Biomedical subjects
M E Cooper
Publications and source records attributed to M E Cooper.
Comparison of sequential cyproterone acetate/estrogen versus spironolactone/oral contraceptive in the treatment of hirsutism.
The effects of the antiandrogen drugs cyproterone acetate (CPA) and spironolactone on hair growth and androgen levels were compared in a randomized study of 48 hirsute women. Twenty six subjects completed 6 months of therapy with 100 mg/day CPA and 19 subjects completed 6 months of 100 mg/day spironolactone. All except 10 subjects received concomitant estrogen therapy. Measured objectively, total hair diameter fell by 17.1% with spironolactone (P less than 0.001), and by 16.8% with CPA (P less than 0.001). The diameter of the hair medulla fell by 17.8% with spironolactone (P less than 0.01), and by 31.7% with CPA (P less than 0.001). There was no difference between the drugs in their effect on hair diameter. Plasma testosterone levels also fell significantly with both drugs. As a subjective assessment of treatment efficacy, the frequency with which subjects performed cosmetic measures was recorded. This fell by 38% with spironolactone and by 44.7% with CPA (P less than 0.001 both drugs), and again there was no difference between the drugs. Side effects caused cessation of treatment in one subject taking CPA and two subjects taking spironolactone, and milder side effects were noted in two further subjects from each treatment group. We conclude that spironolactone and CPA, in the dosages used in this study, are effective and well tolerated agents for the treatment of hirsutism, and that neither drug demonstrates a particular advantage over the other.
Comparison of simvastatin and cholestyramine in the treatment of primary hypercholesterolaemia.
The effects of simvastatin, a competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase, on plasma lipid levels were compared with those of the bile acid sequestrant cholestyramine in a randomized parallel study of 60 subjects with primary hypercholesterolaemia. After a 12-week direct comparison period 37 subjects with inadequate cholesterol reduction received a combination of both drugs and all subjects were followed for a further 40 weeks. Simvastatin was more effective than cholestyramine in lowering total and LDL cholesterol levels and the LDL/HDL ratio (-31.7% v. -19.7% [P less than 0.01], -41.0% v. -31.8% [P less than 0.05] and -46.7% v. -33.6% [P less than 0.01], respectively at Week 12). Only simvastatin significantly increased the HDL cholesterol concentration (+13.3% [P less than 0.01] v. +6.4%). Cholestyramine increased plasma triglyceride levels by 37.5% (P less than 0.01) whereas simvastatin caused a slight non-significant reduction. Combined therapy produced a further decrease in total and LDL cholesterol levels, and in the LDL/HDL ratio, which was sustained for the duration of the study. Simvastatin was better tolerated than cholestyramine (P less than 0.01), and combining the two drugs enhanced efficacy without increasing the frequency of side effects.
Hyperlipidaemia increases albuminuria in hypertensive and normotensive rats.
1. The effects of a high cholesterol diet on urinary albumin excretion were examined in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats over 36 weeks. 2. Cholesterol feeding resulted in an increase in total-cholesterol and a decrease in HDL-cholesterol without influencing triglyceride levels in both strains. 3. Urinary albumin excretion was significantly elevated in cholesterol-fed SHR and WKY rats. 4. These results suggest that hyperlipidaemia may be important in acceleration of experimental nephropathy.
The use of simvastatin, an HMG CoA reductase inhibitor, in older patients with hypercholesterolemia and atherosclerosis.
Epidemiological evidence suggests that elevated serum cholesterol, especially the low density lipoprotein (LDL) fraction, the total/high density lipoprotein (HDL)-cholesterol ratio, and the LDL/HDL-cholesterol ratio, remains a risk factor for atheromatous disease up to the age of 79 years. We studied the efficacy and tolerability of simvastatin, an HMG CoA reductase inhibitor, in 20 patients aged 65 to 75 years with clinical evidence of atheromatous disease. After four weeks of treatment, there was a 29% fall in LDL-cholesterol levels (P less than .01 vs placebo) with low dose simvastatin and a 38% fall with high dose simvastatin (P less than .001 vs placebo). Similar falls were seen in total cholesterol levels and the LDL/HDL-cholesterol and total/HDL-cholesterol ratios. Apoprotein B levels decreased by approximately 20% with both doses (P less than .05 vs placebo). In an open extension of the study, the decreases in lipid parameters were sustained for a further 48 weeks of treatment with doses of simvastatin ranging from 10 to 40 mg. Two patients required the addition of cholestyramine. Although a small study like this cannot establish safety and tolerance, side effects were minor and did not require stopping therapy in any patient. Simvastatin is an effective cholesterol lowering agent in older patients.
