Plasma Propranolol Levels Research Articles

Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study.

Background: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective.Methods: A multi-center open-label trial was conducted to assess the safety and efficacy of propranolol 0.2% eye micro-drops in newborns with stage 1 ROP. The progression of the disease was evaluated with serial ophthalmologic examinations. Hemodynamic, respiratory, biochemical parameters, and propranolol plasma levels were monitored. Demographic and perinatal characteristics, co-morbidities and co-intervention incidences, together with ROP progression, were compared with a historical control group in the same centers participating in the trial.Results: Ninety-eight newborns were enrolled and compared with the historical control group. Populations were not perfectly homogeneous (as demonstrated by the differences in the Apgar score and the different incidence rate in surfactant administration and oxygen exposure). The progression to ROP stage 2 or 3 plus was significantly lower than the incidence expected on the basis of historical data (Risk Ratio 0.521, 95% CI 0.297– 0.916). No adverse effects related to propranolol were observed and the mean propranolol plasma level was significantly lower than the safety cut-off of 20 ng/mL. Unexpectedly, three newborns treated with oral propranolol before the appearance of ROP, showed a ROP that was unresponsive to propranolol eye micro-drops and required laser photocoagulation treatment.Conclusion: Propranolol 0.2% eye micro-drops were well-tolerated and appeared to reduce the ROP progression expected on the basis of a comparison with a historical control group. Propranolol administered too early appears to favor a more aggressive ROP, suggesting that a β-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results.Clinical Trial Registration The trial was registered at ClinicalTrials.gov with Identifier NCT02504944 and with EudraCT Number 2014-005472-29.

Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial

BackgroundRetinopathy of prematurity (ROP) still represents one of the leading causes of visual impairment in childhood. Systemic propranolol has proven to be effective in reducing ROP progression in preterm newborns, although safety was not sufficiently guaranteed. On the contrary, topical treatment with propranolol eye micro-drops at a concentration of 0.1% had an optimal safety profile in preterm newborns with ROP, but was not sufficiently effective in reducing the disease progression if administered at an advanced stage (during stage 2). The aim of the present protocol is to evaluate the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns at a more precocious stage of ROP (stage 1).MethodsA multicenter, open-label, phase II, clinical trial, planned according to the Simon optimal two-stage design, will be performed to analyze the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns with stage 1 ROP. Preterm newborns with a gestational age of 23–32 weeks, with a stage 1 ROP will receive propranolol 0.2% eye micro-drops treatment until retinal vascularization has been completed, but for no longer than 90 days. Hemodynamic and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions, as well as electrocardiogram and echocardiogram, will be periodically performed to investigate treatment safety. Additionally, propranolol plasma levels will be measured at the steady state, on the 10th day of treatment. To assess the efficacy of topical treatment, the ROP progression from stage 1 ROP to stage 2 or 3 with plus will be evaluated by serial ophthalmologic examinations.DiscussionPropranolol eye micro-drops could represent an ideal strategy in counteracting ROP, because it is definitely safer than oral administration, inexpensive and an easily affordable treatment. Establishing the optimal dosage and treatment schedule is to date a crucial issue.Trial registrationClinicalTrials.gov Identifier NCT02504944, registered on July 19, 2015, updated July 12, 2016. EudraCT Number 2014–005472-29.

Propranolol inhibits the human ether-a-go-go-related gene potassium channels

Propranolol is a noncardioselective beta-adrenergic antagonist that has been recently reported to prolong the QTc interval on the surface electrocardiogram in humans when overdosed [Farhangi, V., Sansone, R.A. (2003). QTc prolongation due to propranolol overdose. Int. J. Psychiatry Med. 33, 201−202.]. To examine the underlying mechanisms for these clinical findings, we studied the effects of propranolol on the human cardiac potassium channels encoded by the ether-a-go-go-related gene (ERG) using the whole cell voltage-clamp technique. We found that propranolol blocked hERG currents in a concentration-dependent manner with an IC 50 of 9.9 ± 1.3 μM which is relevant to the predicted plasma level of propranolol in this case report. The present study demonstrated that propranolol can inhibit hERG channels. The interaction between propranolol and hERG channels could lead to delayed cardiac repolarization and might be a molecular mechanism for the previously reported QTc prolongation when propranolol is overdosed.

