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Neglected tropical diseases such as Chagas disease, human African trypanosomiasis, leishmaniasis, and schistosomiasis have a significant global health impact in predominantly developing countries, although these diseases are spreading due to increased international travel and population migration. Drug repurposing with a focus on increasing antiparasitic potency and drug-like properties is a cost-effective and efficient route to the development of new therapies. Here we identify compounds that have potent activity against Trypanosoma cruzi and Leishmania donovani , and the latter were progressed into the murine model of infection. Despite the potent in vitro activity, there was no effect on parasitemia, necessitating further work to improve the pharmacokinetic properties of this series. Nonetheless, valuable insights have been obtained into the structure-activity and structure-property relationships of this compound series.

Quorum-sensing is a communication mechanism between bacteria with the ability to activate signaling pathways in the bacterium and in the host cells. Pseudomonas aeruginosa is a pathogen with high clinical relevance due to its vast virulence factors repertory and wide antibiotic resistance mechanisms. Due to this, it has become a pathogen of interest for developing new antimicrobial agents in recent years. P. aeruginosa has three major QS systems that regulate a wide gene range linked with virulence factors, metabolic regulation, and environment adaption. Consequently, inhibiting this communication mechanism would be a strategy to prevent the pathologic progression of the infections caused by this bacterium. In this review, we aim to overview the current studies about the signaling mechanisms of the QS system of P. aeruginosa and its effects on this bacterium and the host., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The flavoenzyme nicotine oxidoreductase (NicA2) is a promising injectable treatment to aid in the cessation of smoking, a behavior responsible for one in ten deaths worldwide. NicA2 acts by degrading nicotine in the bloodstream before it reaches the brain. Clinical use of NicA2 is limited by its poor catalytic activity in the absence of its natural electron acceptor CycN. Without CycN, NicA2 is instead oxidized slowly by dioxygen (O 2 ), necessitating unfeasibly large doses in a therapeutic setting. Here, we report a genetic selection strategy that directly links CycN-independent activity of NicA2 to growth of Pseudomonas putida S16. This selection enabled us to evolve NicA2 variants with substantial improvement in their rate of oxidation by O 2 . The encoded mutations cluster around a putative O 2 tunnel, increasing flexibility and accessibility to O 2 in this region. These mutations further confer desirable clinical properties. A variant form of NicA2 is tenfold more effective than the wild type at degrading nicotine in the bloodstream of rats., (© 2023. The Author(s).)

Clinical testing typically relies on invasive blood draws and biopsies. Alternative methods of sample collection are continually being developed to improve patient experience; swabbing the skin is one of the least invasive sampling methods possible. To show that skin swabs in combination with untargeted mass spectrometry (metabolomics) can be used for non-invasive monitoring of an oral drug, we report the kinetics and metabolism of diphenhydramine in healthy volunteers (n = 10) over the course of 24 hours in blood and three regions of the skin. Diphenhydramine and its metabolites were observed on the skin after peak plasma levels, varying by compound and skin location, and is an illustrative example of how systemically administered molecules can be detected on the skin surface. The observation of diphenhydramine directly from the skin supports the hypothesis that both parent drug and metabolites can be qualitatively measured from a simple non-invasive swab of the skin surface. The mechanism of the drug and metabolites pathway to the skin's surface remains unknown., Competing Interests: P.C.D is a scientific advisor to Sirenas, Galileo and Cybele and co-founder and scientific advisor to Ometa Labs and Enveda with approval by the University of California San Diego. M.P. is a research consultant to Ometa Labs.

