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1.  Cetirizine from topical phosphatidylcholine-hydrogenated liposomes: Evaluation of peripheral antihistaminic activity and systemic absorption in a rabbit model 
The AAPS Journal  2004;6(3):7-12.
Cetirizine, an effective, minimally sedating, second-generation H1-antihistamine is widely used orally to treat allergic skin disorders. This study was performed to assess the peripheral H1-antihistaminic activity and extent of systemic absorption of cetirizine from liposomes applied to the skin. Cetirizine was incorporated into small unilamellar vesicles (SUV) and multilamellar vesicles (MLV) prepared using L-α-phosphatidylcholine hydrogenated (HPC), and into Glaxal Base (GB) as the control. In a randomized, crossover study, each formulation, containing 10 mg of cetirizine, was applied to the depilated backs of 6 rabbits (3.08±0.05 kg). Histamine-induced wheal tests and blood sampling were performed before cetirizine application and at designated times for up to 24 hours afterwards. Compared with baseline, histamine-induced wheal formation was suppressed by cetirizine in SUV only at 24 hours, in MLV from 0.5 to 24 hours, and in GB from 0.5 to 8 hours (P<.05). Wheal suppression by cetirizine in SUV at 24 hours (91.7%±5.2%) and in MLV from 1 to 24 hours (93.8%±2.2% to 76.2%±6.5%) was greater than in GB (36.5%±7.4% to 60.6%±14.2%) from 1 to 24 hours (P<.05). Faster onset, as well as greater and more persistent suppression was obtained from cetirizine in MLV. Plasma cetirizine concentrations from MLV (area under the curve [AUC] of 221.2±42.3 were lower than from GB (AUC of 248.3±34.6 In this model, cetirizine from MLV had excellent topical H1-antihistamine activity, while systemic exposure was reduced, compared with cetirizine from GB.
PMCID: PMC2751243  PMID: 18465266
cetirizine; L-α-phosphatidylcholine hydrogenated; liposomes; antihistamine; rabbit's skin
2.  In Vitro and In Vivo Evaluation of Hydroxyzine Hydrochloride Microsponges for Topical Delivery 
AAPS PharmSciTech  2011;12(3):989-1001.
Hydroxyzine HCl is used in oral formulations for the treatment of urticaria and atopic dermatitis. Dizziness, blurred vision, and anticholinergic responses, represent the most common side effects. It has been shown that controlled release of the drug from a delivery system to the skin could reduce the side effects while reducing percutaneous absorption. Therefore, the aim of the present study was to produce an effective drug-loaded dosage form that is able to control the release of hydroxyzine hydrochloride into the skin. The Microsponge Delivery System is a unique technology for the controlled release of topical agents, and it consists of porous polymeric microspheres, typically 10–50 μm in diameter, loaded with active agents. Eudragit RS-100 microsponges of the drug were prepared by the oil in an oil emulsion solvent diffusion method using acetone as dispersing solvent and liquid paraffin as the continuous medium. Magnesium stearate was added to the dispersed phase to prevent flocculation of Eudragit RS-100 microsponges. Pore inducers such as sucrose and pregelatinized starch were used to enhance the rate of drug release. Microsponges of nearly 98% encapsulation efficiency and 60–70% porosity were produced. The pharmacodynamic effect of the chosen preparation was tested on the shaved back of histamine-sensitized rabbits. Histopathological studies were driven for the detection of the healing of inflamed tissues.
PMCID: PMC3167254  PMID: 21800216
hydroxyzine HCl; microsponges; oil in oil emulsion solvent diffusion; skin delivery
3.  Effects of first and second generation antihistamines on muscarinic induced mucus gland cell ion transport 
BMC Pharmacology  2005;5:8.
The first generation antihistamines, such as diphenhydramine, are fairly potent muscarinic antagonists in addition to being H1 selective antihistamines. The antimuscarinic action is often not desirable since it is in part responsible for the drying of secretions in the airways and the sedative effect. We therefore examined a number of antihistamines for antimuscarinic effects on ion transport by mucus gland cells isolated from the airways of swine. Enzymatically isolated airway mucus gland cells were purified utilizing density gradients and grown in culture on porous inserts (Millicell HA™) at an air interface. Cells grown in this manner maintain phenotype and polarity. Transport of ions, as short-circuit current measured under voltage-clamp, was measured in response to acetylcholine (ACh) or histamine applied to the serosal side of the gland cell layers. Concentration-response relationships for ACh or histamine were generated in the presence and absence of various drugs. The potencies against muscarinic receptor activation were estimated using the dose-ratio method of Schild.
Three known muscarinic antagonists were used to validate the system. Atropine had a pA2 of 9.4 ± 0.1 (n = 9). 4-DAMP and methoctramine had pA2 values of 8.6 ± 0.1 and 5.6 ± 0.1, respectively (n = 12, 11) all consistent with inhibition of an M3 subtype muscarinic receptor. The rank order of potency of the antihistamines against the inhibition of M3 receptors was desloratadine = diphenhydramine > hydroxyzine (pA2; 6.4, 6.2, 4.8, respectively). pA2 values for fexofenadine, loratadine and cetirizine were not determined since they had no effect on the cholinergic response at the highest drug concentrations tested (10, 10 and 100 μM, respectively). The pA2 values for the antihistamines against the histamine response could not be calculated, but the estimates of the rank order of potency were estimated to be desloratadine> cetirizine ≈ hydroxyzine > fexofenadine > loratadine > diphenhydramine.
The rank order of selectivity for histamine receptors over muscarinic receptors was estimated to be cetirizine ≈ fexofenadine > loratadine > desloratadine ≥ hydroxyzine ≥ diphenhydramine.
PMCID: PMC1079883  PMID: 15790419
4.  Studies of human C5a as a mediator of inflammation in normal human skin. 
Journal of Clinical Investigation  1985;75(2):486-495.
