Effect of Lamivudine on the plasma and intracellular pharmacokinetics of apricitabine, a novel nucleoside reverse transcriptase inhibitor, in healthy volunteers.

Apricitabine is a novel deoxycytidine analog reverse transcriptase inhibitor. In vitro apricitabine competes with other deoxycytidine analogues for intracellular phosphorylation mediated by deoxycytidine kinase. The topic of this study, the effect of concomitant administration of apricitabine and lamivudine on the plasma and intracellular pharmacokinetics of the two compounds, was investigated in healthy volunteers. Participants (n = 21; age, 18 to 30 years) received apricitabine at 600 mg twice daily, lamivudine at 300 mg once daily, and the two treatments in combination for 4 days each in random order. Plasma, urine, and intracellular pharmacokinetics were assessed on day 4 of each treatment period. Apricitabine was rapidly absorbed after oral administration, with peak concentrations being attained after a mean of 1.76 h. Coadministration with lamivudine had no significant effect on the plasma and urine pharmacokinetics of apricitabine. However, the formation of apricitabine triphosphate in peripheral blood mononuclear cells was markedly reduced after the coadministration of apricitabine and lamivudine than after the administration of apricitabine alone: the area under the concentration-time curve from 0 to 12 h for apricitabine triphosphate during combination treatment was ca. 15% of that seen after the administration of apricitabine alone. In contrast, apricitabine had no effect on the plasma pharmacokinetics of lamivudine or on the formation of lamivudine triphosphate in peripheral blood mononuclear cells. These results are consistent with in vitro findings that lamivudine inhibits the intracellular phosphorylation of apricitabine. In conjunction with similar in vitro observations for emtricitabine and apricitabine, these results suggest that apricitabine should not be coadministered with other deoxycytidine analogues for the treatment of human immunodeficiency virus infection.

A double-blind, placebo-controlled study of remacemide hydrochloride in patients with refractory epilepsy following pre-surgical assessment.

This multicentre, randomised, double-blind, placebo-controlled, parallel-group study investigated the efficacy, safety and pharmacokinetics of remacemide hydrochloride in adult patients ( n= 59) with refractory epilepsy, undergoing reduced or discontinued antiepileptic drug (AED) usage, as part of an evaluation for epilepsy surgery. On discontinuation or reduction of maintenance AEDs, patients received remacemide hydrochloride, up to 600 mg daily, or placebo, for up to ten days or until they experienced a fourth complex partial (CPS) or a generalised tonic-clonic (GTC) seizure. Pre- and post-study blood and urine samples were taken for analysis. Remacemide hydrochloride showed a significantly ( P= 0.045) longer median time to fourth seizure compared with placebo (6.8 vs. 3.8 days). Median nine-day seizure counts were significantly ( P= 0.0327) lower with remacemide hydrochloride than placebo (6.2 vs. 12.8). Eleven remacemide hydrochloride patients and six placebo patients completed ten days' treatment. Remacemide and desglycinyl metabolite levels were lower in patients receiving concomitant carbamazepine or phenytoin than in those receiving non-inducing AEDs or remacemide hydrochloride alone. No serious adverse events occurred; all patients receiving remacemide hydrochloride completed the study. Remacemide hydrochloride was well tolerated and showed significant therapeutic activity in this patient population.

Remacemide hydrochloride as an add-on therapy in epilepsy: a randomized, placebo-controlled trial of three dose levels (300, 600 and 800 mg/day) in a B.I.D. regimen.

Remacemide hydrochloride is a low-affinity, non-competitive NMDA receptor channel blocker under investigation for the treatment of epilepsy. This double-blind, placebo-controlled, multicentre study assessed the safety and efficacy of adjunctive remacemide hydrochloride or placebo, in adult patients with refractory epilepsy who were already taking up to three antiepileptic drugs (including an enzyme-inducer). Patients (n= 262) were randomized to one of three doses of remacemide hydrochloride (300, 600 or 800 mg/day) or placebo, in a B.I.D. regimen, for up to 14 weeks. Plasma concentrations of carbamazepine (CBZ) and phenytoin (PHT) were controlled throughout. Patients recorded their seizures on a diary card. There was an increase in the percentage of responders (defined as a reduction in seizure frequency from baseline > or = 50 %), from 15 % (9/60) with placebo, to 30 % (18/60) in the 800 mg/day group. A pairwise comparison between remacemide hydrochloride 800 mg/day and placebo was statistically significant (P = 0.049). Most reported adverse events (mainly CNS and gastrointestinal) were mild or moderate in severity and dose-dependent. Adjunctive remacemide hydrochloride treatment was associated with a higher, dose-related responder rate compared with placebo. The difference reached significance at the highest dose tested (800 mg/day). Remacemide hydrochloride was well tolerated.

