Response to Propranolol and Diazepam in Somatic and Psychic Anxiety

A total of 12 chronically anxious psychiatric outpatients were treated with racemic propranolol (Inderal), diazepam (Valium), and placebo for one week each, using a balanced cross-over experimental design. Six patients had predominantly somatic anxiety, complaining mostly of bodily symptoms, and six had mainly psychic anxiety, complaining primarily of psychological symptoms. Clinical ratings of anxiety were made by patient and psychiatrist after each treatment. Though diazepam was in general more effective than propranolol or placebo in relieving anxiety, propranolol was more effective than placebo in patients with somatic anxiety but not in those with psychic anxiety. We suggest that propranolol should be reserved for patients whose anxiety symptoms are mainly somatic.     

Beta-Adrenergic Modulation of Tremor and Corticomuscular Coherence in Humans

Coherence between the bioelectric activity of sensorimotor cortex and contralateral muscles can be observed around 20 Hz. By contrast, physiological tremor has a dominant frequency around 10 Hz. Although tremor has multiple sources, it is partly central in origin, reflecting a component of motoneuron discharge at this frequency. The motoneuron response to ∼20 Hz descending input could be altered by non-linear interactions with ∼10 Hz motoneuron firing. We investigated this further in eight healthy human subjects by testing the effects of the beta-adrenergic agents propranolol (non-selective β-antagonist) and salbutamol (β₂-agonist), which are known to alter the size of physiological tremor. Corticomuscular coherence was assessed during an auxotonic precision grip task; tremor was quantified using accelerometry during index finger extension. Experiments with propranolol used a double-blind, placebo-controlled crossover design. A single oral dose of propranolol (40 mg) significantly increased beta band (15.3–32.2 Hz) corticomuscular coherence compared with placebo, but reduced tremor in the 6.2–11.9 Hz range. Salbutamol (2.5 mg) was administered by inhalation. Whilst salbutamol significantly increased tremor amplitude as expected, it did not change corticomuscular coherence. The opposite direction of the effects of propranolol on corticomuscular coherence and tremor, and the fact that salbutamol enhances tremor but does not affect coherence, implies that the magnitude of corticomuscular coherence is little influenced by non-linear interactions with 10 Hz oscillations in motoneurons or the periphery. Instead, we suggest that propranolol and salbutamol may affect both tremor and corticomuscular coherence partly via a central site of action.     

A community survey of Parkinson's disease.

In a rural community of 80,000 people 69 patients were identified as having a diagnosis of Parkinson''s disease. After interview and examination we found that 55 met the generally accepted diagnostic criteria for Parkinson''s disease, 4 had possible Parkinson''s disease, 6 had essential tremor, 2 had dementia and 2 had other conditions. The patients with Parkinson''s disease had clinical and epidemiologic characteristics similar to those of patients in previous, mainly hospital-based, studies. These characteristics included mean age at onset (63 years), frequency rate of dementia (20%) and presence of postural tremor (11%). The pattern of treatment varied, some patients receiving more medication than is usual for the severity of their illness, and some patients receiving less than is usual. Parkinson''s disease can be difficult to diagnose and manage because of the clinical variation between patients in presentation and response to treatment.     

Effect of beta-adrenoceptor blockade on thermoregulation during prolonged exercise

The effect of clinically used equipotent doses of nonselective (beta 1/beta 2; propranolol) and selective (beta 1; atenolol) beta-adrenoceptor blockers on thermoregulation was studied during prolonged exercise in the heat. Oral propranolol (160 mg/day), atenolol (100 mg/day) or matching placebo were taken for 6 days each by 11 healthy young adult caucasian males. Subjects participated in 2 h of block-stepping at a work rate of 54 W in an environmental chamber with a temperature of 33.2 +/- 0.3 degree C dry bulb and 31.7 /+- 0.3 degree C wet bulb, 2 h after ingestion of the final dose of each drug. Both active agents produced similar marked (P less than 0.001) increases in subjective perception of effort, the mechanism of which was not immediately evident from changes in serum electrolytes, blood glucose, blood lactate, or ventilatory parameters. Propranolol did, however, cause a greater rise in serum K+ than placebo (P less than 0.02) and atenolol (P = NS) after exercise. Although rectal and mean skin temperatures were insignificantly altered by beta-adrenoceptor blockade, an increased total sweat production was noted with propranolol (P less than 0.01 vs. placebo) and to a lesser degree atenolol (P = NS vs. placebo) therapy. Analysis of the time course of sweat production showed the propranolol-mediated enhancement of sweating to ensue largely during the initial hour of block-stepping and to be transient in nature. The scientific and clinical implications of this observation will be dependent upon the precise underlying mechanism, a factor not identified by the present study.     

