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Fifty-three hospitalized chronic schizophrenic patients were treated with either propranolol, chlorpromazine or placebo in a double-blind randomized trials for up to three months. Propranolol in a usual dose of 640 mg/day, produced marked cardiovascular effects but no improvement in schizophrenic symptomatology relative to placebo. The effects of chlorpromazine were small and inconsistent.
There appears to be a need for a readily and conveniently available close chemical analog of propranolol suitable for use as internal standard in a variety of chromatographic assays of the drug. With this purpose in mind, we developed a simple procedure for the preparation of N-cyclopentyldesisopropylpropranolol. The commercially available and inexpensive starting materials are mixed in a flask and after 48 hr at room temperature the precipitated product is filtered off. Mass spectrometry, melting point determinations, and elemental analysis were used to characterize the product. N-cyclopentyldesisopropylpropranolol was used as internal standard in a liquid-chromatographic assay of ten replicate 50 ng/ml propranolol plasma samples, and gave a coefficient of variation of 3.4%.
The stereoselective hydrolysis of O-isovaleryl propranolol (isovaleryl-PL) was studied using phosphate and Tris-HCl buffers (pH 7.4), dog plasma, and liver preparations. The 10000g supernatant, microsomes, and cytosol were prepared from the liver homogenate. The hydrolysis rate of isovaleryl-PL was accelerated in the order Tris buffer < plasma = phosphate buffer << 10000g supernatant of liver = liver cytosol < liver microsomes. The high plasma protein binding of the prodrug brought about the extremely slow hydrolysis rate of isovaleryl-PL in plasma. No difference was observed in the hydrolysis rate between the isomers of isovaleryl-PL in buffers. The hydrolysis rate was 2-3 times faster with the (R)-isomer than with the (S)-isomer using racemate in dog plasma and liver preparations. The hydrolysis of each enantiomer was inhibited by the other enantiomer. For hydrolysis in microsomes the Km values of (R)- and (S)-isomers were same, and the Vmax of the (R)-isomer was 3 times greater than that of the (S)-isomer. These data suggested the mutual interaction of (R)- and (S)-isomers during the hydrolysis process and the rapid hydrolysis of isovaleryl-PL in liver after absorption. The AUC of PL enantiomers after oral administration of racemic isovaleryl-PL was about 2 times higher compared to 2 mg/kg equivalent molar dose of racemic PL in beagle dogs, and the corresponding plasma levels were not stereoselective from both PL and prodrug. The amount of (R)-PL absorbed after administration of a 5 mg/kg dose of racemic PL was 2-fold greater than (S)-PL, because of the stereoselective oxidation and glucronidation of (S)-PL.(ABSTRACT TRUNCATED AT 250 WORDS)
Repeated oral administration of propranolol (PL, 100 mg/kg daily, for 5, 10 and 15 days) to male Wistar rats increased PL N-desisopropylase and decreased PL 4-,5- and 7-hydroxylase activities in liver microsomes. The increase was highest at the 10 day time point whereas the decrease was relatively constant over the 15 day treatment period. There were no significant changes in the total content of cytochromes P450 (P450) or cytochrome b5 or in NADPH-cytochrome c reductase activity during the PI, treatment. The enhanced N-desisopropylase activities were markedly inhibited by alpha-naphthoflavone (a P450-1A1/2 inhibitor), and moderately by triacetyloleandomycin (a P450-3A1/2 inhibitor) and diethyldithiocarbamate (a P450-2E1 inhibitor). Phenacetin O-deethylase activity, an index of P450-1A2, was significantly increased on day 5, 10 and 15 of the treatment, whereas p-nitrophenol hydroxylase activity was elevated on day 10 only. The PL N-desisopropylation showed a strong and significant correlation with phenacetin O-deethylation, and a weaker but significant correlation with p-nitrophenol hydroxylation. Immunoblot analysis revealed that a protein band corresponding to P450-1A2 was increased by PL pretreatment, and protein band corresponding to P450-3A tended to be increased slightly, but other protein band corresponding to the subfamily of P450-2B, -2C, or -2E was not changed. Pretreatment of rats with P450 inducers (beta-naphthoflavone, phenobarbital, acetone and dexamethasone) increased PL N-dealkylase activity in liver microsomes. Furthermore, antibodies raised against P450-1A and -3A enzymes suppressed PL N-desisopropylation in a concentration-dependent manner, but P450-2E antibody did not. Reconstitution studies showed that P450-1A1, -1A2, -2E1 and -3A2 exhibited catalytic activities for PL N-dealkylation. These results suggest that P450-1A2 is a major PL N-desisopropylase in the PL-treated rats, and P450-3A related enzyme(s) and P450-2E1 as a moderate or minor enzyme are also involved in PL N-dealkylation in native and PL-treated rats.