Human bioavailability of propranolol from a matrix-in-cylinder system with a HPMC-Gelucire® core

The bioavailability of propranolol from a matrix-in-cylinder system for sustained drug delivery, consisting of a hot-melt extruded ethylcellulose pipe surrounding a drug-containing HPMC-Gelucire® 44/14 core, was determined. An oral dose of 80 mg propranolol hydrochloride was administered to healthy volunteers ( n = 10) in a randomized cross-over study design either as a commercial pellet formulation (Inderal retard mitis®) or as a matrix-in-cylinder system. The influence of concomitant food intake on drug release from the matrix-in-cylinder system was also studied. During the first 10 h after administration, the matrix-in-cylinder system resulted in similar plasma levels as the reference formulation Inderal®. The concomitant intake of a high-fat, high-calorie breakfast did not cause dose-dumping. Between 10 h and 24 h after administration of the matrix-in-cylinder system, a remarkable increase of the propranolol plasma levels was noticed (compared to Inderal®). This effect was even more pronounced under fed conditions. The matrix-in-cylinder system had a relative bioavailability of 156% (fasted conditions) and 222% (fed conditions) compared to the marketed reference product. In order to elucidate the origin of this increased bioavailability, Caco-2 experiments and dog lymph studies were performed. However, none of these experiments was able to provide a conclusive answer.

Cardiopulmonary bypass alters the pharmacokinetics of propranolol in patients undergoing cardiac surgery

The pharmacokinetics of propranolol may be altered by hypothermic cardiopulmonary bypass (CPB), resulting in unpredictable postoperative hemodynamic responses to usual doses. The objective of the present study was to investigate the pharmacokinetics of propranolol in patients undergoing coronary artery bypass grafting (CABG) by CPB under moderate hypothermia. We evaluated 11 patients, 4 women and 7 men (mean age 57 +/- 8 years, mean weight 75.4 +/- 11.9 kg and mean body surface area 1.83 +/- 0.19 m(2)), receiving propranolol before surgery (80-240 mg a day) and postoperatively (10 mg a day). Plasma propranolol levels were measured before and after CPB by high-performance liquid chromatography. Pharmacokinetic Solutions 2.0 software was used to estimate the pharmacokinetic parameters after administration of the drug pre- and postoperatively. There was an increase of biological half-life from 4.5 (95% CI = 3.9-6.9) to 10.6 h (95% CI = 8.2-14.7; P < 0.01) and an increase in volume of distribution from 4.9 (95% CI = 3.2-14.3) to 8.3 l/kg (95% CI = 6.5-32.1; P < 0.05), while total clearance remained unchanged 9.2 (95% CI = 7.7-24.6) vs 10.7 ml min(-1) kg(-1) (95% CI = 7.7-26.6; NS) after surgery. In conclusion, increases in drug distribution could be explained in part by hemodilution during CPB. On the other hand, the increase of biological half-life can be attributed to changes in hepatic metabolism induced by CPB under moderate hypothermia. These alterations in the pharmacokinetics of propranolol after CABG with hypothermic CPB might induce a greater myocardial depression in response to propranolol than would be expected with an equivalent dose during the postoperative period.

Obesity influences propranolol pharmacokinetics in patients undergoing coronary artery bypass grafting employing cardiopulmonary bypass

