Repurposing Auranofin and Evaluation of a New Gold(I) Compound for the Search of Treatment of Human and Cattle Parasitic Diseases: From Protozoa to Helminth Infections.

Neglected parasitic diseases remain a major public health issue worldwide, especially in tropical and subtropical areas. Human parasite diversity is very large, ranging from protozoa to worms. In most cases, more effective and new drugs are urgently needed. Previous studies indicated that the gold(I) drug auranofin (Ridaura®) is effective against several parasites. Among new gold(I) complexes, the phosphole-containing gold(I) complex {1-phenyl-2,5-di(2-pyridyl)phosphole}AuCl (abbreviated as GoPI) is an irreversible inhibitor of both purified human glutathione and thioredoxin reductases. GoPI-sugar is a novel 1-thio-ß-d-glucopyranose 2,3,4,6-tetraacetato-S-derivative that is a chimera of the structures of GoPI and auranofin, designed to improve stability and bioavailability of GoPI. These metal-ligand complexes are of particular interest because of their combined abilities to irreversibly target the essential dithiol/selenol catalytic pair of selenium-dependent thioredoxin reductase activity, and to kill cells from breast and brain tumors. In this work, screening of various parasites-protozoans, trematodes, and nematodes-was undertaken to determine the in vitro killing activity of GoPI-sugar compared to auranofin. GoPI-sugar was found to efficiently kill intramacrophagic Leishmania donovani amastigotes and adult filarial and trematode worms.

Is there an oxidative cost of acute stress? Characterization, implication of glucocorticoids and modulation by prior stress experience.

Acute rises in glucocorticoid hormones allow individuals to adaptively respond to environmental challenges but may also have negative consequences, including oxidative stress. While the effects of chronic glucocorticoid exposure on oxidative stress have been well characterized, those of acute stress or glucocorticoid exposure have mostly been overlooked. We examined the relationship between acute stress exposure, glucocorticoids and oxidative stress in Japanese quail (Coturnix japonica). We (i) characterized the pattern of oxidative stress during an acute stressor in two phenotypically distinct breeds; (ii) determined whether corticosterone ingestion, in the absence of acute stress, increased oxidative stress, which we call glucocorticoid-induced oxidative stress (GiOS); and (iii) explored how prior experience to stressful events affected GiOS. Both breeds exhibited an increase in oxidative stress in response to an acute stressor. Importantly, in the absence of acute stress, ingesting corticosterone caused an acute rise in plasma corticosterone and oxidative stress. Lastly, birds exposed to no previous acute stress or numerous stressful events had high levels of GiOS in response to acute stress, while birds with moderate prior exposure did not. Together, these findings suggest that an acute stress response results in GiOS, but prior experience to stressors may modulate that oxidative cost.

Acute ingestion of sugar-free red bull energy drink has no effect on upper body strength and muscular endurance in resistance trained men.

Consumption of energy drinks by both recreational and competitive athletes has increased dramatically in recent years. The primary ingredients in many energy drinks include caffeine (CAF) in various forms and taurine. The purpose of this randomized, double-blind, crossover study was to examine the effect of sugar-free (SF) Red Bull (RB) containing CAF and taurine to a CAF only drink and a SF CAF-free placebo (PL) on 1 repetition maximum (1RM) bench press (BP) and the volume load (VL; repetitions × kg at 70% 1RM) during one BP set to failure in experienced lifters. Seventeen college-age men randomly received the following: (A) 500 mL of SF-RB containing CAF (160 mg) and taurine (2000 mg); (B) 500 mL of a SF drink containing CAF only (160 mg); or (C) a SF CAF-free 500 mL PL drink 60 minutes before testing on 3 separate occasions. After a standard warm-up, the 1RM was determined for each subject and, after 5 minutes rest, they completed repetitions to failure at 70% of their 1RM to assess VL. Differences between trials for 1RM BP and the VL were identified using repeated measures analysis of variance (p < 0.05). The results indicated that neither SF-RB nor the CAF drink had any effect on 1RM BP (115.13 ± 16.19 kg and 114.87 ± 16.16 kg, respectively) or VL (1173.08 ± 170.66 kg and 1164.14 ± 147.03 kg, respectively) compared with PL (1RM = 114.07 ± 16.09 kg; VL = 1141.46 ± 193.41 kg). Although the CAF content in the energy drinks used in the present study was low (∼2.0 mg/kg), the finding of no effect of the CAF containing energy drinks for 1RM BP are in agreement with previous studies using intakes up to 6.0 mg/kg. These findings suggest that SF-RB has no effect on upper body 1RM strength or VL in resistance trained men.

Pyrvinium Pamoate and Structural Analogs Are Early Macrofilaricide Leads.

