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Biomedical subjects

G G Duggin

Publications and source records attributed to G G Duggin.

At least 37 records · Page 2Linked to original sources
PubMed1991

Early blood pressure control improves pregnancy outcome in primigravid women with mild hypertension.

OBJECTIVE AND DESIGN: The aim of this study was to evaluate treatment of mild to moderate hypertension (less than 170/110 mmHg) in pregnancy in a prospective, randomised, double-blind trial. SETTING AND PATIENTS: Pregnancy outcome was studied for 52 primigravid women, managed in hospital from early in the third trimester. INTERVENTIONS: Patients were randomly allocated either to placebo or to active treatment (clonidine plus hydralazine). MAIN OUTCOME MEASURES AND RESULTS: Maternal deterioration dictated withdrawal from trial therapy for eight patients receiving placebo, but for only one receiving active treatment. Maternal proteinuria occurred only in the placebo group. Intention-to-treat analysis showed a significant increase in premature delivery for complications in the placebo group (P less than 0.05), despite active blood pressure treatment for those withdrawn from the group because of severe hypertension (170/110 mmHg or higher). Neonatal respiratory distress requiring intensive care occurred only in babies born to women in the placebo group. There were no perinatal deaths and no adverse effects of treatment in the neonates. CONCLUSIONS: The study indicates that early control of mild hypertension in pregnancy can prevent progression to emergency premature delivery.

Adult↗
PubMed1991

Cyclosporin A blood levels are not influenced by dietary alterations in lipids.

The bioavailability of an oral dose of cyclosporin A (CSA) is variable. CSA is highly lipid soluble with approximately 40% of the CSA in the intravascular compartment bound to lipoproteins. This study was undertaken to determine what effect acute alterations in plasma lipids following a high fat meal would have on CSA whole blood levels 12 to 14 hours after the last dose. Fifteen renal transplant patients with stable renal function and on CSA therapy alone for a minimum of three months were investigated. Anthropometric data was recorded and baseline blood samples were drawn for CSA, liver function, renal function, vitamins A and E. triglycerides, cholesterol and lipoproteins following an overnight fast. The subjects then received a high fat (72.8% of caloric value) or a low fat (12% of caloric value) meal and post-prandial samples were drawn at two and four hours. The correlation between CSA levels (r = 0.72) taken on the two study days (one week apart) was less than expected despite no change in dosage. Cholesterol levels remained unchanged but triglyceride levels rose following the high fat meal. CSA levels did not correlate with the post-prandial changes in triglycerides, nor with any other parameter of lipid metabolism, lipid transport, or total body fat. This study demonstrated that CSA whole blood levels are not influenced by acute variations in lipids following a meal and therefore the time of sampling for a CSA trough level will not be influenced by the proximity to a recent meal.

Adult↗
PubMed1990

Energy supplementation and the nutritional status of hemodialysis patients.

Twenty-one patients undergoing regular hemodialysis completed a trial of energy supplementation. Nine patients added the glucose polymer Polycose to their usual diet and 12 acted as control subjects. The supplemented patients were asked to incorporate 100 or 150 g polymer, equivalent to 1600 or 2400 kJ (400 or 600 kcal) into their usual diet, daily for 6 mo. This resulted in a mean increase in energy intake of 1630 kJ (p less than 0.05) and a mean weight gain of 3.1 kg (p less than 0.005). The addition of glucose polymer to the diet resulted in a mean increase in body fat of 1.8 kg and the lean body mass increased by 1.3 kg. No significant effect on plasma triglycerides, urea, or creatinine was detected. The intake of macro- and micronutrients was not adversely affected and no clinical or psychological side effects were reported. Follow-up of these patients showed that the weight gain was maintained after 6 mo. Glucose polymer was an effective energy supplement that had beneficial effects on the nutritional status of hemodialysis patients.

Adult↗
PubMed1990

Evidence that alterations in renal metabolism and lipid peroxidation may contribute to cyclosporine nephrotoxicity.