Glomerular filtration rate in streptozocin-induced diabetic rats. Role of exchangeable sodium, vasoactive hormones, and insulin therapy.
The interrelationships of sodium and volume status, atrial natriuretic peptide (ANP), plasma renin activity (PRA), insulinlike growth factor I (IGF-I), and kidney weight and their influence on glomerular filtration rate (GFR) were investigated in rats during the first 4 wk of streptozocin-induced diabetes (STZ-D). In each of three experiments, untreated diabetic rats were compared with nondiabetic control rats and rats with varying degrees of glycemic control during insulin therapy. The first experiment evaluated exchangeable sodium, plasma volume, and GFR. In untreated diabetic rats, exchangeable sodium and plasma volume, but not GFR, were increased by approximately 25% compared with control rats. Insulin-treated diabetic rats with plasma glucose levels ranging from 12 to 30 mM had increased GFR, whereas exchangeable sodium and plasma volume were reduced toward control values. Daily insulin therapy, titrated to maintain euglycemia, further reduced exchangeable sodium and plasma volume and decreased but did not normalize GFR. The second experiment evaluated the relationship between vasoactive hormones and GFR. In untreated diabetic rats, plasma ANP levels increased 89% and urinary cyclic GMP (cGMP) excretion increased 94%, with an 85% decrease in PRA, whereas GFR was unchanged. Moderate hyperglycemia (plasma glucose 12-30 mM) was associated with normalized plasma ANP levels and urinary cGMP excretion, a 52% decrease in PRA, and a 13% increase in GFR. The third experiment studied serial changes in food and water intake and vasoactive hormones and end-point measurement of kidney weight, GFR, and plasma IGF-I. In the untreated diabetic group, urinary cGMP excretion was significantly elevated after 3 wk, whereas the reduction in PRA levels was apparent after 1 wk.(ABSTRACT TRUNCATED AT 250 WORDS)
Nephropathy in model combining genetic hypertension with experimental diabetes. Enalapril versus hydralazine and metoprolol therapy.
We compared the effects of the angiotensin-converting enzyme inhibitor enalapril and a conventional antihypertensive regimen (hydralazine and metoprolol) on kidney function, albuminuria, and glomerular ultrastructure in hypertensive diabetic and nondiabetic rats. Diabetes was induced with streptozocin at 8 wk of age in spontaneously hypertensive (SHR) rats. Antihypertensive drugs were administered in drinking water from the time of induction of diabetes in all groups. Blood pressure reduction was equal in the diabetic and nondiabetic SHR rats receiving either enalapril or hydralazine plus metoprolol. In diabetic SHR rats, there was a rise in serum creatinine after 32 wk, which did not occur in diabetic rats treated with either antihypertensive regimen or in nondiabetic rats. Both drug regimens reduced albuminuria in diabetic and nondiabetic SHR rats to a similar degree. Enalapril and the combination of hydralazine and metoprolol were associated with decreased glomerular basement membrane thickness and glomerular volume in diabetic and nondiabetic SHR rats without significant effect on fractional mesangial volume. Thus, antihypertensive therapy retards the development of albuminuria, glomerular basement membrane thickening, and glomerular hypertrophy in the rat in the presence or absence of diabetes. No specific benefit of angiotensin-converting enzyme inhibition was observed in these hypertensive models of nephropathy. Human studies comparing the effects of different classes of antihypertensive drugs on kidney function, proteinuria, and glomerular morphology are warranted.
Reduced bone mass in daughters of women with osteoporosis.