C5a is an 11,000-D fragment of the fifth component of complement (C5) with potent anaphylatoxic and leukocyte chemotactic activities. C5a is believed to play an important role in the pathophysiology of certain skin disorders and systemic diseases with cutaneous manifestations. However, there is very little known about the in vivo reactivity of C5a in man. In this study we examined the effects of intradermal injections of human C5a in 17 normal volunteers. C5a was prepared by interacting highly purified human C5 with zymosan bound alternative pathway C5 convertase under conditions resulting in consumption of approximately 90% of the C5 substrate. C5a produced in this manner was chemotactic for human neutrophils and monocytes (0.5 X 10(-7) to 10(-9) M) and caused neutrophil aggregation and myeloperoxidase release (concentrations greater than or equal to 10(-10) M) in vitro. In vivo, C5a produced immediate wheal and flare reactions in all volunteers, and was active in doses as low as 1 ng (10(-13) mol). Intradermal testing with 20 ng of C5a in eight volunteers produced a maximal mean wheal of 11.75 mm (+/- 0.80 mm SEM) 20 min after anaphylatoxin injection, and a maximal mean erythema of 62.50 mm (+/- 3.27 mm SEM) 10 min after C5a administration. Reactions at C5a test sites were dose-related, associated with marked pruritus in some subjects, resolved without lesion formation, and were not associated with late phase reactions. In vivo testing revealed that human C5a was a more potent mediator of wheal and flare reactions than histamine, 48/80, human C3a, or morphine sulfate. Skin biopsies from eight volunteers 20 min after intradermal injection of 20 ng of C5a revealed a neutrophil-predominant perivascular infiltrate, endothelial cell edema, and sites of leukocytoclasis. Mast cell degranulation was observed on both light and electron microscopy of biopsies from C5a test sites. Although erythema at C5a injection sites was reduced by pretreating volunteers with hydroxyzine, whealing reactions and cellular infiltrates in biopsies were unaffected by this H1-antihistamine. Moderate doses of systemic corticosteroids did not alter clinical or histologic reactions at C5a injection sites in two volunteers. This study, using doses within the potential physiologic range of the anaphylatoxin, provides a comprehensive assessment of the effect of human C5a on normal human skin.
PMCID: PMC423523  PMID: 2982914
5.  Comparison of on-site and photographic evaluations of the suppressive effects of cetirizine, loratadine, and fexofenadine on skin response to histamine lontophoresis: A double-blind, crossover study in healthy volunteers 
The standard method used to determine the potency of antihistaminesis to assess the degree of suppression of skin response to histamine challenge.
The aims of this study were to compare the efficacy of 3 antihistaminesusing a histamine challenge test and the usefulness of on-site evaluation with that of photographic evaluation of skin-test reactions.
In this prospective, double-blind, crossover study, healthy volunteerswere given cetirizine 5 mg (CTZ-5) and 10 mg (CTZ-10), loratadine 10 mg (LOR), fexofenadine 60 mg BID (FEX), and placebo (PLC), in a randomly assigned order, with an interval of at least 1 week between treatments. Before and 0.5 to 24 hours after administration, the areas of flare and wheal induced by histamine iontophoresis were measured directly (on site) by 1 evaluator and by another evaluator using photographic images on a computer monitor.
Ten healthy volunteers (6 men, 4 women; mean age, 28.2 years[range, 20–39 years]; mean weight, 60.7 kg [range, 41–81 kg]) were enrolled. The data from 9 subjects were analyzed; the data from 1 subject were omitted because the subject used an over-the-counter cold medication containing diphenhydramine several times during the study. By both methods, all antihistamines were shown to suppress flare significantly from 4 to 24 hours after administration. CTZ was most potent in suppressing both flare and wheal. For flare, the areas as measured using on-site evaluation were larger overall than those measured using photographic evaluation, but the shapes of the time-course graphs were similar for both. Overall, the flare area measurements started to decrease significantly from baseline values 4 hours after drug administration, reached a nadir at 10.5 hours, and remained significantly lower compared with baseline values at 24 hours. Comparisons between antihistamines showed significant differences in mean flare areas between the 2 doses of CTZ and LOR from 8 to 12 hours after administration in both evaluation methods. The wheal areas were significantly reduced from baseline values by most of the antihistamines 4 to 12 hours after drug administration, reached their lowest values at 10.5 hours, and returned to near-baseline values at 24 hours. Comparisons with PLC values at each time point, however, showed significant differences only for CTZ-5 and CTZ-10 from 4 to 12 hours after administration. Comparison between antihistamines showed significant differences in mean flare areas between the 2 doses of CTZ and LOR from 8 to 12 hours after administration in both evaluation methods. Although the flare areas measured by both methods correlated linearly (r = 0.90; P < 0.001), the correlation for wheal areas was weaker (r = 0.76; P < 0.001).
In this study in healthy volunteers, single doses of CTZ 5 mg and CTZ 10 mg were more potent compared with single-dose LOR 10 mg and FEX 60 mg BID in suppressing skin response. Although linear correlations were found between skin-response areas, as measured by on-site and photographic evaluation, it was difficult to differentiate between wheal and flare by photographic evaluation, especially when a typical wheal was suppressed to slightly edematous erythema by antihistamines.
PMCID: PMC3964551  PMID: 24672131
antihistamine; histamine iontophoresis; histamine challenge test; ImageJ; fexofenadine; loratadine; cetirizine; wheal; flare
6.  Challenges in the Management of Chronic Urticaria 
The World Allergy Organization Journal  2011;4(Suppl 3):S28-S31.
