Metabolic and hemodynamic effects of metformin and glibenclamide in normotensive NIDDM patients.

OBJECTIVE: To compare the metabolic and hemodynamic effects of metformin and glibenclamide in normotensive NIDDM patients. RESEARCH DESIGN AND METHODS: After a 2-wk run-in period on dietary treatment alone, 12 Chinese normotensive patients with uncomplicated NIDDM were randomized to receive either metformin, or glibenclamide for 4 wk before being crossed-over to the alternative treatment for an additional 4 wk. Metabolic and hemodynamic index, including cardiac output estimation by impedance cardiography, were measured at baseline and at the end of each treatment period. RESULTS: Body mass index was reduced more with metformin than with glibenclamide, although glycemic control was similar with both drugs. Plasma total cholesterol concentration fell more with metformin (mean difference -0.65 mM, 95% confidence interval -0.96 to -0.32) than glibenclamide (mean difference -0.20 mM, 95% confidence interval -0.54-0.12) (P < 0.05). Compared with baseline values, erect diastolic blood pressure was reduced more by metformin (12.9% [95% confidence interval -21.5 to -4.4%]) than glibenclamide (-6.8% [95% confidence interval -14.9 to 1.2%]) (P < 0.001). The relative changes in the systemic vascular resistance index also differed between the two treatments (glibenclamide, 6.2 [-4.3 to 16.6%]; metformin, -1.2 [95% confidence interval -8.8-6.4%]) (P < 0.05)]. CONCLUSIONS: In normotensive NIDDM patients, treatment with metformin was associated with greater reductions in body weight, plasma total cholesterol concentration, and erect diastolic blood pressure, whereas the systemic vascular resistance index increased after treatment with glibenclamide. These findings merit long-term investigation.

Cardiovascular effects of a new inotropic drug in dog and normal man.

Cardiovascular effects of 1-butyl-3(1-(6,7-dimethoxyquinazolin-4-yl) piperidin 4 yl urea) (BDPU) were studied in 16 anesthetized dogs and in 7 healthy male volunteers. In animal experiments intravenous doses of 100, 250, and 500 mug/kg/min produced dose-related, significant increases in cardiac output and peak left ventricular dp/dt. No changes in heart rate and blood pressure occurred at 100 mug/kg/min, whereas higher doses caused falls in both systolic and diastolic blood pressures, accompanied by significant rises in heart rate. Inotropic effects could also be demonstrated in man. Changes of the systolic time intervals were dose-related and began at 64 mug/kg/min. At 250 mug/kg/min, the highest dose administered, the pre-ejection period decreased by 14.8 +/- 4.42 msec and its ratio with left ventricular ejection time by 0.049 +/- 0.017 against their respective control values (p less than 0.01). In contrast to animal experiments, no hypotension or tachycardia was observed in any subject. Pharmacokinetic studies showed a plasma elimination half-life of 76 +/- 3 min (mean +/- SE). There were no subjective side effects and standard laboratory tests were not altered, but there was a slight but significant rise in the urinary enzymes, lactic dehydrogenase (LDH) and glutamic oxaloacetic transaminase (GOT), which persisted up to 7 days.

Dilevalol: a dose-response study in normal volunteers.

Dilevalol, 100 mg, 200 mg and 400 mg, and placebo were given to eight normal volunteers and the effect on blood pressure and heart rate studied at rest and on exercise. There was a dose-dependent fall in exercising heart rate and in the increased heart rate on exercise with dilevalol, while exercising systolic blood pressure and the rise in systolic blood pressure on exercise fell dose-dependently up to 200 mg, but the effect of 400 mg was similar. Diastolic blood pressure was not affected. Supine heart rate and blood pressure changes were not different from placebo. Tilt heart rate fell most constantly from 200 mg. Some fall in tilt systolic blood pressure was seen but this was not dose-dependent, diastolic blood pressure was not affected. There was wide variation in plasma concentration of dilevalol, as might be expected from a liver metabolised drug, with a relatively larger amount absorbed of the 400 mg dose compared to the 100 or 200 mg doses.

Heart and catecholamines.

