Cardiovascular beta-adrenergic blocking effects of bornaprolol in humans: relation to dose and plasma concentration

The cardiovascular beta-blocking effects of bornaprolol were studied in healthy male volunteers after four single oral doses. The inhibition of isoproterenol-induced tachycardia was monitored for 72 h in six subjects, and the inhibition of exercise-induced tachycardia and rise of systolic blood pressure were monitored for 167 h in six other subjects. Plasma drug concentrations were determined by gas chromatography. Bornaprolol significantly reduced the resting heart rate, isoproterenol- and exercise-induced tachycardia, and effort hypertension. The peak effect was obtained within 1-2 h of drug administration and was correlated with dose. The effect on the isoproterenol test remained significant for 6 h after administration of 40 mg bornaprolol, and 72 h after 80, 120, and 240 mg. The effect of bornaprolol on the exercise test in comparison with placebo was significant during 23 h (120 and 240 mg) and 47 h (480 and 960 mg). A positive relationship was found for both tests between the maximum effect and the doses administered. A correlation was also found for each group of subjects between the time course of the plasma drug concentration and the effects of each bornaprolol dose on isoproterenol- and exercise-induced tachycardia. The beta-blocking effects in individual subjects, however, often continued long after the disappearance of detectable plasma drug concentrations.     

Determination of the optimal dose of the antihypertensive drug cicletanine hydrochloride in man

The optimal antihypertensive dose of cicletanine (BN 1270) was investigated in 3 short-term and 3 long-term therapeutic trials using doses of 12.5 to 200 mg. There was a dose-response effect such that in double-blind studies of 1 month's duration, 50 mg/d was the minimum effective dose in mild to moderate hypertensive patients, while a higher dose, 200 mg/d, was more effective in patients with severe hypertension. Despite a quicker reduction in blood pressure by 100 mg cicletanine compared with 50 mg, a similar antihypertensive effect resulted after 3 months' treatment. In patients with mild to moderate hypertension the average decrease in blood pressure over this period was 43.7/38.0 mmHg. A daily dose of 50 mg, which may be increased, particularly at the beginning of treatment, is therefore the optimal recommended dose for these patients. Furthermore, the similar efficacy of the 50 mg and 100 mg doses was confirmed in the long-term trial in the elderly. In all studies, at all doses, cicletanine had a gradual antihypertensive effect, avoiding the risks associated with a sudden fall in blood pressure. The different rates of effect of the 50 mg and 100 mg doses are thought to be due to different mechanisms of action: since 50 mg has no natriuretic effect and 100 mg has a slight natriuretic effect, which is even more pronounced at higher doses.     

Bronchial,cardiovascular and secretory responses after central administration of capsaicin in the guinea-pig

Capsaicin was injected intracisternally (i.c.), intrathecally (i.th.) or intravenously (i.v.) into guinea-pigs anaesthetized with urethane and ventilated artificially. The effects of 0.2-100 micrograms capsaicin on insufflation pressure, heart rate, arterial blood pressure and salivation were recorded. Low i.c. doses of 0.2 and 2 micrograms capsaicin induced bradycardia, hypertension and salivation but no change in insufflation pressure. An insufflation pressure increase, i.e. bronchoconstriction, was observed with 20 or 100 micrograms capsaicin i.c. and this was associated with tachycardia and hypertension. Bronchoconstriction after 20 micrograms capsaicin i.c. was augmented by propranolol (1 mg/kg i.v.). It was, however, unaffected by bilateral cervical vagotomy and could also be induced by i.th. capsaicin injections in the lumbar region. Capsaicin (3 micrograms/kg) injected i.v. induced bronchoconstriction and tachycardia. Propranolol enhanced bronchoconstriction but did not reduce the tachycardia indicating that capsaicin led to activation of sympathetic bronchial but not cardiac fibers. These results also indicate that i.c. capsaicin caused reflex responses consisting of salivation, bronchodilatation bradycardia and hypertension. High doses injected i.c. or i.th. also caused tachycardia and bronchoconstriction. This latter effect, however, was neither a vagal reflex nor did it seem to result from activation of central terminals of afferent fibers with subsequent release of mediators from the peripheral endings due to antidromic spread of nerve impulses. Instead, capsaicin seemed to be readily resorbed into the systemic circulation and thus acting at peripheral endings to cause bronchoconstriction and tachycardia.     

