A pharmacokinetic study to determine the drug interaction between valproate and propranolol

A 40-year-old female receiving divalproex sodium (VPA) monotherapy for epilepsy developed a tremor secondary to the drug. Propranolol treatment was initiated. While receiving propranolol 40 mg, VPA clearance was reduced from 1.66 L/hr to 1.19 L/hr and dropped to 1.08 L/hr on propranolol 80 mg. The mechanism of this interaction is unknown. To evaluate the potential for a drug interaction between these two agents, 12 patients on VPA monotherapy, ages 19-55, were studied. The subjects were maintained on a constant dose of VPA. Each was then randomly assigned to receive placebo, or long-acting propranolol 60 mg/day or 120 mg/day. Mean VPA serum concentrations did not change among the three groups. Plasma half-life of VPA ranged from 7.3-18 hours and did not change with coadministration of propranolol. We concluded that VFA metabolism is not affected by coadministration of propranolol in this group of patients.     

Toxic interactions between disopyramide and propranolol in chick embryos

The toxic interaction between disopyramide and propranolol were studied in chick embryos. Fertilized eggs of White Leghorns were incubated and investigated. Disopyramide with and without propranolol was injected into the air sac of a fertilized egg on the 16th day of incubation. Electrocardiograms (ECGs) were recorded 0 to 60 min after the injection. After each drug injection alone, the heart rate was not different compared with control. However, the heart rate was significantly decreased by combination with disopyramide and propranolol. In addition, arrhythmia was produced by disopyramide 1.0 mg/egg alone and in combination with propranolol. These findings indicate that the interaction between disopyramide and propranolol has a marked influence on the heart rate in chick embryos.     

The effect of propranolol upon chick embryo cardiogenesis

The teratogenic effects of propranolol HCl on cardiac development were studied in chick embryos of days 3 and 4 of incubation. Propranolol was injected into the yolk sac at doses ranging from 0.05 to 0.6 mg per egg. All the treated and control embryos were examined on day 7. The LD50 for the embryos treated on the 3rd and 4th day was 0.15 and 0.35 mg per embryo, respectively. Cardiac anomalies such as aortic stenosis ventricular septal defects and common truncus arteriosus were observed. Other malformations included atrial septal defects, thin atrial wall and defects of the pulmonic, aortic and atrioventricular valves. The incidence of cardiac anomalies in the controls was very low. Propranolol was observed to slow the heart rate in the experimental embryos. It is suggested that slowing of heart rate at the early stages of heart development caused aberrant bloodstream flow patterns which probably resulted in the genesis of cardiac anomalies. The results of this study indicate that propranolol has teratogenic effects on chick embryo cardiogenesis.     

Propofol decreases ocular pressure in outpatients undergoing trabeculectomy

OBJECTIVES: The present study was conducted to compare pharmacokinetic behaviors of nicardipine enantiomers given in different doses with different formulations of racemic nicardipine in healthy volunteers. METHODS: One or two 20-mg racemic nicardipine tablets, and a 40-mg sustained-release capsule of nicardipine were administered to eight healthy volunteers in a crossover fashion and pharmacokinetic parameters were evaluated. Enantiomer concentrations were determined by GC-MS combined with chiral stationary phase HPLC. RESULTS AND CONCLUSIONS: Serum concentration of (+)-nicardipine was approximately 2-3 times higher than that of (-)-nicardipine in 20- and 40-mg doses of conventional formulations and a non-linear increase in bioavailability with dose was demonstrated. The value for AUC of (+)-nicardipine was approximately 2.3-2.8 times greater than that of the (-)-nicardipine (P < 0.05) when 20 and 40 mg racemic nicardipine were administered in a conventional preparation. Relative bioavailability of the sustained-release preparation vs the conventional preparation was 28% and 44% for (+)- and (-)-nicardipine, respectively, for the 40-mg dose.     

