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Allergies are a widespread group of diseases of civilization and most patients are still undertreated. Since histamine is considered to be the most important mediator in allergies such as allergic rhinitis and urticaria, the most commonly used drugs to treat these disorders are antihistamines acting on the histamine 1 (H1) receptor. The currently available antihistamines, however, have significant differences in their effects and safety profiles. Furthermore, the Allergic Rhinitis and its Impact on Asthma initiative calls for additional desirable properties of antihistamines. Here, we review the profile of rupatadine, a new dual platelet-activating factor and H1-receptor antagonist that fulfils these criteria and therefore offers an excellent option for the treatment of allergic diseases.

Background: The guidelines recommend that first line treatment of chronic spontaneous urticaria should be second generation non-sedating H(1)-antihistamines with a positive recommendation against the use of old sedating first generation antihistamines. If standard dosing is not effective, increasing the dosage up to four-fold is recommended. The objective of this study was to obtain the chronic spontaneous urticaria-patient perspective on the effectiveness and unwanted effects of H(1)-antihistamines in standard and higher doses., Methodology/principal Findings: This was a questionnaire based survey, initially completed by 368 individuals. 319 (248 female, 71 male, median age 42 years) had a physician-confirmed diagnosis of chronic spontaneous urticaria and were included in the results. Participants believed standard doses (manufacturers recommended dose) of second generation antihistamines to be significantly (P<0.005) more effective than first generation drugs. Furthermore, they believed that second generation drugs caused significantly (P<0.001) fewer unwanted effects and caused significantly (P<0.001) less sedation than first generation antihistamines. Three-quarters of the patients stated that they had up-dosed with antihistamines with 40%, 42% and 54% reporting significant added benefit from taking 2, 3 or 4 tablets daily respectively. The number of reports of unwanted effects and sedation following up-dosing were not significantly different from those reported for standard doses., Conclusions: This survey supports the urticaria guidelines recommendations that the first line treatment for chronic spontaneous urticaria should be second generation rather than first generation H(1)-antihistamines and that, if standard dosing is not effective, the dosage should be increased up to four-fold.

Antihistamines have been classifed as first or second generation drugs, according to their pharmacokinetic properties, chemical structure and adverse effects. The adverse effects of antihistamines upon the central nervous system (CNS) depend upon their capacity to cross the blood-brain barrier (BBB) and bind to the central H1 receptors (RH1). This in turn depends on the lipophilicity of the drug molecule, its molecular weight (MW), and affinity for P-glycoprotein (P-gp) (CNS xenobiotic substances extractor protein). First generation antihistamines show scant affinity for P-gp, unlike the second generation molecules which are regarded as P-gp substrates. Histamine in the brain is implicated in many functions (waking-sleep cycle, attention, memory and learning, and the regulation of appetite), with numerous and complex interactions with different types of receptors in different brain areas. Bilastine is a new H1 antihistamine that proves to be effective in treating allergic rhinoconjunctivitis (seasonal and perennial) and urticaria. The imaging studies made, as well as the objective psychomotor tests and subjective assessment of drowsiness, indicate the absence of bilastine action upon the CNS. This fact, and the lack of interaction with benzodiazepines and alcohol, define bilastine as a clinically promising drug with a good safety profile as regards adverse effects upon the CNS.

H1-antihistamines are probably the most frequently used drugs in allergic diseases, with widely established efficacy, tolerance, and safety. We report a patient with urticaria due to ingestion of ebastine and fexofenadine. Skin prick tests, patch tests, and basophil activation tests with the implicated drugs and antihistamines from other families were negative. The oral challenges with the implicated antihistamines and other antihistamines tested were positive, but the patient tolerated an oral challenge with cetirizine. We present a patient with urticaria induced by different antihistamines in whom the diagnosis was established by oral challenge. The mechanism of sensitization remains unclear.

The incidence of obesity in the United States has reached epidemic proportions. Previous research has shown several medications exert noticeable effects on body-weight regulation. Histamine-1 (H1) receptor blockers commonly used to alleviate allergy symptoms are known to report weight gain as a possible side effect. Therefore, we investigated the association between prescription H1 antihistamine use and obesity in adults using data from the 2005-2006 National Health and Nutrition Examination Survey (NHANES). Adults taking prescription H1 antihistamines were matched by age and gender with controls and compared on the basis of body measurements, plasma glucose, insulin concentrations, and lipid levels. Prescription H1 antihistamine users had a significantly higher weight, waist circumference, and insulin concentration than matched controls. The odds ratio (OR) for being overweight was increased in prescription H1 antihistamine users. H1 antihistamine use may contribute to the increased prevalence of obesity and the metabolic syndrome in adults given these medications are also commonly used as over-the-counter remedies.

Obesity is a major health problem world-wide. Medical intervention is often needed to tackle this problem, and accordingly the need for developing more effective, safer and cheaper weight reducing drugs has become paramount in recent years. In the present study, the effects of lime (Citrus aurantifolia) essential oils in reducing body weight, individually and in co-administration with ketotifen, an antihistaminic drug that causes weight gain, has been investigated using a mouse model. During the 45 days experimental period, the mice that received ketotifen demonstrated an enhancement both in the amount of food intake and body weight compared with the control group. Groups treated with lime essential oil displayed a reduction in body weight and food consumption in mice, possibly through promoting anorexia which might have played a role in weight loss. Interestingly, co-administration of the lime essential oil and ketotifen caused significant suppression in gaining weight, as well as decreased body weights of mice. The data obtained in this study suggested that lime essential oil plays an important role in weight loss and could be useful in the treatment of drug-induced obesity and related diseases. The GC-MS analysis of the essential oils of C. aurantifolia was also performed and approximately 22 main components, with limonene (28.27%) being the principal one, were identified and quantified.

Over-the-counter (OTC) and prescription medication abuse has been rapidly increasing, yet publications on OTC abuse in adolescents are limited. We present a brief literature review and a novel report of antihistamine dependence emerging after admission in an adolescent, subsequently treated with naltrexone. This case highlights the need to take a thorough history of OTC, herbal, and prescription drug use from parents and patients separately and repeatedly, at initial presentation, and again if withdrawal symptoms emerge. General strategies for combating OTC and prescription abuse are given.

