A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.

BACKGROUND: Oral fingolimod, a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes, significantly improved relapse rates and end points measured on magnetic resonance imaging (MRI), as compared with either placebo or intramuscular interferon beta-1a, in phase 2 and 3 studies of multiple sclerosis. METHODS: In our 24-month, double-blind, randomized study, we enrolled patients who had relapsing-remitting multiple sclerosis, were 18 to 55 years of age, had a score of 0 to 5.5 on the Expanded Disability Status Scale (which ranges from 0 to 10, with higher scores indicating greater disability), and had had one or more relapses in the previous year or two or more in the previous 2 years. Patients received oral fingolimod at a dose of 0.5 mg or 1.25 mg daily or placebo. End points included the annualized relapse rate (the primary end point) and the time to disability progression (a secondary end point). RESULTS: A total of 1033 of the 1272 patients (81.2%) completed the study. The annualized relapse rate was 0.18 with 0.5 mg of fingolimod, 0.16 with 1.25 mg of fingolimod, and 0.40 with placebo (P<0.001 for either dose vs. placebo). Fingolimod at doses of 0.5 mg and 1.25 mg significantly reduced the risk of disability progression over the 24-month period (hazard ratio, 0.70 and 0.68, respectively; P=0.02 vs. placebo, for both comparisons). The cumulative probability of disability progression (confirmed after 3 months) was 17.7% with 0.5 mg of fingolimod, 16.6% with 1.25 mg of fingolimod, and 24.1% with placebo. Both fingolimod doses were superior to placebo with regard to MRI-related measures (number of new or enlarged lesions on T(2)-weighted images, gadolinium-enhancing lesions, and brain-volume loss; P<0.001 for all comparisons at 24 months). Causes of study discontinuation and adverse events related to fingolimod included bradycardia and atrioventricular conduction block at the time of fingolimod initiation, macular edema, elevated liver-enzyme levels, and mild hypertension. CONCLUSIONS: As compared with placebo, both doses of oral fingolimod improved the relapse rate, the risk of disability progression, and end points on MRI. These benefits will need to be weighed against possible long-term risks. (ClinicalTrials.gov number, NCT00289978.)

Does availability of AIR insulin increase insulin use and improve glycemic control in patients with type 2 diabetes?

BACKGROUND: In the concordance model, physician and patient discuss treatment options, explore the impact of treatment decisions from the patient's perspective, and make treatment choices together. We tested, in a concordance setting, whether the availability of AIR inhaled insulin (developed by Alkermes, Inc. [Cambridge, MA] and Eli Lilly and Company [Indianapolis, IN]; AIR is a registered trademark of Alkermes, Inc.), as compared with existing treatment options alone, leads to greater initiation and maintenance of insulin therapy and improves glycemic control in patients with type 2 diabetes. METHODS: This was a 9-month, multicenter, parallel, open-label study in adult, nonsmoking patients with diabetes not optimally controlled by two or more oral antihyperglycemic medications. Patients were randomized to the Standard Options group (n = 516), in which patients chose a regimen from drugs in each major treatment class excluding inhaled insulin, or the Standard Options + AIR insulin group (n = 505), in which patients had the same choices plus AIR insulin. The primary end points were the proportion of patients in each group using insulin at end point and change in hemoglobin A1C (A1C) from baseline to end point. RESULTS: At end point, 53% of patients in the Standard Options group and 59% in the Standard Options + AIR insulin group were using insulin (P = 0.07). Both groups reduced A1C by about 1.2% and reported increased well-being and treatment satisfaction. The most common adverse event with AIR insulin was transient cough. CONCLUSIONS: The opportunity to choose AIR insulin did not affect overall use of insulin at end point or A1C outcomes. Regardless of group assignment, utilizing a shared decision-making approach to treatment choices (concordance model), resulted in improved treatment satisfaction and A1C values at end point. Therefore, increasing patient involvement in treatment decisions may improve outcomes.

Relationship between HbA1c and hypoglycaemia in patients with type 2 diabetes treated with different insulin regimens in combination with metformin.