Catecholamines mediate their effects in the heart through beta 1- and beta 2-receptors. Beta 1-receptors mediate the effects of sympathetic nerve stimulation. Alpha-receptors may have a role but, unlike the beta-receptor mediated responses, act without producing any increase in cyclic AMP. Prolonged receptor stimulation results in a reduction in beta-receptor sensitivity. In contrast blockade with a non-agonist agent is associated with an increase in catecholamine sensitivity which may be responsible for the withdrawal reactions that can occur when beta-blocking drugs are rapidly withdrawn in patients with ischaemic heart disease. Experimentally, prolonged noradrenaline infusions result in ventricular hypertrophy. Catecholamines have been implicated in several pathologies. High and rising catecholamine levels are associated with worsening of prognosis in patients with heart failure. These patients show a decreased beta-receptor number and cellular concentration of catecholamines. On the other hand cardiomyopathy is associated with an increased sensitivity to catecholamines. Catecholamines aggravate cardiac damage in ischaemia. Excessively high catecholamine loads cause myocardial damage in otherwise normal hearts, for example in patients with a phaeochromocytoma and those with various forms of cerebral damage such as subarachnoid haemorrhage, cerebrovascular accidents, and head injury.

Bromocriptine in the treatment of hypertension.

The efficacy of bromocriptine in the treatment of hypertension was assessed in a double-blind placebo controlled cross-over study preceded by a dose titration phase. A diuretic and/or a beta-blocker were administered concomitantly in constant dosage to 11 of the 20 patients who received bromocriptine. A wide range of doses of bromocriptine was tolerated. Side-effects of vomiting and postural hypertension did not occur, possibly due to the gradual increase in the administered doses. Plasma prolactin was not raised in this population of hypertensives. In the dose titration phase (n = 20), a small fall in diastolic but not in systolic blood pressure occurred with bromocriptine, but only with the patient standing and after exercise. In the double-blind phase (n = 9), there was no significant difference in blood pressure between the bromocriptine and placebo treatments. It is concluded that bromocriptine was not effective in lowering blood pressure in the present patients with essential hypertension.

Withdrawal phenomena after atenolol and bopindolol: haemodynamic responses in healthy volunteers.

1. The effect of withdrawal of atenolol and bopindolol administration was studied in 12 normal volunteers; six on each drug. 2. Following sub-maximal cycle-ergometer exercise training six sets of base-line observations were made of heart-rate (HR) and blood pressure (BP) responses; supine, 60 degrees head-up tilt, during graduated isoprenaline infusion and sub-maximal cycle exercise. 3. The results show that withdrawal phenomena occur following both drug treatments. Atenolol produced a hypersensitivity to isoprenaline and a small overshoot of HR in response to physiological manoeuvres. In contrast bopindolol produced a prolonged state of reduced sensitivity to isoprenaline and some evidence of overshoot of HR with physiological manoeuvres. The differences between the responses may be explained by the different properties of the two beta-adrenoceptor blocking drugs. 4. Some subjects showed clear evidence of overshoot of HR and BP on exercise demonstrating that certain individuals may be more prone to have withdrawal effects than others. 5. The length of time during which withdrawal phenomena can occur is probably longer than has previously been realised. 6. Hormonal changes were found in the withdrawal period (Walden et al., 1990).

Clinical pharmacology of carvedilol.

Animal work has shown that carvedilol is a nonselective beta-blocking drug. It has a vasodilator action from alpha-receptor blockade, but there is evidence that it has further action to relax smooth muscle, possibly from calcium channel antagonism. Carvedilol is lipid soluble and 25% bioavailable, and it has a half-life of about 7 h. It lowers blood pressure at rest and reduces the tachycardia and the rise of blood pressure on exercise. It reduces the level of blood pressure reached during isometric exercise or the cold pressor test. Cardiac output at rest is maintained, and the haemodynamics in the compromised heart is improved. It has an important peripheral vasodilator action, peripheral flow being maintained to important organs, e.g. kidneys, despite the fall in blood pressure. Exercising renin and noradrenaline levels are increased, as are the latter at rest. Carvedilol is lipid neutral. Carvedilol shifts the dose-response curve to isoprenaline to the right, as well as to alpha-stimulants such as phenylephrine. Responses to angiotensin are little affected. The ratio of beta- to alpha-blockade has been found to be 7.6 for 50 mg and 12.5 for 100 mg of carvedilol. There is no evidence of a decline in alpha-blockade after 1 week of continuous administration.

Withdrawal of beta-blocking drugs.

