Biomedical subjects

K R Lees

Publications and source records attributed to K R Lees.

168 records · Page 10Linked to original sources

PubMed1986

Effects of angiotensin converting enzyme inhibitor, perindopril, on autonomic reflexes.

The effect of the angiotensin converting enzyme inhibitor, perindopril, on autonomic function was assessed in a double blind, placebo controlled, crossover study in 10 normotensive males. Eight milligram of perindopril given orally lowered blood pressure without a change in heart rate. Perindopril enhanced the vagally mediated heart rate variation with deep breathing. There was no impairment of the responses to either bicycle exercise at 175 W for 5 min or isometric handgrip. The pressor response to cold was not changed and the response to the Valsalva manoeuvre was unaltered. These results suggest that the absence of tachycardia after perindopril may be in part related, as has been reported with other converting enzyme inhibitors, to enhanced cardiac parasympathetic tone. Vagomimetic action may be a property of converting enzyme inhibitors in general.

Adolescent↗

PubMed1983

Successful treatment of post-splenectomy sepsis in an 82-year-old male.

Six weeks after splenectomy for idiopathic thrombocytopenic purpura an 82-year-old man suddenly became drowsy with pyrexia and neck stiffness. Pneumococcal meningitis was diagnosed and treated with benzyl penicillin. Subsequently, penicillin-sensitive pneumococci (serotype 23) were isolated from both CSF and blood. He recovered fully. Review of recent literature confirms that absence of the spleen predisposes to overwhelming infection with encapsulated organisms in adults as well as in children. Use of pneumococcal vaccine would appear to be a prudent, if untested measure in all patients undergoing splenectomy.

Aged↗

PubMedDate not supplied

Pharmacokinetics of a glycine site antagonist (gavestinel) following multiple dosing in patients with acute stroke.

OBJECTIVE: The objective of this study was to characterize the pharmacokinetics of gavestinel in patients with acute stroke. METHODS: Gavestinel was administered as an 800-mg loading dose and followed by either 100-, 200-, or 400-mg maintenance doses given every 12 h for five doses. Blood and urine samples were collected for pharmacokinetic evaluation. The pharmacokinetics of gavestinel were determined using compartmental analysis. RESULTS: The mean clearance (CL) and central (Vc) and steady-state (Vss) volumes of distribution across the dose groups were 0.31-0.40 l x h(-1), 3.3-3.9 l, and 9.8-17 l, respectively. The mean terminal half-life ranged from 29 h to 56 h. Gavestinel was extensively bound to plasma protein (median percentage free <0.01). During gavestinel administration, some patients exhibited elevated levels of bilirubin, which may be the result of shared mechanisms of elimination (glucuronide conjugation and excretion in bile). CONCLUSIONS: This study characterized the pharmacokinetics of gavestinel following multiple doses in acute stroke patients and showed that the pharmacokinetics are similar for increasing maintenance doses. The high protein binding of gavestinel was confirmed in acute stroke patients. A pharmacokinetic interaction between gavestinel and bilirubin may contribute to the increase in bilirubin.

Aged↗

PubMedDate not supplied

Safety and tolerability of 619C89 after acute stroke.

