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A S Pappu

Publications and source records attributed to A S Pappu.

36 records · Page 2Linked to original sources
PubMed1990

The effects of simvastatin on plasma lipoproteins and cholesterol homeostasis in patients with heterozygous familial hypercholesterolaemia.

We have examined the influence of simvastatin, a competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase on plasma concentrations of lipids and lipoproteins, the rates of cholesterol biosynthesis and degradation of 125I-labelled LDL by freshly isolated mononuclear leucocytes and the 24 h urinary excretion of mevalonic acid in patients with heterozygous familial hypercholesterolaemia. Patients were treated with progressively increasing doses of simvastatin (20, 40, and 80 mg day-1) taken in a twice-daily dosage for a period of 6 weeks on each dose. Plasma concentrations of LDL cholesterol decreased by 36.6%, 45.6% and 47.1% respectively on the three doses. High-affinity degradation of 125I-LDL by freshly isolated mononuclear leucocytes increased significantly on the 20 mg day-1 dosage but no further increase was observed on doses of 40 and 80 mg of simvastatin per day. Rates of 2-14C acetate incorporation into cholesterol by freshly isolated mononuclear leucocytes (obtained 12-15 h after the last dose of simvastatin) increased by 62%, 71% and 29% in cells isolated from patients on 20, 40, and 80 mg day-1 of simvastatin compared with values at baseline. In contrast, the 24 h excretion of mevalonic acid in the urine fell by 16.9%, 31.4% and 31.9% respectively on these three doses. Our results indicate that the potent hypocholesterolaemic effects of simvastatin are accompanied by increases in high-affinity LDL receptor-mediated degradation of LDL and a compensatory increase in cholesterol biosynthesis in freshly isolated mononuclear leucocytes but that rates of mevalonic acid excretion in the urine decrease.

Adult↗
PubMed1989

Increased urinary mevalonic acid excretion in patients with abetalipoproteinemia and homozygous hypobetalipoproteinemia.

Previous reports in which cholesterol homeostasis has been examined in patients with phenotypic abetalipoproteinemia have shown an increase in whole body cholesterol synthesis when measured by sterol balance techniques but normal rates of cholesterol synthesis when measured by isotopic cholesterol turnover. Recent studies have indicated that increases in cholesterol biosynthesis are paralleled by increases in the plasma concentrations of mevalonic acid and by higher rates of excretion of mevalonic acid in the urine. In the present report we have measured the 24-h urinary excretion of mevalonic acid in 7 patients with phenotypic abetalipoproteinemia and compared this to control subjects. Urinary excretion of mevalonic acid was significantly higher in the patients with abetalipoproteinemia (57.2 +/- 10.2 nmol/kg body weight per day, mean +/- SEM) as compared to control subjects (23.1 +/- 1.5 nmol/kg per day). The magnitude of the increase in urinary mevalonic acid excretion seen in patients with abetalipoproteinemia (148%) is greater than the increase in whole body cholesterol biosynthesis assessed by sterol balance techniques (57% increase). Our results serve to further validate the usefulness of urinary mevalonate as an indicator of relative rates of cholesterol biosynthesis in humans and suggest that this measurement provides a valuable means to potentially screen for disorders associated with an oversynthesis of cholesterol.

Abetalipoproteinemia↗
PubMed1989

Reduction in plasma low-density lipoprotein cholesterol and urinary mevalonic acid by lovastatin in patients with heterozygous familial hypercholesterolemia.

