Subject(s)
Hypertension, Pulmonary/genetics , Mutation , Protein Serine-Threonine Kinases/genetics , Adult , Amino Acid Sequence , Animals , Bone Morphogenetic Protein Receptors, Type II , Cohort Studies , DNA Mutational Analysis , Gene Frequency , Germany , Humans , Molecular Sequence Data , Reverse Transcriptase Polymerase Chain Reaction , Sequence AlignmentABSTRACT
Mice of the Swiss-Webster strain obtained from two suppliers (Taconic, Charles River) were found to differ in their sensitivity to morphine. Mice from Taconic were approximately two-fold more sensitive to the analgesic and lethal effects of morphine compared to the Charles River mice. In a third strain, C3H/HEN, morphine was found to be more than 2.5 times more potent in producing analgesia than in the Charles River mice. Binding studies showed that the Taconic mice and C3H/HEN mice had approximately 40% and 60%, respectively, more specific [3H]naloxone binding sites in brain than did the less sensitive Charles River mice. When treated with chronic naltrexone for 8 days the analgesic potency of morphine was increased by approximately 90% for both Swiss-Webster mice and by 20% for the C3H/HENs. [3H]Naloxone binding was increased by 45-50% in the Swiss-Webster strains, but by only 33% in C3H/HEN mice. These data indicate that receptor upregulation is directly related to increases in morphine potency. Further, these findings suggest that initial sensitivity to morphine can determine the degree of functional supersensitivity and relative receptor upregulation produced by chronic opioid antagonist treatment.
Subject(s)
Analgesia , Brain/metabolism , Morphine/pharmacology , Receptors, Opioid/drug effects , Animals , Brain/drug effects , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred C3H , Naloxone/metabolism , Naloxone/pharmacology , Receptors, Opioid/metabolismABSTRACT
Experiments have been carried out in dogs and man to determine the effect of hydrochlorothiazide (HCT) on the pharmacokinetics of propranolol and to evaluate the bioavailability of two dosage forms containing both propranolol and HCT (40/25 and 80/25 mg, respectively). In adult male beagles, 50 mg of HCT had no apparent effect on AUC, Cmax, Tmax, and T1/2 of propranolol administered concurrently. In man, INDERIDE (40/25 mg) and INDERIDE (80/25 mg) were shown to be similar in bioavailability to the reference formulations, i.e. the same amount of drugs administered as the separate tablets of INDERAL plus HYDRODIURIL.
Subject(s)
Hydrochlorothiazide/metabolism , Propranolol/metabolism , Adolescent , Adult , Animals , Biological Availability , Dogs , Drug Combinations/metabolism , Humans , Kinetics , Male , Species Specificity , TabletsABSTRACT
Nineteen healthy male volunteers were given daily 160 mg propranolol hydrochloride in divided doses, either four 40-mg tablets or two 80-mg tablets, and the plasma propranolol concentration profiles were compared after one and seven consecutive days of drug administration. The results indicate that the relative rate and extent of propranolol absorption were greater after 80 mg given twice daily than after 40 mg given four times per day. Both differences were statistically significant at steady state attained with the seven-day treatment. The variability in the areas under the concentration-time curves of propranolol appeared to be smaller after the 80-mg twice-a-day dosing schedule. The results are in accordance with the observed therapeutic equivalence of the two dosing regimens.
