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PubMed1983

Gemfibrozil in combination with other drugs for severe hyperlipidemia. Preliminary study comprising four cases.

In this very early report, Dr Nash shares his insights into a newly developing approach to hyperlipidemia therapy. Four severely hyperlipidemic patients in whom maximum dietary therapy had proved ineffective showed a dramatic reduction in cholesterol and triglyceride levels when treated with multiple drugs, including gemfibrozil. These cases demonstrate that maximally effective polypharmacy can have striking results in selected patients. These provocative findings should encourage other investigators to verify or refute them.

Adult↗
PubMed1987

The Helsinki Heart Study: basic design and randomization procedure.

The Helsinki Heart Study is a coronary primary prevention trial in a group of middle aged men with lipid abnormalities. Its aim is to investigate the effects on the incidence of coronary heart disease of simultaneously lowering serum total and low density lipoprotein (LDL)-cholesterol and elevating high density lipoprotein (HDL)-cholesterol with gemfibrozil, over a period of 5 years. Participants were selected from a population of 23 531 men between 40 and 55 years of age. The mean serum total cholesterol among 18 966 screened subjects was 6.3 mmol l-1 (245 mg dl-1) and the mean HDL-cholesterol 1.3 mmol l-1 (50.3 mg dl-1). All subjects meeting the lipid acceptance criterion of non-HDL-cholesterol (i.e. total cholesterol minus HDL-cholesterol) greater than 5.2 mmol l-1 (200 mg dl-1) on two separate occasions two to three months apart, who were free from coronary heart disease or other major illness, were invited to participate. The total cholesterol level for the final 4081 study participants was 7.5 mmol l-1 (290 mg dl-1) and HDL-cholesterol was 1.23 mmol l-1 (47.6 mg dl-1). Mean systolic and diastolic blood pressures were 141.7 and 91.3 mmHg. About 15% of participants were hypertensive and 36% were smokers. A total of 2051 men were randomly allocated to receive gemfibrozil 600 mg twice daily and 2030 matching placebo capsules. A cholesterol-lowering diet was also prescribed for all participants. The randomized treatment groups were well balanced. Equal distribution of major risk factors was achieved in relevant sub-groups. This report describes the procedures involved in setting up the study, summarizes the baseline data obtained and reviews the success of the randomization procedure. Finally, it compares the design of this study with that of some other major preventive trials.

Cholesterol, Dietary↗
PubMed1987

Minimal doses of digoxin: a new marker for compliance to medication.

A direct and objective method of measuring compliance to medication is presented. Digoxin is used as a marker in capsules of either gemfibrozil or placebo with a minimal dose of 4.4 micrograms twice a day. Compliance is estimated by measuring the ratio of urinary digoxin to creatinine concentration. By choosing two cut-off points of this ratio patients who are taking their capsules regularly and those who have taken no capsules at all could be distinguished from others. Reduced dosage was easily detected in the marker results. During regular intake of three quarters of the dose, 53% of the samples would have classified the patient to the good compliance group. With half of the dose, 24% of samples and with a quarter of the dose, 5% of samples would have classified the subject to good compliance. Since the digoxin marker was planned for compliance measurements in the Helsinki Heart Study, a primary prevention study of coronary heart disease, it was tested under the conditions of a clinical trial. Digoxin concentrations were measured using a routine method normally applied to serum but shown to be valid for urine. The results of the urinary assays were not affected by storage at room temperature, as occurs during postal transport of samples, nor were they affected by freezing, routinely used for the storage of samples in clinical trials. The results therefore suggest that the digoxin marker represents a particularly effective method to study compliance to medication during such long-lasting clinical investigations.

Clinical Trials as Topic↗
PubMed1987

Comparison of the digoxin marker with capsule counting and compliance questionnaire methods for measuring compliance to medication in a clinical trial.