The effects of lovastatin, an inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG CoA reductase), on 24-hour urinary excretion rates of mevalonic acid (an intermediate in cholesterol biosynthesis) and plasma low-density lipoprotein (LDL) cholesterol concentrations were evaluated in patients with heterozygous familial hypercholesterolemia (FH). The mean rates of urinary mevalonate excretion of 28 FH patients were initially higher (2.95 +/- 0.29 (+/- SEM) mumols/d) than in 17 control subjects (1.82 +/- 0.12 mumols/d). Patients with FH were treated with sequentially increasing doses of lovastatin (10, 20, 40, and 80 mg daily, taken as a twice daily dosage) for a period of 6 weeks on each dose. When compared to baseline, LDL cholesterol levels fell by 22%, 26%, 30%, and 35% respectively, on these different doses. The mean daily urinary mevalonate excretion decreased from baseline by 19% after 4 weeks on 10 mg daily of lovastatin, 35% on 20 mg, and 31% on 40 mg and 80 mg daily. Similar decreases in urinary mevalonate excretions were observed when patients with FH were treated directly with 40 mg (20 mg twice daily) or 80 mg (40 mg twice daily) mg of lovastatin daily. The magnitude of decrease in LDL cholesterol did not show any significant correlation with the changes in urinary excretion of mevalonic acid. Lovastatin therapy decreases rates of urinary mevalonate excretion (which has previously been shown to reflect rates of cholesterol synthesis) by up to 35% at doses of 20 to 80 mg/d; such a decrease seems unlikely to compromise other important cellular requirements for mevalonate.

Adult↗
PubMed1989

Contrasting effects of lovastatin and cholestyramine on low-density lipoprotein cholesterol and 24-hour urinary mevalonate excretion in patients with heterozygous familial hypercholesterolemia.

To further validate the usefulness of quantitative measurements of urinary mevalonic acid excretion as an indicator of rates of cholesterol biosynthesis, we have determined the 24-hour urinary excretion of mevalonic acid in patients with heterozygous familial hypercholesterolemia treated with drugs that have opposing effects on cholesterol biosynthesis. In patients with familial hypercholesterolemia treated with the bile acid sequestrant cholestyramine (16 gms/day), urinary mevalonate excretion increased by 28%, whereas low-density lipoprotein cholesterol concentrations decreased by 21%. In patients with familial hypercholesterolemia treated with the 3-hydroxy 3-methyl glutaryl coenzyme A reductase inhibitor lovastatin (80 mg/day), concentrations of low-density lipoprotein cholesterol and the urinary excretion of mevalonate both decreased (by 40% and 34%, respectively). When cholestyramine was used in combination with lovastatin, low-density lipoprotein cholesterol levels decreased by an additional 14% as compared to monotherapy with lovastatin; urinary mevalonate excretion rose by (25%), but the magnitude of this increase was not statistically significant. We conclude that rates of excretion of urinary mevalonic acid (which may reflect rates of whole body cholesterol biosynthesis) in patients with FH decrease on therapy with lovastatin and increase in response to cholestyramine treatment. When used in combination, these drugs counteract each other's effects on cholesterol synthesis, but low-density lipoprotein cholesterol concentrations decrease further. Measurement of urinary mevalonate excretion affords a practical means of assessing the comparable effects of different dietary or pharmaceutical manipulations on cholesterol biosynthesis in human beings.

Adult↗
PubMed1988

Neutral lipid transfer activities in the plasma of patients with abetalipoproteinemia.

Plasma lipid transfer proteins stimulate transfer and molecular exchange of cholesteryl esters, phospholipids and triglycerides between individual plasma lipoproteins. To assess whether transfer protein activities are influenced by the inherent absence of apo B-containing lipoproteins, we determined cholesteryl ester and triglyceride transfer activities in the plasma of patients with abetalipoproteinemia (ABL). Transfer activities were measured in plasma fractions of d greater than 1.21 g/ml in 2 patients with abetalipoproteinemia and 12 normal volunteers and were expressed as a percent transfer of labeled lipid from donor high density lipoproteins to acceptor very low density lipoproteins. Cholesteryl ester and triglyceride transfer activities were reduced respectively by 50% and 66% in the plasma of patients with ABL. The addition of the plasma fraction d greater than 1.21 g/ml proteins from abetalipoproteinemic subjects resulted in progressive decreases in cholesteryl ester and triglyceride transfer activities. The reduced activities of these transfer proteins may reflect (at least in part) the presence of an inhibitor(s) which is heat-stable and trypsin-sensitive.