Identification of formulation and manufacturing variables that influence in vitro dissolution and in vivo bioavailability of propranolol hydrochloride tablets

The purpose of this study was to evaluate the effect of formulation and processing changes on the dissolution and bioavailability of propranolol hydrochloride tablets. Directly compressed blends of 6 kg (20,000 units) were prepared by mixing in a 16-qt V blender and tablets were compressed on an instrumented Manesty D3B tablet press. A half-factorial (2(5-1), Resolution V) design was used to study the following variables: filler ratio (lactose/dicalcium phosphate), sodium starch glycolate level, magnesium stearate level, lubricant blend time, and compression force. The levels and ranges of the excipients and processing changes studied represented level 2 or greater changes as indicated by the Scale-up and Post Approval Changes (SUPAC-IR) Guidance. Changes in filler ratio, disintegrant level, and compression force were significant in affecting percent drug released (Q) in 5 min (Q5) and Q10. However, changes in magnesium stearate level and lubricant blend time did not influence Q5 and Q10. Hardness was found to be affected by changes in all of the variables studied. Some interaction effects between the variables studied were also found to be significant. To examine the impact of formulation and processing variables on in vivo absorption, three batches were selected for a bioavailability study based on their dissolution profiles. Thirteen subjects received four propranolol treatments (slow-, medium-, and fast-dissolving formulations and Inderal 80 mg) separated by 1 week washout according to a randomized crossover design. The formulations were found to be bioequivalent with respect to the log Cmax and log AUC0-infinity. The results of this study suggest that (i) bioavailability/bioequivalency studies may not be necessary for propranolol and perhaps other class 1 drugs after level 2 type changes, and (ii) in vitro dissolution tests may be used to show bioequivalence of propranolol formulations with processing or formulation changes within the specified level 2 ranges examined.     

Relationship between the amount of propranolol permeating through the stratum corneum of guinea pig skin after application of propranolol adhesive patches and skin irritation

In the present study we evaluated the relationship between the cumulative amount of propranolol permeating through the stratum corneum and the formation of erythema, a skin irritation reaction, after transdermal application of adhesive patches containing propranolol to the skin of guinea pigs. The intensity of erythema was expressed in terms of a* values measured with a chromameter. The a* values increased in guinea pigs after application of the adhesive patches containing 0.4 mg/cm2 of propranolol to the skin. Since the adhesive patches showed good adhesion to the skin (propranolol content is less than the saturated concentration in the adhesive base) and the cumulative amount of propranolol permeating through the stratum corneum is small, the development of erythema was considered to be mainly due to physical factors such as peeling. Even in adhesive patches containing 0.8 mg/cm2 or 1.2 mg/cm2 of propranolol, a* values increased, although adhesion to the skin is low because of crystallization of propranolol in the adhesive base. On the other hand, in these two adhesive patches, the cumulative amount of propranolol permeating through the stratum corneum increased up to 24 h after application. These findings suggest that the skin irritation reaction is due to propranolol mainly absorbed transdermally, because there is a high correlation between the cumulative amount of propranolol permeating through the stratum corneum and the a* values (r = 0.928).     

The pharmacokinetics of propranolol when used with the propercuten transdermal therapeutic system (experimental data)

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.     

A comparison of the beta-blocking activities of practolol, sotalol, and propranolol in human and guinea pig tracheal smooth muscle

Beta adrenergic blockade was studied in vitro with human tracheal muscle strips and guinea pig tracheal chains. It was shown in isolated smooth muscle from both man and guinea pig that the order of potency for the three beta-blocking agents studied was: propranolol greater than sotalol greater than practolol. Under the conditions of this study, propranolol was about 30,000 times and sotalol about 30 times as potent as practolol. The order of potency suggests that the nature of adrenergic blockade induced by practolol on tracheal smooth muscle is only weakly beta2-relative to the blocking effects of propranolol and sotalol. Beta adrenergic blockade by propranolol, sotalol, and practolol produced different degrees of increased histamine lethality in mice. Whereas both propranolol at 0.01 mg/kg and sotalol at 1.0 mg/kg resulted in 100% histamine-induced lethality, practolol at 50 mg/kg resulted in only 50% histamine-induced lethality. These data, when added to those from our previous studies, suggest that the mechanisms responsible for resistance to the effects of histamine in untreated mice are at least partially mediated by the beta2-adrenergic system. Thus, in three different tissues, the blocking activity of practolol was shown to be less than that of sotalol or propranolol.     