Comparative potency of atenolol and propranolol as beta-adrenergic blocking agents in man

Summary The comparative potency of two beta-blockers, propranolol and atenolol, in the inhibition of exercise tachycardia and isoproterenol-tachycardia has been studied in two groups of hypertensive patients, using oral doses which were increased weekly. A linear correlation was observed between the reduction in exercise tachycardia and the dose of each drug, up to a daily dose of propranolol 480 mg and atenolol 600 mg. Propranolol was slightly (0.7/1) more potent in decreasing maximal exercise tachycardia than atenolol when tested in low doses (below 100 mg); at higher doses (480 mg) no differences were found. However, atenolol was 10 times less potent than propranolol in blocking isoprenaline-induced tachycardia, which seems to be related to the cardioselectivity of atenolol.     

EFFECTS OF P-CHLOROPHENYLALANINE ON BLOOD PRESSURE AND HEART RATE IN NORMAL RABBITS AND RABBITS WITH NEUROGENIC HYPERTENSION

SUMMARY 1. Intraperitoneal administration of p -chlorophenylalanine ( p CPA: 100–400 mg/kg per day) reduced central serotonin concentrations to 20–50% of control in the rabbit.
2. Intraperitoneal administration of a single dose of p CPA (400 mg/kg) decreased heart rate by 14% for a period of 1–2 days, but did not affect arterial pressure.
3. Repeated intraperitoneal administration of p CPA (100 mg/kg per day) caused a gradual reduction in arterial pressure to about 90% of control values over a 10 day period, but had no consistent effect on heart rate.
4. In rabbits that received repeated intraperitoneal injections of p CPA (100 mg/kg per day), the tachycardia that followed sinoaortic denervation was not as well sustained as in normal rabbits; the development of neurogenic hypertension was unaltered.
5. Intracisternal administration of p CPA was particularly toxic in the rabbit; the maximum doses tolerated did not succeed in lowering central serotonin concentration and had no effect on blood pressure or heart rate.     

Dose-response relationship of prizidilol hydrochloride (SK&F 92657): a comparison between acute and chronic effects in patients with essential hypertension

Three different doses (50, 100 and 200 mg) of prizidilol hydrochloride (SK&F 92657), a novel antihypertensive agent with vasodilating and beta-adrenoreceptor blocking properties, were given to three (n = 5) groups of essential hypertensive patients in order to evaluate hypotensive dose-response relationship of the drug and its beta-adrenoreceptor blocking properties. Irrespective of the dose given, acute administration of prizidilol did not effectively decrease blood pressure; however after one-week of treatment prizidilol was effective in reducing blood pressure at both the 100 and the 200 mg b.i.d. schedules. At these doses the drug decreased resting heart rate and plasma renin activity for the first 4-6 h after both acute and steady-state dosing. Similarly postdynamic exercise tachycardia was reduced to a significant extent by the drug; after acute administration this effect lasted 2 h with the lowest dose and 4 h with the highest one. After chronic administration this effect lasted up to 10 h for both the 100 and 200 mg doses. These data indicate that: chronic prizidilol treatment can achieve a satisfactory control of blood pressure in patients with mild-moderate essential hypertension; when prizidilol is administered chronically in hypertensive patients, an equally effective control of blood pressure can be obtained with either a 200 mg b.i.d. or a 100 mg b.i.d. schedule; prizidilol possesses beta-adrenoceptor blocking properties in man which can contribute to its pharmacodynamic activity.     

小剂量三磷酸腺苷静脉注射终止阵发性室上性心动过速的临床观察

目的观察静脉注射小剂量三磷酸腺苷（ATP）对阵发性室上性心动过速（PSVT）的终止作用。方法对12例PSVT患者肘静脉快速弹丸式注射ATP5～10mg,给药前1—7min持续进行心电监护,观察起效时间、心率、心律、血压和不良反应。结果静脉快速注射小剂量ATP后,12例患者中10次PSVT得到终止,仅3例次患者发现轻微的不良反应,但均在2min内消失。结论静脉快速注射小剂量ATP能安全有效地终止PSVT。     

A comparison of single doses of bucindolol and oxprenolol in hypertensive patients.