Inhibition of acetylcholinesterase (AChE) by certain organophosphates (OPs) can be life-threatening and requires reactivating antidote accessibility to the peripheral and central nervous systems to reverse symptoms and enhance survival parameters. In considering dosing requirements for oxime antidotes in OP exposures that inactivate AChE, clearance of proton ionizable, zwitterionic antidotes is rapid and proceeds with largely the parent antidotal compound being cleared by renal transporters. Such transporters may also control disposition between target tissues and plasma as well as overall elimination from the body. An ideal small-molecule antidote should access and be retained in primary target tissues-central nervous system (brain), skeletal muscle, and peripheral autonomic sites-for sufficient periods to reactivate AChE and prevent acute toxicity. We show here that we can markedly prolong the antidotal activity of zwitterionic antidotes by inhibiting P-glycoprotein (P-gp) transporters in the brain capillary and renal systems. We employ the P-gp inhibitor tariquidar as a reference compound and show that tissue and plasma levels of RS194B, a hydroxyl-imino acetamido alkylamine reactivator, are elevated and that plasma clearances are reduced. To examine the mechanism, identify the transporter, and establish the actions of a transport inhibitor, we compare the pharmacokinetic parameters in a P-glycoprotein knockout mouse strain and see dramatic enhancements of short-term plasma and tissue levels. Hence, repurposed transport inhibitors that are candidate or Food and Drug Administration-approved drugs, should enhance target tissue concentrations of the zwitterionic antidote through inhibition of both renal elimination and brain capillary extrusion. SIGNIFICANCE STATEMENT: We examine renal and brain capillary transporter inhibition as means for lowering dose and frequency of dosing of a blood-brain barrier permanent reactivating antidote, RS194B, an ionizable zwitterion. Through a small molecule, tariquidar, and gene knockout mice, CNS antidote concentrations are enhanced, and total body clearances are concomitantly diminished. RS194B with repurposed transport inhibitors should enhance reactivation of central and peripheral OP-inhibited acetylcholinesterase. Activities at both disposition sites are a desired features for replacing the antidote, pralidoxime, for acute OP exposure., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Rationale: Cannabidiol (CBD) reduces craving in animal models of alcohol and cocaine use and is known to modulate nicotinic receptor function, suggesting that it may alleviate symptoms of nicotine withdrawal. However, preclinical evaluation of its efficacy is still lacking., Objectives: The goal of this study was to test the preclinical efficacy of a chronic CBD treatment in reducing nicotine dependence using measures of withdrawal symptoms including somatic signs, hyperalgesia, and weight gain during acute and protracted abstinence., Methods: Male and female Wistar rats were made dependent on nicotine using osmotic minipumps (3.15 mg/kg/day) for 2 weeks, after which minipumps were removed to induce spontaneous withdrawal. Three groups received CBD injections at doses of 7.5, 15, and 30 mg/kg/day for 2 weeks, starting 1 week into chronic nicotine infusion. The control groups included rats with nicotine minipumps that received vehicle injections of sesame oil instead of CBD; rats implanted with saline minipumps received sesame oil injections (double vehicle) or the highest dose of CBD 30 mg/kg/day. Throughout the experiment, serum was collected for determination of CBD and nicotine concentrations, mechanical sensitivity threshold and withdrawal scores were measured, and body weight was recorded., Results: CBD prevented rats from exhibiting somatic signs of withdrawal and hyperalgesia during acute and protracted abstinence. There was no dose-response observed for CBD, suggesting a ceiling effect at the doses used and the potential for lower effective doses of CBD. The saline minipump group did not show either somatic signs of withdrawal or hyperalgesia during acute and protracted abstinence, and the highest dose of CBD used (30 mg/kg/day) did not alter these results., Conclusions: This preclinical study suggests that using CBD as a strategy to alleviate the withdrawal symptoms upon nicotine cessation may be beneficial., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Fatalities from organophosphate (OP) insecticide result from both occupational and deliberate exposure; significantly impacting human health. Like nerve agents, insecticides are neurotoxins which target and inhibit acetylcholinesterases (AChE) in central and peripheral synapses in the cholinergic nervous system. Post-exposure therapeutic countermeasures generally include administration of atropine with a pyridinium aldoxime e.g. pralidoxime, to reactivate the OP-inhibited AChE. However, commonly used oximes inefficiently cross the bloodbrain barrier and are rapidly cleared and their benefit is debated. Recent findings have demonstrated the ability of a novel zwitterionic, centrally acting, brain penetrating oxime (RS194B) to reverse severe symptoms and rapidly reactivate sarin-inhibited AChE in macaques, but it has not been tested following OP pesticide poisoning. In the present study, the symptoms following a lethal dose of inhaled paraoxon (100ug/kg), were shown to mimic those in insecticide poisoned individuals and were also rapidly reversed in macaques by post-exposure IM administration of 80mg/kg of RS194B. This occurred with a concomitant reactivation of AChE to 40-100% in<1hr and BChE (40% in 8h). These findings will be used to develop a macaque model with RS194B as a post-exposure treatment for insecticide poisoning and generate efficacy data for approval under the FDA Animal rule., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: Giardia is a serious zoonotic parasite, which causes diarrheal disease in humans and animals including rodents. The purpose of this study was to estimate the prevalence of Giardia spp. in brown rats ( Rattus norvegicus ) in Grenada., Materials and Methods: Intestinal contents from 99 and serum samples from 169 brown rats ( R. norvegicus ) from Grenada were collected. These samples were examined for the Giardia coproantigens using Cryptosporidium / Giardia Quik Chek assay (Tech lab ® Inc., USA), and the serum was screened through an enzyme-linked immunosorbent assay (ELISA) test kit for Giardia antibody (anti-GD) ELISA kit (MyBioSource, San Diego, CA, USA)., Result: Giardia coproantigens were positive in 17.17% (95% confidence interval [CI]; 10.33-26.06%) rats, whereas 55% (95% CI: 47.20-62.68) were positive with serum antibodies (anti-GD) to Giardia ., Conclusion: The prevalence of Giardia spp. in brown rats in Grenada was moderate based on the presence of coproantigens in the intestinal contents and antibody in serum. The findings of Giardia infections and prevalence in brown rats will help veterinarians and physicians to better plan diagnostic and preventative strategies. This is the first report of prevalence of Giardia in brown rats in Grenada.

