PubMed Health⌕ Search

Biomedical subjects

D G Shand

Publications and source records attributed to D G Shand.

At least 91 records · Page 5Linked to original sources
PubMed1979

Intact hepatocyte theory of impaired drug metabolism in experimental cirrhosis in the rat.

The elimination of propranolol by perfused livers of rats made cirrhotic by chronic carbon tetrachloride inhalation during phenobarbital treatment has been compared with control animals receiving only phenobarbital. Cirrhosis reduced propranolol clearance at a constant flow of 20 ml/min from 1.43 +/- 0.08 to 1.12 +/- 0.08 ml/min/g liver (P less than 0.025). In addition, an increase in intrahepatic shunting of 15-micron microspheres from 0.41 +/- 0.01 to 9.4 +/- 4.1% was found in cirrhotic livers (P less than 0.05). Finally, in cirrhotic livers, reducing blood flow did not produce the normal rise in hepatic extraction ratio, which actually fell from 0.873 +/- 0.021 at 20 ml/min to 0.836 +/- 0.025 at 15 ml/min and 0.823 +/- 0.026 at 10 ml/min. At each flow the observed extraction was significantly lower than that predicted to result from a reduced enzyme activity alone, consistent with the development of functionally significant intrahepatic shunts. An operational model is proposed that explains impaired drug metabolism in cirrhosis on the basis of the development of intrahepatic shunts which perfuse nonfunctioning tissue, while the remaining blood flow is exposed to a reduced mass of hepatocytes with an apparently normal amount of drug metabolizing enzyme (the intact hepatocyte theory).

Animals↗
PubMed1978

Pharmacokinetics of antiarrhythmic drugs.

A knowledge of the determinants of the plasma concentrations of antiarrhythmic drugs is important because variation in plasma levels is often greater than the desired therapeutic range. The basic principles of pharmacokinetics are outlined and their application to the design of dosage regimens described. These principles are illustrated in a review of the pharmacokinetics of lidocaine and its congeners, procainamide and its active metabolite (N-acetylprocainamide), quindine, disopyramide, phenytoin and propranolol, with particular emphasis of the factors that contribute to altered disposition.

Administration, Oral↗
PubMed1978

Effects of caffeine on plasma renin activity, catecholamines and blood pressure.

Using a double-blind, randomized, cross-over protocol, we studied the effect of a single dose of oral caffeine on plasma renin activity, catecholamines and cardiovascular control in nine healthy, young, non-coffee drinkers maintained in sodium balance throughout the study period. Caffeine (250 mg) or placebo was administered in a methylxanthine-free beverage to overnight-fasted supine subjects who had had no coffee, tea or cola in the previous three weeks. Caffeine increased plasma renin activity by 57 per cent, plasma norepinephrine by 75 per cent and plasma epinephrine by 207 per cent. Urinary normetanephrine and metanephrine were increased 52 per cent and 100 per cent respectively. Mean blood pressure rose 14/10 mm Hg one hour after caffeine ingestion. There was a slight fall and then a rise in heart rate. Plasma caffeine levels were usually maximal one hour after ingestion but there was considerable individual variation. A 20 per cent increase in respiratory rate correlated well with plasma caffeine levels. Under the conditions of study caffeine was a potent stimulator of plasma renin activity and adrenomedullary secretion. Whether habitual ingestion has similar effects remains to be determined.

Administration, Oral↗
PubMed1978

Prostaglandins and renin release: II. Assessment of renin secretion following infusion of PGI2,E2 and D2 into the renal artery of anesthetized dogs.

The influence of intra-renal infusions of prostaglandin (PG) I2, PGE2 and PGD2 on renin secretion and renal blood flow was investigated in renally denervated, beta-adrenergic blocked, indomethacin treated dogs with unilateral nephrectomy. All three prostaglandins when infused at doses of 10(-8) g/kg/min and 10(-7) g/kg/min resulted in marked renal vasodilation. Renin secretory rates increased significantly with both PGI2 and PGE2 at the 10(-8) g/kg/min and 10(-7) g/kg/min infusion rates in a dose dependent manner. However, PGD2 was inactive. At 10(-7) g/kg/min, PGI2 infusions resulted in systemic hypotension indicated recirculation of this prostaglandin. These findings suggest that PGI2 should be included among the cyclooxygenase derived metabolites of arachidonic acid to be considered as possible mediators of renin release.

