Aphthasol
Pharmacokinetic comparison of a slow-release theophylline-hydroxyzine combination and a plain slow-release theophylline preparation.

Tukiainen H, Silvasti M, Karttunen P, Savolainen K, Kokkonen P, Parviainen M.

Department of Pulmonary Diseases, University of Kuopio, Tarinaharju, Finland.

We have compared the pharmacokinetic properties of a slow-release theophylline-hydroxyzine combination and a slow-release theophylline preparation both after a single dose administration and at steady state after the dosage of twice/day for four days in ten healthy volunteers. After a single dose, theophylline was absorbed slightly faster from the combination preparation (Retafyllin comp.) than from a plain theophylline preparation (Theo-Dur). However, in a steady state phase the pharmacokinetic profiles were quite similar. Hydroxyzine showed a slight delay in absorption from the combination preparation, but in a steady state the overall pharmacokinetic profile of hydroxyzine was similar to that of theophylline. Cumulation of either hydroxyzine or theophylline was not evident. On the basis of the present study, the slow-release combination preparation of theophylline and hydroxyzine seems suitable for twice/day dosage.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3209282&dopt=Abstract hydroxyzine Atarax



Aphthasol
Chloral hydrate sedation of children undergoing CT and MR imaging: safety as judged by American Academy of Pediatrics guidelines.

Vade A, Sukhani R, Dolenga M, Habisohn-Schuck C.

Department of Radiology, Loyola University Medical Center, Maywood, IL 60153, USA.

OBJECTIVE. The purpose of this prospective study was to determine the frequency of adverse events associated with supplemented and unsupplemented chloral hydrate sedation in a select group of children undergoing CT or MR imaging using the revised American Academy of Pediatrics (AAP) monitoring and management guidelines for pediatric sedation. The AAP guidelines do not recommend drug selection or dosages but define patient selection, discharge criteria, and monitoring standards for sedating children. SUBJECTS AND METHODS. This prospective study included 410 children 4 years of age or younger who were scheduled for CT and MR imaging as outpatients. Selected children were physical status 1 or 2 as determined by the American Society of Anesthesiologists physical status classification and had no contraindications to sedation per our institutional sedation policy. Children younger than 1 year old received only oral incremental doses of chloral hydrate. Children 1-4 years old received hydroxyzine plus incremental doses of chloral hydrate. Children between 2 and 4 years old who were not satisfactorily sedated 30 min after hydroxyzine plus incremental chloral hydrate were given 2 mg/kg meperidine intramuscularly, with a maximum dose of 50 mg. All children were monitored according to the revised guidelines recommended by the committee on drugs of the AAP. Vital signs and arterial hemoglobin oxygen saturation (SpO2) were monitored continuously by registered nurses trained in pediatric advanced life support from the time of sedative drug administration until the recommended discharge criteria were met. RESULTS. Mild hypoxia (SpO2, 90-95%) that resolved spontaneously without any therapeutic intervention was seen in 9% of the chloral hydrate group and in 5% of the chloral hydrate-hydroxyzine group. One child in the chloral hydrate group had severe hypoxia (SpO2, 85-89%), and one child in the chloral hydrate-hydroxyzine group had moderate hypoxia (SpO2, < 85%). Both required therapeutic intervention. In both cases, the severity of the underlying medical disease was underestimated at the time of presedation medical screening. The success rate of sedation was 100% for all the children having CT. For those having MR imaging, success was 100% for children 1-4 years old and 97% for children less than 1 year old. CONCLUSION. Use of supplemented and unsupplemented chloral hydrate sedation provides effective and safe sedation in children if the AAP guidelines for patient selection, monitoring, and management are followed. Careful medical screening and patient selection by knowledgeable medical personnel is important to exclude patients at high risk for life-threatening hypoxia. Monitoring with AAP guidelines is essential for prompt detection and management of life-threatening hypoxia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7676990&dopt=Abstract hydroxyzine Atarax



Aphthasol
Predictors of torsades de pointes in rabbit ventricles perfused with sedating and nonsedating histamine H1-receptor antagonists.

Gilbert JD, Cahill SA, McCartney DG, Lukas A, Gross GJ.

Department of Paediatrics and Child Health, University of Manitoba, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Canada.

Several nonsedating histamine H1-receptor antagonists are associated with torsades de pointes ventricular tachycardia. The objectives of this study were to: (i) compare electrocardiographic, monophasic action potential, and arrhythmogenic effects of sedating and nonsedating H1-receptor antagonists, and (ii) identify correlates of drug-induced torsades de pointes in an isolated ventricle model. Isolated, electrically paced (1-3 Hz) rabbit ventricles were Langendorff-perfused with either drug-free Tyrode's solution or one of the following: (i) the sedating H1-receptor antagonist hydroxyzine (0.1-30 microM), (ii) cetirizine, a nonsedating metabolite of hydroxyzine (1-300 microM), and (iii) the nonsedating, putatively arrhythmogenic H1-receptor antagonist astemizole (0.1-30 microM). Volume conducted electrocardiographic signals and monophasic action potentials from the periapical left ventricular endocardium and epicardium were recorded. There were no apparent changes in control (n = 15) or hydroxyzine-perfused (n = 7) hearts. Cetirizine (n = 13) produced a mild biphasic electrocardiographic QT interval prolongation and was associated with early afterdepolarizations, but not with torsades de pointes. Astemizole (n = 11) lengthened QT intervals, and at high concentration (30 microM) induced torsades de pointes in 10 of 11 hearts (P < 0.001 vs. all other groups). These findings are consistent with previously reported repolarizing current inhibition by cetirizine, but may additionally indicate "compensatory" inhibition of inward currents at higher concentrations. By contrast, astemizole-induced changes are consistent with unopposed repolarizing current inhibition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10841436&dopt=Abstract hydroxyzine Atarax



Aphthasol
Enhanced cancer growth in mice administered daily human-equivalent doses of some H1-antihistamines: predictive in vitro correlates.