The term "chronic idiopathic urticaria" denotes a spectrum of conditions with different poorly understood pathogenetic mechanisms in which the release of histamine plays a role. Nonsedating second-generation H1 antihistamines are postulated to be the first line of treatment of chronic idiopathic urticaria by national and international guidelines, but as control is not always achievable with the usually recommended doses, first-generation sedating antihistamines like hydroxyzine and diphenhydramine at high daily doses (200 mg) have been proposed as an alternative before resorting to treatment with systemic corticosteroids and other potentially hazardous agents. Our long time experience and recent research give us grounds to believe that increasing the doses of nonsedating H1 antihistamines up to fourfold improves significantly the chances of successful treatment. Our data suggest that the urticaria-associated discomfort is relieved by higher than conventional doses of levoce-tirizine and desloratadine in about 75% of the patients and that sedation/somnolence does not seem to be a major deterrent. The dose increase also improves the urticaria-specific quality of life. Contrary to the belief that individual patients may benefit from one antihistamine or another, we demonstrate that the drug with better ability to suppress the histamine skin effects in experiments in healthy volunteers (levocetirizine) is also superior in improving the different aspects of control of chronic urticaria (subjective and objective symptoms, quality of life) and that increasing its dose of up to fourfold may even paradoxically reduce the sense of sedation/somnolence in parallel with the relief of urticaria discomfort.
PMCID: PMC3666186  PMID: 23282333
chronic idiopathic urticaria; histamine; nonsedating antihistamines; levocetirizine; desloratadine
7.  Night-time sedating H1-antihistamine increases daytime somnolence but not treatment efficacy in chronic spontaneous urticaria: a randomized controlled trial 
The British Journal of Dermatology  2014;171(1):148-154.
Many physicians believe that the most effective way to treat chronic urticaria is to take a nonsedating second-generation H1-antihistamine in the morning and a sedating first-generation H1-antihistamine, usually hydroxyzine, at night to enhance sleep. But is this belief well founded?
To test this belief by comparing the effectiveness and prevalence of unwanted sedative effects when treating patients with chronic spontaneous urticaria (CSU) with levocetirizine 15 mg daily plus hydroxyzine 50 mg at night (levocetirizine plus hydroxyzine) vs. levocetirizine 20 mg daily (levocetirizine monotherapy).
In this randomized, double-blind, cross-over study, 24 patients with difficult-to-treat CSU took levocetirizine plus hydroxyzine or levocetirizine monotherapy for periods of 5 days each. At the end of each treatment period, assessments were made of quality of life (Chronic Urticaria Quality of Life Questionnaire, CU-Q2oL), severity of urticaria symptoms (Urticaria Activity Score, UAS), sleep disturbance during the night and daytime somnolence.
Both treatments significantly decreased UAS, night-time sleep disturbances and CU-Q2oL scores (P < 0·001) without significant differences between the two. Compared with baseline, daytime somnolence was significantly reduced by levocetirizine monotherapy (P = 0·006) but not by levocetirizine plus hydroxyzine (P = 0·218). Direct comparison of the two treatment modalities in terms of daytime somnolence favoured levocetirizine monotherapy (P = 0·026).
The widespread belief that sleep is aided by the addition of a sedating first-generation H1-antihistamine, usually hydroxyzine, at night is not supported. These results are in line with the urticaria guidelines, which state that first-line treatment for urticaria should be new-generation, nonsedating H1-antihistamines only.
PMCID: PMC4232862  PMID: 24472058
8.  A case of levocetirizine-induced fixed drug eruption and cross-reaction with piperazine derivatives 
Asia Pacific Allergy  2013;3(4):281-284.
Fixed drug eruption is an uncommon adverse drug reaction caused by delayed cell-mediated hypersensitivity. Levocetirizine is an active (R)-enatiomer of cetirizine and there have been a few reports of fixed drug eruption related to these antihistamines. We experienced a case of levocetirizine-induced fixed drug eruption and cross-reaction with other piperazine derivatives confirmed by patch test. A 73-year-old female patient presented with recurrent generalized itching, cutaneous bullae formation, rash and multiple pigmentation at fixed sites after taking drugs for common cold. She took bepotastine besilate (Talion®) and levocetirizine (Xyzal®) as antihistamine. She took acetaminophen, pseudoephedrine 60 mg / triprolidine 2.5 mg (Actifed®), dihydrocodeinebitartrate 5 mg / di-methylephedrine hydrochloride 17.5 mg / chlorpheniramine maleate 1.5 mg / guaifenesin 50 mg (Codening®) and aluminium hydroxide 200 mg / magnesium carbonate 120 mg (Antad®) at the same time. Patch test was done with suspected drugs and the result was positive with levocetirizine. We additionally performed patch test for other antihistamines such as cetirizine, hydroxyzine, fexofenadine and loratadine. Piperazine derivatives (cetirizine and hydroxyzine) were positive, but piperidine derivatives (fexofenadine and loratadine) were negative to patch test. There was no adverse drug reaction when she was challenged with fexofenadine. We report a case of levocetirizine-induced fixed drug eruption confirmed by patch test. Cross-reactions were only observed in the piperazine derivatives and piperidine antihistamine was tolerant to the patient.
PMCID: PMC3826602  PMID: 24260733
Levocetirizine; Fixed drug eruption; Antihistamine
9.  Development of Novel Elastic Vesicle-Based Topical Formulation of Cetirizine Dihydrochloride for Treatment of Atopic Dermatitis 
AAPS PharmSciTech  2013;14(4):1284-1293.
Cetirizine is a piperazine-derived second-generation antihistaminic drug recommended for treatment of pruritus associated with atopic dermatitis. The present investigation encompasses development of a nanosized novel elastic vesicle-based topical formulation of cetirizine dihydrochloride using combination of Phospholipon® 90G and edge activators with an aim to have targeted peripheral H1 antihistaminic activity. The formulation was optimized with respect to phospholipid/drug/charge inducer ratio along with type and concentration of edge activator. The optimized formulation was found to be satisfactory with respect to stability, drug content, entrapment efficiency, pH, viscosity, vesicular size, spreadability, and morphological characteristics. The ex vivo permeation studies through mice skin were performed using Franz diffusion cell assembly. It was found that the mean cumulative percentage amount permeated in 8 h was almost twice (60.001 ± 0.332) as compared to conventional cream (33.268 ± 0.795) and aqueous solution of drug (32.616 ± 0.969), suggesting better penetration and permeation of cetirizine from the novel vesicular delivery system. Further, therapeutic efficacy of optimized formulation was assessed against oxazolone-induced atopic dermatitis in mice. It was observed that the developed formulation was highly efficacious in reducing the itching score (4.75 itches per 20 min) compared to conventional cream (9.75 itches per 20 min) with profound reduction in dermal eosinophil count and erythema score. To conclude, a novel vesicular, dermally safe, and nontoxic topical formulation of cetirizine was successfully developed and may be used to treat atopic dermatitis after clinical investigation.
