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PubMed1982

Efficacy of slow infusion of diazoxide in the treatment of severe hypertension without organ hypoperfusion.

Diazoxide, as usually given in a single bolus, may cause precipitous falls in blood pressure (BP) with resultant tissue hypoperfusion. To examine the efficacy and safety of slow infusion, we treated 18 patients with mean initial BP of 220/143 mm Hg by two regimens: group A (nine patients) received 15 mg/minute; group B (nine patients) received 30 mg/minute. The goal of therapy, diastolic BP of 100 to 105 mm Hg, was reached in 16 of the 18 with no immediate drug-related side effects. Infusion time was 38.1 minutes in group A and 20.7 minutes in group B. Slow intravenous infusion of diazoxide appears to be safe and effective treatment for severe hypertension and should replace the rapid bolus technique.

Adult↗

PubMed1979

Individual titration of diazoxide dosage in the treatment of severe hypertension.

Diazoxide, 300 mg as a single bolus injection, is widely used to treat severe hypertension. Although usually effective, this standard dosage may decrease the blood pressure too much, inducing hypotensive problems. In this study 32 patients with a diastolic blood pressure above 125 mm Hg were treated with smaller bolus injections, 105 or 150 mg, which were repeated every 5 minutes as needed to reduce the diastolic pressure to 110 mm Hg or less. Seven patients of the 32 patients needed only one injection of 150 mg; only one patient needed more than three injections. This individual titration with mini-bolus injections of diazoxide was effective and did not induce hypotension or other side effects.

Adult↗

PubMed1977

Chlorpropamide-induced hypoglycemia: successful treatment with diazoxide.

A healthy adolescent boy was treated on two occasions for an overdose of chlorpropamide (Diabinese). Glucose therapy alone was not sufficient to control the hypoglycemia, but the administration of glucose plus diazoxide raised the blood sugar to supranormal levels. A bolus of intravenous glucagon briefly raised the blood sugar level to within normal limits, increased the blood ketones but also augmented insulin secretion. An overdose of sulfonylurea may cause prolonged and fatal hypoglycemia. Rational therapy, both in diabetic and normal persons, is glucose plus an "insulin antagonist." The administration of diazoxide was effective in our patient, substantially reducing the plasma insulin level; this agent may be the "insulin-antagonist" of choice for use in sulfonylurea-induced hypoglycemia.

Adolescent↗

PubMed1980

Infusion of diazoxide in severe hypertension during pregnancy.

Eight patients with severe pre-eclampsia or eclampsia were treated with diazoxide. The drug was administered on 3 occasions as a bolus injection (300 mg within 10 sec) and on 8 occasions as an infusion (15 mg/min, total amount 5 mg/kg body weight). The hypotensive effect at 30 and 60 min (stable hypotensive effect) and at 7 h (long-term effect) were the same with both modes of administration. The maximal decrease in blood pressure was reached in 5 min after bolus injection, compared to 25 min with the infusion. If diazoxide is used in severe pre-eclampsia and eclampsia, it should be administered preferably by the infusion method, because this results in a more gradual decline in blood pressure. Furthermore, the administration can easily be interrupted in cases of an exaggerated drop in blood pressure.

Adult↗

PubMedDate not supplied

Dilutional hyponatremia due to diazoxide-produced polydipsia.

Subcutaneous injection of diazoxide every 3 hr for a total of 5 doses in 15 hr produced a state of elevated drinking and antidiuresis in rats resulting in a massive, positive, self-imposed water load. Dilutional hyponatremia was present, but not serum hyposmolality, owing to the increased serum glucose and BUN. The mechanism by which diazoxide produces a polydipsia even in the presence of an accumulating water load may illuminate the genesis of other pathophysiological dilutional states.

Animals↗

PubMed1978

Effects of a diazoxide inhibition of insulin release on food intake of normal and hyperphagic hypothalamic rats.

