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Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) strategies with proven in vivo efficacy rely on antiretroviral drugs, creating the potential for drug resistance and complicated treatment options in individuals who become infected. Moreover, on-demand products are currently missing from the PrEP development portfolio. Griffithsin (GRFT) is a non-antiretroviral HIV entry inhibitor derived from red algae with an excellent safety profile and potent activity in vitro. When combined with carrageenan (CG), GRFT has strong activity against herpes simplex virus-2 (HSV-2) and human papillomavirus (HPV) in vitro and in vivo. Here, we report that GRFT/CG in a freeze-dried fast dissolving insert (FDI) formulation for on-demand use protects rhesus macaques from a high dose vaginal SHIV SF162P3 challenge 4 h after FDI insertion. Furthermore, the GRFT/CG FDI also protects mice vaginally against HSV-2 and HPV pseudovirus. As a safe, potent, broad-spectrum, on-demand non-antiretroviral product, the GRFT/CG FDI warrants clinical development.

We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo. We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbit and rhesus macaque models., We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo. We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbit and rhesus macaque models. A dose-ranging study in rabbits demonstrated dose-dependent pharmacokinetics and local inflammation up to severe necrosis around the active implants. The matched placebos showed normal wound healing and fibrous tissue encapsulation of the implant. We designed a second implant with a lower release rate and flux of TAF and achieved a median cellular level of tenofovir diphosphate of 42 fmol per 106 rhesus macaque peripheral blood mononuclear cells at a TAF dose of 10 μg/kg/day. This dose and flux of TAF also resulted in adverse local inflammation and necrosis near the implant in rhesus macaques. The level of inflammation in the primates was markedly lower in the placebo group than in the active-implant group. The histological inflammatory response to the TAF implant at 4 and 12 weeks in primates was graded as a severe reaction. Thus, while we were able to achieve a sustained target dose, we observed an unacceptable inflammatory response locally at the implant tissue interface.

The development of topical inserts for the prevention of sexually transmitted infections (STIs), particularly human immunodeficiency virus (HIV), represents a promising alternative to oral and parenteral pre-exposure prophylaxis (PrEP) dosage forms. They may be used for vaginal and/or rectal administration of a variety of agents with antiviral activity. Topical inserts deliver drugs to the portal of viral entry, i.e., the genital or rectal mucosa, with low systemic exposure, and therefore are safer and have fewer side effects than systemic PrEP agents. They may dissolve fast, releasing the active drugs within minutes of insertion, or slowly for long-acting drug delivery. Furthermore, they are user-friendly being easy to administer, discreet and highly portable. They are also economical and easy to manufacture at scale and to distribute, with excellent stability and shelf-life. Altogether, topical inserts represent a particularly promising form of drug delivery for HIV and STI prevention. Highlighted within this review are end-user acceptability research dedicated to understanding preferred attributes for this form of drug delivery, advantages and disadvantages of the formulation platform options, considerations for their development, clinical assessment of select placebo prototypes, future directions, and the potential impact of this dosage form on the HIV prevention landscape.

Nimodipine is the only drug approved for use by the Food and Drug Administration for improving outcome after aneurysmal subarachnoid hemorrhage (SAH). It has less than optimal efficacy, causes dose-limiting hypotension in a substantial proportion of patients, and is administered enterally 6 times daily. We describe development of site-specific, sustained-release nimodipine microparticles that can be delivered once directly into the subarachnoid space or cerebral ventricles for potential improvement in outcome of patients with aneurysmal SAH. Eight injectable microparticle formulations of nimodipine in poly(DL-lactide-co-glycolide) (PLGA) polymers of varying composition were tested in vitro, and 1 was advanced into preclinical studies and clinical application. Intracisternal or intraventricular injection of nimodipine–PLGA microparticles in rats and beagles demonstrated dose-dependent, sustained concentrations of nimodipine in plasma and cerebrospinal fluid for up to 29 days with minimal toxicity in the brain or systemic tissues at doses

Tenofovir alafenamide (TAF) is a potent prodrug of tenofovir (TFV) for HIV prophylaxis, and HIV and HBV treatment. Compared to oral daily doses, transdermal administration of TAF may be more advantageous for long-term adherence by offering sustained drug delivery and reduced dosing frequency. Here, we described the plasma pharmacokinetics (PK) of an optimized once-weekly suspension transdermal delivery system (TDS) for TAF (96 mg/25 cm2 of TDS) in female hairless rats. Over the study period, the TAF TDS delivered an overall low level of TAF (median: 1.43 [0.02-3.28] ng/mL) and a sustained level of the stable metabolite and parent drug, TFV. Relative to the projected exposure corresponding to six-day oral daily doses, a comparable TAF exposure but a substantially lower TFV exposure was resulted from the TAF TDS, suggesting a lower risk of TFV-associated adverse effects. TAF, TFV, and phosphorylated TFVs (TFV-monophosphate and diphosphate) were found distributed in vaginal tissue, the portal of entry for HIV during male-to-female sexual transmission. Skin adhesion and tolerance were acceptable given the animal model used. PK evaluation of the TAF TDS in hairless rats demonstrates the proof of concept that transdermal delivery can be an alternative route for a sustained, once-weekly systemic delivery of TAF.

Background and Purpose Synthetic cathinones, commonly referred to as ‘bath salts’, are a group of amphetamine-like drugs gaining popularity worldwide. 4-Methylmethcathinone (mephedrone, MEPH) is the most commonly abused synthetic cathinone in the UK, and exerts its effects by acting as a substrate-type releaser at monoamine transporters. Similar to other cathinone-related compounds, MEPH has a chiral centre and exists stably as two enantiomers: R-mephedrone (R-MEPH) and S-mephedrone (S-MEPH).

