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PubMed1978

Correlation between plasma diphenhydramine level and sedative and antihistamine effects.

The sedative and antihistamine effects of diphenhydramine were assessed in relation to plasma concentration after placebo, diphenhydramine 50 mg intravenously, and diphenhydramine 50 mg orally to each of 6 healthy volunteers on three separate occasions. Diphenhydramine plasma elimination t1/2 was 3.0 to 4.3 hr, volume of distribution was 188 to 336 L, and clearance was 637 to 1,014 ml/min. Systemic bioavailability of the oral preparation ranged from 0.26 to 0.60. The sedative effect of intravenous diphenhydramine differed from that of placebo only during the first 3 hr. Antihistamine effect, as measured by reduction of histamine provoked skin wheal diameter, was significantly different from that of placebo for at least 8 hr. There was a positive correlation between plasma diphenhydramine level and sedative and antihistamine effects, but wide variation in the extent and rate of change of these effects were observed between the subject. There appears to be a concentration range of 25 to 50 ng/ml, within which there is significant antihistamine effect without significant sedation.

Administration, Oral↗

PubMed2005

Biopharmaceutical considerations on antihistamine effects of topically administered emedastine.

Antihistamine effects of emedastine applied topically with three vehicles varying in their polarities were investigated in rats. The pharmacological effect of emedastine differed greatly depending on its concentration, treatment time, and vehicle. The antihistamine effect reached a plateau after approximately 2 h of exposure, and the potency of emedastine decreased in the following order by vehicle: isopropyl myristate >geraniol >glycerin. Using a two-layer diffusion model and penetration parameters reported previously (Harada et al., Biol Pharm Bull 23:1224-1228, 2000), transdermal fluxes of emedastine at each time point were calculated. When antihistamine effect of emedastine was plotted against calculated in vitro transdermal flux, not concentration applied, their relationship was sigmoidal and common regardless of the vehicles used. In conclusion, the antihistamine effect of emedastine applied topically varied greatly depending on vehicle, fundamentally due to the difference in skin permeability. The transdermal flux of the drug appears to be a good measure of its pharmacological effect.

Administration, Topical↗

PubMed2006

Simultaneous determination of ten antihistamine drugs in human plasma using pipette tip solid-phase extraction and gas chromatography/mass spectrometry.

Ten antihistamine drugs, diphenhydramine, orphenadrine, chlorpheniramine, diphenylpyraline, triprolidine, promethazine, homochlorcyclizine, cyproheptadine, cloperastine and clemastine, have been found to be extractable from human plasma samples using MonoTip C18 tips, inside which C18- bonded monolithic silica gel was fixed. Human plasma (0.1 mL) containing the ten antihistamines was mixed with 0.4 mL of distilled water and 25 microL of a 1 M potassium phosphate buffer (pH 8.0). After centrifugation of the mixture, the supernatant fraction was extracted to the C18 phase of the tip by 25 repeated aspirating/dispensing cycles using a manual micropipettor. The analytes retained on the C18 phase were then eluted with methanol by five repeated aspirating/dispensing cycles. The eluate was injected into a gas chromatography (GC) injector without evaporation and reconstitution steps, and was detected by a mass spectrometer with selected ion monitoring in the positive-ion electron impact mode. The separation of the ten drugs from each other and from impurities was generally satisfactory using a DB-1MS column (30 m x 0.32 mm i.d., film thickness 0.25 microm). The recoveries of the ten antihistamines spiked into plasma were 73.8-105%. The regression equations for the ten antihistamines showed excellent linearity with detection limits of 0.02-5.0 ng/0.1 mL. The within-day and day-to-day coefficients of variation for plasma were not greater than 9.9%. The data obtained from determination of diphenhydramine and chlorpheniramine in human plasma after oral administration of the drugs are also presented.

Administration, Oral↗

PubMed1983

Clinical investigations into antidepressive mechanisms. I. Antihistaminic and cholinolytic effects: amitriptyline versus promethazine.

It is assumed that established antidepressants exert their clinical efficacy by potentiation or decrease of central noradrenergic and serotonergic neurotransmission. However, recent experimental work suggests that antihistaminic and/or cholinolytic effects may also be involved. This double-blind controlled study compared amitriptyline (catecholamine potentiating, antihistaminic, cholinolytic) with promethazine (antihistaminic, cholinolytic) in 50 severely depressed inpatients over a 30-day treatment period. Analysis of the Hamilton depression rating scale revealed significant clinical superiority of amitriptyline over promethazine in such major depressive symptoms as depressed mood, suicidal ideation, psychic anxiety, and sleep disturbances. No significant difference was evident as far as autonomous side effects were concerned. Similar results were found by analysis of the AMP rating system. It is concluded that antihistaminic or cholinolytic effects per se do not explain the antidepressants' efficacy. However, potentiation of noradrenergic neurotransmission by cholinolytic activity might be the major antidepressive mechanism.