Biphasic pattern of hypersensitivity following acute propranolol withdrawal in normal subjects

The effect of abrupt propranolol withdrawal on exercise-induced changes in heart rate and blood pressure was studied in six normal volunteers. Response to exercise was measured on two occassions during propranolol treatment and 1, 2, 3, 4, 5 and 7 days after the last dose of propranolol. Exercise-induced changes in heart rate were significantly lower than control during propranolol treatment (p less than 0.005). Following propranolol cessation, all subjects showed a biphasic pattern of hypersensitivity. Heart rate response was significantly greater than control 2, 3 and 7 days after the last propranolol dose (p less than 0.05) and not significantly different from control 1, 4 and 5 days after the last dose of propranolol. Exercise-induced changes in pulse pressure showed a biphasic pattern similar to the changes in heart rate.     

L-Dopa in Parkinsonism and the Influence of Previous Thalamotomy

A double-blind cross-over trial over 24 weeks (10 weeks on the active remedy, 4 weeks off treatment, and 10 weeks on placebo) of the effect of L-dopa on idiopathic Parkinsonism (paralysis agitans) has shown no difference in the response obtained in patients who had undergone previous stereotaxic ventrolateral thalamotomy and in those who had not. Of the 34 patients (18 men and 16 women) in the trial 18 had been operated on (nine unilateral, nine bilateral operations) and 16 had not. All patients entering the trial were taking anticholinergic drugs in stable dosage and these were continued throughout. The only factor which seemed to limit the response to treatment was pre-existing hypertension. Of 31 patients who completed the 10-week treatment period, 12 showed marked improvement, 15 moderate improvement, and 4 and mild or negligible change. It seems that previous ventrolateral thalamotomy affords some protection against the development of L-dopa-induced involuntary limb movements on the side contralateral to the operation. As found by others, maximum benefit was seen in bradykinesia and rigidity and related features but a significant reduction in tremor was also noted during treatment. Side effects (nausea, hypotension, and involuntary movements) were common but rarely limited the therapeutic response.     

Effect of nifedipine and propranolol on blood flow,venous compliance and blood pressure in essential hypertension

To determine the efficacy of nifedipine combined with propranolol in the treatment of hypertension, 23 patients with essential hypertension uncontrolled while they were receiving propranolol, 120 mg/d, entered a dose response trial of four 8-week periods while continuing propranolol therapy. Therapy during the four periods consisted respectively of a placebo, 30 mg/d of nifedipine, 30 or 60 mg/d of nifedipine, and 30 or 60 mg/d of nifedipine along with only 60 mg/d of propranolol. Studies of forearm blood flow and venous compliance were carried out in nine of the patients. Ten patients dropped out after the first period. The mean blood pressures while the patients were recumbent after the first, second and third periods were 163 ± 17/100 ± 6, 147 ± 13/89 ± 10 and 141 ± 19/84 ± 10 mm Hg respectively. There was no evidence of tolerance in the four patients who received 30 mg/d of nifedipine during the third period. There was a significant dose-diastolic pressure response (p < 0.0006) without a change in heart rate in the eight who received 60 mg/d of nifedipine during this period. After 16 weeks of therapy with nifedipine 11 patients had a diastolic pressure less than 90 mm Hg while recumbent. While mean blood pressure and heart rate for the group were not significantly increased at the end of the fourth period, in three of the patients the diastolic pressure while recumbent increased to over 90 mm Hg. This suggests that 120 mg/d of propranolol is the minimum dose required for concomitant therapy. Adverse symptoms were mild and transient. Forearm plethysmography showed that nifedipine induced arteriolar but not venous dilation and that propranolol attenuated the vasodilator effect of nifedipine. The author concludes that nifedipine was safe and effective in combination with propranolol in this group of patients with essential hypertension.     