Vaginal tablets are being developed as an alternative to gels as an inexpensive, discreet dosage form for the administration of microbicides. This work describes the pharmacokinetic (PK) evaluation of rapidly disintegrating vaginal tablets containing tenofovir (TFV, 10 mg), emtricitabine (FTC, 10 mg), and the combination of TFV and FTC (10 mg each) under in vitro and in vivo conditions, and in direct comparison to the clinical TFV 1% gel, a microbicide product in Phase III clinical testing. The PK of TFV and FTC from tablets were also evaluated in female rabbits following intravaginal administration. Direct comparison of a single dose of TFV tablets (intact or predissolved at 10 mg/mL) and TFV 1% gel showed no differences in the vaginal PK of TFV between groups, however systemic bioavailability of TFV was significantly higher from the gel. When rabbits were dosed either once or daily for seven days with intact tablets of TFV, FTC, or the combination of TFV/FTC, vaginal and systemic concentrations of TFV and FTC were unaffected by co-formulation. Moreover, plasma PK parameters were similar following a single dose or seven once-daily doses. Tissue concentrations of TFV and FTC in the cranial vagina 4 h after administration ranged between 104 and 105 ng/g. Concentrations of TFV-diphospate (TFV-DP, the active metabolite) were also high (over 103 ng/g or about 3000 to 6000 fmol/mg) in the cranial vagina 4 h after administration and similar to those measured following administration of TFV 1% gel. These data demonstrate that rapidly disintegrating vaginal tablets may be a suitable topical microbicide dosage form providing similar vaginal TFV PK to that of TFV 1% gel. The data also support co-administration of FTC with TFV in a single vaginal tablet to create a combination microbicide in a simple and inexpensive dosage form.

Object The authors hypothesized that chemotherapy infusions directly into the fourth ventricle might potentially play a role in treating malignant fourth ventricular tumors. The study tested the safety and pharmacokinetics of short- and long-term infusions of methotrexate into the fourth ventricle in a new nonhuman primate model. Methods Six rhesus monkeys underwent posterior fossa craniectomy and catheter insertion into the fourth ventricle. In Group I (3 animals), catheters were externalized, and lumbar drain catheters were placed simultaneously to assess CSF distribution after short-term methotrexate infusions. In 2 animals, methotrexate (0.5 mg) was infused into the fourth ventricle daily for 5 days. Serial CSF and serum methotrexate levels were measured. The third animal had a postoperative neurological deficit, and the experiment was aborted prior to methotrexate administration. In Group II (3 animals), catheters were connected to a subcutaneously placed port for subsequent long-term methotrexate infusions. In 2 animals, 4 cycles of intraventricular methotrexate, each consisting of 4 daily infusions (0.5 mg), were administered over 8 weeks. The third animal received 3 cycles, and then the experiment was terminated due to self-inflicted wound breakdown. All animals underwent detailed neurological evaluations, MRI, and postmortem histological analysis. Results No neurological deficits were noted after intraventricular methotrexate infusions. Magnetic resonance images demonstrated catheter placement within the fourth ventricle and no signal changes in the brainstem or cerebellum. Histologically, two Group I animals, one of which did not receive methotrexate, had several small focal areas of brainstem injury. Two Group II animals had a small (≤ 1-mm) focus of axonal degeneration in the midbrain. Intraventricular and meningeal inflammation was noted in 4 animals after methotrexate infusions (one from Group I and all three from Group II). In all Group II animals, inflammation extended minimally into brainstem parenchyma. Serum methotrexate levels were undetectable or negligible in both groups, ranging from 0.00 to 0.06 μmol/L. In Group I, the mean peak methotrexate level in fourth ventricle CSF exceeded that in the lumbar CSF by greater than 10-fold. Statistically significant differences between fourth ventricle and lumbar AUC (area under the concentration-time curve) were detected at peaks (p = 0.04) but not at troughs (p = 0.50) or at all time collection points (p = 0.12). In Group II, peak fourth ventricle CSF methotrexate levels ranged from 84.62 to 167.89 μmol/L (mean 115.53 ± 15.95 μmol/L [SD]). Trough levels ranged from 0.06 to 0.55 μmol/L (mean 0.22 ± 0.13 μmol/L). Conclusions Methotrexate can be infused into the fourth ventricle in nonhuman primates without clinical or radiographic evidence of injury. Observed inflammatory and other histological changes had no clinical correlate. This approach may have pharmacokinetic advantages over current treatment paradigms. Further experiments are warranted to determine if fourth ventricular chemotherapy infusions may benefit patients with malignant fourth ventricular tumors.

Recreational use of illicit methcathinone derivatives is a public health concern in the USA and Europe. Recent reports indicate that mephedrone (MEPH) produces neurochemical and behavioral effects comparable with amphetamines. The present study investigated the effects of a mixture of MEPH and D-amphetamine (AMPH) on the induction and expression of behavioral sensitization. Thirty female CD-1 mice received seven subcutaneous injections of saline, AMPH (1.0 mg/kg), MEPH (3.0 mg/kg), or AMPH (1.0 mg/kg)+MEPH (3.0 mg/kg) over an 8-day period with 48 h between the first and second injection and 24 h between subsequent injections. Activity was assessed immediately following the first and seventh dose. After a 10-day washout, 1.0 mg/kg AMPH was administered to all animals and activity was assessed in a similar manner. Compared with mice treated with AMPH or MEPH, those treated with AMPH+MEPH displayed stronger indices of behavioral sensitization after the seventh dose and in response to AMPH after the washout period. These results suggest that MEPH may enhance sensitivity to the behavioral effects of AMPH. Considered in light of findings that MEPH has comparable neurochemical actions to the amphetamines and is commonly used with other stimulants, further research on the abuse liability of drug mixtures with methcathinones and other psychostimulants is warranted.