Onchocerciasis and lymphatic filariasis are neglected tropical diseases caused by infection with filarial worms. Annual or biannual mass drug administration with microfilaricidal drugs that kill the microfilarial stages of the parasites has helped reduce infection rates and thus prevent transmission of both infections. However, success depends on high population coverage that is maintained for the duration of the adult worm's lifespan. Given that these filarial worms can live up to 14 years in their human hosts, a macrofilaricidal drug would vastly accelerate elimination efforts. Here, we have evaluated the repurposed drug pyrvinium pamoate as well as newly synthesized analogs of pyrvinium for their efficacy against filarial worms in vitro and in vivo. We found that pyrvinium pamoate, tetrahydropyrvinium and one of the analogs were highly potent in inhibiting worms in in vitro whole-worm screening assays, and that all three compounds reduced female worm fecundity and inhibited embryogenesis in the Brugia pahangi-gerbil in vivo model of infection.

Administrative and Registry Databases for Patient Safety Tracking and Quality Improvement.

Acquisition of data on clinical performance is essential to improve outcomes in surgery. Large, national datasets allow hospitals to monitor events involving patient safety, complications, and benchmark against peer hospitals and facilitate quality improvement (QI) development. Although clinical datasets are often preferable, administrative data also have potential for actionable QI. Hospitals should use whatever data resources may be available and be creative in combining data sources for the most clinically meaningful metrics. Although collection of data is essential in understanding the problems an individual hospital is facing, rigorous QI infrastructure is necessary to translate data to action and achieve sustained change.

Evidence Review for the American College of Surgeons Quality Verification Part II: Processes for Reliable Quality Improvement.

After decades of experience supporting surgical quality and safety by the American College of Surgeons, the American College of Surgeons Quality Verification Program was developed to help hospitals improve surgical quality, safety, and reliability. This review is the second of a 3-part review aiming to synthesize the evidence supporting the main principles of the American College of Surgeons Quality Verification Program. Evidence was systematically reviewed for 5 principles: case review, peer review, credentialing and privileging, data for surveillance, and continuous quality improvement using data. MEDLINE was searched for articles published from inception to January 2019 and 2 reviewers independently screened studies for inclusion in a hierarchical fashion, extracted data, and summarized results in a narrative fashion. A total of 9,098 studies across the 5 principles were identified. After exclusion criteria, a total of 184 studies in systematic reviews and primary studies were included for assessment. The identified literature supports the importance of standardized processes and systems to identify problems and improve quality of care.

Feasibility of Enhanced Recovery in Emergency Colorectal Operation.

BACKGROUND: Emergency colorectal operations account for considerable surgical morbidity, leading to increased recognition of the importance of standardized care. Enhanced recovery pathways (ERPs) have successfully provided a framework to standardize elective surgical care, with some ERP elements spreading to emergency procedures. This study aims to characterize the degree of spread and demonstrate feasibility of ERP extension to emergency colorectal operations. STUDY DESIGN: Patients undergoing colorectal operations were identified from a national ERP collaborative. Adherence to ERP process measures-multimodal pain control, early Foley removal, postoperative venous thromboembolism prophylaxis, early mobilization, early feeding, and 30-day clinical outcomes-was analyzed. Multivariable logistic regression was used to evaluate association between process measure adherence and 30-day clinical outcomes. RESULTS: A total of 31,511 patients underwent colorectal operations at 235 hospitals; 3,086 were emergencies and 28,425 were elective. For emergency cases, rates of early Foley removal (92.0%) and venous thromboembolism prophylaxis (75.7%) were highest. Rates of multimodal pain control (55.9%), early mobilization (37.1%), and early liquid intake (33.4%) were modest. Nonadherence was more common in patients younger than 65 years (43.4%), with independent functional status (94%), American Society of Anesthesiologists Physical Status Classification 1 to 3 (62.5%), and without physiologic derangement (39.9%). Lack of mobilization or liquid intake was independently associated with increased odds of ileus (odds ratio [OR] 1.43; 95% CI, 1.18 to 1.75 and OR 2.41; 95% CI, 1.96 to 2.95) and prolonged length of stay (OR 2.29; 95% CI, 1.85 to 2.83 and OR 2.05; 95% CI, 1.70 to 2.47). CONCLUSIONS: Although the unplanned nature of emergency colorectal operations historically excluded patients from ERPs, our findings suggest ERPs have observable diffusion beyond elective surgical procedures. Deliberate implementation with adherence auditing can improve ERP uptake and outcomes in emergency colorectal operations.

An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease.