In order to clarify the role of endogenous insulin in generating normal and pathological feeding behaviors, the effect of an anti-insulin drug, Diazoxide, on the meal pattern has been investigated in both normal and VMH rats. A dose-dependent reduction of food intake under Diazoxide treatment was found in normal rats. The same percentage reduction was obtained at night with a higher dose than required in the daytime. Conversely, hyperphagic VMH rats exhibited a dose-dependent reduction which was identical in the two portions of the diurnal cycle. The dose effective in entirely suppressing eating in VMH rats was twice that required for normal rats in the daytime period and identical at night. The results are discussed in relation to earlier findings concerning the diurnal insulino-secretory pattern in normal and VMH rats.

Animals↗

PubMed2006

Age- and gender-related differences in ischemia/reperfusion injury and cardioprotection: effects of diazoxide.

BACKGROUND: Recent studies have demonstrated that aging is associated with reduced tolerance to ischemia and that the aged (not senescent) female heart has greater susceptibility to ischemia as compared with the aged male heart. Previously, we have shown that ischemia can be modulated with cardioplegia in the male heart; however, efficacy in the female heart was unknown. METHODS: In this study, male and female mature (15 to 20 weeks) aged (>32 months) rabbit hearts (n = 134) were subjected to Langendorff perfusion. Control hearts were perfused for 180 minutes. Global ischemia hearts received 30 minutes of equilibrium, 30 minutes of global ischemia, and 120 minutes of reperfusion. Cardioplegia +/- diazoxide was infused separately, 5 minutes before global ischemia. RESULTS: Global ischemia significantly decreased postischemic functional recovery and significantly increased infarct size in the mature and aged male and female heart (p < 0.05 versus control). The effects of global ischemia were significantly exacerbated (p < 0.05) in the aged heart as compared with the mature heart. Cardioplegia +/- diazoxide significantly increased postischemic functional recovery and significantly decreased infarct size in mature male and female hearts, but these effects were significantly decreased in the aged heart (p < 0.05) and in the aged female as compared with the aged male heart. CONCLUSIONS: Postischemic functional recovery and infarct size are affected by age but not by gender. The cardioprotection afforded by cardioplegia is affected by age and gender with a strong age-by-gender interaction for end-diastolic pressure and infarct size. Our results indicate that currently optimized cardioplegia protocols effective in the male heart are not as efficacious in the aged female heart.

Aging↗

PubMed1999

Effects of high extracellular K(+) concentrations, diazoxide and/or Ca(2+) deprivation upon D-glucose metabolism in pancreatic islets.

A rise in D-glucose concentration may augment insulin release independently of changes in K(+) conductance or Ca(2+) influx in pancreatic islet cells, the insulinotropic action of the hexose remaining dependent on an increased generation of high-energy phosphates. In the present study, therefore, it was investigated to which extent the procedures currently used to assess the modalities of the secretory response to D-glucose independent of its effect on ATP-sensitive K(+) channels and Ca(2+) inflow may themselves affect the catabolism of the hexose in isolated rat pancreatic islets. A rise in the extracellular K(+) concentration from 5 to 30 or 60 mM failed to significantly affect the metabolism of D-glucose. At 90 mM K(+), however, the maximal velocity of the glycolytic flux was decreased and the apparent K(m) for D-glucose lowered, without an obvious alteration of the preferential stimulation of oxidative mitochondrial events in response to a rise in D-glucose concentration. Such a preferential stimulation was abolished, however, either by diazoxide at a low, but not high, K(+) concentration or by Ca(2+) deprivation, in the absence or presence of diazoxide, at a high K(+) concentration. It is speculated that these metabolic changes may be attributable, in part at least, to an altered activity of key cytosolic (e.g. pyruvate kinase) and mitochondrial (e.g. FAD-linked glycerophosphate dehydrogenase) enzymes.

Animals↗

PubMed2000

3-Alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1,1-dioxides structurally related to diazoxide and pinacidil as potassium channel openers acting on vascular smooth muscle cells: design, synthesis, and pharmacological evaluation.

