient has

Doubtful


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not recovered

at the time of

reporting.

55‐year‐old

woman with a

history of

asthma

8 months Cetirizine, seretide,

flixonase

Montelukast

has been

withdrawn;

patient

recovered

after

treatment with

prednisone.

Possible

75‐year‐old

woman with a

history of

asthma

7 days Phenprocoumon,

furosemide, digoxine,

isosorbide mononitrate,

carvedilol, ramipril,

omeprazole, tiotropium

Montelukast

has been

withdrawn;

patient was

treated with

prednisone

and is

recovering.

Possible

59‐year‐old

woman with a

history of

asthma,

rhinitis, and

bronchiectasis

3 months Mometasone, tiotropium,

ciclesonide,

beclometasone/formoterol

Montelukast

has been

withdrawn,

and the

patient is

treated with

prednisone.

She is

recovering.

Probable

75‐year‐old

woman with a

history of

asthma

Unknown Phenprocoumon,

omeprazole, calcium

carbonate, digoxine,

furosemide, ramipril,

isosorbide mononitrate,

beclometasone/formoterol,

tiotropium, carvedilol

Montelukast

has been

withdrawn;

patient

recovered.

Possible

Montelukast and Potential skin hypersensitivity

Although a montelukast is a relatively safe drug, there is a probability of skin bruising and

skin rashes. The reappearance of rashes after montelukast introduction and complete

resolution of the skin rashes after discontinuing it confirms montelukast as an offending drug.

Results The authors presented a case report of a 64-year-old chronic asthmatic female patient

with widespread erythematous rashes with mild bruising and generalized pruritus, mainly

affecting her lower abdomen and upper extremities 28 days after the introduction of

montelukast as add-on therapy to budesonide. The researchers confirmed the relation between

the drug and skin rashes through a de-challenge followed by a montelukast's rechallenge.


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After 28 days of montelukast introduction, the rash's appearance showed the adverse drug

reaction was a type of delayed hypersensitivity. The certainty of definite association with

montelukast was confirmed with a rechallenge with montelukast during the desensitization

procedure. The disappearance of skin rashes after discontinuing montelukast favours the

montelukast being the cause of these adverse effects. Although montelukast packaging lists

skin bruising as one of the AEs, not much has been mentioned in the existing literature. We

emphasize the need for monitoring and reporting even the mild AEs of montelukast through

the present case report.

Levocetirizine

Levocetirizine as an antihistamine

Levocetirizine is classified as a second generation Antihistamine. Levocetirizine is available

for the treatment such as Allergic Rhinitis and chronic idiopathic utricularia. Levocetirizine

,the R-isomer of the racemic mixture cetirizine hydrochloride. Levocetirizine has a high

affinity and selective antagonistic activity against histamine H1 receptors and exerts an

inhibitory effect on eosinophil chemotaxis. Allergic rhinitis and chronic urticarial are highly

burden some diseases, which are increasing in prevalence, especially in the pediatric

population. Despite the availability of a large number of medications for treatment of AR and

CIU symptoms in children.

The H1 antihistamines are associated with marked adverse effects such as sedation,

sleepiness as well as difficulties in learning and cognitive processing; thus, they are

recommended for limited or discontinued use in children with AR or CIU.Levocetirizine is an

over-the counter non sedating antihistamine agent commonly used to treat allergic diseases.

Clinically significant acute liver injury has been very rarely associated with its use .Only 2

cases of acute liver injury associated with levocetirizine have been reported in the literature.

Previous clinical studies and preclinical studies have shown that levocetirizine was rapidly

and extensively absorbed. Levocetirizine does not inhibit cytochrome P450, 2C9, 2C19, 2D6,

2E1 and 3A4 and does not induce uridine at concentrations near the clinical dose, which

produces peak plasma concentrations. Evidence suggests that children do not generally

respond to medications in the same way as adults, primarily due to differences in the

metabolism, renal clearance and other drug disposition mechanisms associated with

anatomical, physiological and developmental differences. As pediatric formulations,

especially for children under 6 years of age, are usually in a liquid form, special knowledge


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and skills are necessary to make them stable, sterile, pleasant tasting, long lasting and with

favorable pharmacokinetic as well as pharmacodynamics properties.

The effects of histamine are exerted through three well defined classical G Protein coupled

histamine receptor subtypes termed H1R, H2R and H3R and the more recently described

H4R.Histamine signaling through H1R is responsible for the majority of the immediate

manifestations of allergic disease. The parent compound cetirizine, a once daily 10 mg

formulation, is also an effective treatment for allergic disease being the most –widely used

second generation antihistamine worldwide. Orally disintegrating tablets are used widely in

drug therapy and are clinically attractive because they are suitable for use in patients with

dysphagia, improve adherence, increase the likelihood of achieving the desired therapeutic

effect, and are convenient to take without water. Anti allergic, drugs, particularly the

antihistamines and intranasal steroids, are among the most commonly prescribed medications

in children as allergic rhinitis is currently one of the most common chronic disorder in the

pediatric populations.