Adult↗

PubMed1990

Effects of antihistaminics on naloxone-induced withdrawal in morphine-dependent mice.

Some histamine H1 (tripelennamine, diphenhydramine and cyclizine) and H2 (ranitidine and cimetidine) antagonists (1 and 10 mg/kg) were administered to morphine-dependent mice to evaluate the changes on naloxone-induced abstinence syndrome. When antihistaminics were administered 30 min before naloxone (1 mg/kg) on day 4 of morphine addiction, the two doses of three H1 antagonists and the higher dose of ranitidine inhibited shaking behavior. Furthermore, the two doses of tripelennamine and the higher dose of diphenhydramine, cyclizine and cimetidine enhanced jumping behavior. When antihistaminics were administered chronically (during the 4 days of morphine addiction), tripelennamine, cyclizine and ranitidine (all at 10 mg/kg) inhibited shaking behavior. The three H1 antihistaminics used enhanced the number of jumps per mouse whereas ranitidine decreased this response. No significant changes were found in the rest of the withdrawal symptoms after the antihistaminics were administered. The participation of serotonergic and catecholaminergic mechanisms is discussed.

Animals↗

PubMed2005

Antihistamine effects of triprolidine from the transdermal administration of the TPX matrix in rats.

The antihistamine effects of the triprolidine were studied in rats to determine the feasibility of their enhanced transdermal delivery from the poly (4-methyl-1-pentene) (TPX) matrix system containing penetration enhancer and plasticizer. The antihistamine effects were determined by the Evans blue dye procedure by comparing the changes in vascular permeability increase following the transdermal administration. The vascular permeability increase was significantly reduced by transdermal administration of the triprolidine-TPX system containing triethyl citrate (TEC) and polyoxyethylene-2-oleyl ether (POE). Both the plasticizer and penetration enhancer played an important role in the skin permeation of triprolidine and increased the antihistamine effects. These results showed that the triprolidine-TPX matrix system containing plasticizer and penetration enhancer could be a transdermal delivery system providing the increased antihistamine effects.

Administration, Cutaneous↗

PubMed1998

[Acoustic rhinometry for evaluating the effectiveness of antihistaminics].

Acoustic rhinometry is a unique non-invasive technique for imaging and measuring the free cross-sectional area of the main nasal cavity. By so doing, reactions of the mucosa can be assessed at any selected site in the nose. The goal of this study was to define the optimal conditions for the utilization of acoustic rhinometry to determine the ability of an antihistamine to alter the effects of histamine in the mucous membrane of the nose. In a group of 30 healthy volunteers subjectively normal nasal breathing, and no history of allergy, rhinometry was performed to measure the cross-sectional area in the region of the head of the inferior nasal concha at 0.5, 10 and 15 min after histamine provocation. The volunteers subsequently received cetirizine as antihistamine. Four hours later, rhinometry was repeated after administration of histamine via the contralateral nostril. Findings showed that conchal dilatation measured 10 min after provocation was statistically less severe in 63.3% of the patients treated with cetirizine. Compared to pretreatment values, the ventilated cross-sectional area became 45.6% larger after administration antihistamine. These findings demonstrated that the nasal swelling measured 10 min after antihistamine administration was due to the effects of histamine and was not due to tactile or physical stimuli. The present studies showed that the new measurement technique is precise and reproducible. These results have also demonstrated that a acoustic rhinometry permits an objective assessment of drug efficacy while making it possible to avoid the errors observed in other variable regions of the nose, such as the nasal isthmus or nasopharynx as well as errors associated with subjective scoring systems.

Adolescent↗

PubMedDate not supplied

Nasal histamine challenge: a method to predict the efficiency of antihistamine treatment.