A series of 3-alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides structurally related to diazoxide and pinacidil were synthesized and tested as possible K(ATP) channel openers on isolated pancreatic endocrine tissue as well as on isolated vascular, intestinal, and uterine smooth muscle. In contrast to previously described 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1, 1-dioxides, most of the new compounds were found to be poorly active on B-cells but exhibited clear vasorelaxant properties. 3-(3, 3-Dimethyl-2-butylamino)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxide (4d) and 7-chloro-3-(3, 3-dimethyl-2-butylamino)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxide (5d), two compounds bearing the alkyl side chain of pinacidil, were found to be the most active representatives of their respective series on rat aorta rings. 3-Cycloalkylalkylamino- and 3-aralkylamino-7-chloro-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides also expressed myorelaxant activity on electrically stimulated guinea pig ileum and on oxytocin-induced contractions of the rat uterus. Further biological investigations ((86)Rb efflux measurements, vasodilator potency on 30 and 80 mM KCl-induced contractions in the absence and presence of glibenclamide) revealed that compounds 4d and 5d, but not compound 5f, expressed the pharmacological profile of classical K(ATP) channel openers. In conclusion, by changing the position of the nitrogen atom in the pyridine ring, we now have obtained a family of drugs expressing an opposite tissue selectivity. Taken as a whole, the present findings also suggest that 3-alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides such as 4c, 4d, 5c, and 5d may be considered as new examples of K(ATP) channel openers expressing a pharmacological profile similar to that of pinacidil and diazoxide.

Animals↗

PubMed1997

Treatment with low-dose diazoxide in two growth-retarded prepubertal girls with glycogen storage disease type Ia resulted in catch-up growth.

Two originally prepubertal girls suffering from glycogen storage disease type Ia and short stature were treated with low-dose diazoxide (3-4.8 mg/kg per day) for 7 and 4 years, respectively. Both showed an impressive catch-up growth following this treatment. This appeared to be due to prolongation of normoglycaemia after meals and reduction of fasting lactic acidosis by diazoxide.

Acidosis, Lactic↗

PubMed1985

Diazoxide prevents the development of hormonal and metabolic abnormalities present in rats fed a sucrose rich diet.

We have previously reported that normal Wistar rats fed an isocaloric, sucrose-rich (63%) diet (SRD) developed glucose intolerance and elevated triglyceride levels in plasma (P) as well as in heart (H) and liver (L) tissue. This metabolic state was accompanied by hyperinsulinism both in vivo and in vitro, suggesting that a state of insulin resistance has developed. In order to gather information on the role of hyperinsulinemia and glucose intolerance in the development of the above lipid metabolism abnormalities, diazoxide, a known insulin release blocking agent was administered (120 mg/kg/day) together with the diet (SRD + DZX) for 22 days. Control groups fed a standard chow (STD) or the STD plus diazoxide (STD + DZX) were included in the study. Under the present experimental design, DZX was able to prevent the development of hyperinsulinism, glucose intolerance and elevated levels of triacylglycerol in plasma, heart and liver present in animals fed on a sucrose rich diet. Our results suggest that mechanisms involved in the development of this nutritionally induced syndrome may include an interaction of hyperinsulinemia, with a direct effect of sucrose on several steps of lipid metabolism.

Animals↗

PubMed1997

The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide.

The ATP-sensitive K-channel (K-ATP channel) plays a key role in insulin secretion from pancreatic beta-cells. It is closed by glucose metabolism, which stimulates insulin secretion, and opened by the drug diazoxide, which inhibits insulin release. Metabolic regulation is mediated by changes in ATP and Mg-ADP, which inhibit and potentiate channel activity, respectively. The beta-cell K-ATP channel consists of a pore-forming subunit, Kir6.2, and a regulatory subunit, SUR1. We have mutated (independently or together) two lysine residues in the Walker A (W(A)) motifs of the first (K719A) and second (K1384M) nucleotide-binding domains (NBDs) of SUR1. These mutations are expected to inhibit nucleotide hydrolysis. Our results indicate that the W(A) lysine of NBD1 (but not NBD2) is essential for activation of K-ATP currents by diazoxide. The potentiatory effects of Mg-ADP required the presence of the W(A) lysines in both NBDs. Mutant currents were slightly more sensitive to ATP than wild-type currents. Metabolic inhibition led to activation of wild-type and K1384M currents, but not K719A or K719A/K1384M currents, suggesting that there may be a factor in addition to ATP and ADP which regulates K-ATP channel activity.