The study consisted of 2 parts: part 1compared the bioavailability of levocetirizine ODT and

levocetirizine IRT taken with water in the fasted state, part 2 compared the bioavailability of

levocetirizine ODT without water and levocetirizine IRT with water in the fasted state.BE

between levocetirizine ODT and levocetirizine IRT was evaluated in 48 healthy Japanese

male subjects in the first study. Because BE was not demonstrated in part 2 of the initial

study, an add on subject study was conducted in 24 subjects using the same methodology as

used in the initial study of part 2 in accordance with the Japanese guideline for

bioequivalence studies in generic products issued by evaluation and licensing division. The

key inclusion criteria were age 20-55 years, body mass index of 18-24.9 kg/m2 and good

general health as determined by medical history, clinical examinations, 12-lead ECG and

clinical laboratory tests.

Treatment of AR in children involves the use of a variety of medications together with

allergen and irritant avoidance measures, and can often be achieved in primary care for most

patients. Pharmacologic management encompasses the use of both over the counter and

prescription drugs including oral and intranasal H1-antihistamines, intranasal steroids,

decongestant, cromons, anti-leukotrienes of which the antihistamines and INS are most

frequently used as first-line treatment, depending on the severity of symptoms of

AR.presently only three H1 –antihistamines have been investigated for long term safety in the


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pediatric populations. The study of loratadine collected safety information over a period of 12

months in similarly aged pediatric populations.

Fifteen patients with refractory CSU were given oral levocetirizine at a dose of 15 mg once

daily for 7 days, and treatment efficiency was determined using the utricularia activity score

and by evaluating wheal and erythema reactions and itching. The serum concentrations of IP3

at specific time points was determined by enzyme –linked immunosorbent assay. All 15

patients were enrolled from outpatients clinics and met the following inclusion criteria.[1]

diagnosis of CSU[2]

repeated use of loratadine, mizolastine or other antihistamine and

complementary medicines such as ruin and vitamin C[3]

UAS2a score calculated by adding

the UAS on the first treatment day to the score on the day prior to treatment initiation; and[4]

no glucose-corticoid treatment within the previous month and no history of other underlying

diseases or family history of other underlying diseases or family history of genetic disease.

In this, hDPCs were cultured in Dulbecco’s modified eagle medium containing different

concentrations of levocetrizine hydrochloride for 48 hrs. The growth of hDPCs was observed

by immunofluorescence staining, and the cell proliferation was detected by MTT assay. After

the hDPCs were cultured in DMEM containing 1, 10, 100, 1000, and 10000 ng/ml

levocetirizine hydrochloride for 48 hrs., the mRNA expressions of cyclooxygenase 2,

prostaglandin D2 synthase, prostaglandin and glycogen synthase kinase were determined by

real time fluorescence –based quantitative polymerase chain reaction and the protein

expressions of PTGDS, phosphorylated protein kinase B and phosphorylated glycogen

synthase kinase were detected by western blotting. After the hDPCs were cultured in DMEM

containing 1, 10, 100, 1000, and 10000 ng/ml levocetirizine hydrochloride for 24 hrs., The

secretion levels of prostaglandin D2 and PGD2 receptor in the culture supernatant were

determined by enzyme linked immunosorbent assay .one way analysis of variance was

performed using SPSS 17.0 software and the LSD_T test was used for pairwise comparisons.

0f the38 and 44 healthy Japanese male subjects screened in the initial study and add on

subject study, respectively , 24 subjects each were randomized and received at least 1 dose of

the investigational products .All subjects expect 1 who were randomized in the initial study

completed the study .One subject was withdrawn from the initial study after receiving the

ODT dose in period 1.He experienced a moderate AE during the washout period , and his

dosing scheduled for period 2 was postponed ;however he withdrew his consent because his

schedule did not suit the new study schedule did not suit the new study schedule for the in-


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clinic stay. The safety profiles were generally similar between levocetirizine ODT and

levocetirizine IRT with no serious adverse events, deaths or adverse events leading to

withdrawal reported during the study.

Cetirizine

[ETAC]

Levocetirizine

[EPAA]

Somnolence 2.3% 0%

Nervousness 1.3% 0.4%

Insomnia 8.8% 1.2%

Fatigue 3.3% 0%

The mean serum concentration of IP3 was 43.54+-41.97 pg./ml prior to treatment , 18.40+-

17.53 pg./ml after treatment, and 1.31+-0.92 pg./ml in a healthy control group. The mean

concentration of IP3 was significantly higher before treatment was significantly higher than

that in the control group. High dose levocetirizine was shown to be effective in the treatment

of CSU. The level of serum IP3 was positively correlated with CSU activity, indicating that

IP3 may play an important role in the pathogenesis of this condition.

