Tolerability,pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor,in healthy subjects

Aims

Two double-blind, randomized studies were conducted to assess the tolerability, pharmacokinetics and pharmacodynamics of oral TA-8995, a new cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

Methods

Study 1: Subjects received single doses of TA-8995 or placebo (fasted). Doses were 5, 10, 25, 50 (fed/fasted), 100 and 150 mg (Caucasian males, 18–55 years), 25 mg (Caucasian males, > 65 years and Caucasian females, 18–55 years), 25, 50, 100 and 150 mg (Japanese males, 18–55 years). Study 2: Caucasian males (18–55 years) received 1, 2.5, 10 or 25 mg once daily TA-8995 or placebo for 21–28 days. Blood and urine for pharmacokinetics and/or pharmacodynamics were collected. Tolerability was assessed by adverse events, vital signs, electrocardiograms and laboratory safety tests.

Results

Peak TA-8995 concentrations occurred approximately 4 h post-dose. Mean half-lives ranged from 81 to 166 h, without an obvious dose relationship. Exposure increased less than proportionally to dose. TA-8995 was not excreted in urine. Following 2.5 to 25 mg once daily dosing, TA-8995 demonstrated nearly complete inhibition of CETP activity (92–99%), increased high density lipoprotein-cholesterol (HDL-C) by 96 to 140% and decreased low density liporotein-cholesterol (LDL-C) by 40% to 53%. There were dose-related increases in apolipoproteins A-1 and E, HDL2-C and HDL3-C, and decreases in apolipoprotein B and lipoprotein A. There was no evidence of significant effects of age, gender, ethnicity or food on pharmacokinetics or pharmacodynamics. All doses were well tolerated.

Conclusions

TA-8995 is a potent CETP inhibitor and warrants further investigation.     

Use of parenteral nutrition in treatment of advanced regional enteritis

Eight patients with advanced regional enteritis characterized by multiple areas of involvement, previous surgery (5 of 8), and failure on medical therapy (6 of 8) were placed on total parenteral nutrition for a period of 30 days. In eight of nine courses administered, definite improvement marked by weight gain, diminished pain, decreased diarrhea, and increased serum albumin was found. However, clinical remission was transient in seven of eight successful courses, indicating that parenteral nutrition is not a definitive form of therapy. However, the results suggest that parenteral nutrition may be useful in patients with regional enteritis to a) restore nutrition, b) induce remission, and c) prepare a debilitated patient for surgery. Additional experience is required to determine the efficacy of parenteral nutrition for therapy of fistulae caused by regional enteritis.     

Dispersive SPE,an alternative to traditional SPE for extraction of 43 doping peptides from equine urine prior to LC–MS screening

Forensic Toxicology - Dermorphin, growth hormone releasing peptide (GHRP), TB-500 and their analogues have been used illegally in the horse racing industry to improve the performance of the horses....     

Comparison of auranofin,gold sodium thiomalate,and placebo in the treatment of rheumatoid arthritis

A prospective controlled, double-blind multi-center trial compared placebo, auranofin (an orally administered gold complex), and parenteral gold sodium thiomalate (GST) in patients with active rheumatoid arthritis (RA). Of 193 patients who received any treatment, the only important improvement identified for either auranofin or GST was for pain/tenderness scores. When 161 patients who completed 20 weeks of treatment were examined, both auranofin and GST treatments were superior to placebo as measured by improvement in number of painful and/or tender joints, joint pain/tenderness scores, physician's assessment of disease activity, and decrease in erythrocyte sedimentation rate when elevated at entry. GST was superior to placebo in improvement of joint swelling scores, anemia, thrombo-cytosis, and rheumatoid factor. No drug-related remissions were observed. The only statistically significant advantages of GST over auranofin for efficacy were an increase in hemoglobin concentration and decrease of thrombocytosis with GST. Withdrawals for adverse effects were 5 times more frequent with GST treatment. Thrombocytopenia, proteinuria, elevated liver enzymes, “nitritoid” reactions, and “gold pneumonitis” were observed only in the GST treatment group. These results confirm that both parenteral and oral gold may be effective for the treatment of RA, that GST tends to show greater efficacy than auranofin, and that auranofin has fewer significant adverse effects than GST. However, long-term benefits, tolerability, and safety cannot be inferred from this study.