Animals↗
PubMed1978

Direct measurement of propranolol bioavailability during accumulation to steady-state.

1. A high performance liquid chromatographic method for the determination of propranolol in human plasma and blood has been developed and used to confirm that cumulation occurred during chronic oral administration, steady-state being achieved within 48 h of beginning 80 mg of the drug every 8 h. 2. The method was adapted to measure [H3]-propranolol and native drug in the same blood sample and was applied to determine simultaneously the disposition of i.v. ([H3]-propranolol) and orally (non-labelled) administered drug after single oral dose of 80 mg and when steady-state had been established on an 80 mg, 8-hourly regimen. 3. Using this approach it was possible to show that a reduced oral clearance at steady-state was associated with a smaller reduction in systemic (i.v.) clearance and no change in liver blood flow. A direct estimate of bioavailability was also possible and was found to be increased at steady-state compared with a single oral dose. 4. We conclude that the accumulation of propranolol during the attainment of steady-state is due to a reduction in intrinsic clearance, resulting in reduced presystemic hepatic extraction.

Administration, Oral↗
PubMed1977

Prediction of hepatic extraction ratio from in vitro measurement of intrinsic clearance.

Under first-order conditions the activity of the hepatic drug-metabolizing enzymes may be closely approximated by the ratio of the in vitro kinetic constants Vmax and Km, which in turn is equivalent to the intrinsic clearance of the drug. In theory, after appropriate consideration for liver weight, blood flow and rug binding in the blood, the intrinsic clearance may be used to predict the extraction ratio for the total organ. This hypothesis was tested by comparing the predicted ratio based on a perfusion-limited model of hepatic elimination with that determined directly in the isolated perfused rat liver. Good agreement was obtained between the predicted and observed hepatic extraction ratios for antipyrine, carbamazepine, hexobarbital, phenytoin, propranolol, alprenolol and lidocaine, which span the extraction ratio from less than 0.1 to greater than 0.9.

Animals↗
PubMed1977

Prostaglandin and histamine involvement in the gastric vasodilator action of pentagastrin.

Male mongrel dogs were anesthetized with 30 mg/kg of pentobarbital and left gastric arterial blood flow (GBF) was measured with electromagnetic flow probes. Pentagastrin, 1microng/kg i.v., produced an initial brief increase in flow followed by a prolonged secondary increase. Histamine, 1 microng/kg, and prostaglandin E2, 0.5 microng/kg, produced monophasic short-lived increases in GBF. The histamine H1 antagonist diphenhydramine and the H2 antagonist metiamide did not affect resting GBF. The prostaglandin synthesis inhibitor, indomethacin, reduced resting GBF by 46%. Responses to histamine were blocked by diphenhydramine by 81% and reduced by indomethacin by 21%. Responses to prostaglandin E2 were reduced by indomethacin by 21%. The primary pentagastrin response was blocked by diphenhydramine by 54%. The secondary pentagastrin response was blocked by both metiamide by 69% and indomethacin by 71%. We conclude that GBF is maintained by a basal production of vasodilatory prostaglandins. Furthermore, pentagastrin can release histamine which by acting on H2 receptors can enhance the production and/or release of prostaglandins to finally mediate an increase in GBF. These actions may partly explain the deleterious effect of indomethacin and the curative effect of prostaglandins on gastric mucosal ulcers.

Animals↗
PubMed1976

Proposed mechanisms of propranolol's antihypertensive effect in essential hypertension.

We studied the antihypertensive effect of propranolol alone and in combination with diuretics in 13 patients with high, 18 with normal and nine with low-renin essential hypertension whose blood-pressure response to diuretics was previously established. Propranolol (160 mg daily) significantly lowered mean arterial pressure in high-renin (129 +/- 2.6 to 114 +/- 2.1 mm Hg) and normal-renin (131 +/- 2.7 to 119 +/- 3.5 mm Hg) patients but not in low-renin patients. A positive correlation (r = 0.36, P less than 0.05) between fall in pressure and fall in plasma renin activity occurred at this dose when the whole group was considered. An antihypertensive effect occurred in both high-renin and low-renin hypertension during large-dose (320 to 960 mg daily) propranolol therapy. This effect was independent of changes in plasma renin activity. The antihypertensive effects of propranolol and diuretics were additive in normal-renin and high-renin hypertension. These data suggest that propranolol's pressure-lowering activity is due to both renin-dependent and renin-independent effects.

Blood Pressure↗