Diazoxide-mediated insulin suppression in obese men: a dose-response study.

BACKGROUND: It has been suggested that diazoxide (DZX)-mediated insulin suppression may be useful to promote weight loss in obese subjects. AIM: To assess the DZX-dose range that is safe to use in obese hyperinsulinaemic men. METHODS: Assessment of DZX efficacy and safety was based on plasma glucose and insulin responses to a standardized 500-kcal breakfast, taken on the sixth day of treatment. Basic information regarding the potential efficacy of DZX treatment was first evaluated in an open-label study in five non-obese men. Subsequently, a double-blind, randomized, placebo-controlled study was performed in 12 obese but otherwise healthy men, comparing placebo treatment with DZX in doses of 50, 75 and 100 mg three times daily for 6 days. RESULTS: In non-obese subjects, DZX 50 mg decreased peak insulin levels by +/-28% and raised peak glucose concentration from 7.1 +/- 0.6 to 7.8 +/- 0.6 mmol/l (p < 0.05). DZX 100 mg reduced peak insulin levels by 45% and caused a rise in peak glucose levels from 7.1 +/- 0.6 to 9.0 +/- 0.9 mmol/l (p < 0.05). In obese men, the 50 and 75 mg doses had no significant effects on glucose or insulin levels. DZX 100 mg reduced the peak insulin levels and insulin area under the curve by +/-20% (p < 0.05) but did not affect fasting or postprandial glucose levels. The relatively limited insulin-suppressive effects in obese subjects were attributed to the low plasma DZX levels that were achieved in this group. For comparable doses, plasma DZX levels were about 30% lower in obese than in non-obese men. Plasma DZX levels were highly dependent on dose (p < 0.001) and body weight (p < 0.001). Ninety-two percent of the total variability in DZX levels was explained by these two parameters. CONCLUSION: DZX-mediated insulin suppression is dose dependent in normal and in obese men. However, the efficacy of DZX is much less in obese than in non-obese subjects. This is attributed to weight-dependent differences in distribution volume that lead to markedly lower plasma DZX levels in obese subjects. Weight-adjusted doses will be needed to achieve biologically effective plasma DZX levels. Extrapolation of the data suggests that effective insulin suppression in obese men will at least require a daily dose of 3.2-4.2 mg/kg.

Caffeine potentiates the renin response to diazoxide in man. Evidence for a regulatory role of endogenous adenosine.

In the rat and dog, exogenous adenosine inhibits renin release and adenosine receptor blockade augments stimulated renin release, suggesting that endogenous adenosine contributes to the regulation of renin release. The present study examines the role of endogenous adenosine in the regulation of renin in humans. The ability of the adenosine receptor blocker, caffeine, to augment renin release in response to the vasodilator, diazoxide, has been investigated in eight normal subjects in a double-blind, placebo-controlled, cross-over study. During each arm of the study, subjects on a 150 mEq of sodium, xanthine-free diet received caffeine (250 mg 3 times daily) or placebo for 3 days before and on the study day, when they were given an i.v. loading dose of diazoxide (4 mg/kg) followed by a 3-hr continuous infusion (0.67 mg/kg/hour). PRA, caffeine and diazoxide levels were measured before, during and after the diazoxide infusion. PRA measurements were repeated with subjects standing, 6 hr after starting diazoxide. Administration of diazoxide resulted in a modest tachycardia and a small, but significant, decrease in BP. Supine PRA was elevated during and after the diazoxide infusion and rose further with standing. Although there was no difference in plasma diazoxide levels, maximal pulse or BP response to diazoxide between the two arms of the study, the renin response was significantly greater in the presence of caffeine. These data confirm that caffeine augments the PRA response to diazoxide and suggest that endogenous adenosine inhibits stimulated renin response in humans.

Diazoxide concentration-response relation in hypertension.

The pharmacokinetic disposition and antihypertensive response of bolus infusions of diazoxide, 1, 2, or 4 mg/kg over 5, 10, or 20 seconds, were examined in seven patients with chronic stable essential hypertension and mean arterial pressures (MAP) between 122 and 155 mm Hg off therapy. Maximal reductions in MAP were noted 2 minutes after each dose, and a linear correlation was obtained in all patients between dose or plasma diazoxide concentration and maximal change in MAP. Individual concentration-time curves were analyzed to determine the apparent volume of distribution at steady state (Vdss range, 0.178 to 0.250 liter/kg), beta t 1/2 (range, 32 to 62.5 hours), and plasma clearance rate (Clp range, 2.2 to 5.3 ml/kg . hour-1) for the calculation of loading and maintenance doses designed to produce steady-state concentrations within 0.5 hours. These infusions resulted in steady-state reductions in MAP (16% to 30%) which could be predicted from the concentration-response curves of each patient after bolus infusions. With the use of kinetic principles, a diazoxide dose regimen (average load, 7.5 mg/kg at 7.5 mg/min; average maintenance, 10% of loading dose every 6 hours) produced gradual and predictable reductions in MAP in patients with accelerated hypertension, since the response was proportional to plasma diazoxide concentrations.

Diazoxide in the management of chlorpropamide overdose.

