Bioavailability assessment of a brompheniramine taste-masked pediatric formulation in a juvenile porcine model.

A brompheniramine taste-masked pediatric formulation was developed as part of the National Institutes of Health Pediatric Formulation Initiative to help address low patient compliance caused by the bitter taste of many adult formulations. To confirm that the taste-masked formulation can provide a similar pharmacological effect to the previous marketed adult formulations, a juvenile porcine model was used to screen the model pediatric formulation to compare the bioavailability between the marketed brompheniramine maleate and the taste-masked maleate/tannate formulation. Pigs were dosed orally with both formulations and blood samples were obtained from 0 to 48 h. Plasma samples were prepared and extracted using solid-phase extraction. The mass spectrometer was operated under selected ion monitoring mode. The selected ion monitoring channels were set to m/z 319.1 for brompheniramine and m/z 275.2 for the internal standard chlorpheniramine. Calibration curves were linear over the analytical range 0.2-20 ng/ml (r2 > 0.995) for brompheniramine in plasma. The intra- and inter-day accuracies were between 98.0 and 105% with 5.73% RSD precision. The bioanalytical method was successfully applied to a preclinical bioavailability study. The bioavailability profiles were not significantly different between the two formulations, which demonstrates that taste-masking with tannic acid is a promising approach for formulation modification for pediatric patients.

Brompheniramine and Chlorpheniramine Pharmacokinetics Following Single-Dose Oral Administration in Children Aged 2 to 17 Years.

Two pediatric studies characterized brompheniramine and chlorpheniramine pharmacokinetics in a total of 72 subjects, aged 2 to 17 years. A single age-/weight-based oral dose, ranging from 1 to 4 mg, was administered with 2 to 6 oz of water at least 2 hours after a light breakfast. Plasma samples were obtained before and for 72 hours after dosing and analyzed using high-pressure liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods; relationships with age were assessed using linear regression. Results indicated that for brompheniramine and chlorpheniramine, Cmax was similar across age groups, although it tended to occur earlier in the youngest group. AUC was ∼15% to 30% higher in the oldest age group. As expected, CLo and Vz /F increased with age; however, following allometric scaling, no age-related differences existed. Because the increase with age for both parameters was similar, no age-related differences in t1/2,z existed (∼15 hours). Overall, the single doses were well tolerated. Sedation was the most common reported AE and appeared to be more prevalent in the 2- to 5-year-old group. Overall, these results indicate that an age/weight dosing nomogram using a 4-fold range of doses achieves similar Cmax and AUC.

Evaluation of enantioselective binding of antihistamines to human serum albumin by ACE.

The drug binding to plasma and tissue proteins is a fundamental factor in determining the overall pharmacological activity of a drug. HSA, together with alpha(1)-acid glycoprotein, are the most important plasma proteins, which act as drug carriers, with implications on the pharmacokinetic of drugs. Among plasma proteins, HSA possesses the highest enantioselectivity. In this paper, a new methodology for the study of enantiodifferentiation of chiral drugs with HSA is developed and applied to evaluate the possible enantioselective binding of four antihistamines: brompheniramine, chlorpheniramine, hydroxyzine and orphenadrine to HSA. This study includes the determination of affinity constants of drug enantiomers to HSA and the evaluation of the binding sites of antihistamines on the HSA molecule. The developed methodology includes the ultrafiltration of samples containing HSA and racemic antihistaminic drugs and the analysis of the free or bound drug fraction using the affinity EKC-partial filling technique and HSA as chiral selector. The results shown in this paper represent the first evidence of the enantioselective binding of antihistamines to HSA, the major plasmatic protein.

The clinical pharmacology of brompheniramine in children.

BACKGROUND: Brompheniramine has been widely used in the treatment of allergic rhinitis and other disorders during the past 4 decades. There are no published studies of its clinical pharmacology in children. OBJECTIVES: This study was performed to test the hypothesis that brompheniramine would have a prompt onset of action and a 24-hour duration of action in children. METHODS: Before brompheniramine 4 mg was ingested, and at intervals from 0.5 to 30 hours thereafter, blood samples were obtained for quantitation of plasma brompheniramine concentrations by means of HPLC. Concurrently, epicutaneous tests with histamine phosphate were performed; wheals and flares were traced at 10 minutes, and the areas were measured by using a computerized digitizing system. RESULTS: In 14 children, mean age 9.5 +/- 0.4 years (SEM), the peak brompheniramine concentration was 7.7 +/- 0.7 ng/mL, and the time at which peak concentrations occurred was 3.2 +/- 0.3 hours. The terminal elimination half-life was 12.4 +/- 1.1 hours, and the oral clearance was 20.2 +/- 2.1 mL/min/kg. Compared with predose areas, the wheals and flares produced by histamine phosphate 1 mg/mL were significantly decreased from 0.5 to 30 hours and from 1 to 30 hours, respectively (P <.05), with mean maximum inhibition at 12 (52% +/- 9%) and 6 hours (72% +/- 10%), respectively. CONCLUSIONS: In children a single dose of brompheniramine produces prompt, long-lasting peripheral H1 -blockade. Revised dosage regimens may be needed in this population.