Abetalipoproteinemia↗
PubMed1985

Inhibition of purified lysosomal phospholipase A1 by beta-adrenoceptor blockers.

Inhibition of rat liver lysosomal phospholipases is one of the main events that leads to accumulation of tissue phospholipids during drug-induced phospholipidosis. Drug inhibition of lysosomal phospholipase A may occur by direct effects of drugs on the enzyme (or substrate) or by drug-induced increases in intralysosomal pH. Although beta-adrenoceptor blockers have not been reported to cause lipid storage, they do inhibit lysosomal phospholipase A. To investigate the structural requirements for drug inhibition, we studied the effects of six beta-adrenoceptor blockers on purified rat liver lysosomal phospholipase A1. The agents studied include: propranolol, timolol, metoprolol, practolol, atenolol and the combined alpha and beta adrenoceptor blocking agent, labetalol. The drugs varied by two logs in their abilities to inhibit phospholipase A1 activity. The relative inhibitory potencies were propranolol greater than labetalol much greater than timolol greater than metoprolol much greater than practolol greater than atenolol. Our studies identify drug hydrophobicity as a key determinant for phospholipase A1 inhibition. A strong negative correlation was noted between the octanol/water partition coefficients and IC50 for phospholipase inhibition (r = -0.91). The ability of propranolol to inhibit phospholipase A1 was identical for the d, l and the d and l stereoisomers.

Adrenergic beta-Antagonists↗
PubMed1985

Diethylaminoethoxyhexestrol causes hypertriglyceridemia in guinea pigs.

Treatment of rats, monkeys and man with diethylaminoethoxyhexestrol causes phospholipid storage in liver and other tissues. However, this drug has not been reported to alter plasma lipoprotein levels. When guinea pigs were treated with diethylaminoethoxyhexestrol, the fasting plasma triacylglycerol levels increased dramatically, from 43 to 1281 mg/dl, after only five doses of 12.5 mg/kg. Diethylaminoethoxyhexestrol-treated guinea pigs had reduced postheparin lipase activity. In addition, in vitro assays showed that this agent inhibited guinea pig postheparin lipoprotein lipase. It is hypothesized that diethylaminoethoxyhexestrol causes hypertriglyceridemia in guinea pigs because these animals are known to have low levels of serum activator for lipoprotein lipase and may be unusually susceptible to agents that inhibit lipoprotein lipase activity. The ability to produce hypertriglyceridemia in guinea pigs provides an animal model in which the metabolic consequences of hypertriglyceridemia can be studied.

Animals↗
PubMed1983

Propranolol-induced inhibition of rat brain cytoplasmic phosphatidate phosphohydrolase.

Propranolol, a cationic amphiphilic drug, caused enhanced incorporation of labeled precursor into phosphatidic acid and its metabolites in rat cerebral cortex mince, suggesting increased biosynthesis or reduced degradation. Inhibition of phosphatidate phosphohydrolase could explain the observed drug-induced accumulation of phosphatidic acid and other acidic lipids. Propranolol exhibited differential effects on the free and membrane-bound forms of phosphatidate phosphohydrolase. The drug inhibited cytoplasmic enzyme in a dose-dependent manner only when membrane-bound substrate was used but had practically no effect on the membrane-bound enzyme irrespective of the nature of the substrate used or on the cytoplasmic enzyme when free substrate was used. Brain cytoplasmic enzyme obtained from rats sacrificed 30 min after intraperitoneal injections of propranolol did not show any inhibition. propranolol bound to membranes may prevent cytoplasmic enzyme action, probably by decreasing the availability of substrate through the formation of stable lipid-drug-protein complexes.

Animals↗
PubMed1982

Phospholipid metabolism changes in rat tissues in vitro after injections of propranolol.

