Rubin Bressler

Principles of drug therapy for the elderly patient.

Physicians will treat larger numbers of elderly patients as the US population ages. Being treated simultaneously for more than 1 condition with multiple prescription drugs is only 1 reason why elderly patients are at greater risk of experiencing adverse drug reactions. The need for physicians to minimize the incidence of these reactions has become incumbent on both physicians and administrators. We review the underlying reasons why the elderly population is at risk of adverse drug reactions and summarize the principles of drug-drug interaction, metabolism, and distribution, which can help elderly patients receive proper pharmacological treatment.

Effect of taurine on a muscle intracellular membrane.

Abstract Sarcoplasmic reticulum from rat skeletal muscle had rates of calcium oxalate uptake dependent upon the speed with which the muscle was removed and homogenized. Rapidly isolated sarcoplasmic reticulum (muscle removed and homogenized within 20 min) showed a 25% increase in rate of calcium oxlate uptake in the presence of 15 mM taurine, and the total sequestering capacity was also increased. The rate of calcium oxalate uptake by more slowly isolated sarcoplasmic reticulum (1 h between sacrifice of first animal and homogenization of the muscle) could be increased by 30% by performing the isolation with 10–15 mM taurine present in all media, compared with a paired isolation in the absence of taurine. Exposure of sarcoplasmic reticulum to taurine throughout isolation led to an increased yield of microsomes and sarcoplasmic reticulum. These effects of taurine on sarcoplasmic reticulum were not duplicated by phosphate, isethionate, KCl, cysteine or histidine, but aminopropane-sulfonic acid showed similar effects. Taurine slowed the rate of loss of calcium transport and ATPase activities of sarcoplasmic reticulum caused by phospholipase C. It is suggested that taurine may function as a membrane stabilizer.

Clinical pharmacology of sulphonylurea hypoglycaemic agents: part 1.

SummaryThe sulphonylureas are drugs of limited efficacy with fairly frequent, although usually reversible, adverse effects.Being highly protein bound, these drugs are subject to potential displacement interactions, which when combined with inhibition of their elimination, may result in profound hypoglycaemia. Due to hepatic metabolism and renal excretion of the parent drug and/or active metabolites, these agents are contraindicated in patients with liver or kidney disease. Oral hypoglycaemic agents are frequently used in elderly patients with limited vision and no dependable relatives, who cannot give themselves insulin. It is these patients — elderly, living alone in poor circumstances, often on several other medications, and possibly malnourished — who are at greatest risk for catastrophic hypoglycaemia with these drugs. Long acting agents like chlorpropamide and glibenclamide should be avoided in the elderly and in patients with irregular eating habits.Diet and exercise remain the primary modes of therapy of non-insulin-dependent diabetes mellitus. With careful patient selection and attention to drug and disease interactions, the sulphonylureas may be a useful adjunct to diet in treating a small proportion of insulin-resistant (so-called adult onset) diabetics. Patients most likely to respond to sulphonylureas are over 40 years old, mildly to moderately obese, have had diabetes for less than 5 years, and have never exhibited ketosis. There is no indication for simultaneous use of sulphonylureas and insulin. With both insulin and the oral hypoglycaemics alcohol is the agent most commonly implicated in lethal interactions.

Radioreceptor Assay for 1α,25-Dihydroxyvitamin D3

A competitive protein binding assay with a sensitivity of 80 picograms has been developed for 1α,25-dihydroxyvitamin D3, the hormonal form of vitamin D3. lα,25-Dihydroxyvitamin D3 displaced tritiated hormone from a cytosol-chromatin receptor preparation isolated from chick small intestine, providing a simple assay for the hormone. The concentration of lα, 25-dihydroxyvitamin D3 in human plasma, as determined by this assay, is approximately 6 nanograms per 100 milliliters; in patients with renal disease the concentration of this kidney-produced hormone is significantly lower.

Prevention of Diabetic Nephropathy by Diet Control in the db/db Mouse

Diabetes in the C57BL/KsJ(db/db) mouse is initially expressed as hyperinsulinemia, followed by hyperphagia, progressive obesity, and widespread pathologic abnormalities. This study was designed to evaluate the effects of metabolic control on the natural history of the diabetic nephropathy. Beginning at 1 mo of age and continuing for 12 wk, diabetic mice were subjected to controlled dietary restriction, such that their weight was maintained similar to that of age-matched, nondiabetic heterozygotes. Diet-restricted diabetics were compared with diabetics fed ad libitum and heterozygote nondiabetics. Significant lowering of fasting blood glucose, water intake, and plasma insulin was achieved by diet restriction. The diet-restricted diabetics demonstrated enhanced metabolic efficiency, consuming approximately half as much food as the nondiabetics, while maintaining a similar weight. Diabetics fed ad libitum evidenced well-defined renal lesions that included 3+ to 4+ immunoglobulin deposition in the glomerular mesangium, and generalized mesangial matrix expansion. These lesions were completely prevented in diet-restricted diabetics whose glomeruli were normal by light microscopy, and demonstrated trace to 1 + mesangial immunoglobulin deposition, features identical in all respects to the nondiabetics. These results indicate that diabetic control achieved by prevention of obesity in the db/db mouse prevents the development of diabetic nephropathy.