Immunofluorescence staining showed that hDPCs in the 100 ng/ml group grew well, with

over 90% confluence .Methyl thiazolyl tetra method showed that the proliferation rate of

hDPCs significantly differed between different levocetirizine hydrochloride groups and blank

control group ,while proliferation rate was significantly higher tin the 100ng/ml than in the

blank control group .The relative mRNA expressions of COX-2, PGF2a,PTGDs,GPR44

showed significant difference in different levocetirizine hydrochloride groups, whereas the

mRNA expressions of PGF2 and GSK3 showed no significant difference. The mRNA

expressions of COX-2, PTGDS and GPR44 in the 100 ng/ml group were significantly lower

than those in the blank control group. There were significant differences in the levels of

PTGDs, PGD2 and PGD2R proteins between the different levocetirizine hydrochloride

groups. The proteins expressions of PTGDS,PGD2 and PGD2R in the 100 ng /ml group were

significantly lower than those in the blank control group, whereas the protein expressions of

Akt AND Gsk3 in the 100 ng/ml group. Levocetirizine hydrochloride may promote the

growth and proliferation of Hdpc in vitro by inhibiting the PGD2-GPR44 pathway and

activating the AKT signaling pathway.

Bioequivalence was demonstrated between levocetirizine IRT 5 mg and ODT 5 mg. The

safety and tolerability of levocetrizine were confirmed following single oral administrations

of levocetrizine IRT 5 mg and ODT 5 mg administered with water or without water. Thus, a


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5 mg levocetirizine ODT tablet can be used as a replacement for a 5 mg levocetirizine IR

tablet at the clinical site. The observed exposures were slightly higher after the administration

of levocetrizine IRT 5 mg with water and without water.

Children appear to be more affected than ever before and suffer from both persistent and

severe symptoms. The use of the first generation H1 antihistamines should undoubtedly be

limited or discontinued in children suffering from AR or CIU and physicians should,

whenever possible, prescribe only the new second generation H1 antihistamines to children

.In view of the data currently available for pharmacokinetics, clinical, efficacy, and general

preference for levocetirizine by both parents and physicians, levocetirizine seems suitable

treatment option for AR and chronic urticaria in children aged 6 months to 12 months.

Cetirizine

Year of

Publishing

Title of the paper Title of the review paper

December

1990 Urticaria: Clinical efficacy of cetirizine in

comparison with hydroxyzine and placebo

Comparison between cetirizine,

hydroxyzine and placebo

1 December

1993

A reappraisal of its Pharmacological

Properties and Therapeutic use in Selected

Allergic Disorders

Pharmacological and Therapeutic use

of Cetirizine

May 1995 Cetirizine in patients with seasonal rhinitis

and concomitant asthma: prospective,

randomized, placebo-controlled trial

Effects of Cetirizine on patients with

seasonal rhinitis and concomitant

asthma

August 1996 Improvement of quality of life by treatment

with cetirizine in patients with perennial

allergic

rhinitis as determined by a French version of

the SF-36 questionnaire

Impact of Cetirizine on Life

March 2011 A comparative analysis of cetirizine,

gabapentin and their combination in the

relief of post-burn pruritus

Comparison between cetirizine and

gabapentin

12 Sept 2012 A review of its use in Allergic Disorders Uses of Cetirizine in allergic disorder

17 Nov 2012 A review of its pharmacological

properties and clinical potential in Allergic

Rhinitis, Pollen induced Asthma and chronic

urticaria

Pharmacological properties of

Cetirizine

Sept 2013 The clinical Use of cetirizine in treatment of

allergic rhinitis

Treatment of Rhinitis with cetirizine

6 December

2019

Focus on the cetirizine use in a clinical

practice: a reappraisal 30 years later

Use of Cetirizine in clinical practices


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Steady urticaria is an issue for both specialist and patient. With the ultimate objective to

avoid the risks related to corticosteroid treatment, some unique H1-receptor adversaries have

been endeavoured and found to incite terrible levels of sedation when given in totals

satisfactory to control urticaria. Cetirizine, a pharmacologically powerful oxidized metabolite

of hydroxyzine, was made to give specific H1-receptor impediment without wretchedness of

the central tangible framework. In a 4-week, multicenter, twofold outwardly hindered,

counterfeit treatment controlled security and practicality study, cetirizine, in a once-a-day

divide (5 to 20 mg), was similar insufficiency to hydroxyzine in disconnected measurements

(25 to 75 mg/day). The pace of drowsiness in the cetirizine pack was not inside and out not

exactly equivalent to that of the phoney treatment gathering. Regardless, in the hydroxyzine

assembling, the recurrence of dormancy was, by and large, higher than that in the phoney

treatment gathering (p=0.001). The outcomes of this assessment show that cetirizine has a

more noticeable security edge over the more prepared parent drug hydroxyzine. Cetirizine,

the carboxylated metabolite of hydroxyzine, is a specific and long-acting histamine H1-

receptor foe. It has checked antiallergic properties and limits eosinophil chemotaxis during

the touchy response. Clinical primer results show that cetirizine is a practical and particularly

suffered treatment for incidental/never-ending excessively touchy rhinitis and tenacious

idiopathic urticaria in adults, and infrequent/enduring vulnerable rhinitis in young people.