To determine whether premenopausal daughters of women with postmenopausal osteoporosis have lower bone mass than other women of the same age, we measured the bone mineral content of the lumbar spine and femoral neck and midshaft, using dual-photon absorptiometry, in 25 postmenopausal women with osteoporotic compression fractures and in 32 of their premenopausal daughters; we then compared the results with those in normal controls. As compared with normal postmenopausal women, women with osteoporosis had lower bone mineral content in the lumbar spine, femoral neck, and femoral midshaft by 33, 24, and 15 percent, respectively (P less than 0.001 for each comparison by the one-tailed t-test). As compared with normal premenopausal women, the daughters of women with osteoporosis had lower bone mineral content at these sites by 7, 5, and 3 percent, respectively (P = 0.03, 0.07, and 0.15, respectively, by the one-tailed t-test). In terms of a standardized score, we calculated that the mean (+/- SEM) relative deficits in bone mineral content in the daughters of women with osteoporosis were 58 +/- 18 percent (lumbar spine) and 34 +/- 16 percent (femoral neck) of the relative deficits in their mothers. We conclude that daughters of women with osteoporosis have reduced bone mass in the lumbar spine and perhaps in the femoral neck; this reduction in bone mass may put them at increased risk for fractures. We also conclude that postmenopausal osteoporosis may result partly from a relatively low peak bone mass rather than from excessive loss of bone.
Enalapril retards glomerular basement membrane thickening and albuminuria in the diabetic rat.
This study has evaluated the effects of the angiotensin converting enzyme inhibitor Enalapril on glomerular ultrastructure and albuminuria in normotensive and hypertensive diabetic rats. Streptozotocin-diabetes was induced in Wistar Kyoto and spontaneously hypertensive rats. Enalapril was administered in drinking water in diabetic normotensive, control hypertensive and diabetic hypertensive rats. Enalapril therapy prevented an increase in glomerular basement membrane thickness in diabetic normotensive, control hypertensive and diabetic hypertensive rats without any significant effect on fractional mesangial volume. Enalapril decreased albuminuria in diabetic normotensive, control hypertensive and diabetic hypertensive rats. Thus, enalapril retards the development of glomerular basement membrane thickening and albuminuria in the rat, in the presence or absence of hypertension.
Ramipril reduces albuminuria in diabetic rats fed a high protein diet.
1. Streptozotocin diabetes was induced in Wistar-Kyoto rats fed a 50% protein diet. Animals were randomized to receive either the ACE inhibitor ramipril, 1 mg/L in drinking water (n = 7), or no treatment (n = 7) and were studied for 6 months. Blood glucose, body weight and glomerular filtration rate (GFR) were measured at 0, 1, 4, 8 and 16 weeks of diabetes and urinary albumin excretion was measured every 8 weeks. 2. In both groups, GFR increased significantly within 1 week of induction of diabetes (P less than 0.001) and thereafter remained stable. There was no difference in GFR between the treated and untreated groups. 3. Urinary albumin excretion increased progressively in both groups throughout the study. Ramipril treatment reduced albuminuria by approximately 50% at weeks 16 and 24 (P less than 0.01). 4. The amelioration of diabetic albuminuria by ACE inhibition, in the setting of high dietary protein intake, may have important implications for the treatment of human diabetic nephropathy.
Triphasic changes in selectivity with increasing proteinuria in type 1 and type 2 diabetes.
Two indices of the selectivity of proteinuria, the immunoglobulin G (IgG)/albumin and the IgG/transferrin clearance ratios, were studied cross-sectionally and serially over 7 years in a cohort of 52 Type 1 and 60 Type 2 diabetic patients without established diabetic nephropathy. In Type 1 and Type 2 diabetic patients with albuminuria less than 30 micrograms min-1, both protein clearance ratios were significantly higher than in 27 control subjects. As albuminuria increased, there was a decrease in both protein clearance ratios. However, at albumin clearances above 90 nl s-1, equivalent to albumin excretion rates of greater than 250 micrograms min-1, a positive correlation was found in Type 2 diabetic patients between protein clearance ratios and albuminuria. In individual Type 1 and Type 2 diabetic patients with progressively increasing proteinuria, serial measurements of selectivity showed a decline in both protein clearance ratios with the onset of microalbuminuria. Episodes of transient microalbuminuria were also associated with a fall in the IgG/albumin clearance ratio. The results suggest that the selectivity of proteinuria undergoes a triphasic change with the development of diabetic nephropathy. In the first phase, proteinuria is non-selective with IgG clearance equal to or exceeding transferrin or albumin clearance. As microalbuminuria develops, there is a progressive increase in selectivity reflecting the preferential excretion of transferrin and albumin compared with IgG. In later stages of nephropathy, as shown in Type 2 diabetic patients with macroalbuminuria, there is a return to non-selective proteinuria.