Beclomethasone dipropionate aerosol in allergic rhinitis.

Treatment with beclomethasone dipropionate aerosol (BDA), 50 mug four times daily in each nostril, was compared with placebo therapy in a double-blind non-crossover trial of 30 matched patients with allergic rhinitis induced by ragweed pollen. The trial was started at the beginning of the ragweed season and continued for 42 days. Response to treatment was assessed from information on daily diary cards, weekly objective measurements of nasal patency and measurement of total eosinophil count (TEC) before treatment and at week 4. Patients in the BDA group had significantly less (P less than 0.05) sneezing, rhinorrhea and nasal stuffiness at 36 days, cough at 10 days and antihistamine consumption at 17 days. There was no significant difference between the groups in eye symptoms, nasal airway inspiratory resistance, maximum inspiratory nasal flow or TEC. Overall comparison with previous pollen seasons by the patients indicated moderate to great improvement in 86% of the BDA group and in 13% of the placebo group (P less than 0.01). Minor side effects were noted by two patients in each group.     

Diazepam withdrawal syndrome: its prolonged and changing nature.

The diazepam withdrawal syndrome was studied in 10 patients who had abused the drug for 3 to 14 years. In the previous 6 months their consumption of diazepam had ranged from 60 to 120 mg daily; none had used other drugs during this period. The withdrawal period lasted about 6 weeks. The intensity of the symptoms and signs was high initially, fell during the first 2 weeks, then rose again in the third week, before finally declining. Three groups of symptoms and signs were identified. Group A symptoms occurred throughout withdrawal and included tremor, anorexia, insomnia and myoclonus. Group B symptoms and signs were largely confined to the first 10 days and were those of a toxic psychosis. Group C symptoms reached a peak in the third and fourth weeks of withdrawal and were characterized by sense perceptions that were either heightened or lowered. The symptom groups, the presence of tremor and myoclonus, and the relief of symptoms by a test dose permit diazepam withdrawal to be distinguished from anxiety. The biphasic course of the symptoms is probably related to the pharmacokinetics of diazepam.     

Objective assessment of antianginal treatment: a double-blind comparison of propranolol,nifedipine, and their combination.

In a double-blind clinical trial the antianginal effects of nifedipine (30 and 60 mg/day) and propranolol 240 and 480 mg/day) and a combination of both drugs were compared with those of placebo in 16 patients with severe exertional angina pectoris. Response to treatment was assessed by the objective criteria of 16-point precordial exercise mapping and 48-hour ambulatory electrocardiographic monitoring and subjectively by analysis of patients'' daily diaries of episodes of angina and consumption of glyceryl trintrate. The incidence of pain and consumption of glyceryl trinitrate were significantly decreased by each drug compared with placebo, and the combination produced a further significant improvement. Objectively the total area and amount of ST depression on the precordial exercise map and the total number of episodes of ST depression detected on ambulatory monitoring confirmed the efficacy of each treatment regimen; the combination was significantly better than either drug alone (p <0.005). The objective methods permitted greater separation of treatment efficacy and showed reliably that the combination of propranolol and nifedipine was significantly better than either drug alone. Thus this combination is a safe and effective form of treatment for angina.     

RETURN OF THE VESTIBULAR FUNCTION FOLLOWING STREPTOMYCIN TOXEMIA

Of 62 patients given 2 gm. of streptomycin daily for an average of 110 days, 42 had complete loss of vestibular response to caloric stimulation. In the great majority of cases, response returned in varying degrees over a period of two years. The incidence of loss of response was higher among patients who weighed less than 125 pounds than among heavier patients, and it was higher among patients over 45 years of age than among those who were younger. Response returned earlier in the younger patients than in the older.Of 215 patients given 1 gm. of streptomycin for an average of 110 days, 18 had complete loss of vestibular response to stimulation. Sixteen regained response within a year, one in 17 months, and one was lost to study.     

