Modification of propranolol's bioavailability by Eurycoma longifolia water-based extract.

WHAT IS KNOWN AND BACKGROUND: Eurycoma longifolia (E. longifolia), a herb commonly consumed for its aphrodisiac properties, is widely used by Asian males. This may include hypertensive patients receiving propranolol which may cause sexual dysfunction as one of its side-effects. There is no published study of the potential pharmacokinetic interaction between propranolol and the herb. OBJECTIVE: To study propranolol's pharmacokinetics when E. longifolia is consumed, comparing volunteers given either propranolol or a placebo. METHODS: This is a placebo-controlled randomized single-blinded crossover study of the effect of a water-based extract of E. longifolia on the pharmacokinetics of a single dose of proporanolol (Inderal(®)) in 14 healthy non-smoker young males. Eighty milligram of propranonol was orally administered with (i) placebo (Lactose) or (ii) 200 mg of water-based extract of E. longifolia (0·0272 ± 0·0026%eurycomanone) following an overnight fasting. Blood samples were collected at 0, 0·5, 1, 1·5, 2, 3, 4, 6, 8 and 10 h for propranolol's plasma concentration determinations using a validated high-performance liquid chromatography (HPLC) method. RESULTS AND DISCUSSION: When propranolol was administered with E. longifolia, its bioavailability (AUC0-∞) decreased by 29% while C(max) was reduced by 42% and T(max) was significantly prolonged by almost 86%. The terminal elimination half-life, however, was not significantly affected. CONCLUSION: The bioavailability of propranolol is significantly decreased when consumed together with E. longifolia. The interaction is due to a reduction in absorption, rather than an increase in propranolol's metabolism. Although the pharmacodynamics of propranolol was not affected in healthy volunteers, caution is still advisable with co-administration of the drug and the herb.

Development of a reservoir-type transdermal enantioselective-controlled delivery system for racemic propranolol using a molecularly imprinted polymer composite membrane.

The aims of this study were to develop a transdermal patch for selective controlled delivery of the active S-enantiomer from racemic propranolol, and to evaluate its performance in vivo using Wistar rats. A molecularly imprinted polymer (MIP) thin-layer composited cellulose membrane with selectivity for S-propranolol was employed as the enantioselective-controlled release system. The effect of gel reservoir (poloxamer and chitosan) on enantioselective delivery was investigated. The chitosan gel allowed excellent selectivity for delivery of the S-propranolol enantiomer, whilst the more rheologically structured poloxamer gel formulation provided no selective release of S-propranolol. The chitosan gel exhibited high flux and had the ability to enantioselective deliver S-propranolol across excised rat skin. The results from confocal laser scanning microscopy study, carried out with the R- and S-propranolol enantiomers labeled with a 1-pyrenebutyric acid probe as fluorescent markers, suggested that the MIP composite membrane selectively regulated the release of the recognised S-enantiomer via a facilitated transport pathway through complex formation with the selective receptor sites, while the release of the R-enantiomer was via a non-selective route. The reservoir patch for enantiomer-controlled delivery of propranolol was therefore fabricated by incorporating the chitosan gel formulation containing racemic propranolol hydrochloride into the MIP composite membrane laminated backing. These patch devices were shown to exhibit the significant stereoselectivity uptake of propranolol when attached to the skin, using pharmacokinetic studies in rats. S-Propranolol enantiomer plasma concentration profiles for the transdermal patch in the in vivo study were comparable to data for the gel formulations that were applied directly to skin, and containing a single S-enantiomer of propranolol. The results demonstrate that the transdermal patch based on the MIP composite membrane-controlled release system may have potential in the enantioselective-controlled delivery of the S-isomer of racemic propranolol.

Pharmacokinetics of propranolol after single and multiple dosing with sustained release propranolol or propranolol CR (innopran XL) , a new chronotherapeutic formulation.

Blood pressure rises rapidly upon waking and may be responsible, in part, for the increased incidence of myocardial infarction and stroke during the morning hours. Current formulations and dosing of antihypertensive drugs do not provide maximum coverage during this vulnerable period. This study was performed to demonstrate that propranolol CR (Innopran XL), a novel chronotherapeutic formulation of propranolol designed for nighttime dosing, has appropriate pharmacokinetics to provide maximum cardioprotective effect in the morning. Pharmacokinetics of propranolol CR and sustained-release propranolol after single and multiple doses were determined in normal male volunteers in this open-label, 2-period crossover study. The drugs were dosed in the evening and serial blood samples were taken for determination of propranolol concentration the next 24 to 72 hours. After a single 160-mg dose of propranolol CR administered at 10 pm, absorption was delayed by about 4 hours, after which plasma concentration rose steadily, reaching a peak at about 10:00 am. In contrast, after dosing with sustained release propranolol, plasma levels of propranolol began to rise almost immediately, reaching a plateau between 4:00 am and 10:00 am. During multiple dosing, steady-state trough plasma concentrations were achieved after 2 days with either drug. After the final dose, the plasma profiles of both drugs were similar to those observed in the single-dose study. Bioavailability was similar for both formulations of propranolol. Propranolol CR exhibited appropriate pharmacokinetics for a chronotherapeutic approach to the treatment of hypertension.