Propranolol plasma levels and kinetic disposition may be altered by hypothermic cardiopulmonary bypass (CPB-H). We investigated the potential influence of obesity on propranolol pharmacokinetics in patients undergoing coronary artery bypass grafting employing CPB-H. Fifteen patients, receiving propranolol perorally pre- (10-40 mg, 2-3 times a day) and post-operatively (10 mg, once a day) were distributed in two groups, based on body mass index (BMI), in obese (n = 9, BMI: mean 29.4 kg/m²) and non-obese (n=6, BMI: mean 24.8 kg/m²). A serial of blood samples was collected at the pre- and post-operative periods at time dosing interval (Ä); propranolol plasma levels were measured one day before and after surgery using a high performance liquid chromatographic procedure described previously. PK Solutions software 2.0 was applied to obtain pharmacokinetic parameters. No changes on kinetic parameters as biological half-life (t1/2, p = 0.0625, NS), volume of distribution (Vd/F, p=0.8438, NS) and plasma clearance (CL T/F, p = 0.1563, NS) were obtained for the non-obese patients, while a prolongation of t1/2 (3.2 to 11.2 h, p< 0.0039), an increase on Vd/F (3.0 to 7.7 L/kg, p<0.0039) and reduction on CL T/F (11.3 to 9.2 mL/min.kg, p<0.0391) were obtained in the post-operative period for obese patients. Pharmacokinetic data could justify propranolol plasma concentrations in obese patients higher than in non-obeses, after surgery.

Pharmacokinetics of propranolol following single and multiple-dosing with Inderal-LA or a chrontherapeutic form of propranolol

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, a novel chronotherapeutic formulation of propranolol designed for nighttime dosing, had appropriate pharmacokinetics to provide maximum effect in the morning. Beta-blockers may be well-suited for the purpose of chronotherapy since they attenuate sympathetic activity and thereby decrease the increase in heart rate and contractility that are seen upon waking. Pharmacokinetics of propranolol CR and Inderal LA following single and multiple doses were determined in normal male volunteers in this open-label, two-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. Following a single 160 mg dose of propranolol CR administered at 10 PM, absorption was delayed by about 4 hrs, after which plasma concentration rose steadily, reaching a peak at about 10 AM. In contrast, after dosing with Inderal LA, plasma levels of propranolol began to rise almost immediately, reaching a plateau between 4 AM and 10 AM. During multiple dosing, steady-state trough plasma concentrations were achieved after 2 days with either drug. Following the final dose, the changes in plasma concentration were similar to those observed in the single dose study. Bioavailability was similar for both formulations of propranolol. In conclusion, Propranolol CR exhibited appropriate pharmacokinetics for the chronotherapeutic treatment of hypertension; moreover, the higher peak plasma levels and the slightly greater bioavailability observed after dosing with propranolol CR offer potential advantages over Inderal LA. See Figure 1.

Propranolol kinetics in patients submitted to cardiac surgery with cardiopulmonary bypass

Propranolol plasma levels and pharmacokinetics (PK) may be altered by cardiopulmonary bypass (CPB). Propranolol kinetic disposition was investigated in patients submitted to myocardial revascularization with mild hypothermic cardiopulmonary bypass (HCPB).

Improvement in exercise tolerance and immediate beta-adrenergic blockade with intranasal propranolol in patients with angina pectoris

A new intranasal spray formulation of propranolol was developed to provide β-adrenergic blocking medication on an immediate basis to patients with angina pectoris. The effects of this spray or placebo were assessed in 16 patients with effort-induced angina in a blinded, randomized, crossover design study that compared placebo with intranasal propranolol spray (5 mg/puff) 15 minutes before exercise on a treadmill (Bruce protocol). One week later, each patient, acting as his/ her own control, received the alternative treatment and repeated exercise. Mean plasma propranolol level with active therapy was 20 ng/ml. Patients with active spray demonstrated a significant increase in total exercise time than patients taking placebo (530 ± 197 vs 460 ± 177 seconds, p = 0.05), an increase in the time to 1 mm ST-segment depression on the electrocardiogram (384 ± 202 vs 327 ± 144 seconds, p <0.05), and an increase in time to onset of angina (452 ± 149 vs 363 ± 175 seconds, p = 0.0005). There was a blunting of maximal exercise heart rate with active therapy compared with placebo (120 ± 13 vs 133 ± 17 beats/min, p <0.01), blunting of maximal exercise systolic blood pressure (185 ± 22 vs 194 ± 21 mm Hg, p < 0.05), and blunting of peak double product (p < 0.0005), with more modest effects on resting heart rate. Propranolol spray is an effective approach for providing immediate β blockade and improving exercise tolerance in patients with angina pectoris.