One year's treatment with propranolol after myocardial infarction: preliminary report of Norwegian multicentre trial.

A prospective, randomised, double-blind study was performed to compare the effects of propranolol and placebo on sudden cardiac death in a high-risk group of patients who survived acute myocardial infarction. Altogether 4929 patients with definite acute myocardial infarction were screened for inclusion: 574 (11.6%) died before randomisation, and 3795 (77%) were excluded. Five hundred and sixty patients aged 35 to 70 years were stratified into two risk groups and randomly assigned treatment with propranolol 40 mg four times a day or placebo. Treatment started four to six days after the infarction. By one year there had been 11 sudden deaths in the propranolol group and 23 in the placebo group (p less than 0.038, two-tailed test analysed according to the "intention-to-treat" principle). Altogether there were 25 deaths in the propranolol group and 37 in the placebo group (P less than 0.12), with 16 and 21 non-fatal reinfarctions respectively. A quarter of the patients were withdrawn from each group. Withdrawal because of heart failure during the first two weeks of treatment was significantly more common among propranolol-treated patients than among the controls, but thereafter the withdrawal rate was the same. The significant reduction in sudden death was comparable with that after alprenolol, practolol, and timolol, which suggests that the mechanism of prevention is beta-blockade rather than any other pharmacological property of the individual drugs.     

MRC trial of treatment of mild hypertension: principal results. Medical Research Council Working Party.

The main aim of the trial was to determine whether drug treatment of mild hypertension (phase V diastolic pressure 90-109 mm Hg) reduced the rates of stroke, of death due to hypertension, and of coronary events in men and women aged 35-64 years. Subsidiary aims were: to compare the course of blood pressure in two groups, one taking bendrofluazide and one taking propranolol, and to compare the incidence of suspected adverse reactions to these two drugs. The study was single blind and based almost entirely in general practices; 17 354 patients were recruited, and 85 572 patient years of observation have accrued. Patients were randomly allocated at entry to take bendrofluazide or propranolol or placebo tablets. The primary results were as follows. The stroke rate was reduced on active treatment: 60 strokes occurred in the treated group and 109 in the placebo group, giving rates of 1.4 and 2.6 per 1000 patient years of observation respectively (p less than 0.01 on sequential analysis). Treatment made no difference, however, to the overall rates of coronary events: 222 events occurred on active treatment and 234 in the placebo group (5.2 and 5.5 per 1000 patient years respectively). The incidence of all cardiovascular events was reduced on active treatment: 286 events occurred in the treated group and 352 in the placebo group, giving rates of 6.7 and 8.2 per 1000 patient years respectively (p less than 0.05 on sequential analysis). For mortality from all causes treatment made no difference to the rates. There were 248 deaths in the treated group and 253 in the placebo group (rates 5.8 and 5.9 per 1000 patient years respectively). Several post hoc analyses of subgroup results were also performed but they require very cautious interpretation. The all cause mortality was reduced in men on active treatment (157 deaths versus 181 in the placebo group; 7.1 and 8.2 per 1000 patient years respectively) but increased in women on active treatment (91 deaths versus 72; 4.4 and 3.5 per 1000 patient years respectively). The difference between the sexes in their response to treatment was significant (p = 0.05). Comparison of the two active drugs showed that the reduction in stroke rate on bendrofluazide was greater than that on propranolol (p = 0.002). The stroke rate was reduced in both smokers and non-smokers taking bendrofluazide but only in non-smokers taking propranolol. This difference between the responses to the two drugs was significant (p = 0.03).(ABSTRACT TRUNCATED AT 400 WORDS)     

Alterations of Benzodiazepine Receptor Binding in Tremor Rats with Absence-Like Seizures