PMCID: PMC3840784  PMID: 23959702
atopic dermatitis; cetirizine; elastic vesicles; oxazolone; topical
10.  Co-Administration of Subeffective Anxiolytic Doses of Diazepam and Hydroxyzine in Elevated Zero-Maze in Mice 
Psychiatry Investigation  2010;8(2):169-173.
Benzodiazepines are from the most common drugs which are used for treatment of anxiety disorders. There are other drugs with antianxiety properties including antihistamines such as hydroxyzine, too. Body of evidence show that co-administration of two drugs which act through different mechanisms, makes the dose of each drug to be reduced, while preserving the desired effect with less adverse drug reactions. The aim of this study was to see whether co-administration of subeffective antianxiety doses of diazepam and hydroxyzine has any antianxiety effect in elevated zero-maze (EZM) in mice.
To find the highest subeffective dose of each drug, different doses of hydroxyzine from 1.5 to 24 mg/kg and diazepam in doses of 0.25, 0.5 and 1 mg/kg were injected to male mice. Thirty minutes later, the animals were placed on EZM and various parameters of anxiety were recorded by a camera to assess later. After determination of subeffective antianxiety dose of the drugs, co-administration of hydroxyzine and diazepam was done and the anxiety parameters were measured.
In co-administration of 0.25 mg/kg of diazepam and 12 mg/kg hydroxyzine, as subeffective antianxiety doses of either drug, there were not any significant differences in main anxiety parameters, i.e., time spent in open areas and open area entries compared to control group. Hence, no anxiolytic effect was seen.
It seems that subeffective doses of diazepam and hydroxyzine may not have any facilitating or synergistic effect on each other in antianxiety responses in mice.
PMCID: PMC3149113  PMID: 21852995
Anxiety; Diazepam; Elevated zero-maze; Hydroxyzine; Mice
11.  Bilastine vs. hydroxyzine: occupation of brain histamine H1-receptors evaluated by positron emission tomography in healthy volunteers 
A close correlation exists between positron emission tomography (PET)-determined histamine H1-receptor occupancy (H1RO) and the incidence of sedation. Antihistamines with H1RO <20% are classified as non-sedating. The objective was to compare the H1RO of bilastine, a second generation antihistamine, with that of hydroxyzine.
This randomized, double-blind, crossover study used PET imaging with [11C]-doxepin to evaluate H1RO in 12 healthy males (mean age 26.2 years), after single oral administration of bilastine (20 mg), hydroxyzine (25 mg) or placebo. Binding potentials and H1ROs were calculated in five cerebral cortex regions of interest: frontal, occipital, parietal, temporal, insula. Plasma bilastine concentrations, subjective sedation (visual analogue scale), objective psychomotor performance (digital symbol substitution test), physiological variables and safety (adverse events, AEs), were also evaluated.
The mean binding potential of all five regions of interest (total binding potential) was significantly greater with bilastine than hydroxyzine (mean value 0.26 vs. 0.13, P < 0.01; mean difference and 95% CI −0.130 [−0.155, 0.105]). There was no significant difference between bilastine and placebo. Overall H1RO by bilastine was significantly lower than that by hydroxyzine (mean value −3.92% vs. 53.95%, P < 0.01; mean difference and 95% CI 57.870% [42.664%, 73.075%]). There was no significant linear relationship between individual bilastine plasma concentrations and total binding potential values. No significant between-treatment differences were observed for sedation and psychomotor performance. Twenty-six non-serious AEs were reported. Sleepiness or sedation was not reported with bilastine but appeared in some subjects with hydroxyzine.
A single oral dose of bilastine 20 mg had minimal H1RO, was not associated with subjective sedation or objective impairment of psychomotor performance and was devoid of treatment-related sedative AEs, thus satisfying relevant subjective, objective and PET criteria as a non-sedating antihistamine.
PMCID: PMC4243871  PMID: 24833043
antihistamines H-1; bilastine; histamine H-1-receptor occupancy; positron emission tomography; PET
12.  Bilastine vs. hydroxyzine: occupation of brain histamine H1-receptors evaluated by positron emission tomography in healthy volunteers 
A close correlation exists between positron emission tomography (PET)-determined histamine H1-receptor occupancy (H1RO) and the incidence of sedation. Antihistamines with H1RO <20% are classified as non-sedating. The objective was to compare the H1RO of bilastine, a second generation antihistamine, with that of hydroxyzine.
This randomized, double-blind, crossover study used PET imaging with [11C]-doxepin to evaluate H1RO in 12 healthy males (mean age 26.2 years), after single oral administration of bilastine (20 mg), hydroxyzine (25 mg) or placebo. Binding potentials and H1ROs were calculated in five cerebral cortex regions of interest: frontal, occipital, parietal, temporal, insula. Plasma bilastine concentrations, subjective sedation (visual analogue scale), objective psychomotor performance (digital symbol substitution test), physiological variables and safety (adverse events, AEs), were also evaluated.
The mean binding potential of all five regions of interest (total binding potential) was significantly greater with bilastine than hydroxyzine (mean value 0.26 vs. 0.13, P < 0.01; mean difference and 95% CI −0.130 [−0.155, 0.105]). There was no significant difference between bilastine and placebo. Overall H1RO by bilastine was significantly lower than that by hydroxyzine (mean value −3.92% vs. 53.95%, P < 0.01; mean difference and 95% CI 57.870% [42.664%, 73.075%]). There was no significant linear relationship between individual bilastine plasma concentrations and total binding potential values. No significant between-treatment differences were observed for sedation and psychomotor performance. Twenty-six non-serious AEs were reported. Sleepiness or sedation was not reported with bilastine but appeared in some subjects with hydroxyzine.