Cetirizine 10 mg/day radiates an impression of being pretty much as amazing as conventional

estimations of other set up antihistamines, for instance, astemizole, hydroxyzine, ketotifen,

loratadine or terfenadine in reducing signs of these issues, and is connected with a lower pace

of sedation than hydroxyzine. Nevertheless, when sedation was uniquely studied, cetirizine

appeared to be more steadying than counterfeit treatment, loratadine or terfenadine in some

clinical starters. This differentiation was not found in a couple of other twofold outwardly

impeded assessments. Alternately, when reviewed fair-mindedly in pharmacodynamic

assessments, cetirizine was rarely more calming than counterfeit treatment or other second-

period histamine H1- receptor foes. Cetirizine may similarly have some work in the treatment

of explicit sorts of genuine urticaria, atopic dermatitis and reactions to mosquito snack.

Besides, it is being pursued for the treatment of overly sensitive asthma in adults and

children. The pharmacokinetic profile and dominatingly renal release of cetirizine suggest

that this expert may have a lessened potential for ominous prescription coordinated efforts

including hepatic impetus systems differentiated and other histamine H1-receptor foes which

are comprehensively prepared. Thus, cetirizine, with its speedy start and long length of


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movement, appears to give a supportive alternative as opposed to the antihistamine experts in

clinical use.

This assessment researched the security and adequacy of cetirizine for the treatment of

excessively sensitive rhinitis and asthma. Daily treatment for about a month and a half with

cetirizine 10 mg was isolated and counterfeit treatment in a randomized, twofold blocked

similar appraisal of patients with conversely weak rhinitis and asthma. This multicenter study

was started not well before the start of the fall dust season. Rhinitis and asthma signs were

focused twofold consistently; spirometry was performed weekly. Placebo-treated patients

experienced a falling to pieces of rhinitis results from measure all through the examination, at

any rate, cetirizine-treated patients had a fundamental improvement in rhinitis signs at week

1, which was kept up in the wake of the start of the development season. Asthma signs in the

cetirizine pack improved from the plan at week 1; results were throughout better showed up

contrastingly corresponding to in the phoney treatment bunch for 5 of about a month and a

fragment of the appraisal. Pneumonic limits didn't decay in patients taking cetirizine or

phoney treatment; there were no partitions between arrangements as composed by

spirometry. Albuterol use was less steady in the cetirizine-treated patients for the whole

evaluation, yet isolates didn't show up at significance. Pseudoephedrine use was close in the

two parties. More cetirizine- treated patients completed the fundamental than faked treatment

treated patients. The two medications were especially determined forward.

Enduring overly sensitive rhinitis upsets public action, anyway it isn't known whether

individual fulfilment may be improved when patients are treated with an H1-blocker. A

randomized, twofold outwardly debilitated, counterfeit treatment controlled examination was

finished with cetirizine to assess the effect of this drug on close to home fulfilment. Methods:

Two hundred 74 patients with ceaseless overly sensitive rhinitis were attempted. Individual

fulfilment was assessed using the Medical Outcome Study Short-Form Health survey.

Following a 2-week spat period, cetirizine, 10 mg once daily, or counterfeit treatment was

given for the accompanying month and a half. The SF-36 survey was overseen after the fight

time frame and following 1 and a month and a portion of treatment. Result remedy scores

were assessed step by step during the study. After the disagreement period, there were no

basic differentiations between the cetirizine and phoney treatment bundles to the extent that

signs or individual fulfilment scores. Following a month and a portion of treatment, the level

of days without rhinitis or with simply delicate rhinitis appearances was more important in


1319


the cetirizine bundle in assessment with the phoney treatment gathering. The whole of the

nine individual fulfilment estimations was in a general sense improved after 1 and a month

and a portion of cetirizine treatment differentiated and counterfeit treatment. There was no

improvement in the phoney treatment gathering. Post-devour pruritus is an upsetting result

having a reported recurrence someplace in the scope of 80 and 100%. The mainstay of the

heads of post-devour shivers has been with antihistamines and emollients yet the treatment is

deficient in an amazingly immense degree of patients. With the affirmation of an undeniable

shiver express neuronal pathway, which has an astounding coordinated effort with torture

pathway, another approach to manage shiver the board has surfaced with the usage of

gabapentin. Gabapentin is an antiepileptic drug which has been adequately used to supervise

neuropathic torture and is offering an explanation to be productive in the organization of a

wide range of shiver. With a shortage of randomized starters surveying the work of

gabapentin in post-burn-through shiver the board the current examination was embraced to

only evaluate gabapentin, cetirizine and their mix in relieving shiver. Twenty patients were

indiscriminately enrolled in all of the three social affairs and dealt with the specific drug in

