Successful treatment of moderate to severe plaque psoriasis with the PEGylated Fab' certolizumab pegol: results of a phase II randomized, placebo-controlled trial with a re-treatment extension.

BACKGROUND: Certolizumab pegol (CZP) is a PEGylated antitumour necrosis factor agent. OBJECTIVES: To evaluate the efficacy and safety of CZP in patients with plaque psoriasis. METHODS: In a randomized, placebo-controlled, double-blind study, 176 patients with moderate to severe psoriasis received placebo or CZP 400 mg at week 0 followed by placebo or CZP (200 or 400 mg) every other week until week 10. Co-primary endpoints were ≥ 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75) and a Physician's Global Assessment (PGA) of clear-almost clear at week 12. A re-treatment extension study was conducted in 71 CZP PASI 75 responders who relapsed during a 12- to 24-week observation period without treatment. RESULTS: PASI 75 was achieved by 44/59 (75%), 48/58 (83%) and 4/59 (7%) patients in the CZP 200 mg, CZP 400 mg and placebo groups, respectively (P < 0·001 for both treatment arms vs. placebo). A PGA score of clear-almost clear was achieved by 53%, 72% and 2%, respectively (P < 0·001 for both treatment arms vs. placebo). In the re-treatment study median PASI scores were similar at week 12 in the first treatment and re-treatment periods for both CZP groups. Serious adverse events occurred in 3%, 5% and 2% of CZP 200 mg, CZP 400 mg and placebo patients, respectively. CONCLUSIONS: Treatment with CZP significantly improved psoriasis at week 12. Similar efficacy was observed at week 12 in patients receiving re-treatment for loss of response after drug withdrawal.

A placebo-controlled pharmacodynamic and pharmacokinetic interaction study between tamsulosin and acenocoumarol.

AIM: To evaluate pharmacokinetic and pharmacodynamic interactions between tamsulosin and acenocoumarol. METHODS: Twelve healthy volunteers received tamsulosin 0.4 mg or placebo once daily for 9 days in a double-blind, cross-over study. On day 5 of each study period, a single 10-mg oral dose of racemic acenocoumarol was administered. RESULTS: The ratios (point estimates (90% confidence intervals)) of values in the presence and absence of tamsulosin were: AUCPT 1.01 (0.98, 1.03); maximum prothrombin time (Ptmax) 0.99 (0.94, 1.05); AUC (R)-acenocoumarol 1.02 (0.90, 1.16), and AUC (S)-acenocoumarol 1.03 (0.89, 1.20). Both combinations, tamsulosin and placebo with acenocoumarol, were well-tolerated. CONCLUSIONS: Multiple doses of tamsulosin had no effect on the pharmacokinetics or pharmacodynamics of a single high dose of acenocoumarol.

Cytogenetic effects on lymphocytes in osteoporotic patients on long-term fluoride therapy.

The genotoxicity of fluoride in vivo in seven patients with osteoporosis was cytogenetically investigated. The patients were treated with fluoride-containing formulations (disodium monofluorophosphate and sodium fluoride) for a period of 15 months up to 49 months. Fluoride intake ranged from 22.6-33.9 mg F/day and serum fluoride concentrations were between 0.1 mg F/l and 0.2 mg F/l. Peripheral blood lymphocytes of these patients were cultured in vitro and examined for chromosomal aberrations, micronuclei in cytokinesis-blocked binucleated lymphocytes as well as cell cycle progression. When a comparison was made between patients' group and a matched control group, it was found that fluoride at the tested concentrations had no detectable genotoxic potential in human.

A phase I double-blind, placebo-controlled, single rising dose study to determine the safety, tolerability, and pharmacokinetics of oral YM934 in healthy male volunteers.

In this phase I study a novel potassium channel opener (YM934) was administered to young healthy male volunteers to identify a dose with minimal cardiovascular effects. The study was carried out using a double-blind, placebo-controlled rising dose design with oral YM934 in single doses of 20 micrograms, 60 micrograms, and 180 micrograms. During each study day frequent blood samples were obtained for drug assay, measurements of cardiovascular parameters, and parasympathetic activity. The drug was well tolerated, with headache being the only significant adverse event. No relationship could be detected between dose or plasma concentration of YM934 and headache. No significant changes in routine laboratory and pharmacodynamic parameters occurred between placebo and active drug treatment. The pharmacokinetics of YM934 were characterized by a rapid oral absorption, an elimination half-life of 30 hours, and an oral clearance of 1.7 L/h. The obtained data allow estimation of a YM934 dose regimen with minimal cardiovascular (side) effects to be used for future efficacy studies.

