GAL-021, a new intravenous BKCa-channel blocker, is well tolerated and stimulates ventilation in healthy volunteers.

BACKGROUND: Potassium-channels in the carotid body and the brainstem are important regulators of ventilation. The BKCa-channel contains response elements for CO, O2, and CO2. Its block increases carotid body signalling, phrenic nerve activity, and respiratory drive. GAL-021, a new BKCa-channel blocker, increases minute ventilation in rats and non-human primates. This study assessed the single-dose safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of GAL-021 in healthy volunteers. METHODS: Thirty subjects participated in a nine-period, randomized, double-blinded, placebo-controlled, crossover, ascending dose, first-in-human study with i.v. infusions of 0.1-0.96 mg kg(-1) h(-1) for 1 h and intermediate doses up to 4 h. RESULTS: Adverse event rates were generally similar among dose levels and between placebo- and GAL-021-treated subjects. At higher GAL-021 doses, a mild/moderate burning sensation at the infusion site occurred during the infusion. No clinically significant changes in vital signs or clinical chemistries were noted. Minute ventilation increased (AUE0-1 h ≈ 16%, P<0.05) and end-tidal carbon dioxide ([Formula: see text]) decreased (AUE0-1 h ≈ 6%, P<0.05) during the first hour at 0.96 mg kg(-1) h(-1) with 1/2-maximal [Formula: see text] and [Formula: see text]-change occurring by 7.5 min. Drug concentration rose rapidly during the infusion and decreased rapidly initially (distribution t1/2 of 30 min) and then more slowly (terminal t1/2 of 5.6 h). CONCLUSIONS: GAL-021 was safe and generally well tolerated with adverse events comparable with placebo except for an infusion site burning sensation. GAL-021 stimulated ventilation at the highest doses suggesting that greater infusion rates may be required for maximum PD effects. GAL-021 had PK characteristics consistent with an acute care medication.

The metabolism and excretion of galantamine in rats, dogs, and humans.

Galantamine is a competitive acetylcholine esterase inhibitor with a beneficial therapeutic effect in patients with Alzheimer's disease. The metabolism and excretion of orally administered (3)H-labeled galantamine was investigated in rats and dogs at a dose of 2.5 mg base-Eq/kg body weight and in humans at a dose of 4 mg base-Eq. Both poor and extensive metabolizers of CYP2D6 were included in the human study. Urine, feces, and plasma samples were collected for up to 96 h (rats) or 168 h (dogs and humans) after dosing. The radioactivity of the samples and the concentrations of galantamine and its major metabolites were analyzed. In all species, galantamine and its metabolites were predominantly excreted in the urine (from 60% in male rats to 93% in humans). Excretion of radioactivity was rapid and nearly complete at 96 h after dosing in all species. Major metabolic pathways were glucuronidation, O-demethylation, N-demethylation, N-oxidation, and epimerization. All metabolic pathways observed in humans occurred in at least one animal species. In extensive metabolizers for CYP2D6, urinary metabolites resulting from O-demethylation represented 33.2% of the dose compared with 5.2% in poor metabolizers, which showed correspondingly higher urinary excretion of unchanged galantamine and its N-oxide. The glucuronide of O-desmethyl-galantamine represented up to 19% of the plasma radioactivity in extensive metabolizers but could not be detected in poor metabolizers. Nonvolatile radioactivity and unchanged galantamine plasma kinetics were similar for poor and extensive metabolizers. Genetic polymorphism in the expression of CYP2D6 is not expected to affect the pharmacodynamics of galantamine.

The effect of ketanserin, a 5-HT2-receptor antagonist, on 5-hydroxytryptamine-induced irreversible platelet aggregation in patients with cardiovascular diseases.

Platelet aggregation in response to 5-hydroxytryptamine was investigated in 40 normal subjects, in 45 patients with acute myocardial infarction, and in 65 patients with peripheral arterial obstructive disease. It was found that of the 110 patients with cardiovascular disease, 40% had a biphasic irreversible platelet aggregation, whereas this phenomenon occurred in only 7.5% of the normal population. A double-blind placebo-controlled study further showed that a subacute treatment with ketanserin, a selective 5-HT2-receptor antagonist both on platelets and on vascular tissue, efficiently abolished the irreversible platelet aggregation in patients hyperreactive to 5-hydroxytryptamine. In an additional open study, including 10 patients with peripheral arterial obstructive disease, a chronic treatment with ketanserin 40 mg t.i.d. for a period of 3 months significantly suppressed the primary platelet aggregation to 5-HT at 2 X 10(-5) M and at 2 X 10(-6) M and significantly lowered the plasma beta thromboglobulin levels. Since 5-HT is a potent mediator of vasospasm, treatment with ketanserin might be of therapeutic value in atherosclerotic diseases, where platelet activation is thought to be involved.

Effect of ketanserin on the hyperreactivity of platelets to 5-hydroxytryptamine in patients with cardiovascular diseases.