Adenosine Diphosphate↗

PubMed1993

Differences in K+ permeability between cultured adult and neonatal rat islets of Langerhans in response to glucose, tolbutamide, diazoxide, and theophylline.

The effects of glucose, tolbutamide, and diazoxide on K+ permeability in neonatal and adult rat pancreatic islets, maintained in culture 1 week, were investigated by measuring the 86Rb outflow rate from prelabeled islets. In the absence of glucose, the 86Rb efflux was significantly lower in neonatal than adult islets. Raising the glucose concentration to 2.8, 5.6, 8.3, and 11.1 mM produced a marked reduction in the 86Rb efflux in adult islets but only a minor reduction in neonatal islets. The effect of tolbutamide to reduce, and diazoxide to increase, the 86Rb efflux was also less in neonatal islets. These results are discussed with respect to previously reported differences in insulin secretion from neonatal and adult islets in culture.

Animals↗

PubMed1973

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.

Adult↗

PubMed1978

Diazoxide in treatment of primary pulmonary hypertension.

Three patients with primary pulmonary hypertension and one man with suspected thromboembolic pulmonary hypertension were given up to 300 mg diazoxide by injection into the pulmonary artery. The three patients with primary pulmonary hypertension responded with a fall in total pulmonary resistance and a rise in cardiac output. The patient with suspected thromboembolic pulmonary hypertension did not respond. Haemodynamic and clinical improvement was maintained by oral diazoxide in two of the responders, and in one the prognosis appeared to be greatly improved.

Adult↗

PubMed1987

Reversibility of primary pulmonary hypertension during six years of treatment with oral diazoxide.

A 32 year old woman presented with a syncopal attack and dyspnoea on exertion. A diagnosis of primary pulmonary hypertension was confirmed by clinical examination, cardiac catheterisation, and pulmonary angiography. Her symptoms resolved completely with oral diazoxide and the pulmonary arterial pressure was reduced to normal levels over a period of six years. When diazoxide was discontinued on two separate occasions pulmonary hypertension recurred. This demonstrated the continued presence of the underlying stimulus for vasoconstriction.

Adult↗

PubMed1977

The action of diazoxide analogs on aortic reactivity in normotensive and spontaneously hypertensive rats.

Diazoxide and four related 1,2,4-benzothiadiazines reduced the maximum responses to noradrenaline (NA) and KCl in aortic rings from normotensive and spontaneously hypertensive rats (SHR). These agents were more active against NA than against KCl responses, and more effective against either NA or KCl responses in aortae from hypertensive animals. Further studies with V (3-cyclopentenyl-6,7-dichloro-1,2,4-benzothiadiazine-1,1-dioxide), the most active member of the series, showed it to be significantly more effective against NA responses; when calcium was added to calcium-free solutions containing eith NA or KCl, V was more effective in inhibiting either response in SHR aortae and was about 100 times more effective in inhibiting the calcium-NA responses. These data are consistent with previous findings that vascular smooth muscle from normotensive and SHR differs in sensitivity to diazoxide. However, the site(s) at which this difference is exhibited remains to be elucidated.

Animals↗

PubMed2001

Management of hyperinsulinemia with diazoxide in an elderly hemodialysis patient.

An elderly, nondiabetic, chronic hemodialysis patient is described here who had profound hypoglycemia for a myriad of reasons including renal failure, malnutrition, and quinine use. Furthermore, by biochemical parameters the patient had hyperinsulinemia, which was consistent with the diagnosis of an insulinoma. However, a tumor was not identified by noninvasive radiologic imaging as is often the case and the patient was not a candidate for surgical exploration. Diazoxide at a dose of 225 mg/day was used to successfully manage this patient's hypoglycemia. Previous experience with the use of diazoxide for hyperinsulinism in the hemodialysis population is limited and this case is the second report of its use for this purpose.

Aged↗