Transdermal absorption of clindamycin and tretinoin from topically applied anti-acne formulations in man.

The percutaneous absorption of clindamycin was studied in healthy male volunteers, comparing two investigative clindamycin (% w/v)/tretinoin (0.025% w/v) gels, containing clindamycin phosphate ester and clindamycin HCl, respectively, relative to a clindamycin phosphate lotion (1% clindamycin; Dalacin T). Formulations were applied daily for 5 days on the face, according to a balanced complete block design. Redness of the skin was scored visually, and blood and urine were collected. Clindamycin plasma levels did not exceed the limit of quantification (5 ng mL(-1)) with the clindamycin phosphate formulations, but one volunteer who received the clindamycin HCl/tretinoin gel showed plasma levels of up to 13 ng mL(-1). Clindamycin urinary excretion for 12 h after application of the clindamycin phosphate/tretinoin gel was comparable to the values of the reference lotion, whereas the clindamycin HCl/tretinoin gel gave significantly higher values. Erythema appeared to be associated with increased urinary excretion. The formulations were tolerated well. In a separate clinical pilot study in acne patients, the transdermal uptake of tretinoin and clindamycin from the clindamycin phosphate/tretinoin gel was monitored. Plasma samples were collected after 4 and 12 weeks of daily treatment. None of the study plasma samples contained measurable tretinoin levels. Clindamycin levels were not quantifiable in the majority (87%) of samples, the highest plasma level was 11 ng mL(-1). The chemical form of clindamycin proved to modulate skin irritation and percutaneous uptake of clindamycin from a gel formulation in healthy subjects. There was no indications for a notable transdermal uptake of tretinoin during daily application of the gel in patients, nor for an enhancing effect of tretinoin on clindamycin uptake.

Multiple dose bioequivalence study with josamycin propionate, a drug with highly variable kinetics, in healthy volunteers.

Josamycin is a macrolide antibiotic with considerable intra- and interindividual variability in kinetics. In the present study bioequivalence of an intact and dispersed josamycin Solutab tablet, containing 1,000 mg of josamycin in the form of josamycin propionate ester, was tested versus a Josacine 1,000 mg reference sachet. The design of this bioequivalence study was adapted to the drug's pharmacokinetic variability, comprising testing in steady-state, testing the reference in replicate, and maintaining a widened bioequivalence margin. The study was performed in a group of 24 male and 12 female healthy subjects, according to a 3-treatment 4-period crossover design. Blood sampling for establishing josamycin propionate and josamycin base serum level profiles were collected during the 12 h dosing interval on day 4. Steady-state serum levels were reached on day 4. With the reference sachet mean peak levels of 1.02 micrograms/ml and 0.36 microgram/ml were observed for parent drug and metabolite, respectively, reached at peak times of 1.5 h and 1.8 h. Comparable profiles were observed with the intact and dispersed Solutab tablets, both tending towards higher serum levels than the sachet. In terms of josamycin propionate levels as well as josamycin base levels, the intact and dispersed Solutab tablet was bioequivalent with the referent sachet within the preset 0.70-1.43 margins. Variability in josamycin kinetics proved to be substantial, maximum differences in peak levels and AUC values being about 10-fold between individuals, and 3-fold within individuals. Retrospectively, the multiple dosing regimen appeared not to result in a clear reduction of intrasubject variability.

Evaluation of the effect of zinc acetate on the stratum corneum penetration kinetics of erythromycin in healthy male volunteers.

Erythromycin with or without additional zinc acetate is used topically in the treatment of acne vulgaris. A potential effect of zinc on the stratum corneum penetration of erythromycin was investigated in human volunteers. Skin surface washings and tape strippings from the skin of the back were collected after drug applications in 12 subjects for quantification of erythromycin levels. Zinc acetate increased the amount remaining on the back skin at 6 h after application from 40 +/- 19 to 56 +/- 15% of the dose and, vice versa, reduced the amount in stratum corneum strips from 22 +/- 7 to 18 +/- 7%, both with statistical significance. The effect varied with body region. Zinc acetate thus provided to prolong the residence time of erythromycin on the skin.