Performance of an ultra-low elution-volume 96-well plate: drug discovery and development applications.

Recently, sample preparation has been considered to be the major cause of bottlenecks during high-throughput analysis. With the assistance of robotic liquid handlers and the 96-well plate format, more samples can be prepared for subsequent liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis. Protein precipitation is still widely used despite potential loss of sensitivity or variable results due to ion suppression. The use of solid-phase extraction (SPE) clearly gives superior results but may not be as cost effective as protein precipitation due to the labor and material costs associated with the process. Here, a novel 96-well SPE plate is described that was designed to minimize the elution volume required for quantitative elution of analytes. The plate is packed with 2 mg of a high-capacity SPE sorbent that allows loading of up to 750 microL of plasma, while the novel design permits elution with as little as 25 microL. Therefore, the plate offers up to a 15-fold increase in sample concentration. The evaporation and reconstitution step that is typically required in SPE is avoided due to the concentrating ability of the plate. Examples of applications in drug discovery/development are shown and results are compared to protein precipitation. Excellent sensitivity and linearity are demonstrated.

Comparison of the properties of polymeric and C8 based materials for solid phase extraction.

The extraction properties of two polymeric solid phase extraction materials, styryldivinyl benzene (SDB) and 'Oasis' have been compared with those of a base deactivated C8 bonded silica gel using a range of acidic and basic test analytes. In the case of the two polymer phases good extraction of all the test compounds from aqueous buffer was obtained over the pH range 2-10. On the C8 material, efficient extraction of the most polar acidic analyte, anisic acid, was only obtained between pH 2 and 6. The use of methanol water mixtures, or methanol water mixtures modified with either trifluoroacetic acid (TFA) or triethylamine (TEA) as eluents was investigated for the recovery of the analytes following extraction. The use of TFA or TEA as ionic modifiers strongly influenced the efficiency of the elution step. The effect of a plasma matrix on extraction efficiency was also investigated, with the result depending upon the analyte. An approach to assessing the performance of the three phases has been developed based on the percentages of methanol in the eluent resulting in the recovery of 50% of the analyte, and in determining the difference between eluents giving recoveries of 10 and 90%.

Effects of a Finnish sauna on the pharmacokinetics and haemodynamic actions of propranolol and captopril in healthy volunteers.

The effects of a Finnish sauna on propranolol pharmacokinetics and on the pharmacodynamics of propranolol and captopril were studied in healthy, young volunteers (2 males, 6 females) in a double-blind, cross-over trial. The subjects received single oral doses of placebo, propranolol (40 mg) or captopril (12.5 mg) in sauna and control sessions at a one-week interval. The sauna sessions consisted of three repetitive 10-min stays in a sauna (85-100 degrees C, relative humidity 25-35%) separated by two 5-min rest periods in a cool room. Sauna bathing started 35, 50 and 65 min after ingestion of the drugs. Venous blood for plasma propranolol measurement were collected before and 15, 30, 45, 60, 75, 90 min and 2, 3, 4, 5, 7 and 24 h after drug intake. The sauna significantly increased the maximum concentration (Cmax 41 vs. 28 ng.ml-1) of propranolol and the mean plasma propranolol concentration 60 and 90 min, and 2 and 3 h after drug administration. It also significantly increased the AUC0-5h (119 vs 71 micrograms.h.l-1) of propranolol from 0 to 5 hours tmax, t1/2 beta and AUC0-24h of propranolol did not differ between the control and sauna sessions. The higher propranolol levels during and after the cessation of sauna bathing did not lead to significant changes in blood pressure or heart rate compared to the control period. Captopril had no major effects on these parameters during the post-sauna phase.(ABSTRACT TRUNCATED AT 250 WORDS)

[The pharmacokinetics of propranolol when used with the propercuten transdermal therapeutic system (experimental data)]. / Farmakokinetika propranolola pri primenenii transdermal'noi terapevticheskoi sistemy properkutena (éksperimental'nye dannye).

The pharmacokinetic studies of propranolol following the application of the propercuten transdermal therapeutic system were performed in conscious rabbits previously assigned to 3 groups. Different forms of propercuten (forte and mite) were used in different groups, different areas of its application being employed. Pulsed intravenous injections of propranolol were given to Group 1 rabbits to conduct another series of pharmacokinetic studies. The rate of drug administration to the systemic bed was 0.08 mg/h per cm propercuten. The constant injection rate was maintained during 5 days, but when propercuten was withdrawn the elimination time of propranolol was 24 hours.