Remacemide hydrochloride as an add-on therapy in epilepsy: a randomized, placebo-controlled trial of three dose levels (300, 600 and 1200 mg/day) in a Q.I.D. regimen.

Remacemide hydrochloride is a low-affinity, non-competitive N-methyl-D-aspartic acid (NMDA) receptor channel blocker, under investigation in epilepsy. This double-blind, placebo-controlled, multicentre study assessed the safety and efficacy of remacemide hydrochloride or placebo, as adjunctive therapy, in 252 adult patients with refractory epilepsy who were already taking up to three antiepileptic drugs (including an enzyme-inducer). Patients were randomized to one of three doses of remacemide hydrochloride (300, 600 or 1200 mg /day) or placebo Q.I.D., for up to 15 weeks. An increasing percentage of responders (defined as a reduction in seizure frequency from baseline of > or =50%) was seen with increasing remacemide hydrochloride dose. At 1200 mg /day, 23% of patients were responders compared with 7% on placebo. This difference was significant (P = 0.016), as was the overall difference between treatments (P = 0.038). Adverse events: dizziness, abnormal gait, gastrointestinal disturbance, somnolence, diplopia and fatigue were mild or moderate in severity. Carbamazepine and phenytoin plasma concentrations were well controlled and maintained within target ranges, with no evidence of improved seizure control due to increases in the concentrations of these drugs. A dose-dependent, significant, increase in responders following adjunctive remacemide hydrochloride compared with placebo was observed. Remacemide hydrochloride was well tolerated.

A randomized, double-blind, placebo-controlled, ascending-dose tolerability and safety study of remacemide as adjuvant therapy in Parkinson's disease with response fluctuations.

The objective of this study was to establish the maximum tolerated dose of the low affinity non-competitive N-methyl-D-aspartate receptor antagonist remacemide in patients who have Parkinson's disease with response fluctuations or dyskinesias, or both. A total of 33 patients were randomly assigned in a 3-to-1 ratio to receive remacemide or placebo. Remacemide was administered orally at 150 mg twice daily, increasing incrementally by 100 mg (50 mg twice daily) at 2-week intervals to a final daily regimen of 400 mg twice daily or until a maximum tolerated dose was identified. The maximum total treatment period was 12 weeks. Of the 23 patients randomly selected to receive remacemide, four completed the study at the maximum permitted dose, compared with four of the 10 patients given placebo. The median maximum tolerated dose of remacemide was 450 mg/d. There was no clinically relevant change in percentage of "on" time between baseline and maximum tolerated dose in either group. At the maximum tolerated dose of remacemide for each patient, the mean Unified Parkinson's Disease Rating Scale (UPDRS) motor examination score (part III) decreased from 33 (SD = 18) to 26 (SD = 13) compared with a decrease from 28 (SD = 12) to 27 (SD = 8) in the placebo group. There was a decrease in the mean UPDRS "complications of therapy" score (part IV) in the remacemide group from 8 (SD = 4) to 6 (SD = 4), and the placebo group remained unchanged at 6 (SD = 4). The most common adverse events associated with remacemide were nausea, vomiting, dizziness, headache, abnormal vision, and hypokinesia. Remacemide was well tolerated at a dose level of 400 mg/d. There was a trend suggesting that remacemide was effective in improving symptoms at patients' individual maximum tolerated doses. These improvements occurred without exacerbating levodopa-induced dyskinesias.

Pharmacokinetics and tolerability of single oral doses of 882C87, a potent, new anti-varicella-zoster virus agent, in healthy volunteers.

882C87 is a nucleoside analog with potent, specific activity against varicella-zoster virus. It is approximately seven times as potent as acyclovir with an in vitro 50% inhibitory concentration of 1 to 2 microM. The tolerability and pharmacokinetics of single doses of 882C87 have been investigated in a series of studies with healthy young and elderly adult volunteers. The young received 50 to 1,600 mg, and the elderly received 50 and 100 mg. Concentrations of 882C87 and its main metabolite, the pyrimidine base 5-(1-propynyl)uracil (5PU), in plasma and urine were assayed by an automated sequential trace enrichment of dialysate-high-performance liquid chromatography procedure, and noncompartmental pharmacokinetic parameters were derived from the data. Concentrations of 882C87 in plasma increased proportionally for doses of up to 400 mg, but after higher doses the increase was less than dose proportional. In young adults, after 200, 400, and 1,600 mg, the maximum concentrations of the drug in plasma were 9.0, 16.3, and 34.7 microM, respectively, and the areas under the concentration-time curve (AUC) from 0 h to infinity were 166.6, 333.7, and 822.9 microM.h, respectively. Elimination half-life was 11.3 to 13.0 h after 50 to 400 mg, increasing to 15.3 h after 1,600 mg, associated with a small decrease in renal clearance. In healthy elderly volunteers concentrations of 882C87 in plasma after 50 and 100 mg were similar to those in young adults after twice the dose; apparent clearance and renal clearance were significantly reduced, and half-life was significantly longer at 15 h. Administration of 882C87 with food produced a small, nonsignificant reduction in mean AUC from 0 h to infinity, but in subjects with a low fasting AUC there was an increase after food and in subjects with a high fasting AUC there was a decrease. Concentrations of 5PU in plasma were one-third to one-half those of 882C87 and, in most subjects, were not dose proportional. There was a lag of at least 5 h after dosing with 882C87 before 5PU was detectable in plasma.