Antihistamines often are self-administered at night as over-the-counter (OTC) sleep aids, but their next-day residual sedative effect has never been evaluated using a reliable quantitative method such as positron emission tomography (PET). We performed a double-blind, placebo-controlled, crossover study in which we evaluated the residual effect the next day after nighttime administration of diphenhydramine, a commonly used OTC sleep aid, in terms of brain H₁ receptor occupancy (H₁RO) measured using ¹¹C-doxepin-PET. We also compared the results of diphenhydramine with those of bepotastine, a second-generation antihistamine. Eight healthy adult male subjects underwent PET measurement the morning (11:00) after random oral administration of diphenhydramine (50 mg), bepotastine (10 mg), or placebo the night before (23:00). Binding potential ratios and H₁ROs were calculated in different brain regions of interest such as the cingulate gyrus, frontotemporal cortex, and cerebellum. Subjective sleepiness and plasma drug concentration also were measured. Calculation of binding potential ratios revealed significantly lower values for diphenhydramine than for bepotastine or placebo in all regions of interest (P < 0.01). Cortical mean H₁RO after diphenhydramine treatment was 44.7% compared with 16.6% for bepotastine treatment (P < 0.01). Subjective sleepiness was not significantly different among the subjects treated with each test drug or the placebo. In conclusion, the next-day residual sedative effect after nighttime administration of the OTC sleep aid diphenhydramine was verified for the first time by direct PET measurement of H₁RO. Taking into account the possible hangover effect of OTC antihistamine sleep aids, care needs to be taken during their administration.

Background: Mast cell activation is thought to be involved in visceral hypersensitivity, one of the main characteristics of the irritable bowel syndrome (IBS). A study was therefore undertaken to investigate the effect of the mast cell stabiliser ketotifen on rectal sensitivity and symptoms in patients with IBS., Methods: 60 patients with IBS underwent a barostat study to assess rectal sensitivity before and after 8 weeks of treatment. After the initial barostat, patients were randomised to receive ketotifen or placebo. IBS symptoms and health-related quality of life were scored. In addition, mast cells were quantified and spontaneous release of tryptase and histamine was determined in rectal biopsies and compared with biopsies from 22 age- and gender-matched healthy volunteers., Results: Ketotifen but not placebo increased the threshold for discomfort in patients with IBS with visceral hypersensitivity. This effect was not observed in normosensitive patients with IBS. Ketotifen significantly decreased abdominal pain and other IBS symptoms and improved quality of life. The number of mast cells in rectal biopsies and spontaneous release of tryptase were lower in patients with IBS than in healthy volunteers. Spontaneous release of histamine was mostly undetectable but was slightly increased in patients with IBS compared with healthy volunteers. Histamine and tryptase release were not altered by ketotifen., Conclusions: This study shows that ketotifen increases the threshold for discomfort in patients with IBS with visceral hypersensitivity, reduces IBS symptoms and improves health-related quality of life. Whether this effect is secondary to the mast cell stabilising properties of ketotifen or H(1) receptor antagonism remains to be further investigated. Trial Registration Number NTR39, ISRCTN22504486.

Oral bepotastine is a second-generation histamine H(1) receptor antagonist that also suppresses some allergic inflammatory processes. Numerous short- and long-term clinical trials and surveillance studies have shown that twice-daily bepotastine is an effective and generally well tolerated antihistamine in the treatment of patients with allergic rhinitis, chronic urticaria or pruritus associated with skin conditions (eczema/dermatitis, prurigo or pruritus cutaneus). Bepotastine 20 mg/day was significantly more effective than terfenadine 120 mg/day in patients with perennial allergic rhinitis, as evaluated by the final global improvement rating and several other endpoints in a phase III trial. In phase III trials in patients with chronic urticaria, bepotastine 20 mg/day was more effective than placebo in improving levels of itching and eruption, and as effective as terfenadine 120 mg/day with regard to the final global improvement rating and other endpoints. In a noncomparative trial in patients with pruritus associated with skin diseases, the majority of bepotastine recipients in the overall population, as well as in the specific skin disease subgroups (eczema/dermatitis, prurigo or pruritus cutaneus), had a final global improvement rating of moderate or greater. Bepotastine was generally well tolerated in adult and paediatric patients with allergic conditions.

In epileptic patients cyproheptadine is frequently prescribed as an appetite stimulant for the treatment of anorexia associated with anti-epileptic drugs and for the management of 'serotonin syndrome' in depressed epileptic patients. However, the study of serotonergic and histaminergic pathway shows that the decreased neurotransmission of serotonin and histamine in the brain reduces seizures threshold. Since, cyproheptadine interferes with these pathways via antagonizing subtypes of 5-HT(1/2) receptors and H(1) receptor, therefore the present study was undertaken to investigate its effect on seizures threshold, so as to substantiate its use in epileptics. In the present study convulsions were induced in mice by, maximum electroshock (MES), picrotoxin, and pentylenetetrazol (PTZ). Cyproheptadine (4 mg/kg, i.p.) was administered per se and along with clinically used anti-epileptic drugs (phenytoin 25 mg/kg, i.p. and diazepam 5 mg/kg, i.p.) in different groups of mice, onset and extent of convulsions in these groups were compared with that of vehicle control and anti-epileptics per se treated groups. Percentage mortality in all groups was also determined. Results depicted a significant increase in duration of tonic hind limb extension in MES and decrease in latency to clonic convulsions induced by PTZ and picrotoxin in cyproheptadine treated groups (per se and along with anti-epileptics), as compared to vehicle control and anti-epileptics per se treated groups respectively. Percentage mortality was also increased with cyproheptadine treatment. Therefore it is concluded that cyproheptadine pretreatment reduces threshold, increases severity of seizures and decreases the efficacy of clinically used anti-epileptic drugs in experimental animal models of convulsions.