Single doses of bucindolol 50, 100 and 200 mg were compared to placebo and single doses of oxprenolol 40, 80 and 160 mg in seven patients with mild hypertension, in a double-blind randomized study. Both bucindolol and oxprenolol inhibited exercise induced tachycardia. The mean maximum inhibition of exercise heart rate was similar after each dose of both drugs (20%, P less than 0.001). Bucindolol produced a significantly greater reduction in blood pressure than either oxprenolol or placebo. This was most apparent in standing systolic and diastolic and post-exercise systolic blood pressures between 1 and 2 h after dosing and was dose-related. All seven patients experienced adverse effects related to hypotension within the first 2 h after ingestion of bucindolol 200 mg. Plasma concentrations of oxprenolol, bucindolol or 5-hydroxy-bucindolol, sampled 2 h after dosing, could not be related to either the changes in blood pressure or to the occurrence of symptoms. The results emphasise the need for careful dose-finding of new drugs prior to their more widespread evaluation in phase 3 studies.     

Effect of the beta-adrenergic blocking agent bupranolol on the plasma renin activity in normotensive rats]

The effects of the beta-adrenergic blocking agent 3-tert.-butyl-amino-1-(6'-chloro-3'-methylphenoxy)-propan-2-ol hydrochloride (bupranolol; KL 255; Betadrenol) on the plasma renin activity (PRA) of normotensive rats were studied in comparison to propranolol. Bupranolol (10--100 microgram/kg) reduced basal PRA and inhibited the isoproterenol as well as dihydralazine induced increase of PRA in a dose dependent fashion. Bupranolol exhibited an effect 2--4 times stronger than that of propranolol. The PRA inhibiting effects of bupranolol seem to be linked to its beta-receptor blocking properties.     

Dose response and length of action of nifedipine capsules and tablets in patients with essential hypertension: A randomised crossover study

Summary Twelve patients with essential hypertension on no other drug treatment were entered into a randomised crossover study of 5, 10 and 20 mg capsules of nifedipine given 3 times a day and 20 mg tablets given twice a day. Each dose was given for 2 weeks in a random order. All forms of nifedipine were effective in lowering blood pressure.However, 5 mg capsules were less effective than the 10 and 20 mg capsules or 20 mg tablets. There was little to choose between the latter. All doses of nifedipine were more effective 1 and 3 h after the dose compared to subsequent times afterwards. Indeed, as time elapsed after the last dose up to 12 h, there was a gradual increase in blood pressure. However, even at 12 h the 10, 20 mg capsules and 20 mg tablets were still causing an approximate 10% reduction in blood pressure.Nifedipine tablets are as effective as capsules though they might be longer acting, particurarly around 6 h after the last dose.     

Serum concentrations and clinical effect of zuclopenthixol in acutely disturbed,psychotic patients treated with zuclopenthixol acetate in Viscoleo®

Zuclopenthixol acetate, 5%, in Viscoleo^sR was administered IM to 19 acutely disturbed, psychotic patients in doses of 50–150 mg. Fifteen patients received one injection, whereas four of the patients had two or three injections, usually with intervals of 3 days. The zuclopenthixol concentrations in serum were measured in series of samples taken from each patient during a 3-day period following the injection. In patients given identical doses serum concentrations of about the same order were obtained. Significant and good correlations were found between dose and maximal serum concentration and between dose and area under the serum concentration curve. The average serum concentration curve obtained when adjusting the data to a 100 mg dose has a maximum of 41 ng/ml after about 36 h, decreasing to 15 ng/ml after 72 h.A dose of 50–150 mg zuclopenthixol acetate in Viscoleo^® appeared to be sufficient for controlling the symptoms for most acutely disturbed, psychotic patients. The frequency of side effects, including extrapyramidal reactions, was low and the adverse reactions mostly mild, indicating that the risks for severe complications generally might be minimal. With a rapid onset of action, few and mild side effects, good tolerability at the injection site, and a duration of effect of 2–3 days, zuclopenthixol acetate in Viscoleo^® appears to offer advantages compared to conventional neuroleptic treatment in patients in whom an acute, calming effect is desired.     