This study was designed to investigate aspects of renal xenobiotic metabolism and the renal cellular response to drug-induced injury, in mediating cyclosporine nephrotoxicity. The relation between CsA and renal enzyme activity has not previously been investigated. In this study, CsA induced alterations in rat renal cortical microsomal NADPH cytochrome P-450 reductase activity, microsomal and mitochondrial lipid peroxidation, and renal cortical glutathione levels were investigated. CsA, in vivo (50 mg/kg/day for 4 days), increased in vitro lipid peroxidation in microsomes and mitochondria. CsA produced a significant uncompetitive inhibition of renal NADPH cytochrome P-450 reductase activity. The low activity and maximal enzyme velocity (Vmax) suggest that the amount of renal enzyme available for metabolism may be a rate-limiting step and could contribute to the development of toxicity. CsA in vivo reduced the renal cortical glutathione ratio (GSH/GSSG), which may also reduce the renal cellular response to CsA injury. This study has demonstrated that CsA nephrotoxicity may, in part, be mediated by CsA-induced alterations in renal xenobiotic metabolism.

Animals↗
PubMed1990

Hemodynamics of conscious unrestrained baboons, including cardiac output.

A method is described for comprehensive hemodynamic study of undisturbed baboons (Papio hamadryas) that incorporates cardiac output measurement by thermodilution. Instrumentation includes arterial, aortic, and central venous catheterization by a surgical technique that does not require entry to peritoneal or thoracic cavities. It provides a means for right atrial indicator delivery with aortic temperature recording of thermodilution curves. Accuracy was confirmed by comparison to measurement by Swan-Ganz catheters. Diurnal variations of systemic arterial pressure in long-term study of conscious baboons were shown to result from significant increases in cardiac output by day (P less than 0.001), despite concomitant falls in systemic vascular resistance. The cardiac output values obtained were 0.13 l.min-1.kg-1 at night and 0.16 l.min-1.kg-1 by day. Comparison of these results to previous reports of cardiac output in baboons highlights the inadequacies of methods that require physical restraint or anesthesia. This technique also leaves the baboons intact for subsequent breeding or experimental use after catheter removal without the need for further surgery.

Animals↗
PubMed1990

Essential hypertension--investigations and management.

When one is faced with the problem of essential hypertension it is prudent to pay attention to lifestyle factors, especially alcohol, smoking and obesity. Modification of salt intake in the diet is a simple measure. Drug therapy will need to be long-term therapy and ease of treatment is important, which means that drugs given once a day or at most twice a day should be used. Diuretics and beta-blockers are inexpensive and well proven but have many side-effects. Newer agents may have fewer side-effects but are more expensive. The choice will be an individual one.

Clinical Protocols↗
PubMed1989

Cyclosporin A inhibits protein kinase C activity: a contributing mechanism in the development of nephrotoxicity?

Cyclosporin A modifies many intracellular functions in a variety of different cells. This study investigated the potential interaction between cyclosporin A and protein kinase C, as a possible mechanism for the development of nephrotoxicity. The activity of protein kinase C, in the cytosol of renal epithelial cells, was shown to be significantly inhibited in a dose-dependent manner by CSA. Activation of protein kinase C by 12-O-tetradecanoylphorbol-13-acetate (phorbol ester) in rat mesangial cells in culture leads to an increase in PGE2 release. Phorbol ester stimulated PGE2 release was significantly inhibited by cyclosporin A. These results would suggest that intracellular site of action of cyclosporin A, in producing alterations in intracellular function and toxicity, may be at the level of protein kinase C.

Animals↗
PubMed1989

Vitamin supplementation of patients receiving haemodialysis.