Filarial worms cause multiple debilitating diseases in millions of people worldwide, including river blindness. Currently available drugs reduce transmission by killing larvae (microfilariae), but there are no effective cures targeting the adult parasites (macrofilaricides) which survive and reproduce in the host for very long periods. To identify effective macrofilaricides, we carried out phenotypic screening of a library of 2121 approved drugs for clinical use against adult Brugia pahangi and prioritized the hits for further studies by integrating those results with a computational prioritization of drugs and associated targets. This resulted in the identification of 18 hits with anti-macrofilaricidal activity, of which two classes, azoles and aspartic protease inhibitors, were further expanded upon. Follow up screening against Onchocerca spp. (adult Onchocerca ochengi and pre-adult O. volvulus) confirmed activity for 13 drugs (the majority having IC50 < 10 µM), and a counter screen of a subset against L. loa microfilariae showed the potential to identify selective drugs that prevent adverse events when co-infected individuals are treated. Stage specific activity was also observed. Many of these drugs are amenable to structural optimization, and also have known canonical targets, making them promising candidates for further optimization that can lead to identifying and characterizing novel anti-macrofilarial drugs.

Evidence Review for the American College of Surgeons Quality Verification Part I: Building Quality and Safety Resources and Infrastructure.

Decades of quality program development by the American College of Surgeons (ACS) have identified the key components of a successful program for optimal surgical care and quality improvement. These key principles have been developed into a verification program-the ACS Quality Verification Program-to guide hospitals to improve surgical quality, safety, and reliability across all surgical specialties. The aim of this review was to synthesize the evidence supporting the first 4 of 12 ACS Quality Verification Program core principles of building quality and safety resources and infrastructure. MEDLINE was searched for articles published from inception to January 2019 for studies describing principles of leadership commitment to surgical quality and safety, a surgical quality officer, a surgical quality committee, and a culture of safety and high reliability. Two reviewers independently screened studies for inclusion in a hierarchical fashion, extracted data, and summarized results in a narrative fashion. A total of 5,332 studies across the 4 principles were identified. After exclusion criteria, a total of 477 studies in systematic reviews and primary studies were included for assessment. Despite heterogeneous study design and lack of randomized controlled trials, the available literature supports the importance of committed top-level hospital leadership, mid-level leadership, and committee dedicated to surgical quality and culture of safety and high reliability. In conclusion, adequate resources and infrastructure integral to the ACS Quality Verification Program are critical to achieving safe and high-quality surgical outcomes.

Macrofilaricidal Benzimidazole-Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness: Part 2. Ketone Linked Analogs.

The optimization of a series of benzimidazole-benzoxaborole hybrid molecules linked via a ketone that exhibit good activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis, also known as river blindness, is described. The lead identified in this series, 21 (AN15470), was found to have acceptable pharmacokinetic properties to enable an evaluation following oral dosing in an animal model of onchocerciasis. Compound 21was effective in killing worms implanted in Mongolian gerbils when dosed orally as a suspension at 100 mg/kg/day for 14 days but not when dosed orally at 100 mg/kg/day for 7 days.

Macrofilaricidal Benzimidazole-Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness: Part 1. Amide Linked Analogs.

A series of benzimidazole-benzoxaborole hybrid molecules linked via an amide linker are described that exhibit good in vitro activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis, also known as river blindness. The lead identified in this series, 8a (AN8799), was found to have acceptable pharmacokinetic properties to enable evaluation in animal models of human filariasis. Compound 8a was effective in killing Brugia malayi, B. pahangi, and Litomosoides sigmodontis worms present in Mongolian gerbils when dosed subcutaneously as a suspension at 100 mg/kg/day for 14 days but not when dosed orally at 100 mg/kg/day for 28 days. The measurement of plasma levels of 8a at the end of the dosing period and at the time of sacrifice revealed an interesting dependence of activity on the extended exposure for both 8a and the positive control, flubendazole.

Efficacy of subcutaneous doses and a new oral amorphous solid dispersion formulation of flubendazole on male jirds (Meriones unguiculatus) infected with the filarial nematode Brugia pahangi.

River blindness and lymphatic filariasis are two filarial diseases that globally affect millions of people mostly in impoverished countries. Current mass drug administration programs rely on drugs that primarily target the microfilariae, which are released from adult female worms. The female worms can live for several years, releasing millions of microfilariae throughout the course of infection. Thus, to stop transmission of infection and shorten the time to elimination of these diseases, a safe and effective drug that kills the adult stage is needed. The benzimidazole anthelmintic flubendazole (FBZ) is 100% efficacious as a macrofilaricide in experimental filarial rodent models but it must be administered subcutaneously (SC) due to its low oral bioavailability. Studies were undertaken to assess the efficacy of a new oral amorphous solid dispersion (ASD) formulation of FBZ on Brugia pahangi infected jirds (Meriones unguiculatus) and compare it to a single or multiple doses of FBZ given subcutaneously. Results showed that worm burden was not significantly decreased in animals given oral doses of ASD FBZ (0.2-15 mg/kg). Regardless, doses as low as 1.5 mg/kg caused extensive ultrastructural damage to developing embryos and microfilariae (mf). SC injections of FBZ in suspension (10 mg/kg) given for 5 days however, eliminated all worms in all animals, and a single SC injection reduced worm burden by 63% compared to the control group. In summary, oral doses of ASD formulated FBZ did not significantly reduce total worm burden but longer treatments, extended takedown times or a second dosing regimen, may decrease female fecundity and the number of mf shed by female worms.