1. Intravenous administration of compound AH 5158, which possesses alpha- and beta-adrenergic receptor-blocking properties, produces haemodynamic effects similar to those seen from the combined effects of propranolol and hydrallazine. 2. Chronic oral administration has demonstrated that compound AH 5158 is an effective hypotensive agent capable of controlling the blood pressure in patients previously requiring large doses of drugs such as methyldopa. Some postural and exercise hypotension may be seen with larger doses.
The aim of this study was to test the effectiveness of isosorbide-5-mononitrate (IM) as an adjunct to propranolol (PR) in the prevention of variceal rebleeding. Ninety-five cirrhotic patients with variceal bleeding were randomly assigned to treatment with PR + IM (46 patients) or PR alone (49 patients). Eighteen patients in the PR + IM group and 28 in the PR group had rebleeding during the 2 years after randomization. The actuarial probability of rebleeding 2 years after randomization was lower in the PR + IM group (40.4% vs. 57.4%) but the difference was not significant (P =. 09). However, the decrease in the risk of rebleeding reached statistical significance after stratification according to age, i.e. less than 50 versus >/=50 years old, (P =.03) or by adding an additional year of follow-up (P =.05). No significant difference was found in rebleeding index and survival. The multivariate Cox analysis indicated first, that both treatment (P =.03) and age (P =. 001) were factors predictive of rebleeding and second, that PR + MI reduced the risk of rebleeding by half (relative risk: 0.51, 95% confidence interval: 0.28-0.95). Seven patients in the PR + MI group and 1 patient in the PR group had to discontinue one of the drugs because of adverse events (P =.03). These results suggest that the addition of IM improves the efficacy of PR alone in the prevention of variceal rebleeding in cirrhotic patients. However no beneficial effects were observed on other parameters reflecting the efficacy of treatment.
The cardiovascular changes during anaesthesia and thyroidectomy have been studied in seven thyrotoxic patients prepared with propranolol. The heart rate and cardiac rhythm remained very stable throughout surgery. A 20% increase in mean arterial pressure occurred during surgical stimulation. A decrease in cardiac output, due to decreased stroke volume, occurred during surgical stimulation. A decrease in cardiac output, due to decreased stroke volume, occurred during surgery, reaching a maximum of 21% during ligation of the thyroid vessels and returning to pre-operative values by the end of surgery. The fall in cardiac output was accompanied by raised central venous pressure and raised total peripheral resistance.
Concentration-dependency in the hepatic elimination of l-propranolol (l-PR) was investigated over a wide range of concentrations from 60 to 2200 microM in an isolated rat liver perfusion system. Under the steady-state condition produced by unlabeled l-PR at various concentrations, 3H-l-PR and 14C-inulin were bolusly injected into the portal vein, and the outflow was collected at 0.5 s intervals over 30 s. Up to 300 microM, the instantaneous hepatic availability of l-PR was approximately 4%, while it abruptly increased when the perfusate concentration exceeded 300 microM. To determine which process (influx or efflux or sequestration process) caused the nonlinearity, we calculated the rate constants k1 (influx), k2 (efflux), and k3 (sequestration) based on the "distributed" model. With increasing l-PR concentration in the perfusate, k2 increased approximately two times, whereas k3 decreased to approximately one-half. In contrast, k1 was independent of the perfusate concentration. The concentration-dependency of k2 was explained by saturation of l-PR tissue binding, since the tissue unbound fraction of l-PR obtained with liver homogenates and isolated hepatocytes increased approximately two times. The efflux and sequestration clearances were then normalized by the unbound fractions in the liver. The efflux clearance for unbound l-PR was constant irrespective of the perfusate concentration, whereas the sequestration clearance for unbound l-PR (CL(int) showed Michaelis-Menten type saturation (Km = 28 microM, Vmax = 2.8 mumol/min/g liver, alpha (nonspecific) = 2- ml/min/g liver).(ABSTRACT TRUNCATED AT 250 WORDS)
The enantioselective oral bioavailability of propranolol (PL) from 0-isovaleryl-PL was determined and compared with parent PL in beagle dogs. The bioavailability of the individual enantiomer from the prodrug increased about 2 fold. The AUC ratio between the S(-)- and R(+)-isomer posed at 0.89 which was statistically not different from that obtained after administration of PL alone. These features indicate that 0-isovaleryl-PL promises to be a potential prodrug of PL from the pharmacokinetic and pharmacodynamic point of view.