An erythrocyte based bioadhesive system for nasal delivery of propranolol

An erythrocyte based bioadhesive system has been developed for controlled systemic delivery of propranolol hydrochloride through the nasal route. Rat erythrocytes were loaded with propranolol HCl by a method based on hypotonic swelling, isotonic resealing and reannealing. The loaded erythrocytes were cross-linked by treating with glutaraldehyde and were characterised in-vitro for drug payload efficiency, propranolol release, drug diffusion through rat intestine, bioadhesion and morphological characteristics. Loaded erythrocytes were found to release propranolol HCl slowly, the release being dependent on the degree of crosslinking. The system was found to possess good bioadhesive properties. In-vivo studies conducted on rats revealed that the developed system maintained constant plasma levels of propranolol for extended periods of time (nearly 10 h). The studies suggest the potential of the system for controlled systemic delivery of propranolol.

Hepatic β-adrenoceptor adaptation during propranolol administration is impaired in ageing rats

Ageing has been associated with changes in β-adrenoceptor responses and adaptation to prolonged removal of catecholamine stimulation. We have examined the effect of chronic propranolol administration on rat hepatic membrane β-adrenoceptor density, agonist affinity and response in young (6–7 months) and old (26-7 months) male Wistar rats. Propranolol administration via miniosmotic pumps for 7 days resulted in similar and sustained plasma propranolol levels (approximately 100 ng/ml) in old and young rats. Pretreatment β-adrenoceptor responses to isoprenaline were significantly higher in old rats. Propranolol administration was associated with significant increases in β-adrenoceptor response and density (B max) in young rats only. Cyclic adenosine 3′5′-monophosphate (cyclic AMP) responses to prostaglandin E 1(PGE 1), guanosine triphosphate (GTP), 5′-guanyl-imidodiphosphate (Gpp(NH)p), forskolin and Mn 2+ were not significantly different between young and old rats and were not affected by propranolol administration. Neither ageing o propranolol administration was associated with a change in β-adrenoceptor agonist affinity. These findings demonsntrate elevated hepatic β-adrenoceptor response and impaired hepatic β-adrenoceptor adaptation to β-adrenoceptor blockade in ageing rats.

Pathway-selective sex differences in the metabolic clearance of propranolol in human subjects.

This study determined the total clearance of propranolol and the partial clearances through each of its three primary metabolic pathways after administration of an 80 mg single oral dose in 28 young, white subjects (13 women; 15 men). The oral clearance of propranolol was significantly higher (63%, p less than 0.02) in the men (65.7 +/- 7.7 ml/min/kg; mean +/- SE) than in the women (40.2 +/- 6.2 ml/min/kg). This sex difference was mainly attributable to a 137% higher clearance through the P-450-mediated side-chain oxidation in the men (p less than 0.001). There was also a 52% higher clearance through glucuronidation in the men (p less than 0.02). In contrast, the clearance through the P-450-mediated ring oxidation was not different between men and women. After administration of simultaneous intravenous doses of hexadeuterium-labeled drug (0.1 mg/kg) to 11 of the subjects, there were no differences between men and women in volume of distribution or half-life. Moreover, there were no sex differences in plasma and blood binding of propranolol. This study thus demonstrates that higher plasma levels of propranolol occur in women than in men after oral doses and suggests that some drug metabolizing enzymes, but not others, are regulated by sex hormones in human beings.

Age-dependent pulmonary first-pass elimination of propranolol in rats.

Plasma levels of propranolol after 2.5 mg kg-1 given i.v. and i.a. have been compared in 3- to 4-week-old rats to evaluate the effect of age on pulmonary first-pass elimination of the drug. In 5- to 52-week-old rats, the area under the plasma concentration-time curve (AUC) after an intra-arterial dose was always larger than that after the i.v. dose. The plasma elimination half-lives after both routes of administration were almost identical, but tended to increase with age between weeks 7 and 104. First-pass pulmonary clearance and extraction ratio tended to decrease with age between weeks 7 and 52.