Tremor rats begin to exhibit clinical or electrical absence-like seizures after 6 weeks of age, and by 14 weeks of age, all have seizures. Central-type benzodiazepine receptor binding was investigated in tremor rats and control rats, aged 4 weeks and 16 weeks. Significantly lower benzodiazepine receptor density and no differences in affinity were found in the hippocampus of the tremor rats in comparison with that of control rats at both ages. This abnormality is considered to be due to a tremor gene and may be the cause of absence-like seizures in tremor rats. A significantly lower receptor density was found in the cerebellum at 4 weeks of age in the tremor rats than in the control rats. These changes may be related to tremorous movements in the tremor rats. Receptor density was significantly lower in the brainstems of tremor rats and control rats at 16 weeks of age than at 4 weeks of age, and the decrease was more marked in control rats. These facts may reflect a reduced decrease in the response to the dysfunction of gamma-aminobutyric acidergic neurons, or the function of the gamma-aminobutyric acid/benzodiazepine receptor system may be secondarily increased to suppress seizures in 16-week-old tremor rats.     

Additive antianginal effect of verapamil in patients receiving propranolol

Ten men with stable angina pectoris not fully relieved by optimal doses of propranolol (mean 218 mg daily) were given a single oral dose of 120 mg verapamil or a placebo on alternate mornings; the order of treatment was double blind. Patients had trained in a protocol that precipitated angina after three to six minutes of exercise on a bicycle ergometer. On test days, and with continued propranolol treatment, bicycle exercise was performed just before the administration of verapamil or placebo and hourly thereafter for eight hours. Mean exercise tolerance was 118 seconds greater one hour after verapamil than one hour after placebo (p <0·001), and a significant though somewhat diminished difference of 66 seconds was still present at six hours (p <0·01). Verapamil lowered resting systolic blood pressure by 12 mm Hg (p <0·01) without changing heart rate. None of the 10 patients showed adverse effects from the verapamil-propranolol combination.The results of this study suggest that verapamil is a highly effective antianginal supplement to propranolol.     

A role for alternative pathway catecholamines in the regulation of steroidogenesis in cow luteal cells

Incubation of bovine luteal cells with the alternative pathway catecholamines octopamine, synephrine and deoxyadrenaline at concentrations of 10(-6) to 10(-3) M enhanced the production of progesterone (P less than 0.05). Tryamine did not alter basal progesterone production (P greater than 0.05). Addition of noradrenaline and adrenaline at concentrations of 10(-4) to 10(-7) M significantly elevated the production of progesterone (P less than 0.05). The steroidogenic response to noradrenaline and adrenaline was greater than that for octopamine, synephrine and deoxyadrenaline (P less than 0.05). Response to both primary (10(-6) M) and alternative (10(-4) M) pathway catecholamines was inhibited by propranolol (10(-5) M, P less than 0.05) but not phentolamine (10(-5) M, P greater than 0.05). These results demonstrate that octopamine, synephrine and deoxyadrenaline can affect steroidogenesis by bovine luteal cells, and their action is mediated by beta-adrenergic receptors.     

Effects of propranolol, clonidine and hydrochlorothiazide treatment and abrupt discontinuation on central and peripheral noradrenergic activity in essential hypertension

This study was undertaken to investigate further the CNS actions of commonly employed antihypertensive drugs. Measurements of cerebrospinal fluid (CSF) and plasma catecholamines (CA) were made in an attempt to estimate the activity of central and peripheral noradrenergic neurons during treatment with or after abrupt discontinuation of treatment with clonidine (CLO), propranolol (PRO), hydrochlorothiazide (HCTZ) or placebo, in patients with essential hypertension. A randomized, parallel, placebo-controlled, single-blind design was employed. BP reductions equal to or greater than 10 mmHg were observed with CLO (0.36 +/- 0.07 mg daily), PRO (160 mg +/- 0 mg daily) or HCTZ (70 +/- 12 mg daily). CLO reduced plasma norepinephrine (NE) by 64% and PRO increased it by 25%. Neither HCTZ nor placebo modified plasma NE. Plasma renin activity (PRA) was reduced by PRO (51%, P less than 0.01) and CLO (35%, P less than 0.05). CSF-NE levels (pg/ml) were significantly lower in the CLO group (CLO: 175 +/- 23; PRO: 278 +/- 35; HCTZ: 255 +/- 34; placebo: 203 +/- 7).     

