Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus.

UNLABELLED: The hepatitis C virus protease inhibitor telaprevir is an inhibitor of the enzyme cytochrome P450 3A, responsible for the metabolism of both cyclosporine and tacrolimus. This Phase I, open-label, nonrandomized, single-sequence study assessed the effect of telaprevir coadministration on the pharmacokinetics of a single dose of either cyclosporine or tacrolimus in two separate panels of 10 healthy volunteers each. In Part A, cyclosporine was administered alone as a single 100-mg oral dose, followed by a minimum 8-day washout period, and subsequent coadministration of a single 10-mg oral dose of cyclosporine with either a single dose of telaprevir (750 mg) or with steady-state telaprevir (750 mg every 8 hours [q8h]). In Part B, tacrolimus was administered alone as a single 2-mg oral dose, followed by a minimum 14-day washout period, and subsequent coadministration of a single 0.5-mg dose of tacrolimus with steady-state telaprevir (750 mg q8h). Coadministration with steady-state telaprevir increased cyclosporine dose-normalized (DN) exposure (DN_AUC(0-∞)) by approximately 4.6-fold and increased tacrolimus DN_AUC(0-∞) by approximately 70-fold. Coadministration with telaprevir increased the terminal elimination half-life (t(½)) of cyclosporine from a mean (standard deviation [SD]) of 12 (1.67) hours to 42.1 (11.3) hours and t(½) of tacrolimus from a mean (SD) of 40.7 (5.85) hours to 196 (159) hours. CONCLUSION: In this study, telaprevir increased the blood concentrations of both cyclosporine and tacrolimus significantly, which could lead to serious or life-threatening adverse events. Telaprevir has not been studied in organ transplant patients; its use in these patients is not recommended because the required studies have not been completed to understand appropriate dose adjustments needed for safe coadministration of telaprevir with cyclosporine or tacrolimus, and regulatory approval has not been obtained.

Pulmonary delivery of anorectic oxyntomodulin in rats: food intake suppression, reduced body weight gain and pharmacokinetics.

BACKGROUND: Oxyntomodulin (OXM1-37) is an anorectic gut-secreting peptide with a promise to treat obesity, but its needle-free delivery has yet to be successful. RESULTS: Pulmonary delivery of OXM1-37, but not its C-terminal octapeptides, caused dose-related, transient 4-6 h food intake suppression in rats. At 0.5 mg/kg, its 30-38% food intake suppression led to 46% reduction in body weight gain by day 8. Its lung absorption was fast, elevating the systemic level rapidly, yet the bioavailability was low at 13%. In the brain, twofold neuronal c-fos activation was seen in the hypothalamus arcuate nucleus and brainstem area postrema. CONCLUSION: Pulmonary delivery is a promising needle-free systemic delivery option for OXM1-37 to treat obesity, as enabling effective lung absorption and brain interaction.

Short-term cigarette smoke exposure potentiates endotoxin-induced pulmonary inflammation.

Long-term cigarette smoke exposure is associated with chronic obstructive pulmonary disease. However, the effects of short-term smoke inhalation are less clear, because it may adversely affect the lung only if underlying disease is present. To test this hypothesis, Syrian hamsters were passively exposed to cigarette smoke for 2 hours per day over a period of 3 days either before or after intratracheal instillation of low-dose (20 microg) Escherichia coli endotoxin. The results indicate that short-term smoke exposure can potentiate endotoxin-induced lung inflammation. They also suggest that nonsmokers with underlying lung disease may be particularly vulnerable to the adverse effects of second-hand smoke.

Hyaluronan: the Jekyll and Hyde molecule.

Hyaluronan (HA) is a variable length, long-chain polysaccharide containing repeating disaccharide units of glucuronic acid and n-acetylglucosamine. Long considered a relatively inert component of the extracellular matrix, HA is now coming under scrutiny as a potential therapeutic agent for a number of different diseases, based on its recently discovered role in modulating inflammation. The effect of HA on the inflammatory response appears to be related to its molecular size, with larger polysaccharide chains having anti-inflammatory activity and smaller ones having proinflammatory properties. This dichotomous behavior presents a challenge to investigators seeking to harness the beneficial effects of this molecule. Rapid breakdown of therapeutically administered HA into smaller fragments may conceivably cause further injury to diseased tissues. With this limitation in mind, the authors discuss their own use of HA to treat experimentally induced lung disease, then suggest possible ways of maximizing the therapeutic potential of this molecule.

Dichotomous effect of aerosolized hyaluronan in a hamster model of endotoxin-induced lung injury.

Inhalation of aerosolized low-molecular-weight (150-kDa) hyaluronan (HA) was previously shown by this laboratory to prevent experimentally induced pulmonary emphysema without associated toxicity. Nevertheless, other investigators have found that low-molecular-weight HA may be proinflammatory, prompting the authors to determine if aerosolized HA could possibly enhance pulmonary inflammation in a different model of lung injury involving intratracheal instillation of endotoxin to hamsters. Results indicate that exposure to HA following endotoxin administration significantly increased lung inflammation, whereas pretreatment with HA had the opposite effect.