El droperidol interactúa con receptores serotonérgicos y adrenoceptores Ó- cardiovasculares / Droperidol interactions with serotonergic and cardiovascular Ó adrenoceptors

En este trabajo se investigó si los receptores cardiovasculares de la serotonina (5-HT) son antagonizados por el droperidol. Los efectos de este fármaco sobre la vasopresión y el cronotropismo positivo obtenidos con la infusión intravenosa de noradrenalina (NA; 1 µg.kg-1.min-1), angiotensina II (1 µg.kg-1.min-1) y quipazina (100 µg.kg-1.min-1) se estudiaron en ratas desmeduladas. El droperidol (0.01 - 1 mg.kg-1,i.v.) revirtió los efectos presores de la NA y la quipazina en forma dependiente de la dosis. El pretratamiento con propranolol, bromefeniramina o atropina (1 mg.kg-1, i.v.; cada uno), no previno los efectos del neuroléptico. Por otra parte, el droperidol no modificó la respuesta presora de la angiotensina II, ni el cronotropismo de las drogas estudiadas. Se observó que los efectos inhibitorios del droperidol (DI50 141 µg/kg; LC 105-191) y de la ketanserina (Di50 110 µg/kg; LC 91-132) sobre la vasopresión de la quipazina, son similares; sin embargo, esta última no fue modificada por la prazosina. Estos resultados indican una interacción del droperidol con los reeptores vasculares 5-HT y confirman su capacidad para bloquear Ó-adrenoceptores

Análisis de las propiedades antihipertensivas del ácido-3-nitropropionico: un compuesto proveniente de plantas del género Astragalus / Antihypertensive properties of 3-nitropropionic acid: a compound derived from the astragalus plant

El ácido 3-nitropropiónico (ANP) es un compuesto proveniente de plantas del género Astragalus que ocasionó relajación dependiente de la concentración en anillos precontraídos de aorta de conejo. La remoción del endotelio o la presencia de atropina, propranolol o bromofeniramina no afectaron el efecto vasodilatador del ANP, el cual fue claramente inhibido por el azul de metileno. Por otra parte, la administración i.v. aguda de ANP en ratas normotensas o crónica por vía oral en perros hipertensos renales, provocó disminución en la presión sanguínea y bradicardia. Finalmente, el ANP ocasionó efectos inotrópicos negativos en aurículas aisladas de cobayos que no fueron bloqueados por atropina e inhibió los incrementos en fuerza y frecuencia de contracción cardíaca provocados por el isoproterenol. Los resultados indican que el ANP posee propiedades vasodilatadoras y antihipertensivas. La actividad vasodilatadora parece ser consecuencia de activación de la guanilato ciclasa, ya que se inhibió con azul de metileno. El efecto hipotensor del ANP fue independiente de la especie del animal o ruta de administración empleada. La bradicardia apreciada en ratas y perros y los efectos inotrópicos y cronotrópico negativos observados en aurículas aisladas, sugieren que el efecto hipotensor del ANP es una mezcla de acciones vasodilatadoras y cardiodepresoras. Los efectos cardíacos del ANP parecen relacionarse con inhibición de las respuestas mediadas por receptores ß-adrenérgicos

Effect of food on bioavailability of pseudoephedrine and brompheniramine administered from a gastrointestinal therapeutic system.

The purpose of this study was to determine how a high-fat meal affects the delivery and absorption of pseudoephedrine and brompheniramine maleate when delivered from a gastrointestinal therapeutic system (GITS). This study was a randomized, complete crossover trial with 12 healthy male volunteers who were given single doses of the 24-h GITS under fed and fasted conditions. Pharmacokinetic parameters for both drugs were comparable between fed and fasted treatments, except for a shorter time to maximum concentration of pseudoephedrine for fed subjects (p = 0.002). Bioavailability of pseudoephedrine was 91% for fed relative to fasted treatment; for brompheniramine it was 89%. These results indicate that codelivery of the two drugs from the GITS is reliable and prolonged, and that the resulting absorption of pseudoephedrine and brompheniramine is minimally affected by food.

The comparative pharmacokinetics of H1-receptor antagonists.

H1-receptor antagonists appear to be absorbed rapidly after oral administration, with peak serum concentrations being reached one to three hours after a dose. For most of these drugs, the absolute bioavailability is unknown because no intravenous formulations are available for comparative purposes. The serum elimination half-life values of these agents are variable: a few hours for terfenadine and triprolidine; about 9 hours for cetirizine, azatadine, and loratadine; from 20 to 25 hours for hydroxyzine, chlorpheniramine, and brompheniramine; and from 5 to 14 days for astemizole. Few pharmacokinetic studies of H1-receptor antagonists in children have been reported. However, it is known that chlorpheniramine, hydroxyzine, cetirizine, and terfenadine have shorter elimination half-life values in children than in adults. Regardless of the age of patients, for most of the H1-receptor antagonists the apparent volumes of distribution and total body clearances appear to be large (3.4 to 18.5 L/kg and 4.4 to 32.1 mL/min/kg, respectively). Cetirizine is an exception, with values of 0.8 L/kg and 0.5 mL/min/kg. Urinary excretion of unchanged antihistamine is higher after cetirizine (60% of dose) than any other H1 blocker. For H1-receptor antagonists with long half-life values, steady state may not be reached for several days (chlorpheniramine and brompheniramine) or several weeks (astemizole), and significant accumulation of drug occurs if the dosing interval is more frequent than every half-life. There is no evidence for the introduction of metabolism of H1-receptor antagonists, even after months of treatment.