doses constrained by starting VAS (visual basic scale) scores. There was no enormous

qualification taking everything together with the three get-togethers concerning mean age,

sex movement, mean degree of TBSA burn through and mean VAS score on day 0. VAS

scores were surveyed over the next 28 days, and no emollients were supported for the

assessment period. The hidden mean VAS score reduced 95% in the gabapentin bundle

appeared differently in relation to 52% for the cetirizine gathering, which was significantly

colossal. There was a 94% decline in mean VAS score in the mix pack which was identical to

the mitigation saw with gabapentin alone. Even the start of action with gabapentin was

snappier than the cetirizine pack as evident from the mean VAS scores on day 3, which

reduced 74% in gabapentin bundle appeared differently in relation to 32% in cetirizine

gathering. While all patients tolerating gabapentin showed up at a shiver free status by day 28

only 3/20 patients showed up at this level with cetirizine alone. It is exceptionally obvious

from this assessment that gabapentin is in a general sense better contrasted with cetirizine as

monotherapy in facilitating post-burn-through shiver and it in like manner has a faster action.

The hypothetical blend of a halfway acting medicine with a by chance acting expert didn't

achieve any better control of post-devour shiver than monotherapy with gabapentin. No

outcomes were represented with gabapentin association anyway all patients tolerating

cetirizine declared sedation. There is presently a need to relook at the antipruritic shows to

devour the board. Cetirizine, a piperazine subordinate and carboxylated metabolite of


1320


hydroxyzine, is an immeasurable histamine H1-receptor enemy with antiallergic properties. It

has checked love for outskirts histamine H1-receptors and, at the standard section of 10mg

reliably, comes up short on the CNS depressant impacts of standard antihistamines. In like

way, it upsets histamine transport and eosinophil chemotaxis during the accomplice time of

the forebodingly feeble reaction. Results from controlled clinical starters show that cetirizine

is persuasive and all around endured treatment of unpredictable and suffering frail rhinitis

and constant idiopathic urticaria. Cetirizine radiates an impression of being on an

exceptionally fundamental level essentially as profitable as standard assessments of

terfenadine, chlorpheniramine and hydroxyzine in decreasing appearances related to these

issues and makes an amazingly lower speed of sedation than chlorpheniramine, hydroxyzine

a couple of other standard antihistamines. Hence, cetirizine seems to give an enormous option

instead of other 'nonsedating' antihistamines; cetirizine may moreover have a future part in

the treatment of inimically weak asthma and express sorts of authentic urticaria. Cetirizine,

a piperazine subordinate and carboxylated metabolite of hydroxyzine, is an unimaginable

histamine H1-receptor enemy with antiallergic properties. It has checked love for fringe

histamine H1-receptors and, at the standard section of 10mg reliably, comes up short on the

CNS depressant impacts of standard antihistamines. In like way, it upsets histamine transport

and eosinophil chemotaxis during the associate season of the forebodingly weak reaction.

Results from controlled clinical starters show that cetirizine is persuading and all around

endured treatment of intermittent and suffering horrendously feeble rhinitis and persistent

idiopathic urticaria. Cetirizine emanates an impression of being fundamentally pretty much as

productive as traditional assessments of terfenadine, chlorpheniramine and hydroxyzine in

decreasing appearances related to these issues and makes an amazingly lower speed of

sedation than chlorpheniramine, hydroxyzine several other standard antihistamines.

Consequently, cetirizine seems to give a huge option instead of other 'nonsedating'

antihistamines; cetirizine may also have a future part in the treatment of adversely

defenceless asthma and explicit sorts of real urticaria.

Cetirizine is among the fundamental second-age H1 antihistamines (SGAHs) made to give

explicit H1 receptor limitation without focal unmistakable structure horror. The motivation

behind this audit is, to sum up, the extent of information gathered from more than 25 years of

clinical utilization of cetirizine and distinction this and information open for other SGAHs in

the association of patients with effortlessly influenced rhinitis (AR). A serious forming look

for scatterings identifying with cetirizine was performed utilizing the Pubmed instructive file,


1321


and huge papers passed on in English were picked for a particular audit. Differentiated and by

far most of other SGAHs, cetirizine was everything considered appeared to have a more

phenomenal pharmacological profile, to be especially endured, be at any rate equivalently or

more convincing in stifling/checking nasal and visual signs and to improve the individual

satisfaction in AR patients. Most clinical starters investigating the impact of SGAHs in AR

patients further displayed that cetirizine was regularly utilized as the pivotal comparator

dynamic medication. Considering the affirmation that cetirizine is a for the most part utilized

dynamic comparator drug in AR, it is unassuming to suggest that cetirizine might be a

reasonable benchmark in the progress of novel pharmacotherapies for AR. Antihistamines

are correct now potentially the most ordinarily oversaw classes of meds. They are used to

treat results that are assistant to histamine release, which is ordinary of certain extremely

touchy conditions, including rhinitis, conjunctivitis, asthma, urticaria, and excessive

touchiness. Cetirizine has a spot with the second-age family, consequently, it is explicit for

peripheral H1 receptors, is exceptional and quickly quiets signs, applies additional foe of

horribly defenceless/ alleviating impacts, and is commonly especially persevered. It was

exhibited 30 years back. In these years, an uncommon assortment of evidence has been

developed. The current study gives a sensible update on the usage of cetirizine in clinical

practice.