In order to assess the necessity of vitamin supplementation for patients who are receiving haemodialysis, measurements of vitamin status were made, and both dietary and supplementary intakes were assessed, in 26 patients who were undergoing haemodialysis. Blood samples were collected from these patients before they underwent haemodialysis, after an overnight fast, for the measurement of plasma retinol, alpha-tocopherol and ascorbate levels. Serum and erythrocyte folate levels were measured also. Thiamin status was assessed by the effect of added thiamin pyrophosphate on erythrocyte transketolase activity and pyridoxine status was assessed by the effect of added pyridoxal-5'-phosphate on erythrocyte aminotransferase activity. All patients had elevated plasma retinol levels; 48% of patients had elevated plasma alpha-tocopherol levels; the plasma ascorbate level was low in 50% of patients but was elevated in 25% of patients; and plasma and erythrocyte folate levels were elevated in 76% and 91% of patients, respectively. Thiamin status was normal in all but one patient and the pyridoxine level appeared to be low in two other patients. Many patients had low dietary intakes of vitamin C, folate and vitamin B6. We conclude that supplements of vitamins A and E are not required and, when dietary intakes of water-soluble vitamins are marginal, these should be supplemented at a dose as near as possible to the recommended dietary intake.

Ascorbic Acid↗
PubMed1989

Structure-activity relationships of cyclosporines. Toxicity in cultured renal tubular epithelial cells.

Proximal (LLC-PK1) and distal (MDCK) renal epithelial cell cultures were used to investigate early biochemical changes in cellular metabolism following exposure to cyclosporine A (CsA). 3H-thymidine and 3H-leucine incorporation into the cells were used as indices of DNA and protein synthesis. The cells were exposed to concentrations of CsA ranging from 0.2 microgram/ml to 20 micrograms/ml. By 20 hr there was a decrease in the total cell count at concentrations of 10 and 20 micrograms/ml that was more pronounced by 5 days of exposure. At 5 days there was also a reduction in cell count at the lower concentrations of CsA. There was an initial increase in DNA and protein synthesis at 2 hr with inhibition of DNA synthesis evident by 20 hr. Protein synthesis was increased in the LLC-PK1 cells and decreased in the MDCK cells. At 5 days there was evidence of increased DNA and protein synthesis, most marked in the remaining viable cells exposed to the higher concentrations of CsA. Similar alterations in cellular metabolism were evident when the cells were exposed to the immunologically inert cyclosporine H (D-N-MeVal11-Cs). These studies demonstrate that cyclosporine produces alterations in cellular function as early as 2 hr after exposure to the drug. At the lower concentrations there is evidence of sublethal cellular toxicity and cellular regeneration. The toxicity appears to be related to the molecular structure of cyclosporine and its incorporation into cell membranes. We postulate that cyclosporine nephrotoxicity is the summation of several subtoxic alterations in cellular function the final expression of which is modified by other factors affecting renal function.

Animals↗
PubMed1989

Malignant lymphoma in a renal transplant patient on cyclosporin A therapy.

Cyclosporin A has been associated with an apparent increased incidence of non Hodgkins lymphoma, most often in conjunction with multiple immunosuppressive agents. We report a patient who developed a non Hodgkins lymphoma arising in the right tonsillar fossa six months following renal transplantation. The development of the lymphoma was associated with seroconversion for the Epstein Barr capsid antigen and nuclear antigen. The patient was receiving cyclosporin A alone as immunosuppression.

Adult↗
PubMed1989

Dietary eicosapentaenoic acid does not modify cyclosporin-induced inhibition of angiotensin II-stimulated prostaglandin synthesis in mesangial cells.

Clinical and experimental cyclosporin A (CSA) nephrotoxicity is characterized by alterations in renal hemodynamics and a reduction in glomerular filtration rate (GFR). The mesangial cell may be a target for the actions of CSA. CSA has been shown to activate the renin angiotensin system and to increase the excretion of TXB2 (the stable metabolite of TXA2). This study investigated the role of CSA and mesangial cell prostaglandin release in mediating some of the alterations in renal hemodynamics. Primary rat mesangial cell cultures (first passage) were exposed to CSA followed by stimulation with angiotensin II (AII) 10(-7) M. PGE2 and TXB2 release was measured after 5 and 15 minutes incubation. Experimental CSA nephrotoxicity in rats has been shown to be reduced by the use of MaxEPA fish oil (containing eicosapentaenoic acid) as the vehicle for CSA. Therefore, the experiments were repeated using mesangial cells obtained from rats fed an enriched eicosapentaenoic acid (MaxEPA) diet for 3 weeks. CSA significantly inhibited AII stimulated PGE2 release in both experiments. There was no increase in TXB2 release. Alterations in membrane fatty acid composition, available for prostaglandin synthesis, did not alter the results. This study demonstrated that CSA significantly inhibits AII-stimulated prostaglandin release. The increased excretion of TXB2, seen with CSA treatment, does not arise from the mesangial cells, and the protective effect of MaxEPA, as a vehicle for CSA, is not due to its effects on mesangial cell prostaglandin release.

