The effect of age on diurnal variation in the pharmacokinetics of propranolol in hypertensive subjects

Summary There is diurnal variation in the absorption rate of propranolol in younger subjects. This study was undertaken to examine the effect of age on the chronopharmacokinetics of propranolol.We gave 20 mg of propranolol orally to 13 younger and 11 older hypertensive subjects at 09.00 h (day study) or 21.00 h (night study) in a cross-over design. Plasma concentrations of propranolol and its metabolites, 4-hydroxypropranolol and naphthoxylactic acid, were determined just before and at 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 h after dosage. In the younger subjects the absorption rate constant (k_a) of propranolol and its maximum plasma concentration (C_max) were significantly higher and the time to maximum concentration (t_max) was significantly shorter in the day than at night. There were similar time-variant changes in C_max and t_max for 4-hydroxypropranolol and naphthoxylactic acid. In contrast, there were no time-variant changes in k_a, C_max and t_max of propranolol and its metabolites in the older subjects.These results suggest that propranolol is absorbed more rapidly after morning dosing than after night-time dosing in younger but not in older subjects. Based on these findings, we speculate that the time-variance in the absorption rate or first-pass elimination, or both, of propranolol diminish with age.     

Effect of a Ca2+ antagonist, nifedipine, on the experimental asthma mediated mainly by slow reacting substance of anaphylaxis

In the asthmatic model mainly mediated by the endogenous slow reacting substance of anaphylaxis (SRS-A) induced by the antigen inhalation to passively sensitized guinea pigs, continuous intravenous infusion of nifedipine (Adalat) at a speed of 7 micrograms/kg/min depressed the airway open pressure by about 68% compared to the saline-treated group and produced a delay in the time to peak response. Moreover, nifedipine inhibited the response of the peripheral airway more strongly than that of the central airway. The same concentration of nifedipine inhibited the airway open pressure by about 43% compared to the saline-treated group in the asthmatic model induced by the inhalation of leukotriene C4. The effect of nifedipine on the central airway was shorter in duration than that on the peripheral airway. The inhibitory effect of nifedipine on the airway response was greater in the asthmatic model mediated mainly by the endogenous SRS-A induced by the antigen inhalation than in the asthmatic model produced by the inhalation of leukotriene C4.     

Mechanism of radiation- and photo-induced polymerizations of styrene elucidated by the stereoregularity of the polymers

The stereoregularity of polystyrenes (PS's) obtained by γ-ray and UV light irradiation was determined by ¹³C NMR spectroscopy, and the mechanism of polymerization was discussed. PS's obtained by ⁶⁰Co γ-ray irradiation in bulk, methylene chloride and carbon tetrachloride at 0°C showed bimodal molecular weight distributions. The stereoregularity expressed by the fraction of racemic dyads in the high molecular weight portions and the low molecular weight ones separated by thin layer chromatography (TLC) was 66 – 67% and 71%, respectively. The results indicate that the former portions are formed by a cationic mechanism and the latter by a radical mechanism. It was also confirmed that the polymerization by UV light irradiation with pyromellitic dianhydride (1,2:4,5-benzenetetracarboxylic dianhydride) as an electron acceptor propagates by a cationic mechanism in polar solvents and by a radical mechanism in the bulk.     

Effect of alismol on adrenergic mechanism in isolated rabbit ear artery

Effects of alismol, a sesquiterpenoid isolated from the rhyzome of Alisma orientale, on adrenergic mechanisms were examined in the isolated rabbit ear artery. Alismol (10(-6) to 10(-4) M) inhibited the contraction of isolated rabbit ear artery by electrical stimulation of the perivascular nerves. The inhibition was concentration-dependent; at a concentration of 10(-4) M, the inhibition was 90% (n = 8). Treatment with 10(-4) M alismol inhibited the increase in 3H-noradrenaline (3H-NAd) release induced by electrical stimulation by 63 +/- 6%. Alismol at 10(-4) M did not affect the neuronal uptake of 3H-NAd in the artery. Alismol at 10(-4) M slightly inhibited contractions induced by exogenously administered NAd. These results demonstrate that alismol inhibits the adrenergic neuro-effector mechanisms in rabbit ear artery, and they suggest that alismol acts primarily on nerve terminals and inhibits their responses to electrical stimulation by interfering with NAd release.     

Multiple myeloma following chronic neutrophilia terminated with acute monocytic leukemia (AML, M 5 b)

A case of a 70 years old female who developed multiple myeloma during a course of neutrophilia, and later on terminated with acute monocytic leukemia (AML, M 5 b) following Melphalan therapy for five years is reported. This patient was first found to have neutrophilia in 1966, After six years, she developed monoclonal gammopathy, (IgG1 kappa type) which coexisted with the neutrophilia. She was put on Melphalan regimen for 5 years which was discontinued due to anemia, leukocytopenia and the reduction of serum IgG. By routine bone marrow examination, she was diagnosed as AMoL (AML, M 5 b) in July 1984. Thereafter, a combination chemotherapy of BH-AC, 6-MP and prednisolone was started and complete remission for the AMoL was achieved after 2 months. Sixteen months later, she relapsed and a similar combination chemotherapy for reinduction regimen was administered. However, the AMoL was resistant and after 7 months, she died of pneumonia and multiple organ failure. The association of neutrophilia with multiple myeloma, the occurrence of AMoL after prolonged Melphalan therapy for the multiple myeloma and the strategy of therapy for secondary leukemia is discussed.