The effects of C1-719 on plasma lipid and lipoprotein concentrations have been examined in four patients with endogenous hypertriglyceridaemia maintained on an isocaloric diet for a period of 6 months. During therapy (400 mg/day) the mean plasma triglyceride and cholesterol concentrations were reduced by 35% and 15% respectively, while the administration of 800 mg/day reduced these by 49% and 31%. This hypolipidaemic effect was due to a reduction in the circulating level of very low density lipoproteins (VLDL) without a change in their composition. Before treatment the plasma VLDL triglyceride turnover, and FFA flux, were higher than that of normal subjects maintained on a similar diet. The plasma VLDL B-apoprotein turnover was similarly higher than in the controls. Administration of C1-719 decreased the plasma VLDL triglyceride turnover, FFA flux and VLDL B-approtein turnover. The drug reduced the insulin response following a glucose load with some decrease in glucose levels. The results suggest that the increase in plasma triglyceride concentration in patients with endogenous hypertriglyceridaemia is due to increased production of plasma VLDL triglyceride and its apoptein associated with an enhanced supply of FFA for hepatic triglyceride synthesis. C1-719 exerts a hypolipidaemic effect through a reduction of VLDL production, consequent upon inhibition of lipolysis as well as decreased synthesis of the apoprotein carrier. These effects could in part be explained by an improvement in peripheral tissue responsiveness to insulin and decreased exposure of the liver to high levels of insulin. However, a direct effect of the drug on adipose tissue and liver metabolism has to be considered.

Adult↗

PubMedDate not supplied

New areas for therapeutic intervention in the treatment of rheumatic disease.

Anti-rheumatic therapy has been targeted against the symptoms arising from chronic inflammation of the joint. This has resulted in the extensive use of non-steroidal anti-inflammatory drugs. It is now becoming apparent that these agents have no beneficial effect on disease progression. This mini review concentrates on the formation and maintenance of pannus, the granulomatous tissue responsible for cartilage and bone erosion. This reveals a number of possible therapeutic targets. Protease inhibitors could be used to interfere with the degradatory processes. The diverse functions of endothelial cells suggest oedema formation, cell accumulation and supply of nutrients to the granulomatous tissue could all be targeted by appropriate therapy. Alternatively the immune processes that control pannus formation and state of activation could be regulated by interfering with antigen presentation and the cytokine network.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMedDate not supplied

Gene probes in diagnosis of familial hypercholesterolemia.

In the United Kingdom, about 5% of patients with familial hypercholesterolemia (FH) have a detectable deletion or rearrangement of part of the LDL-receptor gene, which results in the detection of shorter or abnormally sized fragments of the LDL-receptor gene in a Southern blot hybridization. This gene deletion can be used for following the inheritance of the defective gene and for diagnosis in the families of these individuals. In the families of the remaining patients, diagnosis may be possible using linked restriction fragment length polymorphisms (RFLPs) detected with the LDL-receptor probe. There are now 10 common RFLPs of the LDL-receptor gene, with variable sites in the 3' half of the gene. Over 80% of patients are heterozygous for at least one of these RFLPs, and, therefore, RFLPs are potentially informative for DNA diagnosis. For a fetus at risk of homozygous FH, antenatal diagnosis may also be possible using these methods. However, family studies require samples to be available from affected or unaffected relatives of the patient, and this limits the applicability of the tests. For some mutations, the base-pair change causing the defect in the LDL receptor itself creates or destroys a site for a restriction enzyme. Such "mutation-specific" RFLPs could be used for population screening, but, so far, such use has only been reported for the FH mutation common in Lebanon. In the future, it may be possible to develop mutation-specific oligonucleotide probes for the diagnosis of FH. These would be appropriate for screening populations or patients with hyperlipidemia. This information may also be useful if different mutations require different therapeutic strategies.

Cholesterol↗

PubMedDate not supplied

Genotypic and phenotypic variation in familial hypercholesterolemia.

Familial hypercholesterolemia is characterized by an increase in low density lipoprotein (LDL) cholesterol, tendon xanthomata, and premature atherosclerosis. In homozygotes, phenotypic expression of the disorder is dominated by genotypic variation at the LDL-receptor gene locus, with other influences, like gender, exerting relatively little effect. In contrast, phenotypic variation in heterozygotes is influenced not only by the nature of the underlying gene mutation but also by gender, diet, and other forms of genetic polymorphism, including the apolipoprotein E genotype.

Age Factors↗

PubMedDate not supplied

Six-month prospective cross-over study to determine the effects of 1.1% amino acid dialysate on lipid metabolism in patients on continuous ambulatory peritoneal dialysis.

OBJECTIVE: To evaluate the effect of 1.1% amino acid dialysate (AAD) (Nutrineal, Baxter, Castlebar, Ireland) on lipid metabolism in hyperlipidemic patients on continuous ambulatory peritoneal dialysis (CAPD). DESIGN: Patients were alternately assigned to receive AAD in the first (group A), or the second (group B), 6 months of a prospective cross-over study. SETTING: University teaching hospital. PATIENTS: Eighteen stable CAPD patients with a serum cholesterol 5.5 mmol/L or greater. INTERVENTIONS: One post prandial exchange of AAD during a 24-hour period for 6 months. MAIN OUTCOME MEASURES: A significant change in serum lipid levels. RESULTS: Patients in group A (n = 10) received a single daily exchange of AAD in place of their post prandial dextrose exchange for the first 6 months, and then crossed over to the dextrose phase. Patients in group B (n = 8) continued their usual dextrose dialysis for the first 6 months and then crossed over to receive AAD in the latter 6 months. Measurements of serum lipids and lipoproteins along with other biochemical parameters were made at regular intervals. Although a downward trend in mean serum total cholesterol was seen on AAD in group A, no significant change in total cholesterol, low-density lipoprotein cholesterol, or high-density lipoprotein cholesterol was observed in any group. Mean serum triglycerides fell on AAD in both groups, but were not statistically significant. Serum lipoprotein(a) [Lp(a)] and apolipoprotein B were elevated in both groups but did not change on AAD or with time. No change was observed in serum apoprotein A1 levels. Serum Lp(a) was not correlated to dialysate protein excretion. No change in mean serum albumin was observed, in either group, on AAD. KT/V urea, total weekly creatinine clearance, net ultrafiltration, and dialysate protein excretion remained unchanged on AAD. CONCLUSIONS: The use of AAD, although clinically safe and without side effects, had no effect on the dyslipidemia in our group of CAPD patients.

Adult↗