Parkinson's disease results from the progressive degeneration of dopamine neurons that innervate the striatum. In rodents, glial-cell-line-derived neurotrophic factor (GDNF) stimulates an increase in midbrain dopamine levels, protects dopamine neurons from some neurotoxins, and maintains injured dopamine neurons. Here we extend the rodent studies to an animal closer to the human in brain organization and function, by evaluating the effects of GDNF injected intracerebrally in rhesus monkeys that have had the symptomatology and pathophysiological features of Parkinson's disease induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The recipients of GDNF displayed significant improvements in three of the cardinal symptoms of parkinsonism: bradykinesia, rigidity and postural instability. GDNF administered every four weeks maintained functional recovery. On the lesioned side of GDNF-treated animals, dopamine levels in the midbrain and globus pallidus were twice as high, and nigral dopamine neurons were, on average, 20% larger, with an increased fibre density. The results indicate that GDNF may be of benefit in the treatment of Parkinson's disease.

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AIMSTwo studies were conducted to: (i) quantify the amount of drug-related radioactivity in blood, plasma, urine and faeces following a 14 C-labelled dose of maraviroc; and (ii) investigate the pharmacokinetics, safety and tolerability of intravenous (i.v.) maraviroc and determine the absolute bioavailability of oral maraviroc. Metabolite profiling was also conducted. Data from both of these studies were used to construct a mass-balance model for maraviroc. METHODSStudy 1 was an open-label study in three healthy male subjects. All subjects received a single 300-mg oral solution dose of 14 C-labelled maraviroc. Study 2 included two cohorts of subjects. Cohort 1 involved a double-blind (third party open), four-way crossover study where eight subjects received escalating i.v. doses of maraviroc (3, 10 and 30 mg) with placebo insertion. Cohort 2 involved an open, two-way crossover study where 12 subjects received 30 mg maraviroc by i.v. infusion and 100 mg maraviroc orally in random order. In study 1, blood samples and all urine and faeces were collected up to at least 120 h postdose. In study 2, blood samples were taken at intervals up to 48 h postdose. Urine was also collected up to 24 h postdose in cohort 1 only. RESULTSAfter oral administration in study 1, maraviroc was rapidly absorbed with a plasma Tmax reached by 2 h postdose for all three subjects. The maximum concentrations of radioactivity also occurred within 2 h for all subjects. There was a higher amount of radioactivity in plasma than in blood (blood/plasma ratio~0.6 for AUCt and Cmax). Unchanged maraviroc was the major circulating component in plasma, accounting for~42% of the circulating radioactivity. Following a 300-mg 14 C-labelled maraviroc dose, means of 76.4% and 19.6% of radioactivity were recovered in the faeces and urine, respectively. The mean total recovery of dosed radioactivity was 96%, with the majority of radioactivity being recovered within 96 h postdose. Profiling of the urine and faeces showed similar and extensive metabolism in all subjects. Unchanged maraviroc was the major excreted component (33%). The major metabolic pathways were determined and involved oxidation and N-dealkylation. Intravenous doses of maraviroc (3-30 mg) were well tolerated in study 2, and drug exposure was approximately proportional to dose within the studied range. Approximately 23% of total clearance (44 l h ). Mean volume of distribution at steady state was 194 l. Absolute bioavailability of a 100-mg oral tablet dose, by comparison with a 30-mg i.v. dose, was calculated to be 23.1%. CONCLUSIONSMaraviroc is rapidly absorbed and extensively metabolized, although unchanged maraviroc is the major circulating component in plasma and is the major excreted component after oral dosing. The pharmacokinetics of maraviroc after i.v. administration is approximately proportional over the dose range studied. Renal clearance contributes 23% of total clearance. The absolute bioavailability of 100 mg oral maraviroc is 23%.