Chronic haloperidol treatment with low doses may enhance the increase of homovanillic acid in rat brain

Homovanillic acid (HVA) levels were determined by high performance liquid chromatography with electrochemical detection in the striatum and prefrontal cortex of rats that had received single or repeated injections of various doses of haloperidol. Haloperidol increased the HVA concentrations in both brain regions after both acute and chronic treatment with doses of 0.01-1 mg/kg. The increase in the HVA concentrations in the striatum was blunted after repeated haloperidol injections with doses of 0.5-1 mg/kg, suggesting that haloperidol pretreatment results in a decreased responsiveness to the drug at high doses (tolerance). Tolerance also developed to the effect of long-term haloperidol treatment on the HVA concentrations in the prefrontal cortex at the highest dose used (1 mg/kg). This suggests that the differences in the development of tolerance between the striatum and prefrontal cortex are not qualitative but quantitative. However, repeated haloperidol injections at doses of 0.01-0.05 mg/kg enhanced the increase in HVA concentrations. This suggests that tolerance does not develop after chronic haloperidol treatment with low doses. Decreased HVA concentrations were also found after withdrawal from chronic haloperidol treatment (rebound decrease). However, this rebound decrease was much smaller than the decrease in response of the HVA concentrations to repeated haloperidol injections, suggesting that different mechanisms are involved.     

A comparative study of atenolol and metoprolol in the treatment of hypertension.

1 In an open, randomized cross-over investigation of thirteen patients (nine and four women, aged 37-67 years) with mild or moderate essential hypertension a comparison between atenolol and metoprolol was carried out in order to study the effects of 50, 100 and 200 mg given once daily on blood pressure and heart rate at rest and during exercise. 2 Before one beta-adrenoceptor blocking drug was replaced by the other in a patient an intervening drug-free interval of sufficient length was secured to allow an increase in the blood pressure to pretreatment levels. 3 A maximal fall in blood pressure was achieve with 50 mg atenolol once daily, with no further reduction when the dose was increased to 100 mg or 200 mg. Maximal blood pressure reduction was achieved with 100 mg metoprolol daily, while the hypertensive effect of 50 mg once daily was not consistent. Significant reductions in heart rate in all test situations were observed with 50 mg atenolol, while 200 mg metoprolol 100 was necessary to reduce exercise-induced tachycardia. 4 Atenolol 50 mg and metoprolol 100 mg once daily are efficient in treating mild or moderate hypertension and doses beyond these may not reduce the blood pressure further. On the contrary lower doses than generally recommended may be effective in the individual patient.     

Dose-response relationship in intoxication by the pyrrolizidine alkaloid monocrotaline

Rats develop pulmonary hypertension over a 2-wk period of continuous ingestion of monocrotaline dissolved in drinking water (20 mg/l). The relationship between monocrotaline concentration and duration of exposure was investigated by giving male rats (initial body weight 100 g) monocrotaline in drinking water (5, 10, 20, 40, or 60 mg/l) for 0, 1, 2, 4, 6, 10, or 20 d. Rats were killed 20 d after initiating treatment, and increased lung and right ventricular to body weight ratios were measured as indices of pulmonary hypertension. The accumulative dose of monocrotaline delivered over a 10-d period using a drinking water concentration of 10 mg/l (18 mg/kg) produced the same degree of right ventricular hypertrophy and lung weight increases as the doses ingested over a 4-d period by rats consuming 20 or 40 mg/l monocrotaline water (14 and 29 mg/kg). Phenobarbital pretreatment did not substantially alter the time course of toxicity induced with 20 mg/l monocrotaline water. Ingestion of 60 mg/l monocrotaline water for 1 d (11 mg/kg) resulted in right ventricular hypertrophy at 20 d. Since accumulative doses of less than 11 mg/kg did not produce toxicity and all doses greater than 14 mg/kg did, this range may be considered a threshold for inducing toxicity. However, organ weight increases following threshold exposures reversed over a 4-wk period. Increases in the wall thickness of pulmonary arteries correlated with the development of right ventricular hypertrophy. Pulmonary inflammation was not an early response to monocrotaline administration, since there was no change in the proportion of cell types recovered in lung lavage fluid during the first 6 d of monocrotaline treatment.     