Fexofenadine

Assessment of effects of rifampin on pharmacokinetics of fexofenadine and influence of

Age and Sex

The study was conducted to assess the effects of rifampin on the pharmacokinetics of

fexofenadine and to assess its influence of the advanced age and sex age.

Twelve young candidates and twelve elderly candidates out of which 6 were males and 6

were female in each group were selected for the study. They received a 60mg oral dose of

fexofenadine before and 600mg oral dose of rifampin afterwards for 6 days. Blood and urine

samples were collected 48 hours and assayed for fexofenadine, azacyclonol and rifampin by

HPLC with either mass spectrometry or fluorescence detection.

All of the groups had a significant increase in the oral clearance of fexofenadine after

rifampin treatment. The peak serum concentration of fexofenadine was also significantly

reduced by rifampin treatment, time to maximum concentration, renal clearance and fraction

unbound of fexofenadine showed no significant difference between control and treatment.


1322


The amount of azacyclonol, a CYP3A4 mediated metabolite of fexofenadine, eliminated on

average 2‐fold after rifampin dosing; however, this pathway accounted for less than 0.5% of

the dose. No effect of age or sex on fexofenadine disposition or serum trough rifampin

concentration (0.2 μg/mL to 1.8 μg/mL) was observed before or after rifampin treatment.

It was found that the rifampin significantly increased fexofenadine oral clearance and was

independent of the age and sex. It can be concluded that the increased oral clearance is due to

the reduced bioavailability caused by induction of intestinal P-glycoprotein.

Fexofenadine is an antihistamine that does not cause any sedation and it is used for the

treatment against the symptoms of allergic rhinitis. Almost 95% of fexofenadine is obtained

through urine and feces as it is but, it interacts with cytochrome P450 (CYP) 3A inhibitors

erythromycin or ketoconazole if administered together and hence, results in increase in serum

concentration. Rifampin is an inducer of CYP3A enzyme that causes an upregulation of P-

glycoprotein in cultured human colon carcinoma cells. Fexofenadine is a good probe because

it is found to be the substrate of P-glycoprotein in vivo and is not having any pharmacologic

or toxic effects that require close monitoring. The study was designed to examine the

hypothesis that sex and age modulates P-glycoprotein activity or the responsiveness of P-

glycoprotein expression to rifampin.

The study was carried out with 24 participants out of which 6 were healthy young women, 6

were healthy young men, 6 were healthy older men and 6 healthy older women. All were in

between the age group of 18 to 65. There were no significant health issues in the participants.

The drug quantification of fexofenadine in serum and urine was done by using solid phase

extraction and HPLC with fluorescence detection by doing the modification in the method.

Pharmacokinetic parameters were estimated by noncompartmental analysis with the use of

WinNONlin (Pharsight Corp, Mountain View, Calif). The terminal elimination rate constant

(β) was determined by log-linear regression. The terminal elimination half-life (t1⁄2) was

determined by the following relationship: t1⁄2 = 0.693/β. The effects of sex, age, and rifampin

treatment were analyzed with repeated-measures ANOVA with the use of the PC-SAS

statistical package (SAS Institute, Cary, NC). The primary endpoints were oral clearance and

half-life.

The mean serum concentration-time curve was used to determine the effect of rifampin

treatment on disposition of fexofenadine in young men, young women, elderly men and


1323


elderly women. The average percentages of the fexofenadine dose eliminated unchanged in

the urine were 3.7% ± 1.52%, 5.8% ± 1.77%, 5.4% ± 0.80%, and 4.4% ± 0.95%, respectively,

for young men, young women, elderly men, and elderly women. These percentages decreased

non significantly to 2.4% ± 0.89%, 5.2% ± 0.61%, 2.7% ± 0.79%, and 1.9% ± 0.42%,

respectively, after rifampin treatment. After rifampin treatment, urinary excretion of

azacyclonol increased significantly by approximately 2-fold in men but not in women.

The rifampin pretreatment causes a substantial increase in the oral clearance of fexofenadine.

This observation shows that there is upregulation of P-glycoprotein expression on the apical

surface of the small intestine. The advanced age and sex did not have significant effect on the

induction. The fexofenadine was found to be the relatively inert probe drug.

