Biomedical subjects
Publications and source records attributed to R G Shanks.
We gave 50 consecutive patients with suspected acute myocardial infarction prophylactically lidocaine 300 mg intramuscularly and 100 mg intravenously. Although therapeutic plasma levels were reached, 2 of 24 (8%) patients with acute myocardial infarction had ventricular tachycardia or ventricular fibrillation and 3 of 50 (6%) became hypotensive during the first hour of lidocaine.
The effect of equihypotensive single oral doses of indoramin (mean dose 67 mg), phenoxybenzamine (mean dose 50 mg), hydralazine (mean dose 133 mg) and placebo on arterial pressure and heart rate in the supine and standing position was studied in six normal volunteers. Observations were made before and at 2 and 4 h after drug administration. Plasma noradrenaline (NA) was measured at each time interval in the supine position, and after 4 min of standing. Plasma renin activity (PRA) was measured at each time interval after 30 min in the standing position. The three active drugs reduced systolic arterial pressure in the standing position to a similar extent (indoramin, -24 mm Hg; phenoxybenzamine, -23.4 mm Hg; hydralazine, -30.4 mm Hg). The maximum effect of indoramin and phenoxybenzamine was observed at 4 h, and of hydralazine at 2 h after drug administration. The reductions of arterial pressure in the standing position were accompanied by increases in heart rate, plasma NA and PRA. Small increases were observed after indoramin (heart rate, + 9.2 beats min-1; plasma NA, + 126 pg/ml; PRA, + 0.33 ng angiotensin 1 ml-1 h-1), greater increases after phenoxybenzamine (heart rate, + 20; plasma NA, + 210; PRA, + 0.47), and the greatest increases after hydralazine (heart rate, + 26; plasma NA, + 250; PRA, + 1.16). In the supine position, indoramin and phenoxybenzamine produced no effect on arterial pressure, heart rate or plasma NA. Hydralazine produced small reductions in diastolic pressure, which were accompanied by an increase in heart rate of 25.5 beats min-1 (P less than 0.01 when compared to placebo) and in plasma NA of 223 pg ml-1 (P less than 0.05). Plasma NA, PRA and heart rate increased together and may be regarded as three interdependent indices of sympathetic activity. Indoramin reduced the degree of increase of plasma NA, PRA and heart rate per unit fall in pressure, when compared to phenoxybenzamine and hydralazine. The effect of phenoxybenzamine and hydralazine on the degree of increase was similar. The results are consistent with the hypothesis that indoramin produces selective postsynaptic alpha 1-adrenoceptor blockade in man, and therefore produces relatively less tachycardia and NA increase than does a non-selective alpha-adrenoceptor antagonist (phenoxybenzamine) or an arteriolar vasodilator (hydralazine).
The effects of single oral doses of indoramin (mean dose 58 mg), abetalol (mean dose 150 mg), alinidine 80 mg and placebo on arterial pressure and heart rate in the supine and standing positions were studied in six normal volunteers. Doses were chosen to give equivalent reductions of arterial pressure in the standing position. Observations were made before and at 2 and 4 h after drug administration. Plasma noradrenaline (NA) was measured at each time interval in the supine position, and after 4 min of standing. Plasma renin activity (PRA) was measured at each time interval after 30 min in the standing position. In the supine position, alinidine produced a significant reduction of systolic arterial pressure from 124.0 +/- 3.0 mm Hg to 104.3 +/- 4.1 mm Hg at 2 h (P less than 0.01) and to 101.7 +/- 2.2 mm Hg at 4 h (P less than 0.01). Diastolic pressure was reduced from 74.7 +/- 2.6 mm Hg to 57.0 +/- 4.6 mm Hg at 4 h (P less than 0.01). Arterial pressure was unchanged after indoramin or labetalol administration. In the supine position, heart rate was unchanged after indoramin, and small reductions were observed after labetalol and alinidine. Indoramin produced a significant increase in plasma NA. A small increase of plasma NA was observed after labetalol, and a small decrease after alinidine. In the standing position, the three active drugs reduced systolic arterial pressure to a similar extent (indoramin, -26.7 mm Hg at 4 h after drug administration; labetalol, -21.3 mm Hg at 2 h; alinidine, -21.7 mm Hg at 4 h).(ABSTRACT TRUNCATED AT 250 WORDS)
Cyclosidimine is a new vasodilator drug with a direct action on vascular smooth muscle. Oral administration of 2.5, 5.0 and 7.5 mg in five normal volunteers had no effect on blood pressure in the supine position but reduced systolic and diastolic pressure in the erect position. In both positions heart rate was significantly greater after cyclosidimine than after placebo. Propranolol prevented the increases in heart rate produced by cyclosidimine which then produced greater reductions in blood pressure.
