To increase access to long-acting contraception, we developed a reversible contraceptive microneedle patch that is simple-to-administer, slowly releases contraceptive hormone (levonorgestrel) for >1 month, and generates no biohazardous sharps waste. After manually pressing the patch to skin for 1 min, microneedles rapidly separate from the patch within the skin due to effervescence triggered by contact with skin’s interstitial fluid, as demonstrated in rats and human participants. Long-acting contraception is achieved by formulating microneedles with a biodegradable polymer [poly(lactic-co-glycolic) acid] that slowly releases levonorgestrel for ~1 month in vitro. In rats, the patch maintained levonorgestrel concentration above the human contraceptive threshold level for >1 month, and a placebo microneedle patch was well-tolerated in human participants. Women of reproductive age in three continents demonstrated interest in and preference for long-acting contraception by microneedle patch. These studies indicate that an effervescent microneedle patch could facilitate greater access to long-acting contraception.

García-Silva et al. show for the first time that extracellular vesicles isolated from the exudative seroma obtained from the lymphatic drainage implanted in melanoma patients after lymphadenectomy can be interrogated for melanoma markers and BRAF mutations. Profiling the BRAFV600E mutation in this biofluid is a novel approach to predict disease relapse.

To reduce possible nephrotoxicity, intravenous prehydration with normal saline and administration of probenecid must be used with each infusing of the antiviral cidofovir. The recommended standard-dose probenecid (SDP) regimen is 2 g at 3 hours before cidofovir, then 1 g at 2 and 8 hours after cidofovir (total 4 g). A new regimen of reduced-dose probenecid (RDP), 2 g at 1 hour before cidofovir without additional probenecid administrations after infusion (total 2 g), was compared with SDP using a randomized, open-label, parallel design. A single dose of cidofovir (5 mg/kg) was given as a 1-hour infusion after saline prehydration to 24 HIV-infected patients (11 males, 13 females) with cytomegalovirus retinitis and good renal function. Blood was sampled for 48 hours and urine for 24 hours after the start of the cidofovir infusion. Cidofovir pharmacokinetics did not differ significantly between groups. Average key pharmacokinetic parameters (Cmax, tmax, lambda z, AUC0-infinity, Vss, CL, CLR, fe, ER) for RDP differed by less than 17% from SDP and were consistent with previously reported SDP data. Renal function parameters, other safety endpoints, and adverse events were similar between the groups. Therefore, the reduced-dose regimen of probenecid provided renal protection after a single dose of cidofovir and did not alter the pharmacokinetics of cidofovir in patients with moderately good renal function. Although the overall pharmacokinetic results do not show a significant difference in cidofovir exposure with the new probenecid regimen, the main issue of safety of the new dose regimen, both relating to renal toxicity and probenecid-related adverse events, is not adequately addressed in a small study.

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The safety, tolerability, and pharmacokinetics of PNU-96391, an orally active weak dopamine D2 receptor antagonist with modulatory properties of central dopaminergic function, was characterized. Fifty-three healthy normal volunteers were enrolled in this randomized, double-blinded, placebo-controlled, single-dose study. Subjects were assigned to single oral doses of placebo and 1, 3, 10, 30, 100, 150, and 200 mg PNU-96391. Safety and tolerability were assessed using telemetry, Holter monitoring, surface ECG, vital signs, safety laboratories, and adverse event reports. Pharmacokinetic parameters were determined by model-independent techniques. Adverse events were infrequent, of mild to moderate intensity, and in the dose range of 1 to 150 mg. Dose escalation was stopped at 200 mg because of severe nausea, dizziness, lightheadedness, and tachycardia. Besides the increase in heart rate, no other drug-related effects on vital signs were observed. Safety laboratory measurements were not significantly changed. Evidence of drug activity was demonstrated by a dose-dependent elevation in serum prolactin. PNU-96391 was rapidly absorbed, with maximum concentrations achieved between 0.5 and 4 hours in all subjects. The half-life of the drug was short (2 to 6 h). The main metabolite, PNU-100014, was rapidly formed, with a t(max) ranging from 1 to 6 hours. Peak levels of the metabolite are approximately half of the parent drug, and the half-life is slightly longer (4 to 10 h). Increases in dose resulted in linear increases in exposure for both PNU-96391 and PNU-100014. Hence, PNU-96391 was well tolerated at doses ranging from 1 to 150 mg.

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