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Steroidal and adamantane aminoacridine derivatives were prepared and tested as both botulinum neurotoxin (BoNT) inhibitors and antimalarials. Steroid-bound acridines provided good potency against both the BoNT/A and BoNT/B light chains (LCs). The observed inhibition of the BoNT/B LC by ca. 50% is the highest attained inhibitory activity against this serotype by acridine-based compounds to date. With respect to antimalarial activity, adamantane acridines were the most potent derivatives (IC50 = 6-9 nM, SI > 326), indicating that an adamantyl group is a better carries than a steroidal motif for this indication. [Projekat Ministarstva nauke Republike Srbije, br. 172008]

Efficacious therapeutics for Ebola virus disease are in great demand. Ebola virus infections mediated by mucosal exposure, and aerosolization in particular, present a novel challenge due to nontypical massive early infection of respiratory lymphoid tissues. We performed a randomized and blinded study to compare outcomes from vehicle-treated and remdesivir-treated rhesus monkeys in a lethal model of infection resulting from aerosolized Ebola virus exposure. Remdesivir treatment initiated 4 days after exposure was associated with a significant survival benefit, significant reduction in serum viral titer, and improvements in clinical pathology biomarker levels and lung histology compared to vehicle treatment. These observations indicate that remdesivir may have value in countering aerosol-induced Ebola virus disease., (© 2021. The Author(s).)

Marburg virus (MARV) is a filovirus with documented human case-fatality rates of up to 90%. Here, we evaluated the therapeutic efficacy of remdesivir (GS-5734) in nonhuman primates experimentally infected with MARV. Beginning 4 or 5 days post inoculation, cynomolgus macaques were treated once daily for 12 days with vehicle, 5 mg/kg remdesivir, or a 10-mg/kg loading dose followed by 5 mg/kg remdesivir. All vehicle-control animals died, whereas 83% of animals receiving a 10-mg/kg loading dose of remdesivir survived, as did 50% of animals receiving a 5-mg/kg remdesivir regimen. Remdesivir-treated animals exhibited improved clinical scores, lower plasma viral RNA, and improved markers of kidney function, liver function, and coagulopathy versus vehicle-control animals. The small molecule remdesivir showed therapeutic efficacy in this Marburg virus disease model with treatment initiation 5 days post inoculation, supporting further assessment of remdesivir for the treatment of Marburg virus disease in humans., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Recent Ebola virus (EBOV) outbreaks in West Africa and the Democratic Republic of the Congo have highlighted the urgent need for approval of medical countermeasures for treatment and prevention of EBOV disease (EVD). Until recently, when successes were achieved in characterizing the efficacy of multiple experimental EVD therapeutics in humans, the only feasible way to obtain data regarding potential clinical benefits of candidate therapeutics was by conducting well-controlled animal studies. Nonclinical studies are likely to continue to be important tools for screening and development of new candidates with improved pharmacological properties. Here, we describe a natural history study to characterize the time course and order of progression of the disease manifestations of EVD in rhesus monkeys. In 12 rhesus monkeys exposed by the intramuscular route to 1000 plaque-forming units of EBOV, multiple endpoints were monitored for 28 days following exposure. The disease progressed rapidly with mortality events occurring 7-10 days after exposure. Key disease manifestations observed consistently across the infected animals included, but were not limited to, viremia, fever, systemic inflammation, coagulopathy, lymphocytolysis, renal tubular necrosis with mineralization, and hepatocellular degeneration and necrosis.

The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg(-1) GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.

Background: Transforaminal epidural steroid injections (TFESI) are widely used for the conservative treatment of radicular pain. The use of dexamethasone in TFESIs is relatively new; therefore, immediate and acute adverse effects that it may cause are not fully updated., Objective: To evaluate immediate and acute adverse effects following TFESI with dexamethasone., Study Design: Prospective, observational study., Setting: A spine center affiliated with a rehabilitation hospital., Methods: One hundred fifty consecutive patients receiving TFESI for the management of radicular and axial spinal pain at the cervical, lumbar, and sacral levels with dexamethasone using fluoroscopic guidance with digital subtraction technology were enrolled. The occurrence of adverse effects in patients in the 2-week time period following interventions was monitored through a set of questionnaires followed up by phone calls scheduled for 1 day, day 3, and day 14. Intensity and duration of side effects were recorded., Results: Of the 150 patients enrolled, 31 patients (19.5%) experienced adverse effects within the first 30 minutes following the intervention. The most common adverse effects were numbness and tingling in the limb, which developed in 19 patients (11.95%) followed by perineal pruritus that occurred in 7 cases (4.4%). Patients also reported experiencing adverse effects within the 3 days following intervention; most complained of headaches, insomnia, hiccups, flushing, and increased radicular pain. No major complications were noted., Limitations: The sample size enrolled might be too small to perceive possible rare side effects related to the procedure. The 2-week follow-up period is a limitation for evaluating late side effects., Conclusions: This study offers provision to interventionalists that TFESI with dexamethasone when performed by experienced hands and with proper technique has minor self-limited transient adverse effects that can be easily managed. Patients should be made aware of these adverse effects and their management. Further larger studies are needed to validate the safe use of dexamethasone and the safety of transforaminal epidural injections.