Single-dose interaction study of diprafenone HCl and propranolol HCl in healthy volunteers

Using a 3 x 3 Latin Square design, a possible interaction between diprafenone HCl a class IC antiarrhythmic drug with nonspecific beta-antagonist activity and propranolol HCl was investigated in nine young, healthy, caucasian, male volunteers. The volunteers randomly received 3 single-dose treatments: (A) 200 mg DHCl, (B) 80 mg PHCl, and (C) 200 mg DHCl and 80 mg PHCl. Scheduled blood samples were taken and plasma concentrations of both diprafenone and propranolol were measured by sensitive and specific assay methods. Lead II electrocardiogram intervals at rest, heart rate during erect bicycle ergometry, and echocardiographic variables at rest and shortly after exercise were recorded. The data analysis used compartment model independent methods. There was no evidence for a pharmacokinetic interaction between the two drugs. With DHCl, two of the nine subjects showed greatly increased areas under the plasma concentration-time curves and apparent disposition half-lives in the presence and absence of PHCl, indicating that metabolism of diprafenone may be subject to pharmacogenetic polymorphism. There was evidence for a pharmacodynamic interaction between DHCl and PHCl regarding the negative chronotropic effect at rest and during exercise. There was no difference in the pharmacodynamics and tolerability of the three treatments in suspected "poor" and "extensive metabolizers" of DHCl.     

Effectiveness of slow release L-DOPA/benserazide in treatment of end-of-dose akinesia in Parkinson disease

In an open label study 63 patients with idiopathic Parkinson's disease suffering from end-of-dose akinesia were switched from a treatment with a L-DOPA standard formulation to a combined therapy of L-DOPA standard in the morning and L-DOPA slow release (levodopa, benserazide, Madopar Depot) at the remaining single doses. Substitution of L-DOPA standard by L-DOPA slow release took on average 2-4 weeks. Patients were subsequently treated for 6 months. Due to a lower bioavailability of the slow release formulation--the latter is based on the "hydrodynamically balanced system" (HBS)--, the patients remained initially on their time schedule of drug intake but received a higher dose of L-DOPA slow release compared to the preceding L-DOPA standard therapy. In 20 centers 37 men and 26 women were included into the study. 27 males and 20 females completed the 6 month treatment period. Before switching, the patients received 438 +/- 213 mg a day L-DOPA standard, after conversion, the average dose was 617 +/- 323 mg L-DOPA slow release and 107 +/- 95 mg L-DOPA standard a day. Fluctuations during the day and at night which were rated according to a newly developed clinical 5-point rating scale were significantly improved by the treatment regimen from 2.8 +/- 0.9 to 1.4 +/- 1.2. Additionally, parkinsonian symptoms were significantly reduced during the ON-phase as there was a significant decrease of the Webster rating score from 12.0 +/- 4.6 to 7.1 +/- 4.0. Quality of life as measured by subjective ratings of the patients improved. The tolerability of the new formulation of L-DOPA was rated to be good in 51.1% and very good in 48.9%. The results of this open label study suggest that the combination of L-DOPA standard in the morning and L-DOPA slow release formulation at the following time points can be an efficient therapy in parkinsonian patients who suffer form L-DOPA related end-of-dose motor akinesia.     

