Aspirin protects low density lipoprotein from oxidative modification.

OBJECTIVE: To examine the effects of aspirin on the potential for oxidative modification of low density lipoprotein (LDL). DESIGN: Before and after trial. SETTING: University department of medicine within a district general hospital campus. PATIENTS: Ten healthy normolipidaemic volunteers drawn from laboratory and medical staff. INTERVENTIONS: Aspirin (enteric coated) 300 mg daily for two weeks. MAIN OUTCOME MEASURES: In vitro oxidation of LDL following ultraviolet C (UVC) irradiation with measurements made of malondialdehyde, conjugated dienes, and electrophoretic mobility. RESULTS: There was a significant decrease in malondialdehyde production from LDL modified by aspirin in vivo following exposure to UVC irradiation for 90 minutes, culminating in a 30% decrease by 240 minutes (mean (SD) 64.2 (9.12) v 89.6 (11.6) nmol/mg LDL protein, P = 0.029). These observations were borne out using LDL modified by aspirin in vitro. The UVC induced increase in relative electrophoretic mobility of LDL was also significantly reduced following aspirin treatment (mean (SD) 2.17 (0.16) v 2.66 (0.24), P = 0.012). CONCLUSIONS: Aspirin, both in vivo and in vitro, protects LDL against subsequent oxidative modification, providing an additional mechanism whereby aspirin may protect against atherosclerosis.

Megestrol-induced Cushing's syndrome.

This case describes the first report of a patient developing Cushing's syndrome whilst being treated with the synthetic progestogen, megestrol acetate (Megace). Drugs are the commonest cause of Cushing's syndrome. Some synthetic progestogens are known to have glucocorticoid activity at high doses. On structural grounds neither megestrol nor its major metabolites would be expected to interact with the glucocorticoid receptor, through the manufacturers report that it may have 'weak glucocorticoid activity'.

The effect of a somatostatin analogue (SMS 201-995, Sandostatin) on the concentration of phosphoribosyl pyrophosphate and the activity of the pentose phosphate pathway in the early renal hypertrophy of experimental diabetes in the rat.

The effect of a long-acting somatostatin analogue on the acute renal hypertrophy following induction of experimental diabetes in the rat has been studied. The kidney weight increase occurring at 2 and 7 days after alloxan injection was significantly lower in the diabetic group receiving somatostatin. Similarly, the previously reported increase in glucose-6-phosphate dehydrogenase (EC 1.1.1.49) and 6-phosphogluconate dehydrogenase (EC 1.1.1.44) found in the kidney at 2 and 7 days of diabetes was less marked in the group receiving SMS 201-995. The fall in renal phosphoribosyl pyrophosphate associated with early diabetic renal hypertrophy (7) was also lessened by administration of SMS 201-995. No effects of the drug were found in the normal rat on the same regimen of treatment. These observations indicate involvement of glucagon and/or growth hormone in the initiation of kidney growth in diabetes.

Renal hypertrophy in experimental diabetes. Changes in pentose phosphate pathway activity.

An examination was made of the effect of different periods of experimental diabetes on the activity of the pentose phosphate pathway in rat kidney. A rapid increase in kidney weight, expressed both in absolute terms and in terms of body weight, occurred shortly after the induction of diabetes. The activity of the enzymes of the oxidative segment of the pentose phosphate pathway and the flux of glucose through the pathway were both increased during the first 7 days after induction of diabetes. Thereafter, enzyme activity returned toward control levels, but the increased functional activity of the pathway, as measured using specifically labeled glucose, persisted. In contrast, transketolase was significantly depressed at the time of most rapid kidney growth. A positive correlation was found between the rate of kidney growth and the change in activity of glucose-6-phosphate dehydrogenase and a negative correlation with changes in transketolase activity. The possible roles of the oxidative and nonoxidative segments of the pentose phosphate pathway in the kidney in early diabetes-induced renal hypertrophy are discussed.

Regulation of pathways of glucose metabolism in kidney. Specific linking of pentose phosphate pathway activity with kidney growth in experimental diabetes and unilateral nephrectomy.

The pentose phosphate pathway operates at an elevated level in rat kidney following induction of diabetes and in the compensatory hypertrophy following unilateral nephrectomy in control and alloxan-diabetic rats, as shown by the yields of 14CO2 from [1-14C]glucose, [6-14C]glucose and 3H2O yields from [2-3H]glucose. The elevated flux through the pentose phosphate pathway is correlated with the increased RNA content and weight of the kidney. The direct utilization of NADPH for reductive synthetic reactions and the potential for indirect utilization via the sorbitol route and the linked transhydrogenase reactions of the glucuronate-xylulose pathway, for NADH and ATP generation, are also discussed.