BACKGROUND: 619C89 is a use-dependent sodium channel blocker which reduces hemispheric infarction volume by up to 60% after permanent middle cerebral artery occlusion in rats. Intravenous doses of up to 1 mg/kg have been well tolerated by healthy young and elderly volunteers. This study sought to assess safety and tolerability of 619C89 in the treatment of acute stroke. METHODS: Patients were randomised within 12 h of onset of stroke to receive 619C89 or placebo as an intravenous loading dose, followed by maintenance doses given 8 hourly for 64 h in a double-blind, ascending-dose tolerance study. Dosing commenced at 0.5 mg/kg loading plus 0.25 mg/kg/8 h maintenance for the first group and increased in increments of 0.5 mg/kg loading +0.25 mg/kg/8 h maintenance thereafter. Safety evaluation was continued for 3 months. RESULTS: 48 patients were recruited. 12 received placebo and 36 received 619C89 in doses up to 2.5 mg/kg loading plus 1.25 mg/kg/8 h. Dose escalation was stopped after the occurrence of hallucinations in 5 of 18 patients who received 2 mg/kg/8 h or more. Gastro-intestinal upset and confusion were also possibly drug related. No drug-related effects on cardiovascular function were found. CONCLUSIONS: 619C89 was associated with significant central nervous system side-effects at doses of 2 mg/kg + 1 mg/kg/8 h or greater as discrete intravenous infusions within 12 h of stroke onset. It may also cause gastro-intestinal side-effects. Doses below this are well tolerated in patients. No adverse cardiovascular effects were seen.

Acute Disease↗

PubMedDate not supplied

Cardiovascular safety of lubeluzole (Prosynap(R)) in patients with ischemic stroke.

The cardiovascular safety of lubeluzole was evaluated in patients with ischemic stroke in a double-blind, placebo-controlled trial. Forty-six patients were randomized to receive a continuous daily infusion of lubeluzole 5 mg (loading dose 3.75 mg over 1 h), lubeluzole 10 mg (loading dose 7.5 mg over 1 h), or placebo for 5 days within 24 h of stroke onset. The primary measure of cardiovascular safety was the QTc interval, derived from the continuous electrocardiogram (ECG) and measured during treatment and a 2-day follow-up. Compared with placebo. Neither dosage of lubeluzole had any statistically or clinically relevant effects on the QTc. Neither were there any significant differences among the three treatment groups in the area under the curve for heart rate, QT interval, QT dispersion, or QTlc. Lubeluzole did not increase the frequency of ECG abnormalities. No ventricular fibrillation, ventricular tachycardia, or torsades de pointes were observed in any of the treatment groups. During this trial, 3 patients in the placebo group and 2 patients in the lubeluzole 5-mg group died. There were no deaths in the lubeluzole 10-mg group. Adverse experiences were similar in all three treatment groups except that superficial thrombophlebitis was more frequent in the lubeluzole 10-mg group. In doses to 10 mg/day, lubeluzole has a favorable cardiovascular safety profile, as demonstrated by the lack of clinically relevant effects on heart rate, QT, QTc, and QTlc, and it was well tolerated by patients with ischemic stroke.

Acute Disease↗

PubMedDate not supplied

Phase II clinical trial of sipatrigine (619C89) by continuous infusion in acute stroke.

BACKGROUND: The sodium channel blocker sipatrigine (619C89) prevents ischemia-induced glutamate release and is neuroprotective in animal models of stroke. Previous clinical experience found neuropsychiatric effects attributed to sipatrigine that may have been related to peak plasma concentrations of the drug. METHODS: Patients within 12 h of clinically diagnosed stroke were randomized to placebo or sipatrigine at total doses of 10, 18, 27, or 36 mg/kg by continuous intravenous infusion over 65 h. Pharmacokinetic and routine laboratory analyses were undertaken. The outcome at 30 days or 3 months was assessed by Barthel and Rankin scores. RESULTS: Twenty-seven patients were recruited: 7 of 21 patients stopped the sipatrigine infusion early due to adverse events as compared with none of 6 placebo patients. Neuropsychiatric effects (reduced consciousness, agitation, confusion, visual perceptual disturbance, or frank hallucinations) occurred in 16 of 21 patients receiving sipatrigine and in no placebo patients. Nausea, vomiting, infusion site reactions, and hyponatremia were also commoner in sipatrigine patients. Pharmacokinetic parameters were similar to those observed previously. No effects on outcome measures were demonstrated. CONCLUSIONS: Continuous infusion of sipatrigine is associated with neuropsychiatric effects. No difference in the nature of these events was evident between this regimen and repeated short infusions, but it was possible to administer higher doses.

Acute Disease↗