Effects and plasma levels of propranolol and metoprolol in hyperthyroid patients

The effects and plasma concentrations of different doses of propranolol and metoprolol were studied in 34 hyperthyroid patients. The initial daily doses were propranolol 160 mg or metoprolol 200 mg. If the resting heart rate remained above 75 beats per min after treatment for 4-7 days, the dose was increased and the patient re-examined after a further 4-7 days. Propranolol (n = 17) caused a reduced heart rate, a decrease in serum 3,3',5-triiodothyronine (T3) and an increase in serum 3,3',5'-triiodothyronine (reverse T3, rT3). In 10 patients, there was no change in T3 or rT3 until the daily dose of propranolol had been increased to 240 or 320 mg. The plasma level of propranolol was significantly correlated with the decrease in T3 and the increase in rT3. Metoprolol (n = 17) caused a reduction in heart rate similar to that following propranolol. However, serum T3 was only slightly reduced even after an increase in dose to 300 or 400 mg, and serum rT3 was not altered. Metoprolol concentrations were not significantly correlated with the fall in T3. It appears that the influence of beta-blockers on T4 conversion is of little importance for the clinical improvement in hyperthyroid patients, and rather it is a consequence of beta 1-adrenergic blockade interfering with the effect of T3. In addition, the findings support the assumption that therapeutic failure with beta-blockers in hyperthyroidism may be due to suboptimal treatment, and that individualized dosage is necessary.     

Enhancing the effectiveness of relaxation-thermal biofeedback training with propranolol hydrochloride.

This article evaluated the ability of propranolol to enhance results achieved with relaxation-biofeedback training. Thirty-three patients were randomized to relaxation-biofeedback training alone (administered in a limited-contact treatment format), or to relaxation-biofeedback training accompanied by long-acting propranolol (with dosage individualized at 60, 120, or 180 mg/day). Concomitant propranolol therapy significantly enhanced the effectiveness of relaxation-biofeedback training when either daily headache recordings (79% vs. 54% reduction in migraine activity) or neurologist clinical evaluations (90% vs. 66% reduction) were used to assess treatment outcome. Concomitant propranolol therapy also yielded larger reductions in analgesic medication use and greater improvements of quality of life measures than relaxation-biofeedback training alone but was more frequently associated with side effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Tissue perfusion in relation to cardiac output during continuous positive-pressure ventilation and administration of propranolol or verapamil

BACKGROUND: Our objective was to determine whether administration of propranolol or verapamil modifies the hemodynamic adaptation to continuous positive-pressure ventilation (CPPV), in particular the regional distribution of cardiac output (CO). METHODS: General hemodynamics and regional blood flows assessed by microsphere technique (15 microns) were recorded in 16 anesthetized pigs during spontaneous breathing (SB) and CPPV with 8 cm H2O end-expiratory pressure (CPPV8) before and after intravenous administration of propanolol (0.3 mg.kg-1 followed by 0.15 mg.kg-1.h-1, n = 8) or verapamil (0.1 mg.kg-1 followed by 0.3 mg.kg-1.h-1, n = 8). RESULTS: CPPV8 depressed CO by 25% without shifts in its relative distribution with the exception of a noteworthy increase in adrenal perfusion. Propranolol increased arterial blood pressure, and due to a fall in heart rate, CO dropped by 25%. The kidneys and, to a lesser extent, the splanchic region and central nervous system received increased fractions of the remaining CO at the expense of skeletal muscle flow. Similar patterns were seen during SB and CPPV8 such that the combination of propranolol and CPPV8 depressed CO by 50%. The circulatory effects of verapamil were less evident but myocardial perfusion tended to increase. CONCLUSIONS: The combination of propranolol or verapamil with CPPV does not result in any specific hemodynamic interaction in anesthetized pigs, except that the combined effect of propranolol and CPPV may severely reduce CO.     