OBJECTIVE: The aim of this study was to test the effectiveness of isosorbide-5-mononitrate (IM) as an adjunct to propranolol (PR) in the prevention of variceal rebleeding. METHODS: Seventy-six cirrhotic patients with variceal bleeding were randomly assigned to treatment with PR + IM (34 patients) or PR alone (32 patients). RESULTS: Seven patients in the PR + IM group and 13 in the PR group had rebleeding during the 1 year after randomization. The actuarial probability of rebleeding 1 years after randomization was lower in the PR + IM group but the difference was not significant (P = 0.09). However, by adding an additional 8 months of follow-up, the decrease in the risk of rebleeding reached statistical significance (P = 0.05). No significant difference was found in rebleeding index and survival. The multivariate Cox analysis indicated both treatment (P = 0.04), severity of liver disease (P = 0.03) and age (P = 0.045) were factors predictive of rebleeding and second, that PR + MI reduced the risk of rebleeding by half (relative risk: 0.54). CONCLUSION: These results suggest that the addition of IM improves the efficacy of PR alone in the prevention of variceal rebleeding in cirrhotic patients. However no beneficial effects were observed on other parameters reflecting the efficacy of treatment.
Propranolol (1; Obsidan) relaxes in vitro stripes of smooth muscles of non-pregnant rat's uterus in a concentration dependent manner. In contrast, on uterine muscle stripes of pregnant rats 1 causes small contractions. In an combination of 1 and fenoterol (2; Partusisten) (20:1) 1 prevents the relaxing effect of 2, reported to be an inhibitor of uterine muscle activity. This antagonism is most distinct on stripes of pregnant rat's uterus.
Plasma concentrations of propranolol (PROP) and its active 4-hydroxymetabolite were determined in neurological patients receiving chronic therapy with relatively low PROP doses (40-240 mg/day). Plasma PROP concentrations determined before the morning dose were much lower than, but significantly correlated (r = 0.91) with the drug level two hours after dosing. 4-hydroxypropranolol (4-OH-P) was often undetectable (less than 1 ng/ml) in the early morning samples. Plasma concentrations of both parent drug and metabolite determined two hours after the morning dose correlated weakly with the prescribed daily dose. The intrapatient dose-concentration relationship, on the other hand, was strong, particularly for the parent drug. The ratio between 4-OH-P and PROP in plasma was inversely related to the PROP concentration, at least over the lower PROP concentration range (0-100 ng/ml). The usefulness of determining the concentration of the metabolite in the evaluation of the pharmacological action of low doses of PROP is discussed.
In 31 dogs chronically beta blocked with oral propranolol (12 to 14 mg/kg/day), glucagon (20 micrograms/kg) and combined dopamine (10 micrograms/kg/min) and isoproterenol (0.2 micrograms/kg/min) were given intravenously and tested for hemodynamic efficacy. Dogs were divided into four groups. Basal hemodynamics were obtained In Group I (n = 8) without cardiopulmonary bypass. In Group II (n = 8), hemodynamics were studied after 15 minutes of global ischemia during cardiopulmonary bypass. In Group III (n = 8), hemodynamics were studied after regional ischemia produced by ligation of the proximal left anterior descending coronary artery. In Group IV (n = 7), myocardial oxygen consumption and left ventricular mechanics were studied before and after 1 hour of cardiopulmonary bypass. Our results indicate the following: (1) Dopamine-isoproterenol improves hemodynamics in basal, post-global ischemic, and post-regional ischemic states. Glucagon improves hemodynamics either insignificantly or to a lesser extent than dopamine-isoproterenol. Furthermore, glucagon produces a larger increase in heart rate, which is not desirable. (2) Both dopamine-isoproterenol and glucagon increase myocardial oxygen consumption in comparison with control.
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