Cat is the definitive host of Taenia taeniaeformis (T. taeniaeformis). Cysticercus fasciolaris (C. fasciolaris), the larval stage of T . taeniaeformis, develops in small rodents which act as intermediate host. The aim of this study was to estimate the prevalence of C. fasciolaris in brown rats (Rattus norvegicus) in the densely human populated parishes, St. George's and St. David's of Grenada, West Indies. One hundred and seventy rats were trapped near the residential areas from May to July, 2017 and examined for C. fasciolaris in their liver. Of the 170 rats 115 (67.6%, CI 95% from 60.1 to 74.6) were positive for the larval stage of T. taeniaeformis . One to three cysts were observed in each liver, containing a single larva in each cyst. The prevalence was 77.9% in St. George and 59.1% in St. David which is a significant difference ( p < 0.05) between the two parishes under study. Based on gender, prevalence in males was 60.9% and females 74.7%. Significant difference was observed between young and adult rats ( p = 0.03). Prevalence in young rats was 45.0% compared to adults (70.7%). Further study of risk assessment in the cat population in areas of the present research is strongly suggested.

Purpose: To evaluate anatomical and functional results after surgery of retained nucleus or nuclear lens fragments into the vitreous cavity after phacoemulsification., Methods: Files of 46 patients that underwent vitrectomy for posterior retained nuclear fragments between July 92 and June 96 were studied retrospectively. Minimum follow-up was 6 months. Patients having only cortical material were excluded. In 34 cases the nucleus or nuclear fragments were removed posteriorly during a pars plana vitrectomy using either fragmentation with fragmatome (13 cases) or cutting with the vitreotome tip (21 cases). Anterior removal after pars plana vitrectomy was performed in 12 cases. 20 patients were operated on the first week, 12 during the second week and 14 after the second week following phacoemulsification., Results: Forty-one per cent of the patients reached 20/40 or better. 28% had less than 20/200. 8 (17%) patients presented a retinal detachment, 6 a cystoid macular edema, 6 a bullous dystrophy, and 9 an elevated intraocular pressure. At the end of follow-up 89% have been implanted (50% had been implanted at the end of the cataract surgery). We found no correlation between visual acuity and timing of surgery, anterior or posterior site removal of nuclear fragments or lens implantation during phacoemulsification., Conclusion: Dislocation of the nucleus into the vitreous cavity is a serious event during phacoemulsification because of its inflammatory and retinal complications. Vitreoretinal surgery allows good visual recovery in about half of the patients. Technical handling depends primarily on the nucleus density. An IOL may be placed at the end of phacoemulsification if the nucleus is not too hard and if the anterior segment has been cleaned carefully.