Skin concentrations of H1-receptor antagonists.

BACKGROUND: H1-receptor antagonists are widely used in the treatment of allergic skin disorders. OBJECTIVE: We sought to evaluate the extent of fexofenadine and diphenhydramine distribution into the skin concomitantly with their peripheral H1-receptor antagonist activity. METHODS: In a prospective, randomized, double-blind, parallel-group study, 7 men received 120 mg of fexofenadine, and 7 received 50 mg of diphenhydramine. Before dosing; at 1, 3, 6, 9, and 24 hours after the first dose; and at 168 hours (steady-state), 12 hours after the seventh and last daily dose, blood samples and skin punch biopsy specimens were obtained, and epicutaneous tests with histamine phosphate, 1 mg/mL, were performed. RESULTS: Fexofenadine penetrated the skin to a significantly greater extent than diphenhydramine at 6, 9, 24, and 168 hours (P < or = .05). Maximum skin/plasma ratios of both the H1-antagonists (41.3 +/- 7.8 for fexofenadine and 8.1 +/- 4.4 for diphenhydramine) were obtained at 24 hours. Fexofenadine also produced significantly greater suppression of wheals at 3, 6, and 9 hours and of flares at 3, 6, 9, and 168 hours compared with diphenhydramine (P < or = .05). CONCLUSION: In disorders in which the presence and the effects of H1-receptor antagonists in the skin are clinically relevant, our results support the use of fexofenadine and indicate the need to re-examine the role of diphenhydramine.

Suppression of the early and late cutaneous allergic responses using fexofenadine and montelukast.

BACKGROUND: The relative contribution of histamine and the cysteinyl leukotrienes to the early and late cutaneous allergic responses (ECAR and LCAR) can be studied using antagonists of these mediators. OBJECTIVE: To determine the relative suppression of the ECARs and LCARs using standard doses of an H1-receptor antagonist, a cysteinyl leukotriene1-receptor antagonist, and the two antagonists administered concurrently. METHODS: We carried out a prospective, randomized, double-blind, placebo-controlled, four-way crossover study in 12 highly allergic participants. Intradermal tests with standardized allergen, and with histamine phosphate, LTD4, and saline controls were performed on 5 different test days as follows: pretreatment baseline and at steady state immediately after the seventh and last dose of a 1-week course of treatment with once-daily fexofenadine, 120 mg; montelukast, 10 mg; fexofenadine and montelukast administered concurrently; or placebo. On each test day, the skin test results were read at intervals from 0.25 to 24 hours after the intradermal injections were performed. RESULTS: After allergen injection, compared with baseline, all treatment regimens significantly decreased the ECAR and LCAR. After allergen injection, compared with placebo, fexofenadine significantly decreased the ECAR and the LCAR from 0.25 to 2 hours and at 8 hours. Montelukast did not significantly decrease the ECAR or LCAR. Fexofenadine and montelukast administered concurrently were not more effective than fexofenadine alone at any time. In the control skin tests, compared with placebo, fexofenadine, but not montelukast, significantly decreased the histamine-induced response, and montelukast, but not fexofenadine, significantly decreased the LTD4-induced response. CONCLUSIONS: Fexofenadine and montelukast administered concurrently were not significantly more effective than fexofenadine alone in decreasing the ECAR and LCAR. Montelukast does not need to be discontinued before allergen skin testing. Further studies of the effect of concurrent treatment with higher doses of a histamine antagonist and a leukotriene modifier on the allergic response in the skin are needed.

Results of a clinical trial in humans with refractory cancer of the intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine-HCl, in combination with various single antineoplastic agents.

PURPOSE: We assessed N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine-HCl (DPPE) potentiation of chemotherapy in vitro and performed a pharmacokinetic study and phase I/II trial of DPPE, combined with various single agents, in patients with advanced refractory cancer. PATIENTS AND METHODS: In vitro chemopotentiation by DPPE was assessed in drug-sensitive and -resistant (multidrug resistant-positive [MDR+]) human tumor cells using a colony survival assay. The effect of DPPE and verapamil on the intracellular concentration of daunorubicin in MDR+ cells was compared. For the clinical study, subjects with progressive malignancy received a weekly infusion of a maximally tolerated dose of DPPE (240 mg/m2) over 80 or 440 minutes, in conjunction with a single chemotherapy drug to which, in most cases, the patient's tumor was previously resistant. Concentrations of DPPE in blood and urine were determined by high-performance liquid chromatography (HPLC). RESULTS: In vitro, micromolar concentrations of DPPE potentiated (fivefold to 10-fold) chemotherapy cytotoxicity to both drug-sensitive and -resistant cells, but did not inhibit the p-glycoprotein pump; in vivo, serum levels of DPPE were 3 to 5 mumol/L at the end of 80 minutes and 1 to 2 mumol/L after 440 minutes of infusion. Of 48 patients monitored for a minimum of four DPPE/chemotherapy treatment cycles, 16 (33%) progressed, 12 (25%) stabilized, 12 (25%) improved, and eight (17%) responded (one complete and seven partial remissions). Four of 11 subjects who did not respond to the 80-minute infusion regimen improved with the 440-minute infusion; one had a partial remission of melanoma. In more than 600 patient-treatments, bone marrow toxicity was negligible (mean absolute neutrophil count [ANC] > 2.0 x 10(9)/L). Acute CNS symptoms associated with DPPE infusions were of relatively short duration (1 to 4 hours); delayed toxicity attributable to DPPE consisted of mild nausea and/or fatigue (1 to 2 days). CONCLUSION: Although preliminary, the results suggest that more structured trials should be performed to determine whether DPPE may increase the therapeutic index of certain chemotherapy drugs.

Optimum pharmacological management of chronic rhinitis.

Pharmacological treatment of chronic rhinitis has greatly improved with the introduction of the relatively non-sedating H1-receptor antagonists such as terfenadine, astemizole, loratadine, and cetirizine, and the safe, highly efficacious topical glucocorticosteroids such as beclomethasone dipropionate, flunisolide, budesonide, fluocortin butyl, and triamcinolone acetonide. In patients whose chief complaint is rhinorrhoea, topical ipratropium bromide may be of value. Patients whose major symptom is nasal congestion will benefit from intermittent use of topically or orally administered decongestants. In patients with allergic rhinitis, sodium cromoglycate (cromolyn sodium) or nedocromil sodium applied topically intranasally have a moderate beneficial effect and are associated with a low incidence of adverse effects. Non-pharmacological treatment of chronic rhinitis cannot be ignored. Patients must avoid inhalation of cigarette smoke and other irritants. Patients with chronic allergic rhinitis should avoid antigens to which they have known sensitivity: in addition, selected patients with allergic rhinitis may benefit from immunotherapy with the offending antigen(s).

The pharmacokinetics of procainamide in normal subjects using a specific gas chromatographic assay.

Previous procainamide pharmacokinetic studies have involved the use of colorimetric and fluorimetric methods for the determination of drug concentrations in plasma and urine. However, recent evidence shows that N-acetyl procainamide, the major metabolite in humans, is hydrolyzed during these assay procedures. As a result, a specific gas chromatographic method has been developed for the determination of procainamide in biological fluids. Using this assay procedure, the pharmacokinetics of procainamide were studied in 7 normal subjects following intravenous administration of the drug. The values of half-life (2.08 +/- 0.52 hr), volume of distribution (4.3 +/- 0.6 1/Kg) and total body clearance (1344 +/- 238 ml/min) found in this study differed from those previously reported. These discrepancies could be understood in terms of differences in assay specificity.