The influence of vitamin K3 treatment on the pharmacokinetics and metabolism of (+)-propranolol in the rat.

The effects of vitamin K3 treatment on the pharmacokinetics and metabolism of (+)-propranolol and the consequences of hepatic injury associated with vitamin K3 treatment were examined in groups of male Sprague-Dawley rats. When vitamin K3 (20 mg/kg) in polyethylene glycol 300 (PEG 300) was coinfused with (+)-propranolol (2 mg/kg) into the pyloric vein (a tributary flowing directly into the hepatic portal vein), a significant decrease in the intrinsic clearance of total drug (CLint) from 94.1 +/- 50.1 to 32.9 +/- 11.5 ml/min/kg was observed (p less than 0.01 vs. vehicle control). However, a lower dose of vitamin K3 (2 mg/kg in PEG 300) had little effect on this parameter. Interestingly, the PEG 300 vehicle control group exhibited a significantly (p less than 0.05) higher CLint than that observed in a saline control group (94.1 +/- 50.1 vs. 45.9 +/- 13.7 ml/min/kg). This difference appeared to be due to an increase in the free fraction of propranolol caused by PEG 300, because in vitro addition of this solvent to serum (at estimated in vivo concentrations) with or without added vitamin K3 doubled propranolol free fraction. Furthermore, rats that received the high dose vitamin K3 (20 mg/kg) treatment exhibited a pronounced increase in the serum concentration of enzymes of hepatic origin (alanine aminotransferase and sorbitol dehydrogenase) and in the incidence of hepatic necrosis. It was also observed that high-dose vitamin K3 treatment caused only minor changes in the urinary recovery of propranolol metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative study of the effect of nifedipine versus diltiazem on exercise performance, serum propranolol levels, and ST-segment abnormalities in patients with chronic stable angina taking propranolol.

Twelve patients (10 men and 2 women), mean age 60.6 years (range 50 to 75), with stable angina pectoris were administered propranolol until beta blockade was evident. Treadmill exercise testing was performed, 24-hour ambulatory electrocardiograms were recorded, and serum propranolol levels were assessed at 1 and 2 hours after dosing with propranolol alone, and after 2 weeks of combined therapy with either nifedipine, 10 or 20 mg, or diltiazem, 60 or 120 mg, administered every 8 hours. Patients were assigned to treatment regimens in randomized, double-blind, crossover fashion. At the time of exercise testing, maximal exercise time, time to angina, peak exercise heart rate and systolic blood pressure and time to 1 mm of ST-segment depression were measured. The rate-pressure product was also calculated. Maximal exercise time increased from 708 +/- 140 seconds with propranolol alone to 795 +/- 156 seconds after combined propranolol-nifedipine therapy (p less than 0.05), and to 790 +/- 107 seconds (p less than 0.05) after propranolol-diltiazem therapy. Time to onset of angina increased from 472 +/- 191 seconds with propranolol alone to 564 +/- 123 seconds (p = NS) after propranolol-nifedipine treatment and to 607 +/- 197 seconds (p less than 0.05) after propranolol-diltiazem treatment. Peak exercise heart rate remained unchanged with propranolol-nifedipine therapy (103 +/- 16 beats/min vs 104 +/- 17 with propranolol alone). However, with propranolol-diltiazem therapy, peak exercise heart rate significantly decreased to 95 +/- 14 beats/min (p less than 0.05); peak systolic blood pressure and rate-pressure products were comparable on all treatment regimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Nifedipine-propranolol interaction: dependence of cardiovascular effects on plasma drug concentrations.

The relationships between plasma drug concentrations and cardiovascular effects during combined administration of nifedipine and propranolol were evaluated in dogs anesthetized with thiopental. Three received small intravenous (i.v.) doses of nifedipine followed by propranolol, and 6 were given higher doses of nifedipine followed by propranolol; in 5, the order of drug doses was reversed, with propranolol administration followed by nifedipine. When dosing regimens that produced stable plasma levels of both drugs were used, the observed effects were closely related to the plasma concentrations of the individual agents. When small doses of nifedipine were combined with propranolol, at plasma levels associated with a significant degree of beta-adrenoceptor blockade, moderate decreases in spontaneous heart rate and cardiac output as well as increases in atrioventricular conduction time were produced. With higher doses of nifedipine, combined infusion with propranolol resulted in more pronounced depression in cardiac function, characterized by decreases in cardiac output, heart rate, and mean pulmonary arterial pressure, as well as increases in atrioventricular conduction time. When propranolol administration was followed by nifedipine, similar dose-dependent cardiovascular effects resulted, with profound toxicity apparent when large doses of nifedipine were used. These studies in an acute anesthetized dog model suggest that the magnitude of cardiovascular depression resulting from nifedipine and propranolol in combination is dependent on the plasma concentrations of both agents. Furthermore, in the presence of beta-adrenoceptor blockade, the direct effects of nifedipine on myocardial conducting tissue, which are usually absent when this calcium antagonist is given alone, may become apparent and result in depression of atrioventricular and sinoatrial nodal functions.

