Dose-related haemodynamic effects and pharmacokinetics of oral nicorandil in patients evaluated for chest pain.

We studied the acute haemodynamic dose response of nicorandil, a combined nitrate and potassium channel opener, in patients evaluated for chest pain. Single dose oral nicorandil (5, 10, 20, or 30 mg) or placebo was given to 42 right-heart catheterized patients using a randomized block design. Persistent, significant (P < 0.05) haemodynamic changes occurred primarily after 30 mg. Arterial systolic pressure fell significantly after all doses and remained reduced (maximum, 31 mmHg) up to 6 h after 30 mg; heart rate increased significantly up to 1 h. Individual haemodynamic sensitivity varied and three patients (1, 10 mg; 2, 30 mg) developed transient symptomatic hypotension associated with bradycardia. Pulmonary artery systolic pressure (diastolic was unchanged) declined significantly (maximum, 5 mmHg) up to 6 h after 30 mg whereas pulmonary capillary wedge (baseline normal) and mean right atrial pressures decreased transiently. Cardiac index (baseline normal) declined slightly (significantly after 30 mg); however, stroke volume index and stroke work index were significantly and persistently reduced after all doses. Total systemic vascular resistance declined slightly after 30 mg. Individual plasma nicorandil concentrations were variable and systemic bioavailability was reduced compared with values reported in healthy subjects. Nicorandil demonstrated cardiac unloading actions. Variable plasma concentrations, haemodynamic effects, and patient sensitivity warrant low initial doses with individual dose titration, especially if cardiac filling pressures are low.

Alprazolam and suicidal ideation: a meta-analysis of controlled trials in the treatment of depression.

A meta-analysis of well-controlled studies of alprazolam in depression was performed to assess the possible association of alprazolam and suicidal ideation. Pooled data from 3,217 patients (alprazolam, placebo, and various active-comparative agents) who were enrolled in 22 placebo- and/or active drug-controlled depression studies were retrospectively analyzed to evaluate the emergence, worsening, and improvement of suicidal ideation during treatment with alprazolam, placebo, or other active drugs. Item 3 of the Hamilton Rating Scale for Depression was used to evaluate these events. Neither the risk of emergence nor the risk of worsening of suicidal ideation was significantly different for alprazolam than for placebo; however, alprazolam was significantly superior to placebo in producing improvement of suicidal ideation. There was no significant difference between alprazolam and the active-comparator group in the risk of emergence of suicidal ideation. The risk of worsening of suicidal ideation was significantly less for the active-comparator group (the majority of patients in this group received amitriptyline or imipramine) than for alprazolam, and improvement of suicidal ideation occurred significantly more frequently in that group than in the alprazolam group. Use of alprazolam in depressed patients is not associated with any particular increased risk of suicidality.

The haemodynamic effects and pharmacokinetics of intravenous nicorandil in healthy volunteers.

We have studied the effects of intravenous nicorandil, a mixed arterial and venous vasodilator, in 48 healthy volunteers. Nicorandil (20, 28, 39, 54, 74, 103, 144, or 200 micrograms.kg-1) or placebo were given over 5 min to subjects supine (16 subjects, 2 doses) or sitting (32 subjects, 1 dose) in a single-blind crossover design. Electrocardiographic intervals, blood pressure, and heart rate were measured before and for 8 h after dosing. Blood and urine safety laboratory studies were also performed before and after dosing. All intravenous infusions of nicorandil and placebo were well tolerated and there were no clinically important safety concerns. The most frequent adverse event after nicorandil was headache (24 events by 19 subjects), although its occurrence was not strictly dose related. One subject experienced transient symptomatic hypotension (144 micrograms.kg-1). Mean plasma nicorandil concentrations were dose-related and fell with a half-life of 0.7 to 1.2 h. Systemic clearance and volume of distribution tended to decrease as dose increased. Sitting subjects showed marginally lower (< 20%) systemic clearances and larger values of Cmax and AUC. Nicorandil produced dose-related reductions in blood pressure, with consistent statistically significant differences from placebo after the 144 and 200 micrograms.kg-1 doses. The falls in blood pressure were greater for diastolic pressure and in this supine position. At 200 micrograms.kg-1, the mean falls in systolic/diastolic pressures (mm Hg) during the first hour were 10.9/14.7 supine and 6.1/9.1 sitting; systolic pressure returned to baseline after 8 h and diastolic pressure after 4 h.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics and haemodynamic effects of continuous nicorandil infusion in healthy volunteers.

We have studied the pharmacokinetics and haemodynamic effects of nicorandil after a 12-h infusion. Nicorandil is a mixed vasodilator combining the actions of a nitrate and a potassium channel opener. Nicorandil was infused for 12 h in 21 healthy volunteers at rates of 0.05, 0.10, and 0.20 microgram.kg-1.min-1 using a placebo controlled, crossover design. Systemic blood pressure, heart rate, electrocardiographic (ECG) intervals, and cardiac output (impedance cardiography) were measured supine and standing. Dose-related, steady-state plasma nicorandil concentrations occurred within 3 to 4 h. Nicorandil's pharmacokinetics were linear with dose. Four 0.20 microgram.kg-1.min-1 nicorandil infusions were terminated early primarily because of moderate or severe headaches. There were no safety concerns (ECG intervals, laboratory assays). Blood pressure fell versus placebo only in the standing position and heart rate increased slightly (not significant). That is, standing blood pressure in the 6 to 12 h interval fell from baseline 8.0*/6.8, 1.6/5.1, and 9.8*/7.9* mmHg (systolic/diastolic, * = P < 0.05 versus placebo) at 0.05, 0.10, and 0.20 micrograms.kg-1.min-1 respectively. Cardiac output increased slightly above placebo at lower doses. Haemodynamic changes correlated poorly with plasma nicorandil concentrations. Similar total doses were less well-tolerated when extended over 12 h. We saw no evidence of pharmacodynamic tolerance to nicorandil within 12 h.