Nasal histamine challenge (NHC) was performed on patients suffering from chronic rhinitis. The histamine was administered to the nose in the form of a spray. One hundred sixty-eight patients and 20 healthy subjects were examined. The histamine was sprayed into the nose in seven metered doses, from 0.03 mg to 3 mg. The nose was examined before and 4 minutes after each challenge. A positive reaction to challenge was indicated when the conchae swelled to the point that they impinged against the septum. We found that some patients reacted to a low dose of histamine (0.03 mg to 0.15 mg) while our control group and some other patients reacted positively only to higher doses of histamine (3 mg or more). After the first tests, NHC patients were randomly divided into two groups. One group was treated with placebo and the other group with antihistamines. Three weeks later another NHC was performed (now under treatment) and revealed that patients reacting to low doses of histamine improved significantly with antihistamine treatment, while those reacting to a high dose did not respond to antihistamines. We found the NHC to be a simple test with no complications, and one that is easily tolerated by patients, including children. Nasal histamine challenge helps to identify which patients will improve with antihistamine treatment and aids the evaluation of its efficacy.

Adolescent↗

PubMed1995

Antihistamines, a possible risk factor for Alzheimer's disease.

Antihistamines are frequently administered to psychiatric patients for a variety of purposes. Several large studies of schizophrenics have revealed an extremely high prevalence of Alzheimer's disease neuropathology compared with that in the general population. The neuroleptic treatment of schizophrenia appears to be implicated in this phenomenon. Many of the neuroleptics have anticholinergic effects, some being antihistamines as well, including chlorpromazine. It is proposed here that anticholinergics, including many antihistamines, either exacerbate the Alzheimer process or possibly contribute to its etiology/pathogenesis through their effects on cerebral cholinergic systems. Parsimony in the use of antihistamines thus appears to be warranted both for non-patients and schizophrenics pending the resolution of this issue.

Alzheimer Disease↗

PubMed1995

Terfenadine-associated ventricular arrhythmias and QTc interval prolongation. A retrospective cohort comparison with other antihistamines among members of a health maintenance organization.

This study compared the occurrence of syncope, ventricular arrhythmias, and corrected QT interval (QTc) prolongation over a 2 1/2-year period in persons prescribed terfenadine versus other prescription antihistamines among 265,000 members of the Harvard Community Health Plan (HCHP), the largest staff-model health maintenance organization in New England. HCHP maintains an automated medical record system with coded diagnoses for each ambulatory and hospital visit, and a similar automated pharmacy system with information for each member on all prescriptions filled at its pharmacies. Among 0.86 million exposure days of terfenadine and 1.04 million exposure days of other antihistamines, we found no excess risk of either clinical/arrhythmia events (odds ratio (OR), 0.86; 95% confidence interval (CI), 0.52 to 1.44) or QTc prolongation (OR, 1.00; 95% CI, 0.64 to 1.57) during courses of terfenadine versus those of other antihistamines. Joint courses of antihistamines and oral erythromycin were associated with an increased risk of QTc prolongation (OR, 2.33; 95% CI, 1.31 to 4.15), and there was a trend for this to be observed more frequently with terfenadine (OR, 2.37; 95% CI, 0.73 to 7.51; P = 0.14).

Administration, Oral↗

PubMed2006

Oral antihistamine therapy influences plasma tryptase levels in adult atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is an allergic skin disease that follows a clinical course of 'flare-up' and remission. Histamine and tryptase are inducers of pruritus and non-sedating second-generation antihistamines, including fexofenadine, are widely used for treatment of allergic skin disorders. OBJECTIVE: We assessed the efficacy of a second-generation antihistamine in AD patients and examined its pharmacological effects on chemical mediators. METHODS: The scoring atopic dermatitis (SCORAD) instrument and visual analogue scale (VAS) for pruritus were used to assess disease severity in 349 AD patients. Twenty patients with moderate AD symptoms, who had not received any treatment for 2 weeks, were randomly assigned into two groups. Ten patients underwent fexofenadine and emollient treatment (Group 1) and 10 received fexofenadine and steroid treatment (Group 2) for 1 week. SCORAD and VAS for pruritus, and blood histamine and tryptase levels were evaluated before and after treatment. RESULTS: SCORAD and VAS improved in both Group 1 (p=0.01 and p=0.006, respectively) and Group 2 (p<0.001 and p=0.001, respectively). The improvement in Group 1 showed a significant correlation with the diminution rate of blood tryptase levels (SCORAD: r=0.83 and p=0.013, respectively; VAS: r=0.81, p=0.015, respectively). End-point plasma tryptase levels were significantly lower than baseline levels in Group 2 (p=0.046). Histamine levels did not show any significant changes in either group. CONCLUSION: These results suggest that second-generation antihistamine therapy reduces AD pruritus, resulting in the effective clinical treatment for AD. In addition, monitoring tryptase levels during antihistamine therapy in moderate AD treatment may prove to be useful in establishing treatment effects.

Administration, Oral↗

PubMed1999

The role of potassium channels in antihistamine analgesia.