Antihypertensive effect of arotinolol (S-596), a new adrenergic beta blocking agent, on experimental hypertension

Effects of a new adrenergic beta-blocking agent, arotinolol (S-596), on the blood pressure and heart rate were assessed in comparison with those of other beta-blocking agents in deoxycorticosterone acetate (DOCA)-saline induced and spontaneously hypertensive rats (SHR). The relationship between the antihypertensive effect and the beta- or alpha-adrenoceptor blocking action of S-596 was also investigated in normotensive conscious rats. In the rat, a cannula was implanted chronically in a femoral artery, from which blood pressure was recorded. The test drugs were administered orally once a day for 14 days at several dose levels. The development of hypertension in DOCA-saline treated rats was clearly retarded with the consecutive oral administration of propranolol (100 mg/kg/day) and hydrochlorothiazide (10 mg/kg/day), but not with S-596 (20, 50 and 100 mg/kg/day) or pindolol (10 mg/kg/day). On the other hand, in SHR, S-596 (more than 10 mg/kg/day) propranolol (50 mg/kg/day), pindolol (10 mg/kg/day), labetalol (100 mg/kg/day) and hydrochlorothiazide (10 mg/kg/day) produced definite antihypertensive effects after the chronic administration. In normotensive conscious rats, the vasodepressor responses induced by isoproterenol were reduced by the beta-blocking agents at lower dose levels than those required for development of antihypertensive effects. The acute effects on blood pressure were determined in hypertensive rats during the chronic treatment with the test drugs. In either type of hypertension, S-596, (10-50 mg/kg/day) showed a depressor effect at 4 and/or 8 hr after administration. In normotensive conscious rats, S-596 antagonized the pressor responses to phenylephrine at doses more than 30 mg/kg. It is therefore suggested that an adrenergic alpha-blocking property is at least partly involved in the hypotensive effect of S-596 as labetalol. In the experiment of acute effect in SHR, pindolol and labetalol showed prominent hypotensive effect after the 1st administration, but lesser effect after the 10th administration. Propranolol showed a marked rise in blood pressure in this experiment.     

The pharmacokinetics and pharmacodynamics of doxazosin compared with atenolol during long-term double-blind treatment

Summary The pharmacodynamics of doxazosin and atenolol were compared on single study days in 39 patients with mild to moderate hypertension receiving long-term double-blind treatment. The pharmacokinetics of doxazosin were investigated in the 20 patients receiving doxazosin. Individually titrated once daily doses of doxazosin were 1, 2, 4, 8 or 16 mg and of atenolol 50 or 100 mg. Patients were first investigated after at least one month on constant dose and then again after at least a further three months. Mean plasma concentrations of doxazosin were proportional to dose and the plasma half-life was 11.5 h and independent of dose. There was low variability of doxazosin plasma concentrations between patients receiving the same dose. Concentrations and half-life were unchanged during the period between investigations. Mean reductions of AUC (0–12 h) blood pressure during the 12-h period post-dose and of blood pressure at 24 h post-dose were not statistically different between doxazosin and atenolol. There was effective control of blood pressure by both drugs at all time points of the day. The pharmacokinetic and pharmacodynamic results obtained in this study are compatible with the use of doxazosin in a once daily dose regimen for the treatment of essential hypertension.     