Our early observations indicated that when treatment was changed from propranolol to placebo, anginal patients experienced a higher incidence of chest pain during the first week of placebo treatment compared to the second week. Since then, there have been several reports of myocardial infarction and sudden death occurring when propranolol therapy has been stopped. However, more formal hospital studies have indicated that ischemia from propranolol withdrawal is relatively infrequent. Studies in normal subjects and hypertensive patients have shown an increase in beta-receptor sensitivity as suggested by increased responsiveness to isoprenaline after propranolol withdrawal. Some investigators have found an increase in free triiodothyronine levels. Catecholamine levels do not appear to be raised. Other relevant factors in ischemic patients might be a reversal of the favorable rightward shift of the oxyhemoglobin dissociation curve or a reversal of reduced platelet aggregation produced by propranolol. Last, propranolol withdrawal in patients who have received the drug for a considerable period might unmask a withdrawal in patients who have received the drug for a considerable period might unmask a progression of the disease process, so that in the absence of beta blockade oxygen supply is inadequate to meet the requirements of relatively ischemic areas even at rest. Whether all beta blockers are similar to propranolol in this regard is unknown. We are examining, in normal volunteers, the sensitivity of the beta receptor after the withdrawal of atenolol, pindolol, or propranolol, administered for at least 2 weeks after final dose adjustment to levels sufficient to produce maximum inhibition of exercise tachycardia. The sensitivity of the beta receptor is being assessed by the response of bolus injections of isoprenaline and the response to exercise tachycardia.

Effect of food on the absorption of hydralazine in man.

Single oral doses of hydralazine (Apresoline) 50 mg were administered on two occasions to eight healthy volunteers when fed and fasting. Blood and saliva samples were taken at intervals after dosing and analysed for drug. Heart rate and blood pressure were measured before and at intervals after dosing, at rest, after tilt and exercise. Plasma hydralazine levels showed wide inter-individual variation. The areas under the plasma concentration-time curve (0-8 h), the height of the peak plasma levels and the time to peak were not significantly different between the fed and fasting state. Salivary hydralazine levels were readily measurable but showed little correlation with plasma levels. The heart rate and pulse pressure were increased after drug both at rest, supine and erect, and after exercise for between 6 and 8 h.

The beta-adrenergic blockade withdrawal phenomenon.

Early trials of beta-blocking drugs in angina indicated an increase in symptoms above pretreatment levels when placebo was substituted for active drug. This was followed by some reports of sudden death after beta-blockade withdrawal. There is evidence of increased beta-receptor sensitivity as suggested by increased responsiveness to isoprenaline after propranolol withdrawal. This may be due to an increased beta-receptor population. Other factors may be a reversal of the reduced free triiodothyroxine, of the rightward shift of the oxyhaemaglobin dissociation curve, and of reduced platelet aggregation, when the beta-blocking drug is stopped. Finally, progression of the disease process may take place during treatment, which is unmasked when treatment is withdrawn. beta-Blocking agents may differ; we have observed that in normal volunteers, withdrawal of pindolol, which has partial agonist properties, was not associated with postblockade increase in response to isoprenaline. The beta-blocker withdrawal syndrome is a real phenomenon, although overall the incidence is low. Besides stopping the beta-blocker, exertion may be a frequent prerequisite for the development of significant clinical sequelae, so exertion should be restricted when stopping a beta-blocking drug. Also the dose should be reduced gradually, particularly the final decrements.

The beta-adrenergic blockade withdrawal phenomenon.

Early trials of beta-blocking drugs in angina indicated an increase in symptoms above pretreatment levels when placebo was substituted for active drug. In addition there were reports of sudden death after beta-blockade withdrawal. There is evidence of increased beta-receptor sensitivity as demonstrated by increased responsiveness to isoprenaline after propranolol withdrawal. This may be due to increased beta-receptor population. Other factors may be a reversal of the reduced free triiodothyronine levels or of the favourable rightward shift of oxyhaemoglobin dissociation curve, or increased platelet aggregation when the beta-blocking drug is stopped. Also, progression of the disease process may have taken place during treatment which is unmasked on withdrawal. Studying different beta-blocking agents we have observed that in normal volunteers withdrawal of pindolol, which has partial agonist properties, was not associated with post blockade increase in response to isoprenaline. The beta-blocker withdrawal syndrome is a real phenomenon, although overall the incidence is probably not high. Exertion may be a prerequisite for the development of significant clinical sequelae, therefore exercise should be restricted on withdrawal of beta-blocking drugs. The dosage should be reduced gradually, particularly the final decrement.

