Tiludronate therapy for Paget's disease of bone.

A double-blind, randomized, placebo-controlled study was performed to evaluate the effect of oral tiludronate therapy in 139 patients with active Paget's disease of bone. Patients received placebo (N = 48), tiludronate 200 mg (N = 45), or tiludronate 400 mg (N = 46) once daily for 12 weeks. Biochemical and clinical responses were observed during the 12 week treatment phase and during an additional 12 week observation phase of the study. Both the 200 and 400 mg tiludronate groups experienced significant reduction in serum alkaline phosphatase (SAP) and urinary indices of bone resorption. After 12 weeks of therapy, the SAP levels decreased 46% from baseline values in the 200 mg group and 51% from baseline values in the 400 mg group. At the end of the 24 week study, SAP levels were reduced 47% and 58% from baseline in the 200 and 400 mg groups, respectively. The SAP reduction at 24 weeks was greater in the 400 mg group than the 200 mg group (p < 0.05). At the end of 24 weeks, 51% of patients treated with 200 mg and 72% of those who received 400 mg of tiludronate had experienced a reduction in SAP of greater than 50% (p = 0.043), and 7% and 35% of patients in the 200 and 400 mg groups, respectively, had experienced normalization of SAP (p = 0.001). There was no difference in incidence of side effects in patients taking tiludronate or placebo. In conclusion, oral tiludronate is an effective and well-tolerated therapy for patients with Paget's disease of bone. Daily therapy with 400 mg tiludronate for 12 weeks is more effective than a daily dose of 200 mg for 12 weeks.

Efficacy of oral WIN 54954 for prophylaxis of experimental rhinovirus infection.

The efficacy of oral WIN 54954 for the prevention of rhinovirus infection and illness was tested in two randomized, double-blinded, placebo-controlled volunteer challenge studies. Volunteers were inoculated with rhinovirus type 39 (MIC of WIN 54954, 0.17 microgram/ml) or rhinovirus type 23 (MIC, 0.016 microgram/ml). The volunteers received two doses of drug (600 mg per dose) or placebo on the first day; this was followed by three doses on each of the subsequent 5 days. All volunteers were challenged with virus after the third dose of study drug. No significant antiviral or clinical effect was detected in either study. Pharmacokinetic studies revealed that on the last day of drug administration, 38 of 39 (97%) volunteers had trough levels of WIN 54954 in plasma greater than the MIC for the respective virus. Nasal wash specimens collected on the same day revealed a detectable level in only 6 of 24 (25%) volunteers at the peak (range, 6 to 24 ng/ml) and in only 2 of 14 (14%) volunteers at the trough (range, 6 and 7 ng/ml). These results suggest that the lack of efficacy of WIN 54954 against rhinovirus may be related to an inability to deliver sufficient drug to the site of viral infection.

Events surrounding the early development of euglena chloroplasts: v. Control of paramylum degradation.

The degradation of the storage carbohydrate, paramylum, is induced by light in wild-type Euglena gracilis Klebs var. bacillaris Pringsheim and in a mutant, W(3)BUL, which lacks detectable plastid DNA. Treatment of wild type with cycloheximide in the dark produces 60% as much paramylum breakdown as light, whereas treatment with levulinic acid in the dark yields a slightly greater response than light. Both cycloheximide and levulinic acid produce a greater paramylum breakdown in the light than they do in the dark. Treatment of W(3)BUL with levulinic acid in darkness produces a larger paramylum degradation than light, with values similar to wild type in the light. Treatment of W(3)BUL with cycloheximide induces paramylum degradation in darkness, and as with wild type, light is slightly stimulatory in the presence of both cycloheximide or levulinic acid. Streptomycin brings about only a very small amount of paramylum breakdown in the dark and only slightly inhibits breakdown in the light. Thus paramylum breakdown induced by light does not require the synthesis of proteins on cytoplasmic or plastid ribosomes. A model which explains these results postulates the existence of a protein which inhibits paramylum breakdown. When the synthesis of this protein is prevented either by light, cycloheximide, or by levulinic acid acting as a regulatory analog of delta amino levulinic acid, paramylum breakdown takes place. Because levulinic acid is a better inducer than light in W(3)BUL, W(3)BUL may not be able to form as much delta amino levulinic acid in light as wild type. The small amount of induction by streptomycin is viewed as a secondary regulatory effect attributable to interference with plastid protein synthesis which affects regulatory signals from the plastid to the rest of the cell.