Brandes LJ, Warrington RC, Arron RJ, Bogdanovic RP, Fang W, Queen GM, Stein DA, Tong J, Zaborniak CL, LaBella FS.

Department of Medicine, Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Canada.

BACKGROUND: Present studies of drug-induced tumor growth promotion have evolved from earlier investigations into the mechanism of action of N,N-diethyl-2-[4-(phenylmethyl)phenoxy[ethanamine.HCl, a tamoxifen derivative which potently inhibits lymphocyte mitogenesis in vitro and stimulates tumor growth in vivo. It is thought that potency to bind to intracellular histamine receptors (HIC), some of which are on cytochromes P450, may correlate with tumor growth-promoting activity. PURPOSE: We assessed the effectiveness of five in vitro assays in predicting in vivo tumor growth stimulation by the H1-antihistamines loratadine, astemizole, cetirizine, hydroxyzine, and doxylamine. METHODS: Potency of each agent was ranked 1-5 in each of the following in vitro assays: 1) inhibition of [3H]histamine binding to microsomal HIC, 2) inhibition of histamine binding to microsomal P450, 3) inhibition of the P450-catalyzed demethylation of aminopyrine, 4) inhibition of lymphocyte mitogenesis, and 5) stimulation of tumor colony formation. An overall rank score was assigned to each drug and correlated with tumor growth stimulation in vivo. Two laboratories conducted in vivo studies in a blinded fashion. Female C57BL and C3H mice were given a subcutaneous injection on day 1 of syngeneic B16F10 melanoma cells (5 x 10(5)) or C-3 fibrosarcoma cells (1 x 10(5)), respectively. Mice were randomly assigned to treatment groups, then received a single, daily intraperitoneal injection of an estimated human-equivalent dose (or range of doses) of antihistamine or vehicle control for 18-21 days before being killed. Tumors were surgically removed and wet weights compared statistically among groups. RESULTS: The cumulative potency of each drug in affecting tumor growth or growth mechanisms in the five in vitro assays ranked as follows: Loratidine and astemizole ranked highest and were equally potent, followed in decreasing order by hydroxyzine, doxylamine, and cetirizine. A significant correlation (r = .97; P < .02) was observed between the rank order of potency of the antihistamines in all five in vitro assays and the rank order to enhance tumor growth in vivo: Loratidine and astemizole significantly (P < .001) promoted the growth of both melanoma and fibrosarcoma, hydroxyzine significantly (P < .001) promoted the growth of melanoma, while doxylamine and cetirizine did not promote the growth of either tumor. CONCLUSION: Data demonstrate that the in vitro assays predicted the propensity of each H1-antihistamine to stimulate cancer growth in vivo. IMPLICATION: These in vitro tests may prove valuable to screen potential tumor growth promoters.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7909571&dopt=Abstract hydroxyzine Atarax



Aphthasol
Effect of the H2-receptor antagonist cimetidine, on the pharmacokinetics and pharmacodynamics of the H1-receptor antagonists hydroxyzine and cetirizine in rabbits.

Chen X, Simons FE, Simons KJ.

Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada.

The effects of coadministration of the H2-receptor antagonist cimetidine on the pharmacokinetics and pharmacodynamics of the H1-receptor antagonists hydroxyzine and cetirizine were studied in rabbits. A single dose of hydroxyzine, 10 mg (Experiment A), or cetirizine, 10 mg (Experiment B), was given intravenously on three occasions: 2 weeks before cimetidine administration, after cimetidine, 100 mg/kg, had been given every 12 hr for 1 week, and 2 weeks after the cimetidine was discontinued. Serum concentrations of hydroxyzine and cetirizine, the active metabolite of hydroxyzine arising in vivo (Experiment A), or cetirizine (Experiment B) were measured by HPLC. The pharmacologic effects of hydroxyzine and cetirizine were monitored by measuring the suppression of histamine-induced wheals, using an IBM-PC and digitizer. The hydroxyzine and cetirizine half-life and AUC0-->infinity values were significantly increased and the systemic clearance rates were significantly decreased in the presence of cimetidine. Similar results were obtained when cetirizine was administered de novo. Wheal suppression produced by hydroxyzine or cetirizine was increased and prolonged in the presence of cimetidine. The synergism observed between hydroxyzine or cetirizine and cimetidine in suppression of the histamine-induced cutaneous response may be due to a pharmacokinetic interaction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8165191&dopt=Abstract hydroxyzine Atarax