Stereoselective hydrolysis of O-isovaleryl propranolol and its influence on the clearance of propranolol after oral administration

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)     

Beta-adrenoceptor mediated facilitation of noradrenaline and adenosine 5'-triphosphate release from sympathetic nerves supplying the rat tail artery

1. The effects of prejunctional beta-adrenoceptor activation on electrically evoked noradrenaline (NA) and adenosine 5'-triphosphate (ATP) were studied by use of continuous amperometry and conventional intracellular recording techniques. Excitatory junction potentials (e.j.ps) were used as a measure of ATP release, and NA-induced slow depolarizations and oxidation currents as measures of NA release, from postganglionic sympathetic nerves innervating the rat tail artery in vitro. 2. Isoprenaline (0.1 microM) increased the amplitude of e.j.ps, slow depolarizations and oxidation currents evoked by short trains of stimuli at 1 to 4 Hz. The facilitatory effect of isoprenaline on e.j.ps and oxidation currents was most pronounced on responses evoked by the first stimulus in a train. 3. Isoprenaline (0.1 microM) did not detectably alter the amplitude-frequency distribution of spontaneous e.j.ps. 4. The facilitatory effect of isoprenaline on e.j.ps, slow depolarizations and oxidation currents was abolished by the beta-adrenoceptor antagonist, propranolol (0.1 microM). Propranolol alone had no effect on e.j.ps, slow depolarizations or oxidation currents. 5. Thus, activation of prejunctional beta-adrenoceptors increases the release of both NA and ATP from postganglionic sympathetic nerves. The findings are consistent with the hypothesis that NA and ATP are released from the same population of nerve terminals and presumably from the same vesicles.     

Comparative antihypertensive effects of propranolol and metoprolol in DOC-treated rats

The effects of chronic twice daily s.c. injections of dlpropranolol, metoprolol and d-propranolol on systolic blood pressure and heart rate were assessed in conscious DOC-saline hypertensive rats. Measurements were taken (tail-cuff) 4 hr after the morning injection and 16-18 hr after the afternoon injection during 11 of 19 consecutive treatment days. Only dl-propranolol and metoprolol at 5 mg/kg lowered blood pressure and heart rate significantly relative to the changes occurring in control saline-injected animals. At the lower dose of 0.2 mg/kg, both agents tended to decrease heart rate while having little or no effect on blood pressure. The overall blood pressure and heart rate changes produced by propranolol at 5 mg/kg differed significantly from those of the control group at both the 4 and 16-18 hr post-dosing intervals. Metoprolol at 5 mg/kg produced significant overall changes in blood pressure and heart rate only at the 4 hr post-doing interval. D-propranolol had no effect on either blood pressure or heart rate. The results indicate tha s.c. propranolol and metoprolol lower systolic blood pressure in conscious DOC-saline hypertensive rats only at the higher dose of 5 mg/kg and that cardioselectivity does not afford increased antihypertensive activity in this model.     

Complementary effects of propranolol and nonoxynol-9 upon human sperm motility

The inhibitory effects of nonoxynol-9, DL- and D-propranolol upon human sperm motility were determined in vitro. All three compounds were capable of causing complete cessation of sperm movement. However, greater efficacy was achieved using combinations of nonoxynol-9 and propranolol, suggesting a complementary interaction between these compounds. Investigations of the mechanism of action of propranolol revealed that an influx of calcium accompanied the loss of motility. However, since incubation in the absence of calcium enhanced the spermicidal effects of this compound, it was concluded that this calcium influx did not constitute the primary means by which motility was disrupted. Low doses of propranolol, which did not affect motility, were found to inhibit the capacity of human spermatozoa for sperm-oocyte fusion.     