Dopamine and isoproterenol in imipramine intoxication in the dog

Artificially ventilated anesthetized dogs were given imipramine 7.5 mg/kg/hr i.v. In the first group (n = 6) mechanical cardiac activity was no longer detectable after a cumulative dose of 20.0 +/- 6.6 mg/kg (mean +/- sd). When aortic flow had decreased to 75% of its initial value, in a second group (n = 5) of experiments dopamine 10 micrograms/kg/min and in a third group (n = 5) isoproterenol 1 microgram/kg/min were administered i.v.. The doses of dopamine and isoproterenol were doubled when aortic flow had again decreased to 75% and 100%, respectively, of the original values. Cardiac mechanical activity was not detectable after a cumulative dose of 43.8 +/- 13.3 in the dopamine and 42.5 +/- 8.0 mg imipramine/kg in the isoproterenol group. These values differed significantly from that in the reference group (both 0.01 greater than p greater than 0.001). In the first group plasma imipramine concentrations at the end of the experiments were 3.06 +/- 0.66, in the second 3.36 +/- 0.66 and in the third 3.32 +/- 1.10 mg/1. Desipramine concentrations were 0.078 +/- 0.06, 0.162 +/- 0.076 and 0.383 +/- 0.09 mg/1 respectively. Dopamine induced a hemodynamic profile of low output and high pressure and isoproterenol one of low pressure and high output. It is concluded that dopamine combined with isoproterenol might be effective in counteracting the cardiodepressant action of imipramine.     

Opioid agonist and antagonist behavioural effects of buprenorphine.

1 The agonist and antagonist effects of a range of buprenorphine doses (0.08-20 mg/kg) were studied on the responding of pigeons under a multiple fixed-ratio, fixed-interval schedule of grain presentation. Various doses (0.02-10 mg/kg) of buprenorphine were also tested in pigeons trained to discriminate between injections of 0.05 mg/kg of fentanyl and injections of distilled water. 2 Buprenorphine, over a broad dose range (0.08-5 mg/kg), increased the rates of responding in the fixed-interval component of the multiple schedule and disrupted patterning of responding within the fixed-interval, without affecting fixed-ratio responding even at a dose of 40 mg/kg. The effects of some of the high doses on fixed-interval responding were still evident one and two days after buprenorphine injection. 3 Doses of buprenorphine which produced increases in fixed-interval responding were also effective as antagonists of the behavioural depression produced by 40 mg/kg of morphine, and were discriminated as fentanyl-like by pigeons trained to discriminate between injections of fentanyl and injections of water. 4 These results show that buprenorphine produces marked agonist and antagonist effects over an extremely broad dose range without producing behavioural depressant effects.     

In vivo evidence that isoproterenol may increase heart rate in the rat by mechanisms in addition to activation of cardiac beta(1)- or beta(2)-adrenoceptors

This study demonstrates that the tachycardia produced by systemic injections of the beta-adrenoceptor agonist, isoproterenol (10 microg/kg, i.v.), in conscious rats were not reduced after injection of the selective beta(1)-adrenoceptor antagonist, atenolol (1 mg/kg, i.v.), or after subsequent injection of the beta(1,2)-adrenoceptor antagonist, propranolol (1 mg/kg, i.v.). The hypotensive responses produced by isoproterenol were slightly diminished by atenolol and markedly diminished by propranolol. The tachycardia produced by catecholamines released for cardiac sympathetic nerve terminals were blocked by atenolol. These results suggest that the hypotensive actions of a 10 microg/kg dose of isoproterenol are mediated by activation of beta(1,2)-adrenoceptors whereas the increases in heart rate may be due to activation of another type of beta-adrenoceptor in cardiac pacemaker cells.     

Stimulation of beta-adrenergic receptors and spontaneous motor activity in mice

The effects of 3 beta-adrenergic agonists (clenbuterol, isoproterenol and salbutamol) on the spontaneous motor activity of mice were studied. The present research indicated that motor activity was significantly decreased 30 minutes after IP injection of either clenbuterol (0.06 mg/kg), isoproterenol (0.5 mg/kg) or salbutamol (2 mg/kg). Hypomotility induced by clenbuterol was also significantly antagonized by propranolol in doses ranging from 1 to 8 mg/kg and by penbutolol in doses from 0.03 to 0.5 mg/kg. However, practolol, which does not cross the blood brain barrier, did not antagonize the effect of clenbuterol. Therefore, it may be hypothesized that beta adrenergic agonists decrease motor activity by a central mechanism. It was also found that tachyphylaxis or resistance to treatment, observed in cardiovascular and bronchopulmonary systems with beta-adrenergic agonists, developed after 7 injections of clenbuterol (0.25 mg/kg IP, twice daily) in the behavioral model of spontaneous motor activity in mice.