Three cases of chlorpropamide overdose are reported. Plasma levels of chlorpropamide, diazoxide, glucose, and insulin are presented for each patient during treatment. The simultaneous analysis of chlorpropamide, hydrochlorothiazide, and diazoxide in plasma by high pressure liquid chromatography (HPLC) is also reported. Although all three cases presented at hospital with potentially lethal plasma levels of chlorpropamide, each was successfully treated with intravenous diazoxide and glucose. Plasma diazoxide concentrations between 50-100 microgram/mL appear to be optimal in achieving therapeutic control of chlorpropamide induced hypoglycemia.

Pharmacokinetics and response to diazoxide in renal failure.

Diazoxide is given by rapid intravenous injection for the urgent reduction of high blood pressure in patients with all grades of renal function. Oral diazoxide produces less consistent effects. Protein binding of diazoxide is reduced in renal failure and this can be related to reduction of albumin concentration. There is a relation between impairment of renal function and the hypotensive effect of rapidly injected diazoxide. This is explicable in terms of the greater concentration of free (unbound) drug achieved after rapid injection in patients with renal failure. Renal clearance of diazoxide and its metabolites is impaired in renal failure but this is unlikely to affect its activity.

Renal function, protein binding and pharmacological response to diazoxide.

1 The effect of rapid (10s) injections of diazoxide was studied in ten hypertensive patients with varying degrees of impairment of renal function. 2 There was a significant correlation between the patient's plasma urea concentration and reduction in mean arterial blood pressure. Diazoxide was also shown to be less highly protein bound in patients with renal failure. 3 It is suggested that the explanation for the increased hypotensive effect of diazoxide observed in patients with reduced renal function is related to higher unbound drug concentrations.

Maternal and fetal hemodynamic effects of diazoxide.

Effects of diazoxide on systemic and uterine hemodynamics as well as on fetal circulation and blood respiratory gases were investigated in chronically instrumented pregnant sheep. Diazoxide was administered intravenously either to the ewe or directly to the fetus in doses calculated on the basis of body weight. Transfer of drug across placenta was also investigated. Results showed that: a) when injected into the mother, there was consistent hypotensive effect with increased cardiac output and decreased systemic vascular resistance; uterine blood flow might not change or might decrease slightly with moderate hypotension; when maternal systemic arterial pressure fell to critical closing pressure level, uterine flow decreased significantly; but despite these maternal changes, the fetal circulatory functions were not significantly altered; b) when injected into the fetus in doses up to 15 mg/kg, diazoxide failed to alter fetal circulation appreciably; c) diazoxide crossed the placenta when injected intoeither mother or fetus according to a definite gradient; fetal levels were always lower than maternal levels because of rapid loss of the drug by the fetus; d) moderate maternal and fetal hyperglycemia occurred after drug administration.

Potentiation of the adrenergic beta-receptor-mediated insulin secretion in pertussis-sensitized rats.

The increase in blood insulin level induced by adrenergic beta-stimulants, glucose and tolbutamide was strongly exaggerated in pertussis-sensitized rats. Moreover, the decrease in blood insulin caused by the alpha-receptor-mediated action of epinephrine in glucose- or tolbutamide-treated rats was effectively reversed by pertussis sensitization. The rise of blood insulin concentration due to adrenergic alpha-blockade was also enhanced by pertussis sensitization. It is concluded that the secretion of insulin resulting from the stimulation of adrenergic bate-receptor is enhanced by pertussis sensitization, probably due to activation of a process occurring in the chain of events leading to the discharge of insulin from the pancreatic beta-cell.

Decreased plasma protein binding of diazoxide in uremia.

The effect of uremia on the binding of diazoxide to plasma proteins was studied. An equilibrium dialysis technique, using diazoxide-minus14C at approximately 30 and 300 mug/ml in the plasma phase, was used to measure diazoxide binding to plasma. Serum albumin concentration (Alb) and serum creatinine (Cr) or blood urea nitrogen (BUN) were negatively correlated. By single regression analysis, per cent free diazoxide (%FD) correlated negatively with Alb and positively with Cr or BUN. When %FD was regressed simultaneously against Alb and Cr or BUN, Alb emerged as the sole determinant of %FD (p less than 0.001), indicating that creatinine or BUN correlated with %FD by their inverse correlation to Alb rather than by an effect on drug protein binding. At the levels of Alb studied, %FD varied over a 2-fold range. In a retrospective study of the influence of uremia on diazoxide effect in hypertensive patients, a relatively low correlation (r, 0.59) was found between BUN and hypotensive effect. Prospective studies involving correlations of drug effect with renal function and %FD are required to assess the clinical importance of decreased binding of diazoxide to uremic plasma.

Development of extrapyramidal symptoms in hypertensive patients treated with diazoxide.

Extrapyramidal symptoms developed a variable time after the start of treatment with oral diazoxide in 15% of a series of 100 severely hypertensive patients. Six illustrative cases are described. Treatment with diazoxide could be continued in four of these. The symptoms are usually controllable either by dosage adjustment or by the use of diazepam or procyclidine. There was no evidence of irreversibility of the extrapyramidal syndromes observed.