Safety, tolerability and pharmacokinetics of rilpivirine following administration of a long-acting formulation in healthy volunteers.

OBJECTIVES: This phase I healthy volunteer study (NCT01031589) was carried out to investigate the safety/tolerability and pharmacokinetics of a rilpivirine (RPV; TMC278) long-acting (LA) formulation after single and multiple intramuscular (i.m.) injections. METHODS: In the first part of the study, which had an open-label design, a single RPV LA i.m. injection (300 mg/mL) of 300 (n = 6) or 600 (n = 5) mg was given to the volunteers. In the second part of the study, which had a double-blind, randomized, placebo-controlled design, three RPV LA i.m. injections (one every 4 weeks) at 1200/600/600 mg (n = 6) or placebo (n = 2) were given. Safety and local tolerability were monitored. RPV plasma concentrations were analysed up to 28 days after injection or until they were < 20 ng/mL. RESULTS: Grade 1/2 RPV-related adverse events in the 300, 600 and 1200/600/600 mg groups were: rash (zero, one and one subject, respectively, the last of whom discontinued participation in the study); musculoskeletal stiffness (three, zero and zero subjects, respectively); injection site reactions (one, two and two subjects, respectively). After one injection of 300, 600 or 1200 mg RPV LA, the mean (standard deviation) maximum plasma concentration was 39 (25), 48 (13) and 140 (16) ng/mL, and the mean (standard deviation) area under the concentration-time curve (28 days) was 17,090 (8907), 25,240 (8184) and 55,350 (13,550) ng h/mL, respectively. RPV pharmacokinetics were largely comparable after the 1200 mg loading dose and both 600 mg injections of RPV LA. The mean (standard deviation) RPV plasma concentration across the 28-day dosing interval after the last injection in the 1200/600/600 mg group was 79 (19) ng/mL. CONCLUSIONS: Single and multiple i.m. injections of RPV LA demonstrated favourable local/systemic tolerability in healthy volunteers. RPV pharmacokinetics suggested that clinically relevant plasma concentrations can be achieved with this LA formulation.

Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance.

The 2-year follow-up results for a randomized placebo-controlled study of 47 patients with multidrug-resistant pulmonary tuberculosis treated with either the new diarylquinoline TMC207, recently renamed bedaquiline, or placebo, added to the first 8 weeks of a background regimen, are presented. Bedaquiline significantly reduced the time to culture conversion over 24 weeks (hazard ratio, 2.253; 95% confidence interval, 1.08 to 4.71; P = 0.031). With the exception of nausea reported in 26% of patients receiving bedaquiline and none receiving placebo, adverse events occurred at similar frequencies in both groups of patients: bilateral hearing impairment, extremity pain, acne, and noncardiac chest pain occurred in 13 and 21%, 17 and 13%, 9 and 17%, and 4 and 17% of patients, respectively, receiving bedaquiline or placebo. Excluding resistance to ethambutol and ethionamide, only one patient receiving bedaquiline acquired resistance to companion drugs, but five patients receiving placebo (4.8% versus 21.7%; P = 0.18) acquired resistance to companion drugs, and resistance to ofloxacin was acquired in four patients receiving placebo and none receiving bedaquiline (0% versus 22%; 0 = 0.066). In all, 23 patients (49%), including 13 receiving placebo (54%) and 10 receiving bedaquiline (44%), discontinued the study prior to its completion, 12 during the first 24 weeks of treatment. Eight subjects were withdrawn for noncompliance or default, and seven withdrew consent, citing the rigorous program of investigations for safety and pharmacokinetic monitoring. Bedaquiline may contribute to the management of multidrug-resistant tuberculosis by effecting more rapid sputum culture negativity and by preventing acquired resistance to companion drugs.

Levetiracetam for the treatment of idiopathic generalized epilepsy with myoclonic seizures.