The acute and chronic effect of oxprenolol and propranolol on peripheral blood flow in hypertensive patients

1 The effects of oxprenolol and propranolol on peripheral blood flow were compared in patients with mild and moderate essential hypertension. 2 In an acute double-blind crossover study in which eight patients participated there was a significant reduction in resting forearm blood flow (RFBF) 2 h after 80 mg propranolol (mean +/- s.e. mean) (-0.87 +/- 0.13 microliter min-1 100 g-1) and after 80 mg oxprenolol (-0.30 +/- 0.12) but not after placebo. This reduction was significantly greater after propranolol (P = 0.022). 3 Seven patients continued into a double-blind crossover study comparing the above dose of the two drugs twice a day. On both the beta-adrenoceptor blockers there was a significant reduction in blood pressure after 2 weeks of treatment and also a significant reduction in RFBF. 4 After 6 weeks treatment with propranolol the reduction in RFBF persisted and was significantly less (P = 0.04) than after 6 weeks treatment of oxprenolol, at which time RFBF was back to control. 5 There were no consistent changes in skin temperature. 6 Neither propranolol nor oxprenolol should be used in patients with severe peripheral vascular disease. 7 If beta-adrenoceptor blockade is necessary in patients with mild peripheral vascular disease oxprenolol should be used in preference to propranolol but should be prescribed with caution.     

The effects of propranolol, practolol and metoprolol on exercise-induced tachycardia in relation to plasma levels in man

1. The effects of single oral doses of propranolol, practolol and a new cardioselective beta-adrenoceptor blocking drug, metoprolol, on exercise-induced tachycardia in relation to plasma levels were studied in six normal volunteers. 2. Exercise undertaken on treadmill was submaximal which, under control conditions, increased the heart rate from 74-3 (s.e.m. = 6-8) to 153-8 (s.e.m. = 9.8) beats/min. 3. Plasma concentrations of propranolol and practolol were assayed fluorometrically and of metoprolol by electron-capture gas liquid chromatography, the details of which are described. 4. Between 1-5 and 2 h after drug ingestion 80 mg of propranolol associated with plasma level of 50-60 ng/ml (half-life 2-75 h), reduced the exercise-induced tachycardia by 27%, 250 mg of practolol with plasma levels of 1050-1100 ng/ml reduced it by 28% and 100 mg of metoprolol with plasma concentrations of 140-150 ng/ml (half-life 1-7 h), reduced it by 30%. 5. The resting heart rates were reduced significantly by propranolol and metoprolol but not by practolol. 6. Metoprolol is a potent short-acting beta-adrenoceptor antagonist; its advantages as a cardioselective agent over practolol in therapeutic use are discussed.     

Mechanisms of relaxant action of nicardipine, a new Ca++-antagonist, on isolated dog cerebral and mesenteric arteries

In helically-cut strips of cerebral and mesenteric arteries contracted with prostaglandin (PG) F2 alpha, carbocyclic thromboxane A2 (cTxA2) or K+, the addition of nicardipine caused a dose-related relaxation. Nicardipine-induced relaxation was greater in cerebral than in mesenteric arteries when contracted with PGF2 alpha and cTxA2, but did not appreciably differ in the arteries contracted with K+. Cerebral arteries contracted with hemolysate and PGF2 alpha relaxed in response to nicardipine to a similar extent. The contractile response to PGF2 alpha was attenuated by pretreatment with nicardipine, the attenuation being greater in cerebral than in mesenteric arteries. Ca++-induced contractions in cerebral and mesenteric arteries previously exposed to Ca++-free media and depolarized by excess K+ were attenuated by nicardipine to a similar extent. PGF2 alpha-induced contractions of cerebral arteries exposed to Ca++-free media were attenuated by nicardipine, whereas those of mesenteric arteries were unaffected. Attenuations by nicardipine of the Ca++-induced contraction in PGF2 alpha-treated cerebral arteries were greater than those seen in mesenteric arteries. It may be concluded that nicardipine produces a greater relaxation of cerebral arteries than mesenteric arteries, possibly due to a greater inhibition of the Ca++-influx and to a decrease in the release of Ca++ from intracellular storage sites in cerebral arteries. As far as the concentrations used are concerned, nicardipine appears to attenuate the inward movement of Ca++ across cell membrane in mesenteric arterial smooth muscle, but not the release of intracellularly stored Ca++.