Platelet aggregation in response to 5-hydroxytryptamine (5-HT) was investigated in 110 patients with cardiovascular diseases and in 40 age-matched control subjects. It was found that 40% of those patients had a biphasic irreversible platelet aggregation in response to 5-HT, whereas 92.5% of the control subjects responded with a weak reversible aggregation. A double-blind, placebo-controlled study, including 41 patients, showed that a subacute treatment with ketanserin significantly abolished platelet aggregation in patients hyperreactive to 5-HT. In an additional open study, including 10 patients with peripheral arterial obstructive disease, chronic treatment with ketanserin for a period of 3 months significantly suppressed the primary platelet aggregation to 5-HT at 2 X 10(-5) M and at 2 X 10(-6) M and significantly lowered the plasma beta-thromboglobulin levels.

Ketanserin and red blood cell sodium content in hypertension.

The sodium content of erythrocytes from patients with essential hypertension is increased. In a double-blind, placebo-controlled study, a 5-day treatment with ketanserin, a serotonergic antagonist lowered significantly the sodium content of the red blood cells (RBC). Ouabain induces an increase of sodium content of the RBC, which is paralleled by a decrease in RBC deformability. The ouabain-dependent fraction of RBC deformability is significantly reduced after a single oral dose of ketanserin. In vitro, serotonin (5-HT) decreases RBC deformability; this effect could be antagonized by ketanserin. These data might suggest a regulating role of 5-HT in transmembrane ion fluxes.

Comparison of blood pressure ratio by Doppler velocimetry and by plethysmography during treatment with ketanserin, a 5-HT2 receptor antagonist: a measure of improved collateral and microcirculatory flow.

We could demonstrate a progressive and significant increase in blood pressure ratio (thigh/arm) in 42 patients with intermittent claudication, treated with ketanserin for 9 months, which confirms our earlier double-blind placebo-controlled findings. In an additional experiment comparing blood pressure ratio with Doppler velocimetry and with plethysmography, an upwards shift was observed for the plethysmographic values as compared with the Doppler values during ketanserin therapy, and only at the level of the thigh, which suggests an improvement of the collateral and microcirculatory flow.

Placebo-controlled double-blind trial of ketanserin in treatment of intermittent claudication.

Ketanserin, a selective serotonin (5-HT) antagonist at 5-HT2 receptors, was investigated in a 3-month, double-blind, placebo-controlled study in twenty patients with intermittent claudication. Blood-pressure ratio (thigh/arm), reactive hyperaemia measured with an ECG-triggered venous occlusion plethysmograph, blood filterability, and claudication distance on a treadmill progressively and significantly improved during ketanserin therapy, whereas no such changes occurred in the placebo group. Mean claudication distance improved by 140%; four of the eleven patients on ketanserin were able to keep walking beyond the time limit of the exercise test. The beneficial effect of ketanserin suggests that 5-HT may be involved in the pathogenesis of peripheral arterial obstructive diseases. In an experiment comparing blood-pressure ratio measured by doppler velocimetry and by plethysmography, the plethysmographic values rose during ketanserin therapy only at thigh level, which suggests an improvement in the collateral circulation.

Enumeration of T-lymphocytes and T-lymphocyte subsets in rheumatoid arthritis using monoclonal antibodies.

The number of T-lymphocytes and T-lymphocyte subsets was measured in peripheral blood of 51 patients with rheumatoid arthritis. T-lymphocytes were counted by E-rosette tests and by the immunogold staining method with OKT3.PAN monoclonal antibody. Helper and suppressor T-lymphocytes were determined by the immunogold staining method with OKT4.IND and OKT8.SUP monoclonal antibody. The relative and absolute numbers of T-lymphocytes and helper T-lymphocytes in peripheral blood of patients with RA did not differ significantly from those in the blood of healthy subjects. However, the relative and absolute numbers of suppressor T-cells were significantly lower in patients with RA than in healthy subjects. The decrease of suppressor T-cells in the blood of patients with RA dit not correlate with the activity of the disease nor the presence of the rheumatoid factor.

The antihypertensive effects of a pure and selective serotonin-receptor blocking agent (R 41 468) in elderly patients.

In a first experiment, an acute intravenous administration of 10 mg R 41 468, a pure serotonin-receptor blocking agent with high selectivity for blood vessels and thrombocytes and devoid of central effects, dramatically reduced systolic and diastolic blood pressure in 23 elderly hypertensive patients. Heart rate and cardiac output remained virtually unchanged. In a second double-blind placebo-controlled cross-over study a highly significant decrease of systolic and diastolic blood pressure was obtained in 14 elderly hypertensive patients during an 8-day oral treatment with 40 mg t.i.d. of R 41 468. No serious side-effects were observed. An oral maintenance therapy with R 41 468 for 3 weeks showed a further reduction of blood pressure, resulting in a normalization of blood pressure, taking into account the advanced age of the patients. R 41 468 most probably acts by decreasing the venous capacitance bed constriction. Essential hypertension might be causally related to an impairment of venous function, in which serotonin might be an important pressor factor.