Relationship among beta-adrenergic blockade, propranolol concentration, and liver function in patients with cirrhosis.

In 20 patients with cirrhosis we studied the relationship among the efficiency of beta-adrenergic blockade induced by oral administration of 40 mg propranolol, the plasma level of propranolol, and the liver function. The beta-adrenergic blockade was studied 2 h and 8 h after propranolol administration and assessed by the cardiac chronotropic response to isoprenaline. Liver function was evaluated by a standard liver function test and the Child-Turcotte or Pugh score. The beta-adrenergic blockade and propranolol plasma concentration were higher 2 h than 8 h after propranolol administration. The beta-adrenergic blockade and the propranolol plasma concentration varied widely among patients. No significant correlation was found between the efficiency of beta-blockade and propranolol concentration. The beta-adrenergic response before propranolol administration was correlated with bilirubin level and Child scores, but no significant correlation was found between the beta-blockade and the severity of liver disease. These results suggest that in patients with cirrhosis, differences in response to propranolol are not related to differences in the severity of the liver disease or to differences in propranolol concentration.

The percutaneous absorption of propranolol and prediction of the plasma concentration.

In order to avoid first-pass metabolism and to maintain therapeutically effective concentration of propranolol (PL) for a prolonged time, ointments of PL were prepared and the percutaneous (p.c.) absorption was investigated in rabbits. To describe the plasma PL concentration profile during repeated p.c. administrations, a simple pharmacokinetic model, including a first-order absorption process, was applied. The p.c. absorption of PL from both macrogol (400:4000, 30:40, g/g) and Carbopol 934 ointments was significantly increased by adding Azone (AZ). Effective plasma levels were sustained for about 10-20 h, but the absorption of PL from the macrogol ointment was relatively slow. The bioavailability of PL in the 5% PL Carbopol ointment with AZ was 13%. The plasma level of PL after application of Carbopol ointment was enhanced as PL was increased in the ointment, 3 to 5%. The repeated p.c. absorption studies were carried out by applying the 5% PL ointment daily for 3 d. The use of the pharmacokinetic model was justified by good agreement with the observed data after repeated applications of the ointment. Thus, the plasma PL concentration profile during repeated p.c. administrations can be predicted using the model.

Plasma Propranolol Levels and Their Effect on Plasma Thioridazine and Haloperidol Concentrations

The relationship between chronic oral dosage with a long-acting formulation of propranolol and plasma propranolol levels 22 to 23 hours later is described in 12 adult male patients with organic brain disease. Separately, the effects on plasma levels of thioridazine plus metabolites with concomitant rising dose long-acting propranolol administration were studied in five patients. Significant dose-related increases in levels of thioridazine and metabolites were found when long-acting propranolol was given. No changes in haloperidol levels were found in three patients studied in a similar protocol.

Selective manipulation of neurohumoral control of the cardiac pacemaker by drugs given intrapericardially

A technique of intrapericardial administration of β-adrenoceptor and muscarinic cholinergic receptor antagonist drugs has been tested in conscious rabbits. Intrapericardial propranolol or atenolol (50 μg/kg) had the same effect on isoprenaline heart rate dose-response curves and on the sympathetic component of the arterial baroreceptor-heart rate reflex as did conventional, 5-fold greater, intravenous doses of the drugs. The action of intrapericardial propranolol was attributable to its (−)isomer. Intrapericardial propranolol (50 μg/kg) had little effect on ventricular contractility. Plasma levels of propranolol and atenolol after intrapericardial administration were, respectively, 7- and 40-fold less than after the usual intravenous doses. Intrapericardial hyoscine methyl bromide (10 μg/kg) abolished baroreflex vagal effects on heart rate as effectively as did the conventional, 5-fold greater, intravenous dose. The duration of receptor blockade by both classes of drugs when given intrapericardially was at least 2 hr. We conclude that the rapid diffusion of β-adrenoceptor and muscarinic cholinergic receptor blocking drugs from the pericardial sac to receptors on the sinoatrial cardiac pacemaker, and their prolonged actions, provides a useful technique for preventing the actions of the sympathetic and vagus nerves, and of circulating catecholamines, on the chronotropic functions of the heart.