BACKGROUND: To examine the relationship between glycaemic control and hypoglycaemia in patients with type 2 diabetes treated with metformin (Met) and either insulin lispro mixtures, given twice or thrice daily (LM + Met), or insulin glargine, given once daily (G + Met). METHODS: Data from three randomized clinical trials were pooled to compare effects of LM + Met with G + Met. RESULTS: The LM + Met group achieved lower mean HbA(1c) (mean+/-SE, 7.2+/-0.1 vs. 7.7+/-0.1%, p<0.0001) and all meals combined post-prandial blood glucose (BG) (8.9+/-0.1 vs. 10.2+/-0.1 mmol/L, p<0.0001) compared with the G + Met group, but had higher fasting blood glucose (8.1+/-0.1 vs. 6.8+/-0.1 mmol/L, p<0.0001) and insulin requirement (0.7+/-0.01 vs. 0.6+/-0.01 U/kg, p<0.0001). Over the entire study period, daytime hypoglycaemia was higher for the LM + Met group (10.3 vs. 3.5 episodes/patient/year, p<0.0001) than for the G + Met group; however, nocturnal hypoglycaemia was lower (3.4 vs. 6.6 episodes/patient/year, p=0.003). At endpoint, daytime hypoglycaemia was higher for the LM + Met group (6.2 vs. 1.4 episodes/patient/year, p<0.0001); however, nocturnal hypoglycaemia was similar in both groups (1.9 vs. 3.0 episodes/patient/year). An inverse relationship was observed between all confirmed hypoglycaemia and HbA(1c) at endpoint; for every 1% reduction in HbA(1c), the increase (in slope) was 1.4 episodes/patient/year (p=0.04). Patients with confirmed hypoglycaemia had lower HbA(1c) than patients without hypoglycaemia (7.39 vs. 7.64%, respectively; decrement=0.26%, p=0.026). CONCLUSIONS: These studies demonstrated an inverse relationship between HbA(1c) and 24-h and daytime hypoglycaemia. Lispro insulin mixtures provided lower HbA(1c) and post-prandial blood glucose values than glargine, but caused more daytime hypoglycaemia. Frequency of nocturnal hypoglycaemia was similar and severe hypoglycaemia was rare with both insulin regimens.

The chimpanzee cytochrome P450 3A subfamily: Is our closest related species really that similar?

With the release of the chimpanzee genomic database, much work has been accomplished to understand more fully the closest related species to humans. This study investigates the cytochrome P450 3A (CYP3A) subfamily and examines differences which may be expected between chimpanzees and humans in regards to CYP3A metabolism. A previous publication had reported the presence of five putative chimpanzee CYP3A isoforms, as compared to the four in humans (Williams ET et al., Mol Phylogenet Evol 33, 300-8). Based on the previous report, the chimpanzee CYP3A5 should have had a different C-terminus than its human counterpart; therefore, CYP3A5 and CYP3A67 were cloned. The CYP3A5 clone obtained disputes the previous prediction and confirms that the nucleotide similarity between the two species is 99.7%. While CYP3A67 is most closely related to CYP3A7, with significant differences in the amino acid sequences. Also, the mRNA expression of CYP3A67 can rival the expression of CYP3A4 in the tissues analyzed. CYP3A7 was not found to be expressed in any chimpanzee tissue examined. Total CYP3A protein expression was not significantly different between chimpanzees and humans. Metabolism assays using benzphetamine and erythromycin with chimpanzee liver microsomes did not reveal major differences between chimpanzees and humans. In conclusion, adult CYP3A metabolism may not be significantly different between chimpanzees and humans.

Comparing automatic and manual image processing in FLARE assay analysis for colon carcinogenesis.

Measurement of the amount of oxidative damage to DNA is one tool that can be used to estimate the beneficial effect of diet on the prevention of colon carcinogenesis. The FLARE assay is a modification of the single-cell gel electrophoresis (Comet) assay, and provides a measure of the 8OHdG adduct in the cells. In this paper, we present two innovations to the existing methods of analysis. The first one is related to the FLARE assay itself. We describe automated image analysis techniques that can be expected to measure oxidative damage faster, reproducibly, with less noise, and hence achieve greater statistical power. The proposed technique is compared to an existing technique, which was more manual and thus slower. The second innovation is our statistical analysis: we exploit the shape of FLARE intensity histograms, and show statistically significant diet effects in the duodenum. Previous analyses of this data concentrated on simple summary statistics, and found only marginally statistically significant diet effects. With the new imaging method and measure of oxidative damage, we show cells in the duodenum exposed to fish oil as having more oxidative damage than cells exposed to corn oil.

Estrogen regulation of the cytochrome P450 3A subfamily in humans.

This study examines the possible role of estrogen in regulating the expression of the human CYP3A subfamily: CYP3A4, CYP3A5, CYP3A7, and CYP3A43. To accomplish this goal, mRNA was quantified from human livers and endometrial samples, and total CYP3A protein levels were evaluated by Western immunoblot analysis of the liver samples. The human endometrial samples were from premenopausal and postmenopausal women. The premenopausal endometrium was either in the proliferative or secretory phase, whereas for the postmenopausal endometrium samples, the women had been treated with either a placebo or estropipate, an estrogen substitute. After analyses, CYP3A4 mRNA was shown to have lower hepatic expression in females than in males. In the endometrium, CYP3A4 and CYP3A43 are down-regulated by estrogen, whereas CYP3A5 is expressed at higher levels during the secretory phase. CYP3A7 was not detected in the endometrium. In addition, the CYP3A subfamily showed increased mRNA expression in the liver as age increased. The expression levels of total CYP3A protein and total CYP3A mRNA showed good correlation. Despite apparent regulation of CYP3A4 mRNA expression by estrogen, the effects of estrogen may be overshadowed by additional regulators of gene expression.