A single oral dose of bilastine 20 mg had minimal H1RO, was not associated with subjective sedation or objective impairment of psychomotor performance and was devoid of treatment-related sedative AEs, thus satisfying relevant subjective, objective and PET criteria as a non-sedating antihistamine.
PMCID: PMC4243871  PMID: 24833043
antihistamines H-1; bilastine; histamine H-1-receptor occupancy; positron emission tomography; PET
13.  Post-sedation Events in Children Sedated for Dental Care 
Anesthesia Progress  2013;60(2):54-59.
Moderate oral sedation is used in pediatric dentistry for safe delivery of dental care to children. However, there is a paucity of data on the effects of pediatric dental sedations after discharge of children from the dental office. The purpose of this study was to evaluate and compare the incidence of adverse events occurring with meperidine and hydroxyzine versus midazolam alone 8 and 24 hours after sedation in pediatric dental patients. In this prospective study, a convenience sample of 46 healthy children presenting to a private pediatric dental practice for dental treatment needs was selected. A telephone survey of the parents of children sedated with either meperidine and hydroxyzine or midazolam alone was conducted 8 and 24 hours after the administration of sedation medications. Data analysis included descriptive statistics, frequency and proportion analysis, and Fisher exact test. Forty children were sedated with meperidine and hydroxyzine, and 6 who were sedated with midazolam. In both groups, 50% of the children slept in the car on the way home. Three children in the meperidine and hydroxyzine group vomited in the car. A significantly larger proportion of children in the meperidine and hydroxyzine group experienced prolonged sleep at home (P = .015). More children in the midazolam group exhibited irritability in the first 8 hours (P = .07). There were no statistical differences between the 2 groups with respect to incidence of pain, fever, vomiting, sleeping in the car, snoring, and difficulty in waking up. The lingering effects of orally administered sedation medications can lead to prolonged sleep, irritability, and vomiting in children after they have been discharged from the dental clinic. Most of these events occurred within the first 8 hours, but in some children the effects were seen up to 24 hours later.
PMCID: PMC3683881  PMID: 23763560
Sedation; Children; Adverse events
14.  A Case of Chlorpheniramine Maleate-Induced Hypersensitivity With Aspirin Intolerance 
Antihistamines are commonly used to treat allergic disease, such as allergic rhinitis, urticaria, and angioedema. Although several previous reports describe hypersensitivity to antihistamines such as cetirizine and hydroxyzine, documented cases of chlorpheniramine hypersensitivity are extremely rare. Here, we report the case of a 45-year-old Korean woman who presented with urticaria after ingesting a cold medication. Over the previous 5 years, she had also experienced a food allergy to crab and shrimp, allergic rhinitis, and repeated urticaria after ingesting cold medication. Provocation with aspirin elicited generalized urticaria. Intravenous chlorpheniramine and methylprednisolone was injected for symptom control, but in fact appeared to aggravate urticaria. A second round of skin and provocation tests for chlorpheniramine and methylprednisolone showed positive results only for chlorpheniramine. She was diagnosed with aspirin intolerance and chlorpheniramine hypersensitivity, and was instructed to avoid these drugs. To date, this is the second of only two cases of chlorpheniramine-induced type I hypersensitivity with aspirin intolerance. Although the relationship between aspirin intolerance and chlorpheniramine-induced type I hypersensitivity is unclear, physicians should be aware of the possibility of urticaria or other allergic reactions in response to antihistamines.
PMCID: PMC3005322  PMID: 21217928
Aspirin; chlorpheniramine; drug hypersensitivity; hypersensitivity; urticaria
15.  Effects of anti-allergic drugs on intestinal mastocytosis and worm expulsion of rats infected with Neodiplostomum seoulense 
The effects of anti-allergic drugs on intestinal mastocytosis and the expulsion of Neodiplostomum seoulense were observed in Sprague-Dawley rats, after oral infection with 500 metacercariae. The drugs used were hydroxyzine (a histamine receptor H1 blocker), cimetidine (a H2 blocker), cyclosporin-A (a helper T-cell suppressant), and prednisolone (a T- and B-cell suppressant). Infected, but untreated controls, and uninfected controls, were prepared. Worm recovery rate and intestinal mastocytosis were measured on weeks 1, 2, 3, 5, and 7 post-infection. Compared with the infected controls, worm expulsion was significantly (P < 0.05) delayed in hydroxyzine- and cimetidine-treated rats, despite mastocytosis being equally marked in the duodenum of all three groups. In the cyclosporin-A- and prednisolone-treated groups, mastocytosis was suppressed, but worm expulsion was only slightly delayed, without statistical significance. Our results suggest that binding of histamine to its receptors on intestinal smooth muscles is more important in terms of the expulsion of N. seoulense from rats than the levels of histamine alone, or mastocytosis.
PMCID: PMC2717495  PMID: 12815318
Neodiplostomum seoulense; expulsion of worm; mast cell (mucosal); goblet cell; hydroxyzine; cimetidine; cyclosporin; prednisolone
16.  Design and development of multivesicular liposomal depot delivery system for controlled systemic delivery of acyclovir sodium 
AAPS PharmSciTech  2005;6(1):E35-E41.