Examination of some factors responsible for a food-induced increase in absorption of atovaquone.

1. Atovaquone is a potent antiprotozoal slowly and irregularly absorbed after administration as tablets to fasting volunteers. A series of studies was performed to investigate the effects of food, bile and formulation on atovaquone absorption. 2. In 18 healthy male volunteers, a high-fat breakfast administered 45 min before 500 mg atovaquone as tablets increased AUC by 3.3-fold (95% CI 2.8-4.0) and Cmax 5.3-fold (4.3-6.6) compared with fasting. 3. The absorption of atovaquone from tablets was examined in 12 healthy male volunteers after an overnight fast, following toast alone, toast with 28 g butter (LOFAT), or toast with 56 g butter (HIFAT). Compared with absorption when fasted, toast had no significant effect but LOFAT increased AUC 3.0-fold (2.1-4.2) and Cmax 3.9-fold (2.6-5.8). HIFAT increased AUC 3.9-fold (2.7-5.5) and Cmax 5.6-fold (3.8-8.4). 4. The absorption of atovaquone was examined in nine healthy fasting male volunteers from tablets, an aqueous suspension, and an oily solution/suspension in miglyol (fractionated coconut oil). Compared with tablets, AUC following the aqueous suspension was increased 1.7-fold (1.0-2.7) and Cmax 2.4-fold (1.7-3.5). Following miglyol, AUC was increased to the same extent but Cmax was only increased 1.8-fold (1.2-2.6). 5. Atovaquone absorption was examined in eight healthy fasting male volunteers following an i.v. infusion of cholecystokinin octapeptide (CCK-OP) which decreased gallbladder volume by 82% (73%-90%) on occasion 1 or saline on occasion 2. AUC(0,12) was increased following CCK-OP by 1.6-fold (1.1-2.4) and Cmax by 1.5-fold (0.98-2.4).(ABSTRACT TRUNCATED AT 250 WORDS)

566C80: a potent broad spectrum anti-infective agent with activity against malaria and opportunistic infections in AIDS patients.

566C80 is a novel hydroxynaphthoquinone with broad-spectrum anti-parasitic properties. In vitro the compound was more potent against Plasmodium falciparum than any of the established anti-malarial drugs. It had good activity against the pathogen in Aotus monkeys and was also effective in rodents infected with various drug-resistant strains of P. yoelii and P. berghei. In mice the compound showed significant activity against Toxoplasma gondii. Evaluation of the metabolic stability of 566C80 to NADPH-mediated oxidative metabolism was made using microsome preparations from a number of species including man. Unlike other quinones examined, 566C80 was shown to be inert in these assays. In Phase 1 clinical studies up to 750mg of compound were given as a single oral dose to fasted healthy male adults. This was well tolerated and the plasma drug elimination half-life was approximately 70h. In these subjects a 450mg dose gave plasma concentrations of 0.1-0.3 micrograms/ml which were achieved 1 h post-dosing and remained so for at least 7 days. Volunteers ingesting food prior to drug administration had quinone plasma levels which were significantly higher. Phase II trials are now underway to assess 566C80 for use against malaria and opportunistic infections in AIDS patients.

Transcutaneous oxygen tension during exercise in patients with claudication.

Transcutaneous oxygen tension (TcPO2) was monitored during maximal exercise in 10 patients with stable moderate to severe claudication. The TcPO2 fell by 16% at the onset of claudication and 32% at the maximum walking distance. On resting this decrease reached a maximum of 66% roughly four minutes after exercise. This was followed by a steady recovery. The percentage changes were reproducible in each patient and were appreciably different from the TcPO2 exercise profiles of normal healthy volunteers. TcPO2 monitoring during exercise is a simple, reproducible, cheap, and useful technique for assessing claudication and compares favourably with other techniques used to quantify this condition.