The effect of the administration of pertussis toxin as well as modulators of different subtypes of K+ channels on the antinociception induced by the H1-antihistamines pyrilamine, diphenhydramine and promethazine was evaluated in the mouse hot plate test. Pretreatment with pertussis toxin (0.25 microg/mouse i.c.v.) prevented pyrilamine, diphenhydramine and promethazine antinociception. The K(ATP) channel openers minoxidil and pinacidil potentiated the antinociception produced by the H1-antihistamines whereas the K(ATP) channel blocker gliquidone prevented the anti H1-induced analgesia. The Ca2+-gated K+ channel blocker apamin antagonized pyrilamine, diphenhydramine and promethazine analgesia. Pretreatment with an antisense oligonucleotide (aODN) to mKv1.1, a voltage-gated K+ channel, at the dose of 3.0 nmol/single i.c.v. injection, never modified the antinociception induced by the H1-antihistamines in comparison with degenerate oligonucleotide (dODN)-treated mice. At the highest effective doses, none of the drugs used modified animals' gross behaviour nor impaired motor coordination, as revealed by the rota rod test. The present data demonstrate that both K(ATP) and Ca2+-gated K+ channels, contrary to voltage-gated K+ channel Kv1.1, represent an important step in the transduction mechanism underlying central antinociception induced by H1-antihistamines.

Animals↗

PubMed2003

Prospects for antihistamines in the treatment of asthma.

Antihistamines have been evaluated as potential therapies for asthma for more than 50 years. With first-generation compounds, side effects prevented effective dosing. By reviewing published studies of the effectiveness of terfenadine, cetirizine, and loratadine in clinical asthma, evidence for the relevant effect of the second-generation antihistamines on bronchial asthma can be found. Terfenadine, at doses of 120 or 180 mg twice a day, reduced symptoms and improved pulmonary function in mild and moderate allergic asthma but was ineffective in severe perennial asthma. Fexofenadine at doses used for allergic rhinitis had little effect on seasonal allergic asthma. Research is ongoing to determine the effects of higher doses of fexofenadine. In 5 studies, cetirizine at doses of 10 to 20 mg, once or twice daily, consistently improved asthma symptoms compared with placebo or terfenadine 60 mg twice a day in 2 cases, whereas in 2 studies, loratadine at doses of 10 to 20 mg daily has not produced significant improvement in asthma. However, loratadine 5 mg combined with 60 mg of pseudo-ephedrine twice a day significantly improved both asthma symptoms and peak expiratory flow. Similarly, the combination of loratadine 20 mg and the leukotriene-receptor antagonist montelukast improved asthma symptoms, peak expiratory flow, and beta-agonist use over montelukast alone. Therefore, there might be a role for second- and third-generation antihistamines in treating mild and moderate asthma, which might require administering doses greater than those commonly used to treat allergic rhinitis. If higher doses are sedative, the addition of decongestants or leukotriene-receptor antagonists might enhance the effects of lower doses of the antihistamines.

Anti-Allergic Agents↗

PubMed1990

Antihistamines in the treatment of clinical asthma.

Because the older antihistamines possessed relatively weak antihistaminic action, as well as sedative and anticholinergic effects, they could not be administered in doses high enough to confer relief to atopic patients with asthma. In contrast, the newer nonsedating, more potent H1-receptor antagonists appear to achieve effective histamine blockade in patients with asthma. Terfenadine and astemizole inhibit bronchoconstriction induced by inhaled allergens by 50% in the early asthmatic reaction. High-potency antihistamines also significantly reduce cough and wheeze as compared with placebo in grass pollen-sensitive asthma patients. Significant reductions in symptom severity and bronchodilator use were found with terfenadine, 120 mg twice daily, although these improvements may be confined to younger patients. Some of the newer antihistamines have demonstrated interesting effects on the late-phase allergic response. Azelastine partially inhibits bronchoconstriction in the allergen-induced late reaction of atopic persons with asthma, possibly by suppressing the release of additional inflammatory mediators. In the skin, cetirizine has been found to reduce eosinophil and neutrophil late-phase infiltration and prostaglandin D2 release. These interesting properties now warrant further investigation in clinical studies.

Animals↗

PubMed2004

[Urticaria paradoxically aggraved by H1 antihistamines].