Development of a preliminary in vitro drug screening assay based on a newly established culturing system for pre-adult fifth-stage Onchocerca volvulus worms.

BACKGROUND: The human filarial parasite Onchocerca volvulus is the causative agent of onchocerciasis (river blindness). It causes blindness in 270,000 individuals with an additional 6.5 million suffering from severe skin pathologies. Current international control programs focus on the reduction of microfilaridermia by annually administering ivermectin for more than 20 years with the ultimate goal of blocking of transmission. The adult worms of O. volvulus can live within nodules for over 15 years and actively release microfilariae for the majority of their lifespan. Therefore, protracted treatment courses of ivermectin are required to block transmission and eventually eliminate the disease. To shorten the time to elimination of this disease, drugs that successfully target macrofilariae (adult parasites) are needed. Unfortunately, there is no small animal model for the infection that could be used for discovery and screening of drugs against adult O. volvulus parasites. Here, we present an in vitro culturing system that supports the growth and development of O. volvulus young adult worms from the third-stage (L3) infective stage. METHODOLOGY/PRINCIPAL FINDINGS: In this study we optimized the culturing system by testing several monolayer cell lines to support worm growth and development. We have shown that the optimized culturing system allows for the growth of the L3 worms to L5 and that the L5 mature into young adult worms. Moreover, these young O. volvulus worms were used in preliminary assays to test putative macrofilaricidal drugs and FDA-approved repurposed drugs. CONCLUSION: The culture system we have established for O. volvulus young adult worms offers a promising new platform to advance drug discovery against the human filarial parasite, O. volvulus and thus supports the continuous pursuit for effective macrofilaricidal drugs. However, this in vitro culturing system will have to be further validated for reproducibility before it can be rolled out as a drug screen for decision making in macrofilaricide drug development programs.

Small Molecule Inhibitors of Metabolic Enzymes Repurposed as a New Class of Anthelmintics.

The enormous prevalence of infections caused by parasitic nematodes worldwide, coupled to the rapid emergence of their resistance to commonly used anthelmintic drugs, presents an urgent need for the discovery of new drugs. Herein, we have identified several classes of small molecules with broad spectrum activity against these pathogens. Previously, we reported the identification of carnitine palmitoyltransferases (CPTs) as a representative class of enzymes as potential targets for metabolic chokepoint intervention that was elucidated from a combination of chemogenomic screening and experimental testing in nematodes. Expanding on these previous findings, we have discovered that several chemical classes of known small molecule inhibitors of mammalian CPTs have potent activity as anthelmintics. Cross-clade efficacy against a broad spectrum of adult parasitic nematodes was demonstrated for multiple compounds from different series. Several analogs of these initial hit compounds were designed and synthesized. The compounds we report represent a good starting point for further lead identification and optimization for development of new anthelmintic drugs with broad spectrum activity and a novel mechanism of action.

Outcomes after hospitalization in idiopathic pulmonary fibrosis: a cohort study.

OBJECTIVE: The outcomes of patients with idiopathic pulmonary fibrosis (IPF) who undergo hospitalization have not been well characterized. We sought to determine the frequency of all-cause and respiratory-related hospitalizations and to evaluate their impact on the subsequent course and survival of patients with IPF. METHODS: The records of patients with IPF evaluated at a tertiary center were examined for the cause and duration of hospitalization. Data on subsequent patient outcomes were collated. RESULTS: The IPF cohort consisted of 592 patients, 25.3% of whom were hospitalized subsequent to their IPF diagnosis. A respiratory-related cause accounted for 77.3% of these hospitalizations. The median transplant-free survival for all patients was 23.3 months (interquartile range [IQR], 7.6-63.6 months) from the time of consultation. Transplant-free survival after hospital admission was much lower for patients with a respiratory hospitalization compared with those with a nonrespiratory hospitalization (median survival, 2.8 months [IQR, 0.63-16.2 months] vs 27.7 months [IQR, 7.4-59.6 months]; P = .0004). Multivariate analyses demonstrated that both all-cause and respiratory-related hospitalizations were strongly associated with mortality after adjusting for baseline demographics. Among patients with a respiratory hospitalization, 22.4% died while in the hospital, whereas 16.4% eventually went on to lung transplantation. CONCLUSIONS: Hospitalizations are common events in patients with IPF. Most hospitalizations are respiratory-related and are associated with high in-hospital mortality and limited survival beyond discharge. Both all-cause and respiratory hospitalizations are associated with mortality, and therefore, either could be used as an end point in IPF clinical trials.