Aims To determine the absolute bioavailability, dose proportionality and the effects of food on the pharmacokinetics of single oral doses of sildena®l citrate. Methods Three open-label, randomized crossover studies were conducted in healthy male subjects. Absolute bioavailability was determined by comparing pharmacokinetic data after administration of single oral and intravenous 50-mg doses of sildena®l (n=12 subjects). Food effects were examined by comparing pharmacokinetic data for sildena®l and its primary circulating metabolite, UK-103,320, after administration of a single oral 100-mg dose in the fasted and fed states (n=34 subjects). Dose proportionality was assessed from pharmacokinetic data obtained after administration of four single oral doses of sildena®l (25, 50, 100 and 200 mg) to 32 subjects. The safety and tolerability of sildena®l were also assessed in all of these studies. Results The calculated absolute oral bioavailability of sildena®l was 41% (90% CI: 36 ±47). Food slowed the rate of absorption, delaying mean t max by approximately 1 h and reducing C max by 29% (90% CI: 19±38). Systemic exposure, as assessed by the mean area under the plasma concentration±time curve (AUC), was reduced by 11% (90% CI: 6±16). These food effects were not considered to be of clinical signi®cance. There was statistical evidence of nonproportionality in C max and AUC over the dose range 25±200 mg. However the degree of nonproportionality was small, with predicted increases in C max and AUC of 2.2-and 2.1-fold, respectively, for a doubling in dose, and was thought to be clinically nonsigni®cant. Sildena®l was well tolerated in the three studies; the majority of adverse events were mild and transient. Conclusions Sildena®l had a mean absolute bioavailability of 41%. Food caused small reductions in the rate and extent of systemic exposure; these reductions are unlikely to be of clinical signi®cance. Across the dose range of 25±200 mg, systemic exposure increased in a slightly greater than dose-proportional manner.

Short-term treatment with oral tofacitinib results in significant clinical improvement in patients with moderate-to-severe plaque psoriasis and is generally well tolerated.

Tofacitinib conferred tolerable, dose-dependent changes in haematological parameters during short-term administration in patients with psoriasis. The effects did not appear to be progressive, and were often transient or reversible.

Sebum excretion has generally been accepted as an important factor in the development of acne vulgaris. However, the relationship of sebum excretion and acne outcome has not yet been clearly demonstrated quantitatively. The objective of this analysis was to explore the correlation of sebum and acne by combining data from studies of various acne treatments that have demonstrated effects on both sebum excretion and acne outcome. Acne measures included total lesion count, inflammatory lesion count and acne severity grade. For each acne measure, data were pooled and analysed at the 3- and 4-month endpoints, when sebum reduction has generally equilibrated and efficacy in acne is approaching the maximum effect for most treatments. A linear model was used to describe the percentage reduction in each acne measure as a function of percentage reduction in sebum excretion. Slope values were similar for the three acne parameters and all were significantly different from zero (P < 0·025), suggesting a significant correlation of sebum and acne. The projected sebum reduction required to achieve 50% reduction in acne measures ranged from 30% to 50%. The results shown here suggest that the collective data across multiple studies may provide a useful generalization of the association of sebum reduction and acne outcome. As the relationship apparently remains consistent regardless of the treatment, it can be inferred that extrapolation to novel exploratory treatments may be valid.

The three-item PGA scale has sound psychometric properties with respect to reliability and validity, with equal weighting of the items being appropriate.