Angiotensin II↗
PubMed1988

Synergistic toxicity of cyclosporin A and streptomycin in renal epithelial cell cultures.

Cyclosporin A (CSA) nephrotoxicity was examined in two renal epithelial cell cultures, the LLC-PK1 cell line and the MDCK cell line. Acute changes in cell growth and cellular DNA and protein synthesis were investigated at 2 hours, 20 hours and 5 days. The potential synergistic interaction between streptomycin (a standard additive to most culture media) and CSA was examined. CSA produced significant alterations in cell function as early as 2 hours after exposure and this became more noticeable with increased exposure to CSA. Streptomycin potentiated the toxicity effects on cellular metabolism that was seen with CSA. The use of cell culture models to investigate CSA toxicity must avoid the use of potential agents which may have a synergistic effect on the development of toxicity.

Animals↗
PubMed1987

Effect of angiotensin II on baroreceptor reflex control of heart rate in conscious baboons.

Studies of the baroreceptor-heart rate reflex were performed in four conscious, unrestrained male baboons to determine whether changes in circulating angiotensin II within the physiological range are associated with alterations in baroreceptor reflex sensitivity. With the animals on a high sodium intake, studies were performed before and during graded angiotensin II infusion (10 and 20 ng/kg/min). To separate effects on baroreceptor reflex function mediated by angiotensin II-induced increases in arterial pressure, these studies were repeated on a different day with simultaneous glyceryl trinitrate infusion to prevent increases in pressure during angiotensin II infusion. With the animals on a low sodium intake, studies were performed before and after angiotensin converting enzyme inhibition with captopril (1 and 5 mg/kg). These studies were also repeated on a separate day during simultaneous phenylephrine infusion to prevent a decrease in pressure with captopril. Reduction in sodium intake had no significant effect on arterial pressure, heart rate, or plasma volume, although arterial plasma angiotensin II concentration and renin activity were significantly increased (p less than 0.01). Infusion of angiotensin II produced a significant reduction in baroreceptor reflex sensitivity (p less than 0.01), and converting enzyme inhibition produced a significant increase (p less than 0.05). These effects accompanied significant increases and decreases in arterial angiotensin II concentration, respectively (p less than 0.01), but were independent of angiotensin II-related changes in arterial pressure. The data indicate that physiological variations in circulating angiotensin II have a direct effect on sensitivity of the baroreceptor-heart rate reflex.

Angiotensin II↗
PubMed1987

Verapamil in essential hypertension: a comparison with atenolol plus hydralazine.

The effects of graded doses of verapamil were compared with those of a combination of atenolol and hydralazine in a double-blind, randomised, crossover trial in 16 patients with essential hypertension. During the placebo phase, mean arterial pressure (M.A.P.) was 123 +/- 17 mmHg. Verapamil (dose range 160-480 mg/day) lowered M.A.P. to 109 +/- 7 mmHg (p less than 0.01 vs placebo). The combination of atenolol (50-100 mg/day) and hydralazine (50-200 mg/day) lowered M.A.P. to 100 +/- 11 mmHg (p less than 0.001 vs placebo, p less than 0.05 vs verapamil). Neither regimen produced any deleterious effects on electrocardiographic intervals, echocardiographic indices of left ventricular function or plasma lipids. Verapamil was well tolerated and provided satisfactory alternative therapy in these patients with mild-to-moderate essential hypertension.

Adult↗