The Effect of ??-Adrenergic Blockade on the Cardiovascular Response to Diltiazem or Verapamil in Dogs

Diltiazem or verapamil were each given at two different infusion rates to pentobarbital-anesthetized dogs with or without a concurrent infusion of propranolol. Changes in cardiovascular function, in reflex activation as reflected by circulating catecholamine levels, and in the chronotropic response to an exogenous beta-adrenergic agonist, isoproterenol, were measured. When administered alone, diltiazem or verapamil, at plasma concentrations of 160 and 370 ng/ml, or 230 and 500 ng/ml, respectively, prolonged atrioventricular conduction and caused systemic vasodilation with a decrease in mean arterial pressure. Cardiac index increased, associated with an increase in arterial norepinephrine level. Heart rate increased with the lower level of verapamil; left ventricular dP/dt increased with both levels of verapamil and at the higher level of diltiazem. Plasma propranolol levels of approximately 35 ng/ml were well tolerated in the absence of diltiazem or verapamil. When added to diltiazem or verapamil, propranolol resulted in an increase in systemic vascular resistance to near control values; a decrease in cardiac index, left ventricular dP/dt, and heart rate; and worsened atrioventricular conduction. Three of nine animals in the high verapamil-propranolol group were unable to maintain a mean arterial pressure greater than 50 mm Hg, and developed a low cardiac index with an elevated systemic vascular resistance, despite very high levels of circulating catecholamines. Compared to the anesthetized state, greater amounts of isoproterenol were needed to effect the same increase in heart rate with the addition of diltiazem, verapamil, or propranolol alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Short-term effects of propranolol on portal venous pressure.

The present study was designed to investigate the effect of propranolol on portal pressure of patients with alcoholic cirrhosis and portal hypertension and to correlate these effects with clinical and laboratory parameters. The mean baseline hepatic venous pressure gradient in the 50 patients studied was of 18.2 +/- 4.1 mm Hg. It decreased significantly 2 hr after the oral administration of 40 mg of propranolol to 15.7 +/- 4.2 mm Hg (a mean reduction of 13.4 +/- 17%). This reduction in hepatic venous pressure gradient resulted mainly from a decrease in mean wedged hepatic venous pressure. There was no correlation between the decrease in hepatic venous pressure gradient and the decrease in heart rate. When results were analyzed individually, only 15 (30%) showed a large decrease in hepatic venous pressure gradient (greater than 20%), 15 (30%) showed a moderate decrease (10 to 19%), and in 20 patients (40%) there was no reduction or an increase in hepatic venous pressure gradient. Comparison of "responders" (those that reduced hepatic venous pressure gradient greater than 10%) and "nonresponders" (hepatic venous pressure gradient reduction less than 10%) showed no significant differences in baseline laboratory and hemodynamic parameters, in the severity of the liver disease, in the heart rate and blood pressure response to propranolol, nor in the propranolol plasma levels achieved 2 hr after propranolol administration. Propranolol plasma levels correlated with the reduction in heart rate but not with the reduction in hepatic venous pressure gradient. Of 14 nonresponders to 40 mg of propranolol who received additional doses, six showed a reduction in hepatic venous pressure gradient.(ABSTRACT TRUNCATED AT 250 WORDS)

A Modified, Sensitive Liquid Chromatographic Method for Measurement of Propranolol with Fluorescence Detection

A simple, sensitive, and rapid fluorometric-high-perform-ance liquid Chromatographic method for quantitating human and animal plasma and blood levels of propranolol has been developed. The procedure, which requires microliter volumes of triethylamine in the mobile phase mixture and microliter volumes of plasma or blood (50–100 μL), may be applied in routine clinical analysis as well as in pharmacokinetic studies using small laboratory animals. A single, selective extraction step precedes the analysis. The limiting concentration that can be detected is 1ng/mL.