Withdrawal phenomena after atenolol and bopindolol: hormonal changes in normal volunteers.

1. In order to observe and compare the withdrawal phenomena which follow treatment with the beta-adrenoceptor blocking drugs, bopindolol (with partial agonist activity PAA) and atenolol (without PAA), two groups of six normal volunteers were studied before, during and after 16 days drug administration. 2. Measurements of plasma levels of cortisol, prolactin, insulin, noradrenaline, adrenaline, glucose and potassium were made during a pre-treatment baseline period, on maximum dose and for 21 days after drug withdrawal. Isoprenaline infusions were given to determine sensitivity of heart rate responses and haemodynamic changes measured in response to physiological manoeuvres. 3. Following atenolol withdrawal the results show hormonal evidence of adrenergic overactivity in the form of elevation of plasma cortisol, insulin and glucose levels. After bopindolol withdrawal there was, in contrast, an overshoot of plasma prolactin and a persistent elevation of plasma potassium and adrenaline post-isoprenaline. 4. The hormonal changes which follow withdrawal of atenolol and bopindolol are associated with haemodynamic changes reported elsewhere (Walden et al., 1990). 5. These observations provide confirmatory evidence of a post beta-adrenoceptor blockade withdrawal syndrome which differs between the two drugs studied and this may reflect the properties of the drugs, in particular the PAA of bopindolol.

Trace element and vitamin deficiency in alcoholic and control subjects.

A wide range of trace elements and vitamins was studied in alcoholic patients admitted for detoxification and in healthy controls. Alcoholic subjects were found to be deficient relative to controls in magnesium and vitamin E, while a relative excess of serum iron and copper, and sweat nickel, was noted. A surprisingly wide range of deficiencies, as compared with standard laboratory ranges, was seen in the control group. This finding emphasizes the need for adequate control groups in nutritional studies of alcoholism, the insufficiency of an adequate diet alone to guarantee adequate nutrition, and the likely high prevalence of undetected nutritional deficiency in the general population. Further research is required on the clinical benefits of nutritional supplementation as part of the treatment of alcoholism, and the value of conventional supplements as a routine treatment is questioned.

Dose-titrated, double-blind, cross-over comparison of a selective beta-blocker and methyldopa in the treatment of hypertension.

The efficacy and toxicity of tolamolol and methyldopa in hypertensive patients has been compared by a dose-titrated, double-blind, cross-over study. Thirteen patients completed the trial. Within the dose ranges investigated (tolamolol - 300 mg/day - 900 mg/day; methyldopa - 750 mg/day - 2250 mg/day)both drugs produced significant falls in laying and standing, systolic and diastolic blood pressures. Although the hypotensive effects of methyldopa were more marked than tolamolol, these only achieved conventional (P less than 0.05) levels of significance for lying blood pressure. There were no objective changes in haematological or biochemical indices during treatment with either drug, but patients complained of tiredness, weak limbs and mouth dryness significantly more during methyldopa treatment, than during either placebo or tolamolol therapy.

The effect of intrinsic sympathomimetic activity on beta-receptor responsiveness after beta-adrenoceptor blockade withdrawal.

1 Heart rate (HR) and blood pressure (BP) changes supine, at 60 degrees tilt and in response to increasing exercise loads, and HR responses to Valsalva's manoeuvre and to isoprenaline bolus injections were studied in 19 healthy volunteers to assess the response to abrupt withdrawal of atenolol n = 6, propranolol n = 6 and pindolol n = 7. 2 The dosage of each drug administered double-blind was gradually increased over a period of 2 weeks and the dose to produce maximum inhibition of exercise-induced tachycardia was continued for one further week. 3 Plasma renin activity, plasma noradrenaline and serum free thyroid hormones were measured during control periods, maximum dosage and withdrawal periods. 4 An increased sensitivity to isoprenaline injections was seen on Day 5 after withdrawal in the atenolol treated group whereas the pindolol treated group showed decreasing hyposensitivity to isoprenaline for the 13 days of observation after withdrawal and propranolol showed an intermediate effect. 5 There was no overshoot in HR or BP measurements at rest or in response to tilting, Valsalva's manoeuvre or exercise with atenolol or propranolol and with pindolol the HR response to tilt only was significantly higher on the third day post-drug. 6 Plasma noradrenaline and serum free T3 were reduced on drug treatment and further reduced in the early withdrawal period but there were no consistent changes in plasma renin activity.