Background and Objectives: Cognitive impairment is common among persons with ESRD, but the underlying mechanisms are unknown. This study evaluated the prevalence of cognitive impairment and association with modifiable ESRD- and dialysis-associated factors in a large group of hemodialysis patients., Design, Setting, Participants, & Measurements: Cross-sectional analyses were conducted on baseline data collected from 383 subjects participating in the Frequent Hemodialysis Network trials. Global cognitive impairment was defined as a score <80 on the Modified Mini-Mental State Exam, and impaired executive function was defined as a score >or=300 seconds on the Trailmaking B test. Five main categories of explanatory variables were examined: urea clearance, nutritional markers, hemodynamic measures, anemia, and central nervous system (CNS)-active medications., Results: Subjects had a mean age of 51.6 +/- 13.3 years and a median ESRD vintage of 2.6 years. Sixty-one subjects (16%) had global cognitive impairment, and 110 subjects (29%) had impaired executive function. In addition to several nonmodifiable factors, the use of H1-receptor antagonists and opioids were associated with impaired executive function. No strong association was found between several other potentially modifiable factors associated with ESRD and dialysis therapy, such as urea clearance, proxies of dietary protein intake and other nutritional markers, hemodynamic measures, and anemia with global cognition and executive function after adjustment for case-mix factors., Conclusions: Cognitive impairment, especially impaired executive function, is common among hemodialysis patients, but with the exception of CNS-active medications, is not strongly associated with several ESRD- and dialysis-associated factors.

Adequate treatment is critical for maintaining a good level of quality of life (QOL) during the pollen season in patients suffering from seasonal allergic rhinitis (SAR). Olopatadine, a histamine H(1)-receptor antagonist, has been approved in the United States and Europe for the treatment of AR and allergic conjunctivitis as a nasal spray and an ophthalmic solution, respectively. We conducted a randomized, double-blind, placebo-controlled study to determine whether orally administered olopatadine for prophylactic purposes might also be effective for the control of nasal allergy symptoms, especially nasal congestion, in patients with SAR due to Japanese cedar pollen (SAR-JP). A total of 110 patients with SAR caused by JP were randomized to the treatment. The subjects recorded their nasal and ocular allergic symptom scores in a diary, and their QOL was assessed by the Japanese version of the Rhinoconjunctivity Quality of Life Questionnaire. Treatment with oral olopatadine significantly suppressed sneezing (p < 0.001), rhinorrhea (p < 0.001), and nasal congestion (p < 0.05). The total QOL score during the peak JP season was superior in the olopatadine group than in the placebo group (p < 0.05). However, orally administered olopatadine did not exert any significant effect against eye itching and watering of the eyes, unlike olopatadine nasal spray. Treatment with olopatadine tablets yielded superior QOL scores in the domains of usual daily activities and outdoor activities when compared with placebo. No serious adverse effects of the treatment were reported during the study period. These results suggest that oral olopatadine treatment may be a useful alternative treatment strategy for AR.

Chronic idiopathic urticaria (CIU) is a serious disorder that can greatly compromise quality of life. While H1 antihistamines are the accepted first-line treatment for CIU, older generations of these agents (e.g., hydroxyzine, diphenhydramine) are associated with anticholinergic and CNS effects, such as drowsiness and sedation, that can pose risks to patients, especially when driving. Second-generation agents available in the United States (U.S.) (e.g., cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine) has greatly reduced these CNS effects, making them the current treatments of choice in CIU, but their potency and tolerability profiles vary. Differences in duration of in vivo receptor occupancy may affect the potency of H1 antihistamines. Levocetirizine appears to have greater in vivo H1 receptor occupancy compared with later generation H1 antihistamines, which may confer an advantageous efficacy/safety profile. This has been confirmed in a recent head-to-head study showing that levocetirizine was more effective than desloratadine in improving pruritus in CIU patients. Fexofenadine has been shown to have a low occupancy of H1 antihistamine receptors in the brain, which reduces the likelihood of sedation. More studies are required to further assess receptor occupancy and other factors that may differentiate the second-generation H1 antihistamines.

Background: First-generation H(1)-antihistamines obtained without prescription are the most frequent form of self-medication for allergic diseases, coughs and colds and insomnia even though they have potentially dangerous unwanted effects which are not recognized by the general public., Aims: To increase consumer protection by bringing to the attention of regulatory authorities, physicians and the general public the potential dangers of the indiscriminate use first-generation H(1)-antihistamines purchased over-the counter in the absence of appropriate medical supervision., Methods: A GA(2)LEN (Global Allergy and Asthma European Network) task force assessed the unwanted side-effects and potential dangers of first-generation H1-antihistamines by reviewing the literature (Medline and Embase) and performing a media audit of US coverage from 1996 to 2008 of accidents and fatal adverse events in which these drugs were implicated., Results: First-generation H(1)-antihistamines, all of which are sedating, are generally regarded as safe by laypersons and healthcare professionals because of their long-standing use. However, they reduce rapid eye movement (REM)-sleep, impair learning and reduce work efficiency. They are implicated in civil aviation, motor vehicle and boating accidents, deaths as a result of accidental or intentional overdosing in infants and young children and suicide in teenagers and adults. Some exhibit cardiotoxicity in overdose., Conclusions: This review raises the issue of better consumer protection by recommending that older first-generation H(1)-antihistamines should no longer be available over-the-counter as prescription- free drugs for self-medication of allergic and other diseases now that newer second- generation nonsedating H(1)-antihistamines with superior risk/benefit ratios are widely available at competitive prices.

Suppression of left ventricular (LV) remodeling secondary to heart failure seems critical to improve the prognosis of hemodialysis (HD) patients. This is a retrospective study on the relationship of an antiallergic drug and antihistamines with LV hypertrophy. A total of 149 patients (88 males and 61 females) were entered in the study. Mean age was 66.7 years and mean duration of dialysis 14.4 years. Twenty-three patients received oral treatment with an antiallergic drug or second-generation antihistamines, 3 with the antiallergic drug and 20 with antihistamines. The multivariate analysis using LV mass index (LVMI) as the objective variable extracted the following independent factors: male sex, erythropoietin (EPO)/w, uric acid (UA), total cholesterol, antihistamines, antiallergic drug, and calcium channel blocker (CCB), with a standard regression coefficient of 0.187, 0.196, 0.212, -0.262, -0.215, -0.149 and -0.173, respectively. This study suggests a suppressive role of second-generation antihistamines on LV remodeling. Male sex, high-dose EPO/w, and elevated UA were considered as aggravating factors, and CCB as a suppressive factor.

