Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Clinical and immunologic effects

Forty-nine patients with active rheumatoid arthritis completed a 24-week, prospective, double-blind, randomized study of dietary supplementation with 2 different dosages of fish oil and 1 dosage of olive oil. Clinical evaluations were performed at baseline and every 6 weeks thereafter, and immunologic variables were measured at baseline and after 24 weeks of study. The 3 groups of patients were matched for age, sex, disease severity, and use of disease-modifying antirheumatic drugs (DMARDs). Subjects continued receiving DMARDs and other background medications without change during the study. Twenty patients consumed daily dietary supplements of n3 fatty acids containing 27 mg/kg eicosapentaenoic acid (EPA) and 18 mg/kg docosahexaenoic acid (DHA) (low dose), 17 patients ingested 54 mg/kg EPA and 36 mg/kg DHA (high dose), and 12 patients ingested olive oil capsules containing 6.8 gm of oleic acid. Significant improvements from baseline in the number of tender joints were noted in the low-dose group at week 24 (P = 0.05) and in the high-dose group at week 18 (P = 0.04) and 24 (P = 0.02). Significant decreases from baseline in the number of swollen joints were noted in the low-dose group at weeks 12 (P = 0.003), 18 (P = 0.002), and 24 (P = 0.001) and in the high-dose group at weeks 12 (P = 0.0001), 18 (P = 0.008), and 24 (P = 0.02). A total of 5 of 45 clinical measures were significantly changed from baseline in the olive oil group, 8 of 45 in the low-dose fish oil group, and 21 of 45 in the high-dose fish oil group during the study (P = 0.0002). Neutrophil leukotriene B4 production decreased by 19% from baseline in the low-dose fish oil group (P = 0.0003) and 20% in the high-dose group (P = 0.03), while macrophage interleukin-1 production decreased by 38.5% in the olive oil group (P not significant), 40.6% in the low-dose group (P = 0.06), and 54.7% in the high-dose group (P = 0.0005). Tritiated thymidine incorporation in peripheral blood mononuclear cells after stimulation with concanavalin A increased significantly in all 3 groups after 24 weeks, compared with baseline values. We conclude that the clinical benefits of dietary supplementation with omega-3 fatty acids are more commonly observed in patients consuming higher dosages of fish oil for time intervals that are longer than those previously studied. Dietary supplementation with olive oil is also associated with certain changes in immune function, which require further investigation.     

FAM chemotherapy +/- aminoglutethimide in the treatment of pancreatic carcinoma

Human pancreas contains receptors for estrogens and androgens as well as aromatase activity. FAM chemotherapy was administered to 14 patients with pancreatic cancer (seven at Stage IV). The median survival of these patients was 24.4 +/- 4.8 weeks. FAM chemotherapy plus aminoglutethimide/hydrocortisone (AG/HC) (250 mg bid AG + 20 mg bid HC) was administered to 14 patients (seven at stage IV). The median survival of this group was 17.3 +/- 2.9 weeks (P = 0.74 vs FAM alone). We conclude that addition of AG/HC does not add to the survival of patients with carcinoma of the pancreas treated with chemotherapy.     

Multivariate risk estimation for coronary heart disease: the Busselton Health Study

Coronary heart disease (CHD) is a multifactorial disease and CHD risk should be estimated by assessing all cardiovascular risk factors simultaneously. Simply adding up the number of factors with 'at risk' values fails to identify high-risk subjects with multiple risk factors at moderately elevated values. A more efficient approach is to use a quantitative multivariate risk score. A number of overseas studies have produced CHD risk scoring systems for men. There are few risk scores developed for women and no CHD risk scores have been developed from Australian data. This study used data on CHD risk factors and morbidity/mortality follow-up for the 1978 Busselton Health Survey participants to provide age-specific estimates of absolute risk of CHD hospitalisation or death, and to develop multivariate CHD risk scoring systems for men and women. The scores are based on age, blood pressure, anti-hypertensive medication, total and HDL cholesterol, smoking, diabetes, left ventricular hypertrophy and previous history of CHD. The generalisability and applicability of these risk estimation systems to Australian populations in the late 1990s is discussed.     