During the last quarter of the third year of follow-up in the Helsinki Heart Study, compliance to medication was measured in 1739 patients with digoxin used as a marker substance, capsule counting and a compliance questionnaire. The estimates for good and poor compliers were found to be highly dependent on the method and the cut-off points chosen for the compliance allocation. The methods studied here were more reliable for the detection of poor rather than good compliance. In the poor compliance group, defined with the use of the digoxin marker, there was 39% of subjects who returned less than 5% of their capsule dosage or reported a deviation less than 5%. In the good compliance group, defined by the digoxin marker, only 11.8% of patients either returned or reported a deviation of at least 25% of their dose. The compliance was better when measured by the questionnaire than by capsule counting. The size of the poor compliance group, defined by the use of the digoxin marker, was as large as a group who had returned at least 27% of their capsule dose and a group who had reported a deviation of 11% or more from their dosing schedule. The size of the group allocated to the good compliance category by the use of the digoxin marker was equivalent in size to a group of patients who had returned less than 15% of their prescribed dose or reported a deviation of less than 6% from their prescription. When the strictest criteria for the combination of all three methods were used, 57% of subjects were classified as good and 31% as poor compliers to medication in the third year of the primary prevention trial designed to reduce the incidence of coronary heart disease.

Capsules↗
PubMed1982

Plasma prekallikrein, kallikrein inhibitors, kininogen and lipids during gemfibrozil treatment in type II dyslipidaemia.

The effects of gemfibrozil on plasma prekallikrein, kallikrein inhibitors, kininogen and plasma lipids were investigated in 31 male subjects having either type IIA or IIB dyslipidaemia. During gemfibrozil use, plasma prekallikrein and kininogen were increased significantly while kallikrein inhibitors increased only slightly. Total cholesterol and triglycerides decreased while HDL cholesterol was increased. Changes in prekallikrein and HDL cholesterol were correlated, whereas no other significant correlations between changes in lipid and kinin parameters were seen. The observed changes in prekallikrein and kininogen possibly indicate a shift in the thrombo-haemorrhagic balance in favour for increased fibrinolysis. If so, the effects of gemfibrozil in prevention and management of atherosclerosis would not be solely due to correlation of the dyslipidaemia but also to protection against the accelerated coagulation tendency seen in type II dyslipidaemia.

Adult↗
PubMed1974

Role of the leu-3 cistron in the regulation of the synthesis of isoleucine and valine biosynthetic enzymes of Neurospora.

The production by Neurospora of the enzymes of isoleucine and valine synthesis in response to specific end product-derived signals depends upon the presence of an effective leu-3 regulatory product and its effector alpha-isopropylmalate (alpha-IPM). In leu-3(+) strains, threonine deaminase production is repressed as a function of available isoleucine, acetohydroxy acid synthetase as a function of valine, and the isomeroreductase and dihydroxy acid dehydratase as a function of isoleucine and leucine. In the absence of an effective leu-3 regulatory product, alpha-isopropylmalate, or both, the production of isoleucine and valine biosynthetic enzymes is fixed at or near fully repressed levels even under conditions of severe end product limitation. Thus, in addition to its involvement in the regulation of expression of the three structural genes of leucine synthesis, the leu-3 alpha-IPM regulatory product is necessary for full expression of at least four genes specifying the structure of the enzymes of isoleucine and valine synthesis. It is suggested that the leu-3 alpha-IPM regulatory element may facilitate transcription of the genetically dispersed cistrons either by imposing specificity on ribonucleic acid polymerase for structurally similar promoters adjacent to each of the cistrons or by "opening" promoters after interaction with nearly identical stretches of deoxyribonucleic acid near each of the structural genes.

Alcohol Oxidoreductases↗
PubMed1975

Microbial transformation of artificial estrogens of the allenolic group.

When 2,2-dimethyl 3-(2'-naphthyl 6'-hydroxy) pentanoic acid, an artificial estrogen of the allenolic acid group, was added to an exponential-phase growth culture of Neurospora crassa (in Horowitz medium), it was transformed into its hydroxylated derivative, 2,2-dimethyl 3-(2'-naphthyl 4',6'-dihydroxy)pentaoic acid. To study this transformation, radioactive 2-methyl-[2-14-C=A1methyl 3-(2'-naphthyl 6'-hydroxy) pentanoic acid has been prepared. The rate of metabolism of allenolic acids varies in the same way as their estrogenic activity.

Carbon Radioisotopes↗
PubMed1983

Complementation studies of isovaleric acidemia and glutaric aciduria type II using cultured skin fibroblasts.