Ciglitazone, a new hypoglycaemic agent. 4. Effect on pancreatic islets of C57BL/6J-ob/ob and C57BL/KsJ-db/db mice.

Pancreases of treated and control male C57BL/6J-ob/ob and C57BL/KsJ-db/db mice were evaluated by qualitative and morphometric microscopic techniques to determine the effects of chronic ciglitazone treatment on the morphology of beta cells and surface area and number of pancreatic islets. The beta cells of treated ob/ob and db/db mice displayed moderate to heavy granulation whereas most beta cells of untreated obese and diabetic mice were extensively degranulated. Although moderate proliferation of the rough endoplasmic reticulum and Golgi apparatus was evident in some beta cells of treated db/db mice, both groups of treated ob/ob and db/db mice displayed an improved pattern of insulin synthesis and storage. In contrast, the beta cells of untreated ob/ob and db/db mice were in a severe state of stress which was indicated by extensive hypertrophy of the rough endoplasmic reticulum, Golgi apparatus and mitochondria. Some beta cells of untreated db/db mice also displayed lysosome aggregates indicative of early stages of necrosis. Morphometric analysis revealed that the surface area of islets of treated ob/ob mice was significantly smaller in comparison with that of untreated ob/ob mice. Since the surface area of islets of treated C57BL/6J-+/? mice (lean littermates of ob/ob mice) was less than that of treated ob/ob mice, the progression of islet hypertrophy in the obese mice was probably arrested or attenuated but not to the level of the treated +/? mice. The number of pancreatic islets was significantly greater in treated than in untreated db/db mice. A majority of the islets of untreated db/db mice were atrophic and consisted of acinar and endocrine cells whereas most of the islets of treated db/db mice appeared to be intact and unremarkable. The results of this study suggest that ciglitazone is an effective hypoglycaemic agent which may directly or indirectly promote beta-cell regranulation and an improved pattern of insulin synthesis and storage in ob/ob and db/db mice. However, in treated db/db mice, there still was some evidence of stress in the beta cells. Overall, the prolonged treatment with ciglitazone also seemed to inhibit the hypertrophy of islets in ob/ob mice and protect the structural integrity and viability of islets in db/db mice.

Ciglitazone, a new hypoglycemic agent. 5. Effect on renal lesions in C57BL/KsJ-db/db mice.

Kidneys of treated and control C57BL/KsJ-db/db mice were analyzed by semiquantitative light microscopy to determine the effects of ciglitazone on the deposition of fluorescein-conjugated IgM and IgG and of PAS-positive material in the glomerular mesangium and renal tubules. Long-term administration (12 and 20 weeks) of ciglitazone significantly improved the blood glucose of most of the treated db/db mice. There appeared to be a reduction of glomerular IgM and IgG in the treated compared with the control group, although IgM did not achieve statistical significance due to heavy stain deposition in two of the treated mice with continuous and severe hyperglycemia. Treated and control mice displayed a similar diffuse expansion and mild thickening of the glomerular mesangium characterized by moderate deposition of PAS-positive material. Expansion of the mesangium was probably not retarded or prevented by ciglitazone therapy since this pathologic process may be controlled by an interaction of metabolic factors other than hyperglycemia per se in the db/db mouse. Glycogen vacuolization (Armeni-Epstein lesion) of the renal tubules was completely ameliorated in the treated mice which showed a reduction of hyperglycemia. The results of this study suggest that prolonged treatment with ciglitazone elicits an improvement of hyperglycemia which seems to retard or reverse glomerular immunopathology and completely reverse tubular derangement but does not prevent expansion of the glomerular matrix in severely diabetic C57BL/KsJ-db/db mice.

Hemodynamic and neurohumoral responses to intravenous nicorandil in congestive heart failure in humans.

Nicorandil is a vasodilator drug that combines potassium channel opening properties with nitrate effects. The resulting potent and unique vasodilating properties suggest a potential therapeutic role in congestive heart failure. We therefore studied the acute hemodynamic and neurohumoral responses to nicorandil, given as single intravenous bolus doses of 158, 251, 398, or 630 micrograms/kg, to 22 patients with chronic congestive heart failure (ejection fraction less than 40%). Hemodynamic responses occurred within 5 min of dosing and terminated within 240 min. The heart rate was significantly increased only at 5 min after the 158 micrograms/kg dose, and was unchanged after all other doses. The mean arterial pressure was reduced only by the 398 and 630 micrograms/kg doses. The pulmonary capillary wedge pressure and right atrial pressure were significantly reduced by all doses within the initial 30 min; this reduction in pulmonary capillary wedge pressure was better sustained over time by the two larger doses, whereas the reduction in right atrial pressure was sustained only by the 158 micrograms/kg dose. The cardiac index was reduced by the 158 micrograms/kg dose, but increased after 251, 398, and 630 micrograms/kg of nicorandil. Plasma nicorandil concentrations were positively correlated with changes in cardiac index, systemic arterial pressure, pulmonary capillary wedge pressure, heart rate, and systemic vascular resistance. When measured 1 h after dosing, plasma immunoreactive ANF decreased, norepinephrine concentrations did not change, and plasma renin activity increased, but only at the 630 micrograms/kg dose level.(ABSTRACT TRUNCATED AT 250 WORDS)