The purpose of this study was to assess efficacy and safety of 3 doses (6.25 mg, 12.5 mg, 25 mg) of intravenous (IV) promethazine in treatment of established nausea and vomiting (N/V) in hospitalized elderly patients. Study participants aged > or =65 years received at least 1 dose of IV promethazine for treatment of N/V. Outcomes were degree of efficacy and safety. Efficacy was measured by time to relief and whether relief occurred. Safety was measured by the incidence of adverse drug reactions (ADRs). The results showed no difference in the time to relief and proportion of patients who felt relief between the 6.25-mg and 12.5-mg groups. The median frequency of ADRs in the 6.25-mg group, based on total administrations, was significantly less than the 12.5-mg group (P = .048). This study suggests a starting dose of 6.25 mg IV promethazine is as effective as higher doses and has fewer ADRs., (Copyright 2010 Mosby, Inc. All rights reserved.)

The histamine I receptor antagonist diphenhydramine is a freely available, over the counter medication for sleep and the most frequently used antihistamine drug. It inhibits the fast sodium channels and, at higher concentrations, the repolarising potassium channels, particularly Ikr which leads to prolongation of the action potential and the QT interval. The toxicity of diphenhydramine is dose-dependent, with a critical dose limit of 1.0 g. We report a case of a young woman who consumed more than 3 g of diphenhydramine in the setting of alcohol intoxication and developed QTc prolongation with nonsustained polymorphic ventricular tachycardia. These changes reverted to normal with supportive treatment. An overdose of diphenhydramine with concomitant alcohol use can induce torsade de pointes in an otherwise normal heart.

Histamine is the main mediator of urticaria and H1-receptor antagonists represent the treatment of choice in all patients with chronic urticaria. Leukotriene receptor antagonists as montelukast have also been used in patients with chronic urticaria unresponsive to H1-antihistamines alone. We report a patient with chronic urticaria whose disease was paradoxically exacerbated by H1-antihistamines and montelukast, and controlled by immunosuppressive drugs as ciclosporin and azathioprine. Urticaria exacerbations were caused by different molecules including either piperidine (fexofenadine, desloratadine, ebastine, rupatadine) or piperazine (hydroxyzine, cetirizine) derivatives as well as by montelukast suggesting that an IgE-mediated mechanism was not involved. A possible explanation of the observed urticaria exacerbation is that H1-antihistamines and montelukast may shift the H1 histamine receptor and the leukotriene receptor to the active conformation instead of the inactive state. The beneficial effects of ciclosporin and azathioprine confirm that immunosuppressive drugs have an important role in the treatment of refractory chronic urticaria and back the hypothesis that an autoimmune/autoreactive mechanism often underlies the disease.

Pediatric insomnia is common in children and adolescents, particularly in children who have comorbid medical, psychiatric, and neurodevelopmental disorders, and may be associated with cognitive, emotional, and psychosocial impairments that often result in significant caregiver burden. Although several behavioral interventions for pediatric insomnia are effective, there is a relative paucity of empiric evidence supporting the use of pharmacologic treatment. Sedative/hypnotic drugs are frequently used in clinical practice to treat pediatric insomnia, and guidelines for the use of these medications in general as well as for specific medications have been developed. This review presents expert consensus guidelines for the use of these medications in clinical practice, with a focus on the different classes of pharmacologic agents that are most commonly prescribed.

A case of anaphylaxis occurring during a general anesthesia is presented. The reaction was severe with bronchospasm and hypotension (grade 2 in the severity of per-operative anaphylactic shock). The responsibility of hydroxyzine, administered for premedication was suspected by intradermal testing with the molecule, which was twice positive at a 10(-2) dilution of the commercial solution. The same test remained negative in 5 control subjects. All the other drugs received during anesthesia gave negative results. Using the same protocol excepted for the use of hydroxyzine a new general anesthesia could be performed under a premedication with dexchlorpheniramine without any allergic reaction. Anaphylactic reactions are very rare with hydroxyzine used in premedication for anesthesia in regard to the large prescription of the drug. Only two previous cases were reported but attention of the allergist must be also pointed towards the medications received in the perioperative period as for the anesthetic drugs.

In dermographic urticaria (DU), shearing forces on the skin result in weals and itching. Second-generation antihistamines are recommended as the first-line treatment, but to date only a few have ever been tested for this condition. The objective of this pilot study was to assess the safety and efficacy of ebastine in preventing symptoms of DU. Seven adult patients with DU participated in a double-blind cross-over trial of ebastine 20 mg. Safety was assessed using a sensitive psychometric battery, testing cognitive performance and mood. Efficacy was assessed by rating weals, erythema, pruritus and burning after challenge. Ebastine had no negative effective on cognitive performance or mood. Weals, pruritus and burning were greatly reduced for most subjects. This pilot study suggests that ebastine is safe and effective in preventing the symptoms of DU and should be tested on a larger scale.

Drugs used in anaesthesia may provoke torsadogenic changes in cardiac repolarisation. The aim of this study was to assess the effect of promethazine on the parameters of ventricular repolarisation: QTc interval and transmural dispersion of repolarisation. Forty patients were randomly allocated to receive promethazine (25 mg) or midazolam (2.5 mg). Changes in the ECG and arterial blood pressure were recorded. Correction of QT interval was calculated using Bazett's formula and Fridericia's correction; transmural dispersion of repolarisation was determined as T(peak)-T(end) time. Significant prolongation of QT interval, corrected with both formulae, was detected in patients receiving promethazine, while no change in the QTc value was observed in the midazolam group. There were no significant differences in T(peak)-T(end) time either between or within the groups. In conclusion, promethazine induces significant QTc prolongation but the lack of influence on transmural dispersion of repolarisation makes the risk of its torsadogenic action very low.