A rapid purification of L-glutamic acid decarboxylase from the brain of the locust Schistocerca gregaria.
L-Glutamic acid decarboxylase (GAD; EC 4.1.1.15) was purified to apparent homogeneity from the brain of the locust Schistocerca gregaria using a combination of chromatofocusing (Mono P) and gel filtration (Superose 12) media. The homogeneity of the enzyme preparation was established by native polyacrylamide gel electrophoresis (PAGE) with silver staining. The molecular weight of the purified enzyme was estimated from native gradient gel electrophoresis and gel filtration chromatography to be 97,000 +/- 4,000 and 93,000 +/- 5,000, respectively. When analysed by sodium dodecyl sulphate-PAGE, the enzyme was found to be composed of two distinct subunits of Mr 51,000 +/- 1,000 and 44,000 +/- 1,500. Tryptic peptide maps of iodinated preparations of these two subunits showed considerable homology, suggesting that the native enzyme is a dimer of closely related subunits. The purified enzyme had a pH optimum of 7.0-7.4 in 100 mM potassium phosphate buffer and an apparent Km for glutamate of 5.0 mM. The enzyme was strongly inhibited by the carbonyl-trapping reagent aminooxyacetic acid with an I50 value of 0.2 microM.
Comparison of early renal dysfunction in type I and type II diabetes: differing associations with blood pressure and glycaemic control.
This study has investigated the relationship of glycaemic control, blood pressure and proteinuria to early renal dysfunction in a cohort of 50 type I and 65 type II diabetics, with renal function ranging from normal to mildly impaired (serum creatinine less than 0.2 mM). Repeated measurements were made over a mean interval of 7 years and mean data from each subject were analysed by stepwise multiple linear regression. This enabled associations to be determined independently of the confounding influence of age and duration of disease. In type I diabetics, mean creatinine clearance was inversely related to systolic blood pressure (P less than 0.001), glycosylated haemoglobin (P less than 0.05), fasting plasma glucose (P less than 0.05) and to the renal clearance of albumin (P less than 0.001), transferrin (P less than 0.01) and IgG (P less than 0.05). By contrast, in type II diabetics, none of these associations were significant. No significant relationships were found with the rate of decline of creatinine clearance in either type of diabetic. Further studies will be needed to determine whether the changes in blood pressure and glycaemic control precede or follow the development of renal disease. However, these findings raise the possibility of a difference in the pathogenesis of renal disease in type I and type II diabetes.
Isolation and characterization of insulin-stimulated, high-affinity cAMP phosphodiesterases from rat liver.
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Effect of early menopause on bone mass in normal women and patients with osteoporosis.
PURPOSE: Early menopause is widely regarded as a risk factor for osteoporosis. The aim of this study was to determine whether this risk is conferred by a lower bone mass. PATIENTS AND METHODS: Two hundred thirteen normal postmenopausal women and 55 women with postmenopausal osteoporosis (vertebral fractures) underwent bone mass measurements at the lumbar spine, femoral neck, and midshaft using dual-photon absorptiometry. To examine the effect of early menopause, postmenopausal normal women were stratified according to whether menopause occurred before or after the age of 50 years. Patients with osteoporosis were stratified in the same way. RESULTS: Patients with osteoporosis had menopause at an earlier age than control subjects, but the difference in bone mass between the patients with osteoporosis and the control subjects could not be attributed to this earlier age at menopause. Furthermore, within the osteoporotic patient group, those with early menopause did not have lower bone mass than those with normal age at menopause. Similarly, within the normal subject group, those with early menopause did not have lower bone mass than those with normal age at menopause. CONCLUSION: Patients with osteoporosis have lower bone mass, which is independent of the age at menopause. Although a small effect (less than or equal to 5 percent) of early menopause on bone mass cannot be entirely excluded, these data suggest that the amount of bone lost following menopause is the same irrespective of the age at which menopause occurs. If early menopause is a risk factor for osteoporosis, the risk is not conferred by a bone mass substantially lower than predicted had menopause occurred later, but may be related to the duration of exposure to minimal trauma at low bone mass.
Genetic hypertension accelerates nephropathy in the streptozotocin diabetic rat.