Significantly more potent second generation 4-amino-7-chloroquinoline (4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A (BoNT/A) light chain were synthesized. Introducing an amino group at the C(3) position of the cholate component markedly increased potency (IC50 values for such derivatives ranged from 0.81 to 2.27 μM). Two additional subclasses were prepared: bis(steroidal)-4,7-ACQ derivatives and bis(4,7-ACQ)cholate derivatives; both classes provided inhibitors with nanomolar-range potencies (e.g., the Ki of compound 67 is 0.10 μM). During BoNT/A challenge using primary neurons, select derivatives protected SNAP-25 by up to 89%. Docking simulations were performed to rationalize the compounds' in vitro potencies. In addition to specific residue contacts, coordination of the enzyme's catalytic zinc and expulsion of the enzyme's catalytic water were a consistent theme. With respect to antimalarial activity, the compounds provided better IC90 activities against chloroquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2.

Structurally simplified analogues of dual antimalarial and botulinum neurotoxin serotype A light chain (BoNT/A LC) inhibitor bis-aminoquinoline (1) were prepared. New compounds were designed to improve ligand efficiency while maintaining or exceeding the inhibitory potency of 1. Three of the new compounds are more active than 1 against both indications. Metabolically, the new inhibitors are relatively stable and nontoxic. 12, 14, and 15 are more potent BoNT/A LC inhibitors than 1. Additionally, 15 has excellent in vitro antimalarial efficacy, with IC90 values ranging from 4.45 to 12.11 nM against five Plasmodium falciparum (P.f.) strains: W2, D6, C235, C2A, and C2B. The results indicate that the same level of inhibitory efficacy provided by 1 can be retained/exceeded with less structural complexity. 12, 14, and 15 provide new platforms for the development of more potent dual BoNT/A LC and P.f. inhibitors adhering to generally accepted chemical properties associated with the druggability of synthetic molecules.

Objective: Percutaneous neuromodulation therapy (PNT) is a new minimally invasive, office-based treatment for low back pain in which electrical stimulation is delivered to the paraspinal peripheral nerves. The purpose of this study was to determine the safety, tolerability, and clinical efficacy of PNT in a population of patients with subacute low back pain with radiation to the lower extremity., Design: Open label prospective clinical trial., Setting: Multi-center outpatient setting., Participants: We enrolled 83 patients who had radiating low back pain for 4 weeks to 6 months with a pain intensity of at least 4 on a visual analog scale of 0-10., Interventions: Subjects were treated with PNT 1 to 2 times per week for at least 4 weeks. Based on clinical response patients were treated up to an additional 8 weeks., Main Outcome Measures: We recorded baseline visual analog scale (VAS) scores of radiating pain, low back pain, physical activity, and sleep, as well as the Oswestry Disability Questionnaire. Follow-up assessments were performed at each session, and at 5 and 12 weeks. Patients benefiting from treatments at 12 weeks were followed-up at 6 months., Results: Fifty-nine patients completed the study protocol. Mean VAS scores improved as follows: leg/buttock pain decreased by 37% to 4.0 +/- 2.6 from a baseline of 6.6 +/- 1.7 (P < 0.001); low back pain decreased by 26% to 3.9 +/- 2.4 from a baseline of 5.5 +/- 2.2 (P < 0.001); activity levels improved by 38% to 3.6 +/- 2.2 from a baseline of 6.0 +/- 2.2 (P < 0.001); and sleep improved by 27% to 3.1 +/- 2.5 from a baseline of 4.8 +/- 3.0 (P < 0.001). The Oswestry Low Back Pain Disability scores improved by 24% to 32 +/- 16 from a baseline of 43 +/- 15 (P < 0.001). Pain relief was sustained over a 3-month observation period., Conclusion: For many patients with subacute radiating low back pain, PNT significantly reduced pain and self-rated disability, and improved sleep quality and activity level. PNT is safe and generally well tolerated.