Objective: To review the pharmacoeconomic literature evaluating use of antihistamines in treating allergic rhinitis (AR) in the US., Methods: Three independent reviewers conducted a comprehensive search of the current literature with PubMed. They identified articles describing original research comprising US cost analyses or pharmacoeconomic evaluations that reported both costs and consequences of using second-generation anthistamines (SGAs), first-generation antihistamines (FGAs), or both for the treatment of patients with AR. The search was limited to studies performed in humans and published in English between 1998 and 2008., Results: Five of 200 articles met the inclusion criteria and examined costs associated primarily with chlorpheniramine, diphenhydramine, cetirizine, and fexofenadine. The first two studies retrospectively analyzed a claims database and concluded that fexofenadine was associated with slightly lower overall costs than loratadine and cetirizine. A third study compared total healthcare costs associated with FGAs and SGAs, concluding that despite their higher prescription cost, SGAs result in lower medical resource use and lower cost for treatment of AR versus FGAs, although no individual SGA could be distinguished as providing substantial healthcare cost savings or increased cost-effectiveness over the other SGAs. Two studies investigated the impact of transitioning a prescription SGA to over-the-counter status and concluded that such a transition would provide cost savings to healthcare plans, but did not address the cost or health effect of such a switch on specific populations whose plans might no longer cover prescription SGAs., Conclusions: Preliminary evidence suggests that newer SGAs offer clinical, pharmacodynamic, and pharmacokinetic advantages that may translate into superior cost-effectiveness in the treatment of AR. Further study is warranted to clarify the pharmacoeconomic impact of the newer SGAs and to establish their relative cost-effectiveness.

We searched the Spanish and Portuguese pharmacovigilance databases for spontaneous case reports of heart rhythm disturbances associated with rupatadine and other new H1 antihistamines. Five cases were found involving patients treated with rupatadine (13.9% of all reports relating to this drug). In all five cases, the reaction started after exposure and resolved when the drug was discontinued. In two cases, rupatadine was the only medication being taken by the patient, and no other condition that could explain the heart rhythm disturbances was diagnosed. The reporting odds ratio was 3.2 (95% confidence interval, 1.0-10.5). The reporting rate was 2 cases per 100,000 patients treated per year (95% confidence interval, 0.4-6.0). These results suggest a causal relationship between rupatadine and heart rhythm disturbances.

Background and Purpose: Centrally active antihistamines impair cognitive performance, particularly sensorimotor performance. The aim of the present study was to further elucidate the scarcely studied subprocesses involved in sensorimotor performance, which may be affected by H1 receptor blockade. Better knowledge about the cognitive deficits associated with histamine dysfunction can contribute to better treatment of clinical disorders in which histamine hypofunction may be a contributing factor, such as in schizophrenia., Experimental Approach: Interactions of dexchlorpheniramine with specific task manipulations in a choice reaction time task were studied. Task demands were increased at the level of sensory subprocesses by decreasing stimulus quality, and at the level of motor subprocesses by increasing response complexity. A total of 18 healthy volunteers (9 female) aged between 18 and 45 years participated in a three-way, double-blind, crossover design. Treatments were single oral doses of 4 mg dexchlorpheniramine, 1 mg lorazepam and placebo. Behavioural effects were assessed by measuring reaction times and effects on brain activity by event-related potentials., Key Results: Dexchlorpheniramine significantly slowed reaction times, but did not significantly interact with task manipulations. However, it did significantly interact with stimulus quality, as measured by event-related potentials. Lorazepam slowed reaction times and interacted with perceptual manipulations, as shown by effects on reaction times., Conclusions and Implications: The results confirm that the histamine system is involved in sensory information processing and show that H1 blockade does not affect motoric information processing. Histamine hypofunction in clinical disorders may cause impaired sensory processing, which may be a drug target.

H(1)-antihistamines are widely used in the treatment of various allergic diseases. Particularly, a cornerstone of the management of chronic idiopathic urticaria is treatment with H(1)-antihistamines. However, a few cases of H(1)-antihistamine-induced urticaria have been reported. A 34-year-old woman presented with a 4-month history of recurrent urticaria, which was prominently exacerbated by the administration of H(1)-antihistamines. The patient consented to a provocation test of fexofenadine among drugs including cetirizine and hydroxyzine, which were suspected of inducing severe symptoms in episodes. One hour after challenge with 12 mg fexofenadine (one-fifth of the therapeutic dose), a urticarial reaction rapidly developed on nearly the entire body with remarkably increased levels of plasma histamine (190 nmol/L) and plasma leukotriene B4 (150 pg/mL). In challenge tests with other antihistamines, generalized urticaria occurred 5 and 1 h after intake of 10 mg loratadine and 10 mg bepotastine, respectively, whereas challenges with chlorpheniramine, mequitazine and azelastine were all negative. Skin prick tests with H(1)-antihistamines used in the challenges were all negative, indicating that the urticarial reactions after challenges with the causative drugs might not be immunoglobulin E-mediated. Among the causative drugs in our case, cetirizine and hydroxyzine are the piperazine derivatives, whereas fexofenadine, bepotastine, ebastine and loratadine are the piperidine derivatives. The chemical structures of both derivatives are very similar. Therefore, in this case, H(1)-antihistamine-induced urticaria may have been due to cross-reactivity between metabolites of these drugs, but not to drugs before metabolization. Hypersensitivity to H(1)-antihistamines should be considered when urticarial lesions worsen after H(1)-antihistamine treatment.

Doxepin is a tricyclic antidepressant with a subnanomolar affinity for the histamine H(1) (H(1)) receptor. It has a long history of use for depression at doses higher than those needed for antagonism of H(1) receptors. Recent work has focused on its use at low doses (1, 3 and 6 mg) in patients with chronic primary insomnia. Two phase II studies and four phase III studies have investigated its efficacy on both objective and subjective sleep measures in both adults and elderly patients. It was effective on a variety of sleep onset, maintenance and early awakening outcomes and had minimal effects on sleep architecture. There was no signal for tolerance, psychomotor impairment, residual sedation, rebound insomnia or discontinuation symptoms in trials of up to 3 months duration. Doxepin was well tolerated; sedation/sleepiness and headache were the most common adverse events but these were mainly at placebo level or less. Further work is required to establish doxepin's low-dose effect on hypnotic activity., (Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.)