Finding the efficacy and safety levels of fexofenadine compared to other antihistamines

The study was conducted to find the efficacy and safety levels of fexofenadine compared to

other antihistamines and also the effect of fexofenadine over the driving abilities and

cardiovascular health at high doses. A study was reviewed in which the efficacy of

fexofenadine was compared to loratadine through the rhinoconjunctivitis quality of life

questionnaire (RQLQ) which is commonly used to evaluate the treatment effects of drugs in

patients with allergic rhinitis. It was found that fexofenadine was more effective than the

loratadine. In another study, the incidence of drowsiness and fatigue in patients consuming

fexofenadine and cetirizine was compared where cetirizine was found to cause more fatigue

and drowsiness than fexofenadine.

Previously used antihistamines were found to interrupt the central nervous system

functioning and caused sedation which includes a group of symptoms like lack of

concentration, drowsiness, fatigue, etc. The recently used antihistamines to be precise

fexofenadine does not cross the blood-brain barrier and does not affect the central nervous

system. Positron emission tomography was used for the study to determine whether the

central H1-receptor distribution of C-doxepin in the human brain could be altered by single

oral doses of antihistamines. Fexofenadine has no effect while carrying out a skilled task

which includes machine work or public service vehicles thus recommended to use. The

studies regarding drug interaction indicated cardiovascular safety of the drug. The

pharmacokinetics of fexofenadine are similar to that of healthy subjects to that of impaired

liver function. Fexofenadine shows antihistaminergic effects along with its ability to attenuate

inflammatory mediator release which might contribute to its pharmacological properties.


1324


In a trial including 688 people with SAR it was found that the primary efficacy measure was

24hr reflective Total Symptom Score (TSS) by adding an individual score of each symptom

with a maximum possible TSS of 16. There was no significant difference in the overall TSS

of fexofenadine and loratadine but the symptoms were treated well with fexofenadine

compared to loratadine.

The older antihistamines were demonstrating sedative and anticholinergic effects however,

several studies exhibited the fexofenadine did not exhibit significant sedation or the effect on

the central nervous system. Positron emission tomography was used to determine whether the

central H1-receptor distribution of C-doxepin in the human brain could be altered by single

oral doses of antihistamines.

It was found that previously used older generation antihistamines had reported some

cardiovascular events in rare cases but they were fatal forms of ventricular arrhythmia

characterised by prolonged QT intervals and twisting of QRS complexes. The drug

interaction studies conducted demonstrated the cardiovascular safety of fexofenadine with no

adverse effects. Along with this antiallergic effects were also studied which shows the

efficacy of fexofenadine in treating symptoms of running, itchy nose, watery eyes, nasal

congestion, etc.

Fexofenadine was found useful in treating the allergic symptoms with no significant adverse

effects. The cardiovascular safety of fexofenadine was found to be efficient. There is no

crossing of the blood-brain barrier and hence the sedative effects are not seen.

A comparison between fexofenadine and the second generation antihistamine for cough

reflex sensitivity and pulmonary function.

Most of the patients in the United States complain about coughs commonly towards the

medical practitioner. It is found that the most common cause of chronic cough is rhinitis/post

nasal drip syndrome (PNDS). The first generation antihistamines are found to be more

effective than the newer generation antihistamines for the treatment of chronic cough caused

by PNDS. As the antitussive activity of second generation antihistamine, fexofenadine is not

yet found, the effect of fexofenadine on capsaicin induced cough in healthy volunteers and in

patients with acute viral upper respiratory tract syndrome was studied.

Participants of the study were selected by considering 12 healthy volunteers with no


1325


symptoms of cough and 12 otherwise healthy volunteers with symptoms of acute viral URI. It

was made sure that the patients were nonsmokers and had no history of pulmonary disease

and gastroesophageal reflux. The doses of fexofenadine and placebo in randomized double

blind fashion were given and then after two hours of ingestion of the study drug, the

spirometry test and capsaicin cough challenge testing was performed to correlate with high

plasma levels of fexofenadine.

As for the subjects with URI the, no significant differences in cough reflex sensitivity and

pulmonary were found after the induction of five or more coughs in participants. In

participants with no symptoms of URI, no differences in cough sensitivity were noticed. It

was found that the second generation antihistamines and fexofenadine had no effect over the

cough reflex sensitivity in both healthy as well as participants with URI. The first generation

antihistamines with the combination of decongestants are recommended for chronic cough

with PNDS. A bronchodilator activity was observed in participants with no URI rather than

the participants with URI which was quite surprising but this finding was very little and of

least clinical significance. There needs to be a further investigation done in this direction

Bioequivalence of fexofenadine and pharmacokinetics in the form of oral suspension

This study was conducted for studying the bioequivalence of fexofenadine in oral suspension

and solid formulations of fexofenadine, pharmacokinetics of fexofenadine and the effect of

fruit juices on the absorption of fexofenadine. Fexofenadine interacts with lots of drugs at p-

glycoproteins and anion transporter polypeptides. The fexofenadine affects the working of

certain inflammatory mediators which can affect the inflammatory response of acute

inflammatory response to certain anti-allergic reactions.