The aim of the present study was to design a depot delivery system of acyclovir sodium using multivesicular liposomes (MVLs) to overcome the limitations of conventional therapies and to investigate its in vivo effectiveness for sustained delivery. MVLs of acyclovir were prepared by the reverse phase evaporation method. The loading efficiency of the MVLs (45%–82%) was found to be 3 to 6 times higher than conventional multilamellar vesicles (MLVs). The in vitro release of acyclovir from MVL formulations was found to be in a sustained manner and only 70% of drug was released in 96 hours, whereas conventional MLVs released 80% of drug in 16 hours. Following intradermal administration to Wistar rats, the MVL formulations showed effective plasma concentration for 48 hours compared with MLVs and free drug solution (12–16 hours). Cmax values of MVL formulations were significantly less (8.6–11.4 μg/mL) than MLV and free drug solution (12.5 μg/mL). The AUC0–48 of the MVL formulations was 1.5- and 3-fold higher compared with conventional liposomes and free drug solution, respectively. Overall, formulations containing phosphatidyl glycerol as negatively charged lipid showed better results. The MVL delivery system as an intradermal depot offers the advantage of a very high loading and controlled release of acyclovir for an extended period of time. The increase in AUC and decrease in Cmax reflects that the MVL formulations could reduce the toxic complications and limitations of conventional IV and oral therapies.
PMCID: PMC2750409  PMID: 16353961
multivesicular liposomes; acyclovir sodium; herpes simplex virus; sustained delivery; intradermal depot systems
California Medicine  1951;74(4):256-259.
Utilizing histamine electrophoresis, the degree and duration of “antihistaminic” effect of varying doses of Pyribenzamine® administered by different routes were studied.
Delayed action Pyribenzamine in 50 mg. and 100 mg. dosage exerted a small but measurable anti-whealing effect five hours after ingestion. The larger dose exerted approximately twice the effect of the smaller. The anti-whealing activity lasted five to six hours.
Pyribenzamine given intravenously affected the whealing response one hour after administration. A peak of activity was reached two to two and a half hours after injection, and “antihistaminic” effect continued for a total of five hours.
The inunction of 250 mg. and 500 mg. of Pyribenzamine in an ointment base resulted in sufficient absorption of the drug to produce a measurable anti-whealing effect. The “antihistaminic” activity was noted three hours after application and lasted 10 to 12 hours from the time of inunction.
PMCID: PMC1520894  PMID: 14821823
18.  Effects of the histamine H1 receptor antagonist hydroxyzine on hERG K+ channels and cardiac action potential duration 
Acta Pharmacologica Sinica  2011;32(9):1128-1137.
To investigate the effects of hydroxyzine on human ether-a-go-go-related gene (hERG) channels to determine the electrolphysiological basis for its proarrhythmic effects.
hERG channels were expressed in Xenopus oocytes and HEK293 cells, and the effects of hydroxyzine on the channels were examined using two-microelectrode voltage-clamp and patch-clamp techniques, respectively. The effects of hydroxyzine on action potential duration were examined in guinea pig ventricular myocytes using current clamp.
Hydroxyzine (0.2 and 2 μmol/L) significantly increased the action potential duration at 90% repolarization (APD90) in both concentration- and time-dependent manners. Hydroxyzine (0.03–3 μmol/L) blocked both the steady-state and tail hERG currents. The block was voltage-dependent, and the values of IC50 for blocking the steady-state and tail currents at +20 mV was 0.18±0.02 μmol/L and 0.16±0.01 μmol/L, respectively, in HEK293 cells. Hydroxyzine (5 μmol/L) affected both the activated and the inactivated states of the channels, but not the closed state. The S6 domain mutation Y652A attenuated the blocking of hERG current by ∼6-fold.
The results suggest that hydroxyzine could block hERG channels and prolong APD. The tyrosine at position 652 in the channel may be responsible for the proarrhythmic effects of hydroxyzine.
PMCID: PMC4003299  PMID: 21892192
histamine antagonists; hydroxyzine; cardiomyocytes; hERG channels; K+ channel; proarrhythmic effects
19.  Small Cationic DDA:TDB Liposomes as Protein Vaccine Adjuvants Obviate the Need for TLR Agonists in Inducing Cellular and Humoral Responses 
PLoS ONE  2012;7(3):e34255.
Most subunit vaccines require adjuvants in order to induce protective immune responses to the targeted pathogen. However, many of the potent immunogenic adjuvants display unacceptable local or systemic reactogenicity. Liposomes are spherical vesicles consisting of single (unilamellar) or multiple (multilamellar) phospholipid bi-layers. The lipid membranes are interleaved with an aqueous buffer, which can be utilised to deliver hydrophilic vaccine components, such as protein antigens or ligands for immune receptors. Liposomes, in particular cationic DDA:TDB vesicles, have been shown in animal models to induce strong humoral responses to the associated antigen without increased reactogenicity, and are currently being tested in Phase I human clinical trials. We explored several modifications of DDA:TDB liposomes - including size, antigen association and addition of TLR agonists – to assess their immunogenic capacity as vaccine adjuvants, using Ovalbumin (OVA) protein as a model protein vaccine. Following triple homologous immunisation, small unilamellar vesicles (SUVs) with no TLR agonists showed a significantly higher capacity for inducing spleen CD8 IFNγ responses against OVA in comparison with the larger multilamellar vesicles (MLVs). Antigen-specific antibody reponses were also higher with SUVs. Addition of the TLR3 and TLR9 agonists significantly increased the adjuvanting capacity of MLVs and OVA-encapsulating dehydration-rehydration vesicles (DRVs), but not of SUVs. Our findings lend further support to the use of liposomes as protein vaccine adjuvants. Importantly, the ability of DDA:TDB SUVs to induce potent CD8 T cell responses without the need for adding immunostimulators would avoid the potential safety risks associated with the clinical use of TLR agonists in vaccines adjuvanted with liposomes.
PMCID: PMC3314611  PMID: 22470545
20.  Randomized, single-blind, crossover comparison of two rupatadine tablet formulations on histamine-induced cutaneous response in healthy adult volunteers 
Background: Rupatadine is a histamine receptor type 1 antagonist that has been used to treat allergic rhinitis and urticaria.
Objective: The aim of this study was to compare the effect of 2 rupatadine tablet formulations on the inhibition of histamine-induced wheal-and-flare cutaneous responses.