A series of novel 4-(3-ethylphenyl)-1-substituted-4H-[1,2,4] triazolo[4,3-a]quinazolin-5-ones (4a-j) were synthesized by the cyclization of 3-(3-ethylphenyl)-2-hydrazino-3H-quinazolin-4-one (3) with various one-carbon donors. The starting material, compound 3, was synthesized from 3-ethyl aniline by a new innovative route with improved yield. When tested for their in vivo H1-antihistaminic activity on conscious guinea pigs, all test compounds protected the animals from histamine induced bronchospasm significantly. Compound 4-(3-ethylphenyl)-1-methyl-4H - [1,2,4]triazolo[4,3-a]quinazolin-5-one (4b) emerged as the most active compound of the series and it is more potent (74.6 % protection) compared to the reference standard chlorpheniramine maleate (71 % protection). Compound 4b shows negligible sedation (10 %) compared to chlorpheniramine maleate (30 %). Therefore compound 4b can serve as the leading compound for further development of a new class of H1-antihistamines.

Background: Various trials showed benefit of the prophylactic agent ketotifen in prevention of recurrent wheezing in young children, but no such clinical trial with loratadine or comparison trial is available., Objective: To study the efficacy and safety of loratadine syrup compared with ketotifen and placebo in prevention of recurrent wheezing in young children., Material and Method: Randomized double-blind placebo controlled trial on 90 recurrent wheezing children aged less than 6 years old was done. Children were randomized to receive loratadine, ketotifen syrup, or placebo with dose of 0.25 cc/kg once a day for four months. Blood biochemistry (CBC, LFT) and EKG were performed pre and post treatment period. Assessment of symptoms--wheezing and night cough including use of bronchodilators was done daily via patient diary card. Subjects were asked to do monthly visits to the clinic for physical examination. At those visits, the doctors questioned the patients about adverse event., Result: Of the 90 children enrolled, 12 dropped out. Thus, 27 children remained in the loratadine, 26 in the placebo, and 25 in the ketotifen group. The demographic data were comparable among the three treatment groups. It was noted that wheezing decreased significantly at 2 months in the ketotifen (p = 0.008) and at 3 months in the loratadine (p = 0.029) but not in the placebo group. Coughing at night decreased significantly at 3 months in both the loratadine (p = 0.005) and the ketotifen (p = 0.036) group. The use of bronchodilator drug was significantly decreased at 2 months in the ketotifen (p = 0.028) and placebo (p = 0.025) group, and at 3 months in the loratadine (p = 0.009) group. Only a few patients had mild adverse events in all groups., Conclusion: Loratadine and ketotifen are safe and effective significantly in prevention of recurrent wheezing in young children.

Background: Rupatadine (Rupafin), a novel antihistamine approved recently in Europe for the treatment of allergic rhinitis (AR) and chronic idiopathic urticaria in patients aged>or=12 years, has been shown to be highly efficacious, and as safe and well tolerated as other commonly employed antihistamines in the treatment of allergic disease. There are, however, few data on the long-term safety of these antihistamines derived in accordance with the clinical safety recommendations of the European Agency for the Evaluation of Medicinal Products (EMEA) and the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use Guideline., Objective: To assess the safety and tolerability of treatment with rupatadine 10 mg/day for 12 months in subjects with persistent AR (PER)., Methods: A multicentre, open-label, phase IV study in patients recruited from 33 centres in Spain, from September 2002 to November 2005. The study enrolled 324 male and female patients (aged 12-70 years) with a medical history of PER for at least 12 months and a documented positive skin-prick test to an appropriate allergen. On 4 of the 7 days prior to start of treatment, the patients were required to have a minimum total nasal symptom score (TNSS [for sneezing, rhinorrhoea, nasal obstruction/congestion and nasal itching]) of >or=5. Of the 324 eligible patients starting treatment, 120 needed to be treated for more than 6 months and were followed up until the end of 12 months. All patients received rupatadine 10 mg/day and were allowed to continue their normal concomitant medication for all conditions, other than rhinitis, for up to 6 or 12 months. Safety was assessed by means of adverse events (AEs) reported by patients or detected by investigators, scheduled centralized ECG with special attention to Bazzet corrected QT interval (QTcB) and standard laboratory investigations., Results: Assessment of treatment compliance rates indicated 90% and 83% of patients to be compliant during the 1-6 months and 1-12 months treatment periods, respectively, with compliance rates>80% being associated with the majority of the study population reporting at least one AE. Overall, 74.1% and 65.8% of the patients reported at least one AE during the 1-6 months and 1-12 months treatment periods, respectively, compared with 20.4% and 10.8% of patients reporting at least one treatment-related AE during these periods. Disorders of the nervous system and respiratory thoracic and mediastinal system, in particular headache, somnolence and catarrh, were the three most common AEs reported by >5% of the patients during both treatment periods. Detailed ECG assessments demonstrated no clinically relevant abnormal ECG findings, nor any QTcB increases >60 msec or QTcB values>470 msec for any patient at any time during treatment. Serious AEs were reported in seven patients, of whom six were considered as unlikely to be related to rupatadine treatment, whereas one involving increased blood enzyme levels was considered as possibly related to rupatadine treatment., Conclusion: This study confirmed the good long-term safety and tolerability of rupatadine at the therapeutic dose of 10 mg/day in patients with PER.

Background: Desloratadine is a non-sedating, long-acting histamine H(1) receptor antagonist indicated for the symptomatic relief of allergic rhinitis (AR) and chronic idiopathic urticaria in patients aged>12 years., Objective: To monitor the safety of desloratadine as prescribed in England, using the observational cohort technique of prescription event monitoring (PEM)., Methods: Exposure data were derived from dispensed prescriptions written by primary care physicians (general practitioners [GPs]) for desloratadine (March-May 2001); patient demographics, indication, pattern of use and outcome (event) data were obtained via simple questionnaires returned by GPs. Incidence density observation rates (IDobs) were calculated to compare the difference in event rates between months 1 and 2 (m1/m2) and were compared for the whole cohort and by groups defined by indication and pattern of use., Results: The cohort comprised 11 828 patients (median age 37 years [interquartile range 22, 54]; 59.9% were female). The most frequent indication was AR (n=8001; 67.6%). After 2 months, 36.8% (n=2464) of patients were still taking desloratadine. 'Condition improved' was the most common event and reason for stopping. Headache/migraine was uncommon but associated with starting treatment (IDobs(m1/m2) ratio 3.99 [95% CI 1.70, 10.83]). Cardiovascular events occurred rarely or very rarely, as did central and peripheral nervous system events. No serious adverse drug reactions (ADRs) were reported. Events related to effectiveness were more frequent in month 1 than month 2 for all patient subgroups., Conclusions: This postmarketing surveillance study shows that desloratadine is well tolerated when used in general practice in England. No previously unrecognized ADRs were detected. This study highlights how modifications to PEM are contributing to the evaluation of drug utilization factors in relation to risks.