When added to incubations in vitro. (+/-)-propranolol, a cationic amphiphilic drug, causes profound alterations in incorporation of [32P] orthosphosphate into rat cerebral cortex phospholipids. These include increases in the labeling of phosphatidic acid and polyphosphoinositides abd a decrease in the labeling of phosphatidylcholine. Similar changes occurred in a dose-dependent manner in incubations of cerebral cortex mince, prepared from animals injected i.p. 30 min before death with doses of propranolol ranging from 7.5 to 45 mg/kg. All changes in total incorporation and in labeling pattern had disappeared 3 hr after injection, indicating the reversibility of the effect. Repeated injections of low doses of propranolol (7.5 mg/kg) brought about significant changes in the labeling of brain cortex mince phospholipids, and especially a reduction in total incorporation. Addition of propranolol to kidney and liver minces caused reductions in the labeling of phosphatidylcholine and phosphatidylethanolamine and selective increases in the labeling of acidic lipids, restricted to phosphatidic acid in liver and phosphatidylinositol in kidney. After injection of 45 mg of propranolol per kg, but not at 15 mg/kg, some alterations in the labeling pattern were observed in liver and kidney minces. The differential response of tissues to propranolol injections can be explained on the basis of the pharmacokinetics of drug distribution and clearance and metabolic capacities of the tissues. Changes in phospholipid metabolism may be in part responsible for deleterious side effects that can occur during therapy with high doses of propranolol.

Animals↗
PubMed1981

Alterations of phospholipid metabolism in rat cerebral cortex mince induced by cationic amphiphilic drugs.

Cationic amphiphilic drugs (CADs) of varied clinical use were screened to determine their capacity to alter the pattern of labeling with 32Pi of cerebral cortex mince phospholipids. The altered phospholipid labeling patterns were qualitatively similar, the prominent features being reduced incorporation into phosphatidylcholine and increased incorporation into phosphatidic acid. Relative potencies were: (/-+)-propranolol greater than chlorpromazine = 4,4'-bis(diethylaminoethoxy) alpha,beta-diethyldiphenylethane greater than desipramine greater than dibucaine greater than pimozide greater than oxymetazoline = fenfluramine = haloperidol = chloroquine greater than amphetamine = no drug added. Propranolol was used to study the action of CADs further. Its effect was time- and dose-dependent but in contrast with pineal gland, no label appeared in phosphatidyl-CMP (CDP-diacylglycerol), nor did dialysis of the mince to reduce diffusible substrates or exogenous addition of substrates cause appearance of liponucleotide. Thus lack of diffusible precursors is not responsible for CAD effects in vitro. Pulse-chase experiments with 32Pi and [2-3H]glycol suggested that inhibition of phosphatidate phosphohydrolase may be partly responsible for the observed alterations in phospholipid labeling in the presence of CADs.

Animals↗
PubMed1978

Phospholipase A2 of rat liver mitochondria in vitamin E deficiency.

1. There is a more than 2-fold increase in phospholipase A(2) activity (EC 3.1.1.4) of liver mitochondria isolated from vitamin E-deficient rats compared with that in normal rats. 2. alpha-Tocopherol in lipoprotein-bound form is more effective than free alpha-tocopherol in restoring the enzyme activity to normal.

Animals↗
PubMed1978

Possible interrelationship between vitamins E and b12 in the disturbance in methylmalonate metabolism in vitamin E deficiency.

1. The disturbance in 2-methylmalonate metabolism resulting in its increased urinary excretion observed in vitamin E deficiency is not caused by increased formation of methylmalonate from propionate as is evident from the activity of the enzyme propionyl-CoA carboxylase (EC 6.4.1.3), but can be traced to an impairment in the conversion of methylmalonate into succinate by the vitamin B12-requiring enzyme, methylmalonyl-CoA mutase (EC 5.4.99.2) in rat liver. 2. It is shown that the decrease in the activity of methylmalonyl-CoA mutase in vitamin E deficiency is not a consequence of a secondary vitamin B12 deficiency. Peroxidative destruction of the coenzyme in vitamin E deficiency was also ruled out. The results suggest a defect in the conversion of cyanocobalamin into its coenzyme form.

Animals↗