AIMSTo evaluate the influence of cytochrome P450 (CYP) 3A4 inhibitors on the clinical pharmacokinetics of maraviroc, a novel CCR5 antagonist. METHODSFour open-label, randomized, placebo-controlled studies were conducted in healthy subjects to assess the effect of separate and distinct combinations of CYP3A4 inhibitors on the steady-state pharmacokinetics of maraviroc. Study 1 was a two-way crossover study investigating the influence of saquinavir (SQV; 1200 mg t.i.d.) and ketoconazole (400 mg q.d.) on the pharmacokinetics of maraviroc (100 mg b.i.d.). All subjects received maraviroc for 7 days in both study periods. Cohort 1 subjects also received SQV or placebo and cohort 2 subjects also received ketoconazole or placebo. Study 2 was a parallel-group study including four treatment groups investigating the effects of ritonavir-boosted lopinavir (LPV/r; 400 mg/100 mg b.i.d.), ritonavir-boosted saquinavir (SQV/r; 1000 mg/100 mg b.i.d.), and low-dose ritonavir (RTV; 100 mg b.i.d.) on the steady-state pharmacokinetics of maraviroc (100 mg b.i.d.), and exploring whether maraviroc dose adjustment can compensate for interaction effects. Treatment lasted 28 days and comprised three distinct phases: (i) maraviroc alone on days 1-7; (ii) maraviroc + interactant on days 8-21; and (iii) maraviroc (adjusted dose) + interactant on days 22-28. Study 3 was a two-way crossover study investigating the effects of atazanavir (ATZ; 400 mg q.d.) and ritonavir-boosted atazanavir (ATZ/r; 300 mg/100 mg b.i.d.) on the pharmacokinetics of maraviroc (300 mg b.i.d.). All subjects received maraviroc on days 1-14 of both study periods. Subjects also received ATZ on days 1-7 and ATZ/r on days 8-14 of one treatment period, and placebo on days 1-14 of the other treatment period. Study 4 was a two-way crossover study investigating the effects of ritonavir-boosted tipranavir (TPV/r; 500 mg/200 mg b.i.d.) on the pharmacokinetics of maraviroc (150 mg b.i.d.). Subjects received maraviroc plus TPV/r or placebo on days 1-8. RESULTSAll of the drugs/drug combinations tested (except for TPV/r) increased maraviroc exposure, albeit to different degrees of magnitude. SQV/r caused the largest increase in maraviroc exposure (8.3-fold increase in AUCt), whereas RTV caused the smallest increase in maraviroc exposure (2.6-fold increase in AUCt). Downward adjustment of the maraviroc dose in study 2 during co-administration of HIV protease inhibitors was able to compensate for the interactions. TPV/r had no clinically relevant effect on maraviroc exposure at steady state. There were no treatment-related serious adverse events or discontinuations due to adverse events in any of the studies, and most adverse events were mild or moderate in severity and resolved without intervention. CONCLUSIONSPotent CYP3A4 inhibitors, including ketoconazole and protease inhibitors (except TPV/r), increase maraviroc exposure. Downward adjustment of the maraviroc dose during co-administration with protease inhibitors can compensate for the interaction. TPV/r does not affect the steady-...

Net ion transport by jejunum of rats immunized against Trichinella spiralis on challenge with parasite-derived antigen was measured in Ussing chambers as a rapidly expressed, biphasic rise and fall (phase I and II) in short-circuit current (delta Isc). This delta Isc is triggered by mucosal anaphylaxis. Our objective is to identify mast cell-derived substances that mediate the epithelial response. Antigenic challenge of sensitized jejunum caused the release of 5-hydroxytryptamine (5-HT), histamine, and prostaglandin E2 (PGE2). The antigen-induced phase I response was mimicked by exogenous 5-HT or histamine and blocked by pretreatment of tissue with 5-HT and histamine H1-antagonists; the phase II response was mimicked by exogenous PGE2 and blocked by an inhibitor of prostaglandin synthesis. Atropine and tetrodotoxin significantly blunted the phase I response as well as the delta Isc caused by exogenous 5-HT or histamine while only slightly reducing the phase II response and not affecting the delta Isc induced by PGE2. Results support the conclusion that 5-HT, histamine, and PGE2 mediate the antigen-induced change in Isc through direct and neurally mediated stimulation of jejunal epithelium.