Exercise induces pentane production and neutrophil activation in humans. Effect of propranolol

The effect of beta-adrenergic receptor blockade on exercise-induced lipid peroxidation in man has been examined by measuring the production of pentane in expired air. For this purpose, five healthy male subjects were subjected to dynamic exercise of graded intensity on a cycle ergometer (10 min at 45%, 5 min at 60% and 75% maximal oxygen uptake 1 h after ingestion of either a placebo or 40-mg propranolol. At rest, mean pentane concentration [( pent]) with placebo was 4.13 pmol.l-1, SD 2.14. After exercise, this value significantly increased by 310% (17.1 pmol.l-1, SD 7.73, P less than 0.01). Oral administration of 40-mg propranolol significantly lowered the mean resting [pent] to 1.75 pmol.l-1, SD 0.77, P less than 0.05. After exercise, the increase of [pent] was much smaller (240%) and was less significant (P less than 0.2) than with the placebo. The mechanism of this inhibitory effect of propranolol remains to be elucidated. However, as indicated by the measurement of plasma myeloperoxidase concentration, it can be concluded that the antioxidant property of propranolol cannot be attributed to the inhibition of neutrophil activation, a possible source of free radicals during exercise.     

Course of blood pressure in mild hypertensives after withdrawal of long term antihypertensive treatment. Medical Research Council Working Party on Mild Hypertension.

A series of 1418 men and 1,347 women with mild hypertension (diastolic phase V 90-109 mm Hg) aged 35-64 who had either had long term antihypertensive treatment with bendrofluazide or propranolol or taken placebo tablets for a similar period were randomly allocated to groups in which their tablets were either stopped or continued. The course of blood pressure and of biochemical variables was followed up for two years. Mean blood pressures rose rapidly after the withdrawal of active treatment, and between nine months and one year after stopping treatment the antihypertensive effect had almost disappeared. The effect persisting longer than this, and possibly due to resetting of the baroreceptors or of other blood pressure control mechanisms, was very small, and as the rise in mean pressure was due to an upward movement in general distribution there was no evidence of a subgroup in whom these mechanisms had been permanently reset to a clinically important extent. After withdrawal of propranolol the rise in pressure was more rapid in younger than in older people. After stopping bendrofluazide pressure rose more rapidly in men who had had higher pressures before and during treatment; this effect was not seen in women. Disturbances in biochemical variables associated with drug treatment had largely resolved by the end of two years after withdrawal. Stopping placebo tablets made no consistent difference to blood pressure.     

Neuroanatomical Heterogeneity of Essential Tremor According to Propranolol Response

Background

Recent studies have suggested that essential tremor (ET) is a more complex and heterogeneous clinical entity than initially thought. In the present study, we assessed the pattern of cortical thickness and diffusion tensor white matter (WM) changes in patients with ET according to the response to propranolol to explore the pathogenesis underlying the clinical heterogeneity of ET.

Methods

A total of 32 patients with drug naive ET were recruited prospectively from the Movement Disorders outpatient clinic. The patients were divided into a propranolol-responder group (n = 18) and a non-responder group (n = 14). We analyzed the pattern of cortical thickness and diffusion tensor WM changes between these two groups and performed correlation analysis between imaging and clinical parameters.

Results

There were no significant differences in demographic characteristics, general cognition, or results of detailed neuropsychological tests between the groups. The non-responder group showed more severe cortical atrophy in the left orbitofrontal cortex and right temporal cortex relative to responders. However, the responders exhibited significantly lower fractional anisotropy values in the bilateral frontal, corpus callosal, and right parietotemporal WM compared with the non-responder group. There were no significant clusters where the cortical thickness or WM alterations were significantly correlated with initial tremor severity or disease duration.

Conclusions

The present data suggest that patients with ET have heterogeneous cortical thinning and WM alteration with respect to responsiveness to propranolol, suggesting that propranolol responsiveness may be a predictive factor to determine ET subtypes in terms of neuroanatomical heterogeneity.