To evaluate whether hypertension is a cause or just an association with diabetic renal disease, diabetes was induced in both normotensive Wistar-Kyoto and spontaneously hypertensive rats (WKY and SHR). Animals were assessed monthly for 8 months before sacrifice. When compared to normotensive diabetic rats (WKY-STZ), hypertensive diabetic rats (SHR-STZ) had an earlier and more rapid rise in urinary albumin excretion. In addition, SHR-STZ had increased glomerular basement membrane thickness when compared to WKY-STZ or SHR. In a separate experiment, Enalapril therapy (35 mg/L) was administered in drinking water to WKY-STZ and SHR-STZ. Enalapril significantly reduced blood pressure in both animal groups, and this was associated with a decrease in urinary albumin excretion. The SHR-STZ model has accelerated nephropathy as determined by both functional and structural parameters. Angiotensin-converting enzyme inhibition is associated with a reduction in albuminuria in both hypertensive and normotensive models of diabetic nephropathy.
Effects of genetic hypertension on diabetic nephropathy in the rat--functional and structural characteristics.
Streptozotocin (STZ) diabetes was induced in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. Body weight, blood pressure, renal function, glycaemic control and proteinuria were assessed monthly for 32 weeks. At 32 weeks, the animals were killed and glomerular basement membrane (GBM) thickness and fractional mesangial volume were measured. There was no significant difference in renal function between diabetic SHR and diabetic WKY. Diabetic SHR showed an earlier and larger rise in total proteinuria and urinary albumin excretion than diabetic WKY. Urinary albumin excretion was increased more than tenfold in diabetic SHR compared to diabetic WKY after 32 weeks of diabetes. GBM thickness was significantly increased in diabetic SHR compared with diabetic WKY. Both diabetic WKY and diabetic SHR showed mesangial expansion when compared to their nondiabetic counterparts. On the other hand, both hypertensive models showed increased glomerular volume, which was not influenced by the presence of diabetes. The diabetic SHR model has features of accelerated nephropathy, as evidenced by increased albuminuria and GBM thickness. This suggests that pre-existing hypertension may play an important role in the progression of diabetic renal disease.
The insulin- and glucagon-stimulated 'dense-vesicle' high-affinity cyclic AMP phosphodiesterase from rat liver. Purification, characterization and inhibitor sensitivity.
The hormone-stimulated 'dense-vesicle' cyclic AMP phosphodiesterase was solubilized as a proteolytically 'clipped' species, and purified to apparent homogeneity from rat liver with a 2000-3000-fold purification and a 13-18% yield. It appeared to be a dimer (Mr 112,000), of two Mr-57,000 subunits. Solubilization of either a liver or a hepatocyte membrane fraction, with sodium cholate in the presence of the protein inhibitor benzamidine, identified three protein bands which could be immunoprecipitated by a polyclonal antibody raised against the pure enzyme. The major band at Mr 62,000 is suggested to be the native 'dense-vesicle' enzyme, having a Mr-5000 extension which serves to anchor this enzyme to the membrane and which is cleaved off during proteolytic solubilization; the Mr-200,000 band is an aggregate of the Mr-62,000 species, and the Mr-63,000 species is possibly a precursor. The purified 'clipped' enzyme hydrolysed cyclic AMP with kinetics indicative of apparent negative co-operativity, with a Hill coefficient (h) of 0.43 and limiting kinetic constants of Km1 = 0.3 +/- 0.05 microM, Km2 = 29 +/- 6 microM, Vmax.1 = 0.114 +/- 0.015 unit/mg of protein and Vmax.2 = 0.633 +/- 0.054 unit/mg of protein. It hydrolysed cyclic GMP with Michaelis kinetics, Km = 10 +/- 1 microM and Vmax. = 4.1 +/- 0.2 units/mg of protein. Cyclic GMP was a potent inhibitor of cyclic AMP hydrolysis, with an IC50 (concn. giving 50% inhibition) of 0.20 +/- 0.01 microM-cyclic GMP when assayed at 0.1 microM-cyclic AMP. This enzyme was inhibited potently by several drugs known to exert positive inotropic effects on the heart, was extremely thermolabile, with a half-life of 4.5 +/- 0.5 min at 40 degrees C, and was shown to be distinct from the rat liver insulin-stimulated peripheral-plasma-membrane cyclic AMP phosphodiesterase [Marchmont, Ayad & Houslay (1981) Biochem. J. 195, 645-652].