BACKGROUND: Currently, there are no published randomized controlled trials evaluating the efficacy and safety of adjunctive antiepileptic therapy in idiopathic generalized epilepsy with myoclonic seizures. METHODS: This randomized, double-blind, placebo-controlled multicenter trial assessed the efficacy and tolerability of adjunctive treatment with levetiracetam 3,000 mg/day in adolescents (>or=12 years) and adults (or=8 days during a prospective 8-week baseline period, despite antiepileptic monotherapy. The 8-week baseline period was followed by 4-week up-titration, 12-week evaluation, and 6-week down-titration/conversion periods. RESULTS: Of 122 patients randomized, 120 (levetiracetam, n = 60; placebo, n = 60) were evaluable. Diagnoses were either juvenile myoclonic epilepsy (93.4%) or juvenile absence epilepsy (6.6%). A reduction of >or=50% in the number of days/week with myoclonic seizures was seen in 58.3% of patients in the levetiracetam group and in 23.3% of patients in the placebo group (p < 0.001) during the treatment period. Levetiracetam-treated patients were more likely to respond to treatment than patients receiving placebo (OR = 4.77; 95% CI, 2.12 to 10.77; p < 0.001). Levetiracetam-treated patients had higher freedom from myoclonic seizures (25.0% vs 5.0%; p = 0.004) and all seizure types (21.7% vs 1.7%; p < 0.001) during the evaluation period. The only adverse events more frequent with levetiracetam were somnolence and neck pain. CONCLUSION: These results suggest that levetiracetam is an effective and well-tolerated adjunctive treatment for patients with previously uncontrolled idiopathic generalized epilepsy with myoclonic seizures.

Intravenous nitrates for pharmacological stimulation during head-up tilt testing in patients with suspected vasovagal syncope and healthy controls.

Nitrates may be used for pharmacological stimulation during tilt testing for the diagnosis of vasovagal syncope. In this study we assessed the diagnostic value of intravenous nitrates during tilt testing in patients with a typical history of vasovagal syncope. Twenty patients and 23 controls were tilted at 700 for a maximum duration of 30 minutes. After a 10-minute baseline supine phase, the test started with a continuous nitrate infusion at 1 microg/kg/min and increased every 5 minutes by 1 microg/kg/min, to a maximum of 6 microg/kg/min at the end of the test. The test was ended if the subjects developed a positive response (syncope or presyncope). Nineteen patients (95%) and 17 (74%) of the controls had a positive response. At test end sensitivity was 95%, but specificity was 26% and accuracy was 58%. Receiver operator characteristics (ROC) analysis revealed a maximum accuracy of 79% at 18 minutes, with a sensitivity of 80% and a specificity of 78%. Intravenous nitrates during tilt testing in patients with typical clinical criteria of vasovagal syncope is highly effective in provoking vasovagal syncope. Based on the ROC analysis, a maximum accuracy of 79% was attained at 18 minutes (at a dose of 4 microg/kg/min), suggesting a good diagnostic performance when tilt duration is limited to this point. A positive result requiring more than 18 minutes of stimulated tilting should be interpreted with caution, due to the accompanying considerable decrease of specificity.

Distortion product oto-acoustic emissions as objective audiometry in a group of children with ventilation tubes.

The aim of this study was to evaluate distortion product oto-acoustic emissions (DPOAEs) as a means of objective audiometry in a population of children with ventilation tubes. We measured DPOAEs at two different stimulus levels--recorded transient evoked oto-acoustic emissions (TEOAEs) and obtained pure-tone audiometry (PTA). DPOAEs were compared with the normal range proposed by the Madsen company: the CELESTA 503 provides a 'normalized' distortion-product-gram which we compared with the pure-tone threshold of the test group. DPOAEs at 60 dBSPL were more easily obtained in the test group than TEOAEs and PTA. Correlation between 'normalized' DPOAEs and pure-tone thresholds was the strongest at 2 and 4 kHz. Surprisingly, DPOAEs at 60 dBSPL showed significant differences also at 2 and 4 kHz compared with the Madsen data. DPOAEs at 60 dBSPL might be an easy, objective test for evaluating auditory function and for determining hearing threshold at 2 and 4 kHz.

Microbiology of the middle meatus in children requiring adenotonsillectomy.

Middle meatus samples were cultured in 120 children undergoing adenotonsillectomy with, or without, insertion of ventilation tubes. Every child (except one) had positive cultures. Haemophilus influenzae (62 per cent of the children), Moraxella catarrhalis (53 per cent) and Streptococcus pneumoniae (48 per cent) were the most commonly isolated bacteria. The presence of Moraxella catarrhalis and (to a lesser extent) Streptococcus pneumoniae was higher in younger children, while Haemophilus influenzae was cultured independently of age. Culture results of these middle meatal samples, carefully taken in order to avoid any contamination, probably reflect some ongoing sinus infection in these children requiring adenotonsillectomy. The problems inherent in the interpretation of surface cultures are addressed.