Methods: In this single-blind, single oral dose, crossover study, healthy male volunteers were randomized to receive 10 mg of either a rupatadine reference or test formulation after an overnight fast. After a 10-day washout period, the subjects were crossed over to receive the other formulation. Subjects were asked to sit with their arm resting on the table while histamine was injected intradermally. The skin prick test was performed on the upper half of the volunteers' forearms before administration and at 1, 2, 4, 6, 12, and 24 hours after study drug administration. Fifteen minutes after each skin prick test, the wheal-and-flare responses were visualized under a bright lamp. AUC0–24 was the primary end point.The 90% CI of least squares mean ratio (%) of the test: reference formulations for maximum inhibition of histamine-induced wheal-and-flare response (Imax%), Tmax, AUC0–24 mm2/h, and AUC0–24%/hr were expected to be within 80% to 125% of untransformed data and 80% to 120% of log-transformed data for the 2 formulations to be considered pharmacodynamically equivalent. Subjects were monitored for any spontaneously reported adverse event (AE) throughout the study. In addition, they were specifically asked about the occurrence of any AEs on a checklist (ie, drowsiness, dizziness, dryness of mouth, itching sensation, headache, nausea) throughout the study.
Results: Of the 15 subjects assessed for inclusion, 12 healthy male volunteers (mean [SD] age, 30 [5] years; height, 162 [6] cm; weight, 58 [6] kg) participated in the study. Administration of reference and test formulations of rupatadine significantly inhibited the histamine-induced cutaneous responses in all subjects (P <0.001). Wheal Imax% with the reference and test formulations was 67.97% (11.57%) and 66.76% (9.40%), respectively. Flare Imax% was 59.06% (11.95%) and 56.92% (16.31%), respectively. None of the subjects withdrew from the study due to AEs. Both formulations were well tolerated except for an itching sensation on injection of histamine in all patients; no subject complained of any adverse drug reaction.
Conclusion: In this small study of healthy adult males, the test formulation of the rupatadine tablet was found to be pharmacodynamically equivalent to the reference formulation, as measured by inhibition of histamine-induced cutaneous wheal-and-flare responses.
PMCID: PMC3969931  PMID: 24692771
rupatadine; healthy subjects; pharmacodynamic equivalence; histamine-induced cutaneous response
21.  592 A Case of Multiple Simultaneous Urticarial Syndromes Refractory to Treatment 
We report the case of a patient with 3 forms of physical urticaria and his response to treatment.
An atopic asthmatic 11 year old male was evaluated for a history of recurrent pruritus with a variable, erythematous rash unresponsive to therapy. Since the age of 5 years, he has experienced small red, raised, pinpoint, pruritic “bumps” over his entire body except the palms of his hands and soles of his feet. The duration of the lesions was generally 5 minutes to about 1 hour. They occurred with exercise, stress, cold air, and cold water. At the time of the evaluation, the patient was treated with oral levocetirizine 5 mg daily and hydroxyzine 50 mg at bedtime without resolution of symptoms.
In clinic, the patient had a positive ice cube test, a positive dermatographia test and a negative warm test tube test. Methacholine and autologous sweat testing were declined. Otherwise he had a normal physical examination with a negative Darier sign. Laboratory studies did not reveal a disease process responsible for the urticaria. Based upon his historical symptoms and clinical findings, he was diagnosed with 3 distinct types of physical urticaria; cholinergic urticaria, cold urticaria and dermatographia. The dose of anti-histamine therapy was doubled and the patient returned to clinic in 4 weeks to report that his symptoms were slightly improved but had not resolved.
Physical urticarias are usually controlled by antihistamine therapy but refractory cases are not uncommon. This patient also has poorly controlled asthma for which he is scheduled to start omalizumab therapy upon turning 12 in 1 month. We will continue to follow this case to observe if omalizumab has an effect upon his urticarial symptoms.
PMCID: PMC3513100
22.  Generalised anxiety disorder 
Clinical Evidence  2011;2011:1002.
Up to one in five people may have generalised anxiety disorder (GAD) at some point, and most have other health problems. Less than half of people have full remission after 5 years. GAD may have a genetic component, and has also been linked to previous psychological or other trauma.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for GAD? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 74 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: abecarnil, antidepressants (duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, opipramol, paroxetine, sertraline, and venlafaxine), antipsychotic drugs (trifluoperazine), applied relaxation, benzodiazepines, buspirone, cognitive behavioural therapy, hydroxyzine, and pregabalin.
Key Points
Generalised anxiety disorder (GAD) is excessive worry and tension about everyday events, on most days, for at least 6 months, to the extent that there is distress or difficulty in performing day-to-day tasks. However, diagnosing GAD accurately can be difficult. Up to 1 in 20 people may have GAD at any one time, and most have other health problems. Less than half of people have full remission after 5 years.GAD may have a genetic component, and has also been linked to previous psychological or other trauma.
In adults:
CBT (including exposure, relaxation, and cognitive restructuring) improves anxiety compared with waiting list control, treatment as usual, or enhanced usual care. It is unclear whether CBT is more effective than supportive therapy.
Applied relaxation may be as effective as CBT, but we found insufficient RCT evidence about applied relaxation compared with no treatment.
Various drug treatments, such as benzodiazepines, buspirone, hydroxyzine, antidepressants, and pregabalin may all reduce symptoms of anxiety in people with GAD, but they can have unpleasant adverse effects, and most trials have been short term. Benzodiazepines increase the risk of dependence, sedation, and accidents, and can cause adverse effects in neonates if used during pregnancy.Buspirone may be less effective if used in people who have recently been taking benzodiazepines.Antidepressants (imipramine, paroxetine, sertraline, escitalopram, venlafaxine, and opipramol) have been shown to reduce symptoms compared with placebo, but antidepressants can cause a variety of adverse effects including sedation, dizziness, falls, nausea, and sexual dysfunction.In general, comparisons between different antidepressants have shown similar effectiveness in reducing anxiety, although one RCT found limited evidence of an increased benefit with escitalopram compared with paroxetine.
Antipsychotic drugs may reduce anxiety in people who have not responded to other treatments, but these drugs may have adverse effects including drowsiness, and movement disorders.