Fexofenadine is widely used as a selective H1 antagonist and also found to have anti-

inflammatory properties. Several studies were reviewed which included administration of

fexofenadine by either solid tablet formulations or by oral suspension, equivalent area under

the curve and mean maximum plasma concentration were found in people with various age

groups.

The pharmacokinetics studies were also reviewed and it was found that if fexofenadine was

consumed alone, it had no side effects as such but when consumed with some other drugs

there was an increased risk of adverse effects. It did not react with P450 CYP 3A4 but

interacted with other drugs at P- glycoprotein and the organic anion transporter polypeptide.


1326


It was found from various studies that the fexofenadine should not be consumed along with

grape juice or apple juice as the bioavailability is reduced. Fexofenadine reduces the immune

activities during the allergic reaction due to which the inflammatory responses to certain

allergens has seen to be increased which suggests for a better activity of selective H1

antagonist to be formulated further.

Administration of fexofenadine did not generate any adverse effects other than rare cardiac or

rash problems in some patients, it was found to be effective for allergic rhinitis and chronic

idiopathic urticaria and can be useful for patients with asthma. In conclusion fexofenadine is

useful as a selective antihistamine H1 antagonist but it can cause certain adverse effects if

interacted with other drugs through P-glycoprotein and organic anion transporter peptides.

The subjects tolerated fexofenadine well and the safety profiles of fexofenadine were found

to be clear. The antihistamine effects of fexofenadine were found to be useful and the

cardiovascular safety was also found. Anti Inflammatory and anti allergic treatment of

fexofenadine was also found to be effective. It was found to have less bioequivalence in the

presence of certain foods like grape juice.

Antihistamine effects and safety of fexofenadine: a systematic review and Meta-analysis

of randomized controlled trials

This study was aimed to determine the antihistamine effects and safety of fexofenadine

compared to the other antihistamines and drugs. An electronic literature survey was

conducted using some tools like Embase, Pubmed and Cochrane from 2018 for randomized

controlled trials (RTC) for antihistamine effects of fexofenadine compared to placebo and

other antihistamine drugs in healthy subjects.

It was found that amongst 51 studies and 14551 participants met the required criteria.

Randomized controlled trials (RCT) were conducted to compare the antihistamine effects of

either fexofenadine or the other antihistamines or placebo. A systematic literature mining was

conducted from softwares like Embase, Cochrane and Pubmed. The outcomes were measured

using various parameters like wheal flare, AE frequency, changes in cognitive/psychomotor

function score. Data analysis was performed using Revman 5.3 program and comparative

meta analysis V2.


1327


As compared to the first generation antihistamine fexofenadine produced significantly lower

side effects such as drowsiness, loss of motor ability or psychomotor functions. The

comparison with second generation antihistamines demonstrated least sedative effects and

almost no change in cognitive or psychomotor functions. Fexofenadine has significantly more

antihistamine properties than placebo. The first generation antihistamines that were used

before exhibited cardiotoxicity. Some second generation antihistamines also exhibit

cardiotoxicity and hence are rarely used. Fexofenadine on the other hand is a new generation

antihistamine and an active metabolite of terfenadine- a highly selective H1 antagonist, it has

a positive antihistamine effect. Fexofenadine has no cardiotoxicity and minimal toxic effects

on the liver as only 5% of the total dosage is metabolized by the liver. The meta-analysis

conducted demonstrated that fexofenadine has better safety profiles compared to second

generation antihistamines. It was also found that subjects that consumed fexofenadine had

better information processing ability compared to the other ones who consumed second

CONCLUSION

This research review’s purpose is to help the reader understand different aspects posed by the

research on the Montelukast, Levocetirizine, Cetirizine & Fexofenadine. This is significant

because it gives insights about commonly used antihistamines and its effects on multiple .

There has been much research and discussion conducted on these opinions of montelukast,

levocetirizine, cetirizine and fexofenadine. Most of the research found was on the details of

levocetirizine, cetirizine, montelukast, fexofenadine, rhinitis and seasonal allergies. More

research and testing is required to gain better understanding for a comparative evaluation.

ACKNOWLEDGEMENT

We would like to thank our supervisor/guide Bharat Kwatra, from Invenzion Labs Inc. whose

expertise was invaluable in formulating the research questions, methodology and drawing

conclusions. His insightful feedback and guidance pushed us to sharpen our thinking and

brought our work to a higher level.

Ethics Approval and Consent to participate

Not applicable.

Human and Animal rights

No Animals/Humans were used for studies that are the basis of this research.


1328


Consent for publication

Not applicable.

Availability of Data and Materials

The author confirms that the data supporting the findings of this research are available within

the article.

Funding Acknowledgement and Conflict of interest

The authors whose names are listed immediately above certify that they have NO affiliations

with or involvement in any organization or entity with any financial interest (such as

honoraria; educational grants; participation in speakers’ bureaus; membership, employment,

consultancies, stock ownership, or other equity interest; and expert testimony or patent-

licensing arrangements), or non-financial interest (such as personal or professional

relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed

in this manuscript.

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