Haemodynamic effects of verapamil administration after large doses of fentanyl in man.

Thirteen patients with good left ventricular function undergoing coronary artery revascularization were studied to determine the cardiovascular effects of verapamil, 75-150 micrograms X kg-1, after a large dose (100 micrograms X kg-1) of fentanyl, with pancuronium for muscle relaxation. The patients were continued on their usual cardiovascular medications until the time of surgery, which included nitrates, beta adrenergic blockers, and nifedipine. Anaesthesia with fentanyl was associated with decreases in mean arterial blood pressure, systemic vascular resistance, left ventricular stroke work index, and circulating catecholamine levels. Mean values were not further changed by verapamil, but individual patients had additional modest decreases in blood pressure and systemic vascular resistance. Cardiac index, however, was well maintained. Plasma catecholamines remained depressed after verapamil under the study condition. Thus, in patients with good left ventricular function, clinically relevant doses of verapamil were well tolerated even in the presence of an anaesthetic that included large doses of fentanyl, with suppression of circulating catecholamine levels.

Cigarette smoking and the treatment of angina with propranolol, atenolol, and nifedipine.

To determine whether cigarette smoking affects the results of drug treatment for angina, we studied 10 cigarette smokers with angina who were given placebo, nifedipine (60 mg per day), propranolol (240 mg per day), and atenolol (100 mg per day), each for one week. The four-week double-blind study was repeated with the same randomly determined order of drug sequences, after all 10 subjects had stopped smoking. Before and after the subjects stopped smoking, all three drugs significantly reduced the frequency of angina, as measured with angina diaries, and improved the results of maximal exercise testing and 48-hour ambulatory monitoring of ST segments (P less than 0.01). However, during the nonsmoking phase of the study, there was an overall decline in the frequency of angina and an improvement in performance on exercise testing (P less than 0.05) as compared with the smoking period, although the results of 48-hour ambulatory monitoring remained unchanged. The improvement after patients stopped smoking was greater during treatment with nifedipine than during administration of the other two drugs or placebo. Blood levels of propranolol were increased when patients stopped smoking; levels of nifedipine and atenolol were unchanged. Our data show that smoking had direct and adverse effects on the heart and interfered with the efficacy of all three anti-anginal drugs, but with nifedipine the most.

Improved exercise tolerance after propranolol, diltiazem or nifedipine in angina pectoris: comparison at 1, 3 and 8 hours and correlation with plasma drug concentration.

Exercise tolerance 1, 3 and 8 hours after 80 mg of propranolol, 120 mg of diltiazem and 20 mg of nifedipine, and after 20 minutes of 0.6 mg of sublingual nitroglycerin were compared with placebo in 15 men who had chronic stable angina pectoris. Three hours after drug ingestion, the exercise time was prolonged by 72 +/- 26, 162 +/- 27 and 161 +/- 30 seconds (p less than 0.05) for propranolol, diltiazem and nifedipine, respectively, and by 123 +/- 35 seconds (p less than 0.001) 20 minutes after sublingual nitroglycerin compared with placebo. The onset of ST-segment depression greater than or equal to 0.1 mV was delayed by 120 +/- 34, 203 +/- 29 and 189 +/- 35 seconds (p less than 0.05) and by 79 +/- 23 seconds (p less than 0.05), respectively. After propranolol, the peak rate-pressure product decreased compared with placebo (15.1 +/- 1.1 U [10(-3)] vs 20.0 +/- 1.5 U, p less than 0.01). In contrast, the peak rate-pressure product was greater after diltiazem and nifedipine than after placebo (22.2 +/- 1.3 U [p less than 0.05] and 23.8 +/- 1.4 U [p less than 0.01]). The maximal increase in exercise tolerance was most marked for each drug at 3 hours, but was also significant at 1 hour for nifedipine and at 8 hours for diltiazem. At 3 hours, an increase in exercise time of more than 2 minutes was observed in 4 of 6 patients who had plasma propranolol concentrations greater than 40 ng/ml, 8 of 9 who had a plasma diltiazem concentration greater than 150 ng/ml, and in 7 of 7 who had a plasma nifedipine concentration greater than 90 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)