Using cultured skin fibroblasts, we studied the heterogeneity of inborn errors of leucine metabolism such as isovaleric acidemia (IVA), glutaric aciduria type II (GA II), and multiple carboxylase deficiency (MC). We first developed a simple macromolecular-labeling test to measure the ability of cells to oxidize [1-14C]isovaleric acid in situ in culture. Cells from two different lines were fused using polyethylene glycol, and the ability of the heterokaryons to oxidize [1-14C]isovaleric acid was tested by the macromolecular-labeling test. The MC line complemented with all 10 IVA lines tested; heterokaryons showed 99 +/- 68% more activity than the unfused mixture of component cells. GA II/IVA heterokaryons exhibited poor growth, but when the culture remained confluent, the GA II cells complemented with all six IVA lines tested, showing a 71 +/- 41% increase in activity. The relatively large standard deviations are due to a few experiments in which significant enhancement of macromolecular-labeling test activity was not observed upon fusion, but significant complementation was clearly observed in repeats of the same combinations. These results are consistent with our previous findings, which indicated that the decreased ability of GA II cells to oxidize isovaleryl-CoA involves a defective electron-transporting system rather than a defective isovaleryl-CoA dehydrogenase. IVA/IVA heterokaryons showed no complementation in any combination tested, indicating no detectable heterogeneity in isovaleric acidemia. This finding indicates that the same gene is mutated in all IVA lines. Previous results indicated that this gene codes for isovaleryl-CoA dehydrogenase.

Amino Acid Metabolism, Inborn Errors↗
PubMed1986

Isovaleryl-CoA dehydrogenase activity in isovaleric acidemia fibroblasts using an improved tritium release assay.

Isovaleric acidemia is a disorder of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase. At least two clinical subgroups of patients exist: a severe form, in which symptoms occur within the 1st wk of life, and a milder variant in which manifestations develop later in life. We developed a modified version of the tritium release assay to accurately measure residual isovaleryl-CoA dehydrogenase activity in fibroblasts from patients with both forms of isovaleric acidemia. In the modified assay, specific isovaleryl-CoA dehydrogenase-catalyzed tritium release from [2,3-3H]isovaleryl-CoA was determined by including an inhibitor of isovaleryl-CoA dehydrogenase, (methylenecyclopropyl)acetyl-CoA, in one of the tubes in paired assays, to determine the nonspecifically released 3H2O. Residual activities of the nine isovaleric acidemia lines tested ranged from 0 to 0.67 pmol 3H2O/min/mg protein (controls 19.4 +/- 8.0). The three lines from mildly affected individuals all had no detectable activity, whereas the severe cases had a mean of 0.41 pmol 3H2O/min/mg protein. Normal human fibroblast isovaleryl-CoA dehydrogenase had a Km for isovaleryl-CoA of 22 microM, with a Vmax of 51 pmol 3H2O/min/mg protein. The Ki of isovaleryl-CoA dehydrogenase by (methylenecyclopropyl)acetyl-CoA was approximately 2 microM.

Amino Acid Metabolism, Inborn Errors↗
PubMed1983

Effects of ammonia and organic acids on the intradental sensory nerve activity.

Ammonia and organic acids constitute a major part of the bacterial metabolites formed in carious decay. The aim of the present study was to investigate their effect on the intradental sensory nerves. Nerve impulse activity was recorded from canine teeth in cats after application of the test solutions in deep dentinal cavities. Ammonia (17-134 mM) consistently generated nerve impulses, whereas organic acids (0.001-1 M) failed to induce any impulse activity. In contrast, acid application resulted in an inhibition of the ongoing nerve activity induced by various stimuli (hypertonic NaCl solution, mechanical pulp exposure, and compound 48/80). However, acid treatment of the cavities resulted in an enhanced neural response to ammonia stimulation. Thus, the present results demonstrate that these bacterial metabolites can influence intradental sensory nerve activity. It is suggested that they may also modulate the symptoms from decayed teeth.

Acetates↗
PubMed1984

3-Hydroxy-3-methylglutaric aciduria.

3-Hydroxy-3-methylglutaric aciduria was found in a newborn infant whose parents are first cousins. The patient presented at 5 days of life with hyperammonemia, hypoglycemia, and metabolic acidosis. There was no ketonuria. Diagnosis was made by analysis of the pattern of organic acids excreted in the urine. A profound deficiency in activity of 3-hydroxy-3-methylglutaryl-coenzyme A lyase was found in cultured skin fibroblasts. The parents had intermediate levels of enzyme activity.

Cells, Cultured↗
PubMed1988

The effects of 4-pentenoic and pentanoic acids on the isolated rat atria.