Like any other drugs, antiallergic medications can be associated with large inter- and intraindividual variability in their disposition. The best-documented examples belong to the H1 antihistamines. Variable drugs are more likely to show unpredictable therapeutic response with both increased risks of side effects and subtherapeutic dosing in individual subjects. This article will review the main factors contributing to intervariability in pharmacokinetics with a special emphasis on gender differences, genetic polymorphism, and food habits.

A series of 1-substituted-4-(3-methoxyphenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones were synthesized by the cyclization of 2-hydrazino-3-(3-methoxyphenyl)-3H-quinazolin-4-one with various electrophile. The starting material 2-hydrazino-3-(3-methoxyphenyl)-3H-quinazolin-4-one was synthesized from 3-methoxy aniline by an innovative route. Title compounds were tested for their in vivo H1-antihistaminic activity on guinea pigs; all the tested compounds protected the animals from histamine induced bronchospasm significantly. Compound 1-methyl-4-(3-methoxyphenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (II) emerged as the most active compound of the series and was more potent (72.76%) than the reference standard chlorpheniramine maleate (71%). Compound II showed negligible sedation (10%) when compared to chlorpheniramine maleate (25%). Hence it could serve as prototype molecule for further development as a new class of H1-antihistaminic agents.

Fluticasone furoate nasal spray (FFNS) is a novel, enhanced-affinity glucocorticoid administered in a unique side-actuated device for the treatment of allergic rhinitis. No previous clinical studies have compared the efficacy of FFNS with another intranasal steroid. The purpose of this study was to compare the efficacy and safety of FFNS, 110 microg/day, once daily with fluticasone propionate nasal spray (FPNS), 200 microg/day, twice daily in patients with Japanese cedar pollinosis to support the regulatory filing in Japan. In this multicenter, randomized, placebo-controlled, double-blind, parallel-group study, patients (>or=16 years old) were randomized to receive 2 weeks of treatment with FFNS (n = 151), FFNS placebo (n = 72), FPNS (n = 148), or FPNS placebo (n = 75). FFNS once daily was noninferior to FPNS twice daily in mean change from baseline in three total nasal symptom scores (3TNSS; sneezing, rhinorrhea, and nasal congestion; -1.23 +/- 0.140 and -1.06 +/- 0.142, respectively). Compared with placebo, FFNS was superior in reducing 3TNSS (p < 0.001). Both FFNS and FPNS showed similar mean changes from baseline in 4TNSS (3TNSS and nasal itching) and individual nasal symptom scores. The onset of action for FFNS was observed from the 1st day of treatment, whereas in the FPNS group it was observed on the 2nd day. There were similar improvements in rhinoscopy findings, activity of daily life interference, and patient-rated overall evaluation to therapy in the FFNS and FPNS groups. FFNS was well tolerated. Treatment with once-daily FFNS was effective and noninferior to twice-daily FPNS in reducing nasal symptoms. Faster onset of action for FFNS was observed.

Peripheral anti-H1 and central nervous system (CNS) activities after single (day 1) and repeated (day 7) administrations of increasing doses of bilastine (BIL) were assessed in 20 healthy volunteers throughout a crossover, randomized, double-blind, placebo (PLA)-controlled study. Repeated doses of BIL 20, 40, or 80 mg and hydroxyzine 25 mg (HYD) as positive standard were administered on 7 consecutive days. Before and at several time points after drug intake, skin reactivity to the intradermal injection of histamine, objective tests of psychomotor performance, and subjective mood scales were evaluated. All active treatments led to a significant and similar reduction in the wheal reaction in relation to PLA after both the single (P < 0.001) and repeated administrations (P < 0.001). No delay was observed in the onset of its peripheral activity after the first dose of BIL as compared with HYD. No tolerance or sensitization was seen when comparing acute and repetitive assessments. Central nervous system effects showed that HYD induced the greatest psychomotor impairment (P < 0.05). Repeated HYD intake showed a lower number of significant alterations in comparison to acute administration. Bilastine 80 mg also showed some impairment (P < 0.05). Subjectively, the only active treatment that could not be differentiated from PLA was BIL 20 mg. Hydroxyzine 25 mg showed the greatest differentiation (P < 0.01). A clear dissociation between peripheral anti-H1 and CNS activity was found after BIL treatment. Significant and sustained peripheral H1-blocking effects were observed after both single and repeated administrations of the therapeutic dose of 20 mg BIL. The 40-mg dose of BIL produced subjective report of sedation, whereas unwanted objective CNS side effects were observed only with the 80-mg dose.

Numerous "antihistamines" as well as various psychotropic medications with antihistamine properties are widely utilized to treat insomnia. Over-the-counter sleep aids usually contain an antihistamine and various antidepressants and antipsychotics with antihistamine properties have sedative-hypnotic actions. Although widely used for the treatment of insomnia, many agents that block the histamine H1 receptor are also widely considered to have therapeutic limitations, including the development of next-day carryover sedation, as well as problems with chronic use, such as the development of tolerance to sedative-hypnotic actions and weight gain. Although these clinical actions are classically attributed to blockade of the H1 receptor, recent findings with H1 selective agents and H1 selective dosing of older agents are challenging these notions and suggest that some of the clinical limitations of current H1-blocking agents at their currently utilized doses could be attributable to other properties of these drugs, especially to their simultaneous actions on muscarinic, cholinergic, and adrenergic receptors. Selective H1 antagonism is emerging as a novel approach to the treatment of insomnia, without tolerance, weight gain, or the need for the restrictive prescription scheduling required of other hypnotics.

