Comparison of the steady-state pharmacokinetics, metabolism, and variability of a transdermal testosterone patch versus a transdermal testosterone gel in hypogonadal men.

AIM: To compare the pharmacokinetics (PK), metabolism, intra- and inter-subject variability of a permeation-enhanced testosterone patch versus a topical testosterone gel. METHODS: 28 hypogonadal men were treated with a testosterone patch (5 mg/day applied at 2200 h) and a 1% testosterone gel (5 g/day applied at 0800 h; nominal delivery 5 mg/day), each for 14 days, in an open-label crossover design. PK profiles of total testosterone (TT) and calculated free testosterone (cFT) were measured on day 7 and day 14 of each treatment, with patches or gel applied to the abdomen; dihydrotestosterone (DHT) and estradiol (E2) profiles were measured on day 14. The time-average (Cavg), maximum (Cmax), time of maximum (Tmax) and minimum concentrations (Cmin) were derived from each profile. The intra- and inter-subject coefficients of variation (CVintra and CVinter) of the TT and cFT parameters were computed by ANOVA. RESULTS: Nightly applications of the patch produced a mean TT profile that mimicked the circadian pattern of healthy men. Morning applications of the gel produced a flatter mean profile; though individual subjects exhibited significant peaks at variable times. For TT, the mean and 90% confidence intervals of the patch/gel ratio of Cavg (1.030; 0.936-1.133; P > 0.05) and Cmax (1.086; 0.974-1.211; P > 0.05) met the criteria for bioequivalence. Cmin was lower for the patch. DHT levels and DHT/T ratios were 2 to 3-fold higher for the gel (P < 0.0001). E2 levels and E2/T ratios were comparable. CVintra and CVinter for Tmax approached 100% for the gel and were 23% and 42%, respectively, for the patch (P < 0.0001). Other variability parameters were generally comparable. Both products were well tolerated, and the patches adhered well. CONCLUSIONS: These findings reflect the different mechanisms of transdermal absorption from the patch and gel and provide new considerations for selecting testosterone replacement therapies in hypogonadal men.

Transfer of transdermally applied testosterone to clothing: a comparison of a testosterone patch versus a testosterone gel.

AIM: To assess the amount of testosterone transferred from the abdominal application sites of a transdermal testosterone patch and a transdermal testosterone gel to cotton T-shirts worn for 24 hours during each treatment. METHODS: During a crossover study comparing the pharmacokinetics of a testosterone patch versus a testosterone gel in 28 hypogonadal men, subjects wore fresh cotton T-shirts for 24 hours on the seventh and fourteenth days of each treatment and during a 24-hour baseline period. At the end of each evaluation, the abdominal section of the shirt was carefully cut out, extracted in alcohol, and analyzed for testosterone by a direct radioimmunoassay. The minimum quantifiable amount of testosterone was 0.03 microg per T-shirt sample. RESULTS: The median amounts of extracted testosterone were 0.44 microg for the baseline samples, 25.4 microg for the average of the two patch samples, and 6,762.7 microg for the average of the two gel samples (all comparisons P < 0.0001). Significant correlations were observed between the day 7 and day 14 data for both the patch (R = 0.4982; P < 0.01) and the gel (R = 0.8383; P < 0.0001). No significant correlations were found between the baseline, patch, or gel data, or between these and any demographic or pharmacokinetic parameters. A quantitative interpretation of the findings suggests that the baseline results are consistent with the transfer of testosterone in sweat; the patch results are probably due to the transfer of a small amount of residual testosterone left on the abdominal skin from the prior day's patches; and the gel results reflect the desquamation of stratum corneum containing a portion of the abdominally applied testosterone. CONCLUSIONS: There are large differences in the amount of testosterone that can be transferred from the application sites of transdermal patches and gels. The latter should be covered with clothing to minimize transfer through intimate skin-to-skin contact.

Ammonium-induced impairment of axonal growth is prevented through glial creatine.

Hyperammonemia in neonates and infants affects brain development and causes mental retardation. We report that ammonium impaired cholinergic axonal growth and altered localization and phosphorylation of intermediate neurofilament protein in rat reaggregated brain cell primary cultures. This effect was restricted to the phase of early maturation but did not occur after synaptogenesis. Exposure to NH4Cl decreased intracellular creatine, phosphocreatine, and ADP. We demonstrate that creatine cotreatment protected axons from ammonium toxic effects, although this did not restore high-energy phosphates. The protection by creatine was glial cell-dependent. Our findings suggest that the means to efficiently sustain CNS creatine concentration in hyperammonemic neonates and infants should be assessed to prevent impairment of axonogenesis and irreversible brain damage.