Application of bioluminescent urine screens in a tertiary care facility

Two adenosine triphosphate (ATP)-detection systems for quantitating bacteriuria, the LUMAC (noncentrifugation method) and MONOLIGHT (centrifugation method) urine screens, were separately evaluated for their capacity to detect bacteriuria in specimens from patients at a tertiary care teaching hospital. Results of each study were compared with the findings of conventional culture. Indices of test efficacy, sensitivity/predictive value for a negative test, were as follows: at greater than or equal to 10(4) CFU/ml--LUMAC 88%/93% and MONOLIGHT 82%/88%; and at greater than or equal to 10(5) CFU/ml--LUMAC 99%/99% and MONOLIGHT 97%/99%. Both systems were satisfactory urine screens for catheterized and midstream urine specimens when used at the traditional level of significance (greater than or equal to 10(5) CFU/ml). An assessment of the MONOLIGHT noncentrifugation protocol demonstrated efficacy of the system to detect significant bacteriuria at greater than or equal to 10(5) CFU/ml. Decreased numbers of false-positive results compared to the centrifugation method were obtained with this assay. False-positive and false-negative results were attributable to threshold sensitivity of the instruments. The presence of somatic cells and yeasts were associated with false-positive results. False-positive results might stem from the inability of conventional culture to recover selected microorganisms. Time and cost analyses of the LUMAC system indicated that significant savings over conventional methodology were not effected.     

The fibrinolytic system in experimental prostate tumor

Hypofibrinogenemia and disseminated intravascular coagulation are common events in patients with metastatic prostate carcinoma. This study tests the hypothesis that prostate tumor growth and metastasis is associated with sustained activation of fibrinolysis secondary to increased release of plasminogen activator. We implanted an androgen-insensitive prostate tumor into an inbred strain of rats and serially measured plasminogen, plasminogen activator, plasmin and fibrinogen. Control groups included animals without tumor and a group implanted with transitional cell bladder carcinoma, a locally infiltrating tumor not usually associated with hemostatic complications. Our results showed a significant and steady rise in plasma plasminogen activator, plasmin and fibrinogen levels in animals implanted with prostate cancer. This, however, is not specific for prostate tumor. Similar, perhaps more profound changes were noted in animals implanted with the transitional cell carcinoma.     

A 7-deaza-adenosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties

Improved treatments for chronic hepatitis C virus (HCV) infection are needed due to the suboptimal response rates and deleterious side effects associated with current treatment options. The triphosphates of 2'-C-methyl-adenosine and 2'-C-methyl-guanosine were previously shown to be potent inhibitors of the HCV RNA-dependent RNA polymerase (RdRp) that is responsible for the replication of viral RNA in cells. Here we demonstrate that the inclusion of a 7-deaza modification in a series of purine nucleoside triphosphates results in an increase in inhibitory potency against the HCV RdRp and improved pharmacokinetic properties. Notably, incorporation of the 7-deaza modification into 2'-C-methyl-adenosine results in an inhibitor with a 20-fold-increased potency as the 5'-triphosphate in HCV RdRp assays while maintaining the inhibitory potency of the nucleoside in the bicistronic HCV replicon and with reduced cellular toxicity. In contrast, while 7-deaza-2'-C-methyl-GTP also displays enhanced inhibitory potency in enzyme assays, due to poor cellular penetration and/or metabolism, the nucleoside does not inhibit replication of a bicistronic HCV replicon in cell culture. 7-Deaza-2'-C-methyl-adenosine displays promising in vivo pharmacokinetics in three animal species, as well as an acute oral lethal dose in excess of 2,000 mg/kg of body weight in mice. Taken together, these data demonstrate that 7-deaza-2'-C-methyl-adenosine is an attractive candidate for further investigation as a potential treatment for HCV infection.