QT prolongation, a risk factor for arrhythmias, can result from genetic variants in one (or more) of the genes governing cardiac repolarization as well as intake of drugs known to affect a cardiac K(+) channel encoded by human ether-a-go-go-related gene (HERG). In this paper, we will report a case of drug-induced long QT syndrome associated with an H(1)-receptor antagonist, hydroxyzine, in which a mutation was identified in the HERG gene. After taking 75 mg of hydroxyzine for several days, a 34-year-old female began to experience repetitive syncope. The deleterious effect of hydroxyzine was suspected because QTc interval shortened from 630 to 464 ms after cessation of the drug. Later on, the patient was found to harbor an A614V-HERG mutation. By using the patch-clamp technique in the heterologous expression system, we examined the functional outcome of the A614V mutation and confirmed a dominant-negative effect on HERG expression. Hydroxyzine concentration-dependently inhibited both wild-type (WT) and WT/A614V-HERG K(+) currents. Half-maximum block concentrations of WT and WT/A614V-HERG K(+) currents were 0.62 and 0.52 microM, respectively. Thus, accidental combination of genetic mutation and intake of hydroxyzine appeared to have led to a severe phenotype, probably, syncope due to torsade de pointes.

Background: Activation of the serotonergic system is an important factor in the pathogenesis of intrathecal morphine-induced pruritus. Mirtazapine is a new antidepressant that selectively blocks 5-HT(2) and 5-HT(3) receptors. We therefore tested the hypothesis that preoperative mirtazapine would reduce the incidence of intrathecal morphine-induced pruritus., Methods: One hundred and ten ASA I patients undergoing lower limb surgery under spinal anaesthesia were randomly allocated into two equal groups and received either mirtazapine 30 mg or an orally disintegrating placebo tablet 1 h before operation in a prospective, double-blinded trial. All patients received an intrathecal injection of 15 mg of 0.5% isobaric bupivacaine and 0.2 mg preservative-free morphine. The occurrence and the severity of pruritus were assessed at 3, 6, 9, 12, and 24 h after intrathecal morphine., Results: Pruritus was significantly more frequent in the placebo group compared with the mirtazapine group (75% vs 52%, respectively; P=0.0245). The time to onset of pruritus in the two groups was also significantly different. The patients who experienced pruritus in the placebo group had a faster onset time than that in the mirtazapine group [mean (sd): 3.2 (0.8) vs 7.2 (4.1) h, P<0.0001]., Conclusions: Mirtazapine premedication prevents pruritus induced by intrathecal morphine in patients undergoing lower limb surgery with spinal anaesthesia.

(1) Most sleep complaints involve difficulties in getting to sleep or staying asleep, or not feeling refreshed on awakening. Misconceptions and worrying over the lack of sleep and its consequences can contribute to reinforcing these disorders; (2) How can patients who complain of poor-quality sleep be helped, without resorting to treatments that can have adverse effects? To answer this question, we conducted a systematic review of the literature based on the standard Prescrire procedure; (3) One effective approach is to explain the basic physiology of sleep, to discuss misconceptions, and to adopt a strategy of "stimulus control". This method has a similar efficacy to prescribing a benzodiazepine. and the effect is longer lasting; (4) Moderate, regular physical exercise, especially in the morning, seems to help some patients, but the evidence is weak; (5) Some clinical trials of phytotherapy have shown a positive risk-benefit balance of weak aqueous or hydroalcoholic valerian extracts. Efficacy is limited, however; (6) A meta-analysis of placebo-controlled trials showed that benzodiazepines and related drugs increase the duration of sleep and help patients to fall asleep sooner. However, none of these trials provides comparative data spanning periods of more than two weeks. Efficacy is uncertain in the longer term, as patients quickly develop a tolerance to the hypnotic effects of benzodiazepines; (7) The adverse effects of benzodiazepines include frequent memory disorders, daytime drowsiness, falls, fractures and road accidents, and a withdrawal syndrome after treatment cessation. Related drugs such as zolpidem and zopiclone provoke similar adverse effects; (8) Sedative antihistamines have not been as well-evaluated as benzodiazepines in this setting. Small comparative trials of doxylamine and diphenhydramine showed no major difference in efficacy versus benzodiazepines and related drugs. The main adverse effects of sedative antihistamines are daytime drowsiness and altered vigilance, and atropinic effects; (9) Case-control studies showed a statistical link between benzodiazepine use in early pregnancy and birth defects such as cleft lip. In contrast, data on the use of doxylamine during pregnancy are reassuring; (10) Other sedative psychotropics have not been adequately tested in this setting or have been shown to have a negative risk-benefit balance; (11) In practice, patients who complain of poor-quality sleep should be given appropriate information on the mechanisms of normal sleep and related misconceptions, on the best methods for getting to sleep, and on the dangers of sedative psychotropics (dependence, withdrawal syndrome). When prescribing or dispensing a benzodiazepine to a woman of child-bearing age, the risk of birth defects, although not clearly demonstrated, must be mentioned.

Background: H(1) antihistamines are widely used as therapeutics for allergic diseases. Sedation is a well-known side effect of H(1) antihistamines and sometimes it is life-threatening for patients. Thus it is important to evaluate the sedative properties of H(1) antihistamines to avoid side effects. For this purpose, histamine H(1) receptor (H1R) occupancy and proportional impairment ratios (PIR) are now being used. However, it is not easy to obtain these parameters. Here, we sought to evaluate the sedative properties of H(1) antihistamines by means of a large-scale surveillance at health insurance pharmacies., Methods: The survey was conducted at 37 health insurance pharmacies. The therapeutic efficacy and the degree of sleepiness were quantified through a questionnaire using the visual analog scale (VAS) directly from 1742 patients who received H(1) antihistamines., Results: The degree of sleepiness caused by the first-generation antihistamines was significantly higher than that of the second-generation antihistamines. The high VAS score in case of efficacy was found in d-chlorpheniramine, olopatadine, and ebastine. Among the mean values of efficacy, all second-generation antihistamines except for loratadine, bepotastine, and mequitazine were significantly higher than that of clemastine. Regarding the degree of sleepiness, clemastine scored the highest VAS score, and significantly lower scores were obtained in all second-generation antihistamines., Conclusions: The sedative properties of the H(1) antihistamines obtained from VAS analysis were very similar to those of H1R occupancy from positron emission tomography (PET) studies and PIR from meta-analysis. Our results indicate that large-scale surveillance using VAS might be useful to evaluate the profiles of H(1) antihistamines.