BACKGROUND: H1 antihistamines (anti-H1) are the treatment of choice in chronic urticaria. We report five cases of urticaria, induced or aggravated by H1 antihistamines. METHODS: The immunoallergological investigations included prick-tests and intradermal tests with the antihistamine responsible for acute urticaria. RESULTS: The skin tests confirmed the non-IgE dependent nature of the urticarial eruptions and anti-leukotrienes (montelukast, Singulair) were effective in controlling chronic urticaria in 3/4 patients. DISCUSSION: Two hypotheses are discussed to explain the paradoxical aggravating effect of H1 antihistamines on the urticaria: 1) the patients are sensitive to the toxic, pro-inflammatory effect of the drug, which is the source of nonspecific activation of mast cells; 2) the fact that the urticaria is sensitive to anti-leukotrienes suggests that histamine is not the principal mediator of urticaria in these patients.

Adult↗

PubMed1988

Chronic urticaria: review of nonsedating H1 antihistamines in treatment.

Antihistamines are the drugs of choice in the symptomatic relief of chronic urticaria; however, the usefulness of classic antihistamines has been limited by side effects, especially daytime sedation. In the 1980s a new class of antihistamines has been developed that maintains effectiveness and produces less sedation. This review analyzes each of the new nonsedating antihistamines and evaluates its clinical efficacy, safety, and convenience in the treatment of chronic urticaria.

Chronic Disease↗

PubMed2001

Simultaneous screening and quantitation of 18 antihistamine drugs in blood by liquid chromatography ionspray tandem mass spectrometry.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method is presented for the simultaneous screening and quantitation of 18 antihistamine drugs in blood samples. Sample pretreatment involved liquid-liquid extraction of the basic antihistamines followed by a second extraction of the acidic antihistamines. The recoveries were 43-113% for basic drugs and 23-66% for acidic drugs. The combined extracts were run by LC on C(18) reversed phase column using acetonitrile-ammonium acetate mobile phase at pH 3.2. The mass spectrometric analysis was performed with a triple stage quadrupole mass analyzer. Screening was performed using multiple reaction monitoring (MRM) and any compounds tentatively identified as antihistamine drugs were then automatedly verified by their Product Ion Spectra in a subsequent MS/MS run. Quantitation was based on the MRM data from the screening step. In validation tests, the method showed good linearity at the relevant concentrations. The attained limits of quantitation varied between 0.0005 and 0.01mg/l in blood and were lower than the therapeutic concentrations (C(max)). The limits for identification by Product Ion Spectra were also lower than C(max), except for clemastine, which has exceptionally low concentrations in blood. The intra-assay relative standard deviations were better than 10% and the inaccuracy varied between 39% for levocabastine and 5% for cyclizine, the majority of the values being <20%.

Chromatography, Liquid↗

PubMed2000

Onset-of-action for antihistamine and decongestant combinations during an outdoor challenge.

BACKGROUND: Medications containing a combination antihistamine-decongestant are commonly used for allergic rhinitis yet onset-of-action comparisons for symptom relief after a single dose have not been performed. OBJECTIVE: To determine the onset of symptom relief and efficacy of antihistamine-decongestant medications (acrivastine-pseudoephedrine and loratadine-pseudoephedrine) compared with placebo in an outdoor park. METHODS: This study was conducted during the spring of 1997 using a double-blind, placebo-controlled design. Patients completed baseline rhinitis symptom diaries from 7:30 to 9:30 AM. Subjects with qualifying symptom scores received one dose of either acrivastine-pseudoephedrine, loratadine-pseudoephedrine, or placebo at 10:00 AM. Symptom diaries were recorded for the next 4 hours. RESULTS: Of 593 patients randomized to treatment, 592 were included in efficacy analysis. Acrivastine-pseudoephedrine and loratadine-pseudoephedrine demonstrated a mean onset-of-action by 45 and 30 minutes respectively for total symptom and rhinitis symptom scores for the five sites. Onset-of-action for nasal congestion scores was 45 minutes for both medications. Sites having higher pollen exposure (>100 pollen grains over 6 hours) demonstrated a difference between the antihistamine combinations: acrivastine-pseudoephedrine had an onset of action at 45 minutes for total symptom and rhinitis symptom scores, and 15 minutes for nasal congestion scores whereas loratadine-pseudoephedrine had onset-of-action for nasal congestion score of 105 minutes but failed to reach significance at any timepoint for total symptom and rhinitis symptom scores. CONCLUSIONS: Both antihistamine-decongestant combinations demonstrate an onset-of-action within 60 minutes of administration but under conditions of higher pollen exposure, the acrivastine combination was more effective for total symptoms, rhinitis symptoms, and nasal congestion with an onset-of-action within 45 minutes for rhinitis symptoms and 15 minutes for congestion.

Adult↗