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Between 1972 and 1980 Hospital Activity Analysis from 5 Northern Ireland Hospitals demonstrated a gradual increase in the number of patients discharged for all diagnoses whilst there was a decline in discharges for peptic ulcer related disease, (duodenal ulcer, gastric ulcer, gastrojejunal ulcer, peptic ulcer site unspecified and hiatal hernia). The mean number of peptic ulcer related disease discharges per year for 1977-80, when cimetidine became generally available, was 10% lower than that of 1972-76, mainly due to a decline in male patient numbers. The mean annual number of male patients with a duodenal ulcer fell significantly by 18% (U = 1, p less than or equal to 0.025) during the 1977-80 period, whereas female discharges decreased by only 4%. Between 1972-76 and 1977-80 the mean annual number of duodenal ulcer perforations decreased significantly by 21% in males but only by 4% in females. Surgery for peptic ulcer related disease was 47% less in 1977-80 period, with significant decreases in duodenal ulcer, gastric ulcer and hiatal hernia procedures. From 1977 to 1980 there was considerable growth in Northern Ireland general practice cimetidine prescribing with 300,000 prescriptions being dispensed over the period. Apart from male duodenal ulcer cases, hospitalisation for peptic ulcer related diseases did not decrease substantially after the introduction of cimetidine but duodenal ulcer perforation and conditions warranting surgery did decline.
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1 Increases in heart rate and forearm blood flow following graded intravenous bolus injections of isoprenaline sulphate, were measured in a double-blind randomised study of six subjects who received either placebo, practolol 50 mg, practolol 200 mg, propranolol 10 mg or propranolol 40 mg. 2 Dose related increases in forearm blood flow were produced by the graded boluses of isoprenaline sulphate. 3 Practolol 50 mg attenuated the heart rate response to isoprenaline but did not significantly affect the changes in forearm blood flow. Practolol 200 mg further attenuated the heart rate responses but also decreased the forearm blood flow responses. 4 Propranolol 10 mg and propranolol 40 mg significantly attenuated both the heart rate and forearm blood flow responses. The effect on forearm blood flow tended to be greater than the effect on heart rate. 5 Practolol 200 mg had the same effect on heart rate responses as propranolol 10 mg but a significantly smaller effect on the forearm blood flow responses. 6 The measurement of forearm blood flow following intravenous bolus injections of isoprenaline provides useful information about the beta 2-adrenoceptor antagonism of propranolol and practolol. However, application of the technique may be limited by the magnitude of the heart rate response and by the short-lived nature of the increase in forearm blood flow.
1 The present study compared the effects in healthy volunteers of the acute and chronic administration of placebo, pindolol and propranolol to see if the partial agonist activity of pindolol was reduced by the beta-adrenoceptor blocking activity of pindolol on chronic administration. 2 Five subjects received in random order for 8 days placebo, propranolol 160 mg and pindolol 10 mg; on days 1 and 8 treatments were given twice at 0 and 2 h. Heart rate in supine position and at end of exercise was recorded before dosing and at 2 and 4 h post-dosing on days 1 and 8. 3 Propranolol and pindolol reduced exercise heart rate to the same extent on days 1 and 8. 4 Propranolol reduced supine heart rate more than pindolol on days 1 and 8 but the difference was only significant on day 8.
Five healthy volunteers (mean age 20.6 years, mean weight 71 kg) received in random order on day 1 and day 8 a single dose of alinidine 40 mg, clonidine 0.1 mg or placebo and on days 2-7 alinidine 40 mg, clonidine 0.1 mg or placebo given three times a day with 1 week between treatment periods. Blood samples were taken for measurement of concentrations of alinidine and clonidine during alinidine administration and of clonidine during clonidine dosing. Heart rate and blood pressure were recorded in supine and standing positions and heart rate after 3 min exercise. Plasma concentrations of alinidine reached a maximum of 163.6 +/- 10.0 ng/ml 2 h after alinidine administration on day 1 and during chronic administration similar concentrations were achieved. Clonidine plasma concentrations reached 0.3 +/- 0.11 ng/ml 6 h after alinidine 40 mg on day 1, and during chronic administration of alinidine, increased to a steady state on day 5 with trough and 2 h values of 0.73 +/- 0.15 and 0.86 +/- 0.14 ng/ml respectively. After the first dose of clonidine on day 1, the maximum plasma concentration of clonidine was 0.32 +/- 0.1 ng/ml at 4 h, during chronic administration clonidine plasma concentration rose to 1.04 +/- 0.14 ng/ml 2 h after a dose on day 5. Alinidine produced a greater reduction in the exercise tachycardia than clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)
All patients with a presumptive diagnosis of myocardial infarction, who were seen within six hours of the onset of symptoms and had no reason for exclusion, were considered for entry into a trial to compare the effects of metoprolol and placebo on creatine kinase MB isoenzyme release. The trial was randomised and double blind. The median time from onset of symptoms to receiving trial drug was just under two hours. Two hundred and four patients (of whom 120 had myocardial infarction) received metoprolol and 187 (of whom 105 had myocardial infarction) received placebo. Infarct size was estimated semiquantitatively using cumulative release of the cardiospecific isoenzyme, creatine kinase MB. Mean creatine kinase MB isoenzyme was less in patients who received metoprolol, but the reduction did not achieve statistical significance. Clinical problems related to early intravenous metoprolol were uncommon.