We don't know whether abecarnil reduces anxiety as the RCTs we found reported inconsistent results.
In children and adolescents:
CBT improves symptoms compared with waiting list control or active control. Most RCTs of CBT in children and adolescents have included other anxiety disorders.
We found limited RCT evidence regarding the efficacy of antidepressants for childhood GAD. SSRIs (fluvoxamine, fluoxetine, sertraline) have shown some promise, but antidepressants are associated with abdominal pain and nausea, and other well documented adverse effects.
We found no RCT evidence on the effects of applied relaxation, benzodiazepines, buspirone, hydroxyzine, abecarnil, pregabalin, or antipsychotics in children and adolescents.
PMCID: PMC3275153  PMID: 22030083
23.  Comparison of reservoir effect of topical corticosteroids in an experimental animal model by histamine-induced wheal suppression test 
Indian Journal of Pharmacology  2012;44(6):722-725.
Topical corticosteroids used in various dermatological diseases are available in different potencies and different formulations. The reservoir effect of different potency corticosteroids in the stratum corneum will help the clinicians to choose an appropriate topical steroid to maximize their efficacy and safety as therapeutic agents.
This study was designed to compare the duration of reservoir of different potency topical corticosteroids experimentally in rabbits using histamine-induced wheal suppression test.
Materials and Methods:
The study was carried out in albino rabbits (as their skin is similar to humans) using four different concentrations of topical steroids, namely mometasone furoate ointment (0.1%), fluticasone propionate ointment (0.005%), betamethasone valerate cream (0.1%), and hydrocortisone butyrate cream (0.1%). These were applied on the back of rabbit on one side and the vehicle was applied on the other. One hour later, histamine-induced wheal suppression test was performed on both sides and wheal area was measured at 10 min for 7 days. Statistical analysis was done by ANOVA followed by post hoc test.
Maximum wheal suppression was seen on day 1 (P<0.001) in all four groups, both at test and at control sites. Interday comparison of mean wheal size by topical steroids showed that the reservoir of mometasone furoate ointment (0.1%) persisted till day 4 in the stratum corneum of the skin. In case of fluticasone propionate ointment (0.005%) and betamethasone valerate cream (0.1%), the reservoir persisted till day 2 and for hydrocortisone butyrate cream (0.1%), the reservoir was present only on day 1.
It is concluded that the duration of reservoir depends on the potency of topical steroids. Higher the potency more is the duration of reservoir in stratum corneum and vice versa.
PMCID: PMC3523499  PMID: 23248401
Potency; reservoir; topical corticosteroids; wheal suppression
24.  Liposomes as an ocular delivery system for acetazolamide: In vitro and in vivo studies 
AAPS PharmSciTech  2007;8(1):E1-E12.
The purpose of this study was to formulate topically effective controlled release ophthalmic acetazolamide liposomal formulations. Reverse-phase evaporation and lipid film hydration methods were used for the preparation of reversephase evaporation (REVs) and multilamellar (MLVs) acetazolamide liposomes consisting of egg phosphatidylcholine (PC) and cholesterol (CH) in the molar ratios of (7∶2), (7∶4), (7∶6), and (7∶7) with or without stearylamine (SA) or dicetyl phosphate (DP) as positive and negative charge inducers, respectively. The prepared liposomes were evaluated for their entrapment efficiency and in vitro release. Multilamellar liposomes entrapped greater amounts of drug than REVs liposomes. Drug loading was increased by increasing CH content as well as by inclusion of SA. Drug release rate showed an order of negatively charged > neutral > positively charged liposomes, which is the reverse of the data of drug loading efficiency. Physical stability study indicated that approximately 89%, 77%, and 69% of acetazolamide was retained in positive, negative, and neutral MLVs liposomal formulations up to a period of 3 months at 4°C. The intraocular pressure (IOP)-lowering activity of selected acetazolamide liposomal formulations was determined and compared with that of plain liposomes and acetazolamide solution. Multilamellar acetazolamide liposomes revealed more prolonged effect than REVs liposomes. The positively charged and neutral liposomes exhibited greater lowering in IOP and a more prolonged effect than the negatively charged ones. The positive multilamellar liposomes composed of PC:CH:SA (7:4:1) molar ratio showed the maximal response, which reached a value of −7.8±1.04 mmHg after 3 hours of topical administration.
PMCID: PMC2750424
Acetazolamide; multilamellar liposomes; reverse-phase evaporation liposomes
25.  Membrane permeability alteration of some bacterial clinical isolates by selected antihistaminics 
Brazilian Journal of Microbiology  2011;42(3):992-1000.
Several antihistaminics possess antibacterial activity against a broad spectrum of bacteria. However, the exact mechanism of such activity was unclear. Hence, the aim of this study is to investigate their mechanism of antibacterial activity especially their effect upon the permeability of the bacterial cytoplasmic membrane. The effects of azelastine, cetirizine, cyproheptadine and diphenhydramine were studied using Gram-positive and Gram-negative multiresistant clinical isolates. Leakage of 260 and 280 nm UV-absorbing materials was detected upon treatment with the tested antihistaminics; indicative of membrane alteration. Using an artificial membrane model, cholesterol-free negatively-charged unilamellar liposomes, confirmed the effect of antihistaminics upon the membrane permeability both by showing an apparent membrane damage as observed microscopically and by detection of leakage of preloaded dye from the liposomes colorimatrically. Moreover, examination of the ultrastructure of cells treated with azelastine and cetirizine under the transmission electron microscope substantiated the detected abnormalities in the cell wall and membrane. Furthermore, the effect of pretreating certain isolates for both short and long periods with selected antihistaminics was followed by the viable count technique. Increased vulnerability towards further exposure to azelastine was observed in cells pretreated with azelastine for 2 days and those pretreated with azelastine or cetrizine for 30 days.
PMCID: PMC3768765  PMID: 24031716
antihistaminics; azelastine; bacteria; cytoplasmic membrane; liposomes; permeability alteration

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