Taurine Concentrations in Congestive Heart Failure

The concentration of taurine in the left ventricular muscle of hearts of patients who died of chronic congestive heart failure was twice that of patients who died of other causes and had no cardiac pathology. There was no corresponding difference in taurine concentrations in aortic tissue between the two groups. Stress-induced hypertension in rats also led to an increase in taurine concentration in the heart, whereas that in skeletal muscle and brain showed no significant alteration when compared to unstressed animals. Spontaneously hypertensive rats, of the Wistar-derived Okamato strain, showed a similar elevation in cardiac taurine compared to age-matched control Wistar rats.

Lipid metabolism in the newborn heart.

In recent years long chain fatty acids have been shown to be the principal metabolic fuel of the adult heart (1-3). For the tissues of the mammalian fetus, however, carbohydrates rather than lipids appear to serve as the primary source of energy (4, 5). This difference in energy metabolism related to maturation suggested that the heart of the newborn, in contrast to that of the adult, might be unable to utilize long chain fatty acids and perforce must rely on glucose as the major substrate for energy production. After the observation that the rate of long chain fatty acid oxidation in tissues was enhanced by carnitine (y-trimethyl ammonium 18-hydroxybutyrate) (6), intensive investigation was undertaken to elucidate the mechanism of action of this compound. Carnitine, a normal constituent of many tissues, is especially abundant in myocardium (7, 8). From the evidence obtained in several laboratories (9, 10), it has been proposed that carnitine effects a stimulation of long chain fatty acid oxidation by functioning as a carrier of activated long chain fatty acyl groups from the extramitochondrial cytoplasm to the intramitochondrial sites of fatty acid oxidation. In this operation, a reversible transesterification between long chain fatty acyl CoA and carnitine has been demonstrated whereby long chain fatty acylcarnitine is formed. As acylcarnitine esters, the long chain fatty acids can be translocated across the mitochondrial membrane, which is relatively impermeable to acyl CoA molecules. The transesterification reaction is catalyzed by a long chain fatty acyl CoA-carnitine transferase, which has been

In vitro and in vivo suppression of gluconeogenesis by inhibition of pyruvate carboxylase

The mechanism of inhibition of gluconeogenesis by phenylalkanoic acids was studied in vitro and in vivo. In vitro production of 14CO2 from labeled glucose or palmitate was not inhibited at 4 mM, a concentration of phenylacetic acid that inhibited gluconeogenesis from lactate/pyruvate. In vitro studies with isolated mitochondria showed that the CoA ester of phenylacetic acid was formed. The parent phenylalkanoic acid had no effect on purified pyruvate carboxylase activity, but phenylacetyl CoA ester decreased pyruvate carboxylation in a concentration-dependent manner. Phenylacetic acid inhibited gluconeogenesis in isolated rat liver cells from 10 mM lactate/1 mM pyruvate (decreased 39%, P < 0.05), but not 10 mM L-glutamine or [14C]aspartate, showing that the inhibition of gluconeogenesis occurred at the level of pyruvate carboxylase. A 20 mg bolus with infusion of 1 mg/min of phenylpropionic acid decreased blood glucose levels of normal [110 +/- 12 to 66 +/- 11 mg/dL, N = 7, P < 0.05 (unpaired Students t-test vs control)] and streptozocin diabetic rats [295 +/- 14 to 225 +/- 12 mg/dL, N = 7, P < 0.01 (paired t-test vs basal)]. Hepatic glucose production in control and diabetic rats was suppressed under conditions where liver glycogen was depleted, indicating that gluconeogenesis had been inhibited in vivo. The results suggest the possibility that the inappropriate overproduction of glucose can be controlled by inhibitors of pyruvate carboxylase. This class of inhibitors may be useful in the treatment of non-insulin-dependent diabetes mellitus.

Insulin treatment in diabetes.

Efficacy of and indications for the use of purer forms of insulin have now been established, and arguments showing the relation of blood glucose control to the development and progression of complications have been strengthened.

New Pharmacological Approaches to Therapy of NIDDM

Currently available pharmacological agents have not been completely successful in restoring euglycemia in the non-insulin-dependent diabetes mellitus (NIDDM) patient. Several new approaches to the therapy of NIDDM have been formulated in recent years and are in various stages of laboratory or pharmaceutical development. Several of these agents are discussed in this article under categories relating to their mechanisms of lowering blood glucose: 1) inhibition of the release or action of counterregulatory hormones; 2) inhibition of postprandial glucose rise; 3) sensitization of tissues to insulins actions; and 4) inhibition of gluconeogenesis, including inhibition of the long-chain acyl-CoA-carnitine acyltransferase I, the long-chain acylcarnitine translocase, and pyruvate carboxylase.