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Neurotoxicity in vincristine treatment has generally been considered a consequence of the cumulative dose of the drug, and liver dysfunction had been recognised as an indication to reduce the dosage. We demonstrate that neurotoxicity is also related to individual doses and that even when there is no other evidence of liver dysfunction, a raised level of serum alkaline phosphatase may predict severe neurotoxicity. Exposure to vincristine following IV injection of the drug was studied in 27 subjects by measuring the area under the vincristine plasma concentration time curve (AUC 0-infinity). A statistically significant relationship was found between the AUC0-infinity and the degree of neurotoxicity. The AUC0-infinity was related both to dose and to elevation of serum alkaline phosphatase, suggesting that elimination of the drug is impaired when serum alkaline phosphatase is raised. Among patients with elevated serum alkaline phosphatase, a small reduction in the dose of the drug resulted in lower vincristine plasma AUC0-infinity and less neurotoxicity.
A radioimmunoassay has been used to investigate the pharmacokinetics of vincristine in 39 cancer patients who received between 0.4 and 1.54 mg vincristine/m2 as part of standard treatment protocols. There was wide interindividual variation in both the terminal elimination half-life of vincristine (t1/2beta) and the associated volume of distribution (Vd), resulting in an 11-fold range of dose-corrected area under the plasma concentration versus time curve values (AUC0-infinity). Elevated vincristine AUC0-infinity values were observed in those patients with raised serum alkaline phosphatase at the time of vincristine estimation. The t1/2beta was significantly longer in these patients than in those with serum alkaline phosphatase within normal limits, suggesting that biochemical evidence of cholestasis is associated with reduced clearance of vincristine. Evidence is also presented to suggest that the clearance of vincristine is dose-dependent within the therapeutic dose range. We observed a disproportionate rise in vincristine plasma concentration at doses exceeding t1/2beta compared with that observed for patients receiving 1 mg vincristine/m2 or less.
Serum methotrexate (MTX) concentrations were measured by immunoassay in 28 children receiving maintenance therapy for acute lymphoblastic leukaemia. Patients were studied either after a single weekly dose or on the first day of a 5-day course of treatment. A standard dose (15 mg/m2) was given PO and/or IV. After PO dose the peak serum MTX concentration and its timing varied widely between cases and there was a significant positive correlation between the rate of serum concentration rise and the area under the concentration curve up to 4 h. The absorption rate constant showed a biphasic distribution and correlated less closely with early serum concentrations. After IV and PO administration drug disposition was triphasic with an initial rapid distribution phase, an intermediate phase, and a prolonged terminal elimination phase. The intermediate phase half-life was significantly longer after PO than after an IV dose. The MTX clearance rate was consistently lower than the glomerular filtration rate and there was no significant correlation between the two. The mean bioavailability (PO/IV) was 42%, but bioavailability was as low as 6% in some cases due to prolonged high serum concentrations after an IV dose, which was not seen with the equivalent PO dose.
1 Alinidine (N-allyl clonidine) pharmacokinetics were investigated in healthy volunteers following acute administration of 40 mg orally and intravenously (i.v.) and chronic administration of 40 mg daily and twice daily for 8 days. 2 After acute oral administration the following values were obtained; Cmax -- 166.5 +/- 18.5 ng/ml at 1.8 +/- 0.7 h (mean +/- s.d., n = 5); AUC -- 1122.9 ng ml-1 h; VdSS -- 190.71 and T1/2 -- 4.2 h, and after i.v. administration: AUC -- 1046.7 ng ml-1 h; VdSS -- 190.71 and T1/2 4.2 h. 3 Clonidine was identified in plasma and urine samples following oral and i.v. administration; clonidine Cmax was 0.26 +/- 0.06 ng/ml at 8.4 +/- 2.2 h and 0.5 +/- 0.2 ng/ml at 4.8 +/- 2.5 following oral and i.v. alinidine respectively. Urinary excretion of clonidine represented 0.1% of the administered dose of alinidine. 4 During administration of alinidine 40 mg daily for 8 days, peak and trough plasma levels reached steady state after day 2 (223.1 +/- 123.9 and 9.03 +/- 6.7 ng/ml respectively). During alinidine 40 mg twice daily for 8 days peak and trough plasma levels on day 2 were 356.2 +/- 92.0 and 80.0 +/- 35.8 ng/ml respectively, these levels did not change (P greater than 0.05) between days 2 and 8. Urine elimination of alinidine did not change (P greater than 0.05) between days 5, 6, 7 and 8. 5 Clonidine plasma concentration following alinidine 40 mg daily and twice daily were 0.47 +/- 0.18 and 0.84 +/- 0.21 ng/ml respectively 2 h after administration on day 2 and did not change (P less than 0.05) between days 2-8. 6 It is unlikely that clonidine formed from alinidine contributes to the pharmacological action of alinidine.