No abstract

Acid-catalysed dehydration of 3-substituted benzene cis-l,2-di hydrodiols exhibits a Hammett plot with p = -8.2, consistent with reaction via a benzenonium ion-like intermediate; however, correlation of +M resonance substituents such as Me and Me0 by q, rather than (J+ constants indicates a marked imbalance between resonance and inductive stabilisation of the transition state.

Risedronate is a pyridinyl bisphosphonate approved for the treatment of Paget's disease (US-FDA) and in development for the treatment and prevention of osteoporosis. This study examined risedronate pharmacokinetics and tolerability after oral administration using a randomized, double-blind, parallel-group design. Healthy male and female volunteers (n = 22-23 subjects per dose) received a single oral dose of 2.5, 5, or 30 mg risedronate. Serum and urine samples were collected for 72 and 672 hours, respectively, and risedronate concentrations were determined by ELISA. Safety was evaluated by monitoring adverse events, clinical laboratory measurements, vital signs, and electrocardiograms. Mean Cmax (0.41, 0.94, and 5.1 ng/mL for 2.5, 5, and 30 mg, respectively), AUC (1.8, 3.9, and 21 ng.h/mL for 2.5, 5, and 30 mg, respectively), and urinary excretion (22, 63, and 260 micrograms for 2.5, 5, and 30 mg, respectively) were dose proportional, and there were no significant differences in tmax or CLR among the three doses. All doses were well tolerated; no serious adverse events occurred, and all but one of the adverse events were mild or moderate in severity. There was no evidence of an acute phase reaction occurring after oral administration of risedronate.

Aims To determine the relationship between risedronate pharmacokinetics and renal function. Methods Risedronate was administered to adult men and women (n=21) with various degrees of renal function (creatinine clearance 15-126 ml min −1 ) as a single oral dose of 30 mg. Serum samples were obtained for 72 h after dosing, and urine samples were collected for 72 h after dosing and then periodically for 6 weeks. Risedronate concentrations were determined using an enzyme-linked immunosorbent assay (ELISA). Risedronate serum concentration-time and urinary excretion rate-time profiles were analysed simultaneously using nonlinear regression.Results Renal clearance and volume of distribution were linearly related to creatinine clearance (r 2 =0.854, P<0.001; and r 2 =0.317, P<0.01, respectively). Decreases in predicted renal clearance and volume of distribution of 82 and 69%, respectively, were observed when creatinine clearance decreased from 120 to 20 ml min . A 64% decrease in predicted oral clearance was observed when creatinine clearance decreased from 120 to 20 ml min −1 ( P=0.064). Iohexol clearance, a predictor of renal function, produced similar results to those observed with creatinine clearance. Risedronate was well tolerated by the study population. Conclusions Risedronate renal clearance was significantly related to a decrease in renal function. There was a consistent reduction in oral clearance with a decrease in creatinine clearance. However, based on the regression analysis, generally no dosage adjustment appears to be necessary for most patients with mild or moderate renal impairment (creatinine clearance >20 ml min −1 ).

We wish to report measurements of rates of acid-catalyzed dehydration of the three isomeric hydrates of naphthalene (1-3).As part of our program directed toward synthesis of the unknown cage compounds 1, 2, and related "phosphocarbons"