The peak developed tension and the pacemaker frequency of the isolated atria from fed and fasted rats, declined progressively during the incubation in a glucose-free medium containing 2-deoxyglucose. The atria from fed rats exhibited a faster decline than those from fasted rats, which was associated to a slower triacylglycerol lipolysis. 4-Pentenoic acid inhibited the lipolysis of both groups of atria but did not alter the atrial contractile performance. However, it enhanced the decline of the pacemaker frequency in the atria from fasted rats whereas, in contrast, it alleviated the decline in the fed atria. n-Pentanoic acid ameliorated the impairment of the contractile and pacemaker activities in both groups of atria, without affecting the lipolysis. It was concluded that, since the inhibition of the intramyocardial lipolysis did not correlate with changes of the atrial functions, 4-pentenoic acid was not appropriate to assess about the contribution of endogenous triacylglycerol to the maintenance of the atrial contractile and pacemaker activities.

Animals↗
PubMedDate not supplied

[Biotechnological potential of methylotrophic bacteria: a review of current status and future prospects].

Major results of the authors' findings on the implementation of biotechnological potential of aerobic methylobacteria and methanotrophs for obtaining forage proteins, biopolymers (polybutyrate and polysaccharides), enzymes (oxidoreductases), and bioprotectors (ectoin), as well as for degrading toxic C1 and Cn compounds have been reviewed. Unique features of the structural and functional organization of the metabolism of extremophilic (tolerant) methylotrophs are discussed, with a view for their prospective use in various fields of modern biotechnology, including biocatalysis and nanotechnology.

Amino Acids, Diamino↗
PubMed1990

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency as detected by radiochemical assay in cell extracts by thin-layer chromatography, and identification of three new cases.

In this rapid radiochemical assay for 3-hydroxy-3-methylglutaryl-coenzyme A lyase (I) activity in cell extracts, DL-3[glutaryl-3-14C]hydroxy-3-methylglutaryl-coenzyme A is used as substrate and the radiochemical product, [3-14C]acetoacetic acid, is converted to the more stable [3-14C]-3-hydroxybutyric acid in the presence of added NADH and 3-hydroxybutyrate dehydrogenase. Substrate and product are separated and quantified by thin-layer chromatography on cellulose (solvent system: butanol/water/formic acid, 77:13:10 by vol). All reagents for the assay are commercially available. No detailed column chromatography or spectrophotometry is required. Thus the assay is suited for any clinical laboratory. Using this procedure, we studied cultured fibroblasts or lymphocytes isolated from whole blood from five patients in whom the urinary organic acid profile was suggestive of deficiency of I. Three patients had less than or equal to 18% of control I activity in fibroblast or lymphocyte extracts. The other two had activity within the normal range. In one of the latter cases, urinary excretion of three of the characteristic acids disappeared with age, and 3-hydroxyisovaleric acid excretion was within normal limits. The other case presented with urinary excretion of moderate amounts of all four metabolites and the characteristic absence of urinary ketone bodies. Evidently, confirmatory enzyme studies should be undertaken, even when the profile of urinary organic acids appears definitive for this deficiency.

Cells, Cultured↗
PubMed1978

[Chemical modification of lysine epsilon-NH2-groups in horseradish peroxidase. Its effect on enzyme stability. Temperature dependence of thermo-inactivation constants for native and modified peroxidase].

Thermostability of horseradish peroxidase modified by acetic, propionic, butyric, valeric and succinic anhydrides and trinitrobenzolsulfonic acid (TNBS) is studied within the temperature range of 56-80 degrees C. Acylation of 4 amino groups and arylation of 3 amino groups with TNBS are found to stabilize the enzyme, while modification of 6 groups decreases the enzyme stability. Chemical modification of peroxidase does not change its pH-dependence with respect to enzyme thermostability. Thermodynamic activation parameters of irreversible thermoinactivation are determined for native and modified peroxidase. Native peroxidase has deltaH not equal to = 30+/-1 kcal/mole and deltaS not equal to = 14 e. e.; modified by acid anhydrides peroxidase has deltaH not equal to within 64-87 kcal/mole and deltaS not equal to within 110-178 e. e. depending on the nature of a modifying agent. The effect of the structure of a radical introduced into the enzyme molecule, and of a number of modified epsilon-amino groups on thermoinactivation deltaH not equal to and deltaS not equal to values is discussed.

Acylation↗