Peer Review of “No Time to Waste: Real-World Repurposing of Generic Drugs as a Multifaceted Strategy Against COVID-19”
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ABSTRACT:
SUBMITTER: Howlett S
PROVIDER: S-EPMC10414506 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Project description:Real-world drug repurposing-the immediate "off-label" prescribing of drugs to address urgent clinical needs-is an indispensable strategy gaining rapid traction in the current COVID-19 crisis. Although off-label prescribing (ie, for a nonapproved indication) is legal in most countries, it tends to shift the burden of liability and cost to physicians and patients, respectively. Nevertheless, in urgent public health crises, it is often the only realistic source of a meaningful potential solution. To be considered for real-world repurposing, drug candidates should ideally have a track record of safety, affordability, and wide accessibility. Although thousands of such drugs are already available, the absence of a central repository of off-label uses presents a barrier to the immediate identification and selection of the safest, potentially useful interventions. Using the current COVID-19 pandemic as an example, we provide a glimpse at the extensive literature that supports the rationale behind six generic drugs, in four classes, all of which are affordable, supported by decades of safety data, and pleiotropically target the underlying pathophysiology that makes COVID-19 so dangerous. Having previously fast-tracked this paper to publication in summary form, we now expand on why cimetidine/famotidine (histamine type-2 receptor antagonists), dipyridamole (antiplatelet agent), fenofibrate/bezafibrate (cholesterol/triglyceride-lowering agents), and sildenafil (phosphodiesterase-5 inhibitor) are worth considering for patients with COVID-19 based on their antiviral, anti-inflammatory, renoprotective, cardioprotective, and anticoagulation properties. These examples also reveal the unlimited opportunity to future-proof public health by proactively mining, synthesizing, and cataloging the off-label treatment opportunities of thousands of safe, well-established, and affordable generic drugs.
| S-EPMC7954442 | biostudies-literature
Project description:PurposeGeneric drugs use in the Liguria region is higher than the Italian average, but lower than in other European countries. No data exist about real-life prescription and level of awareness of generic drugs. In this study, we analyzed demographic, social, economic and cultural factors that may affect the level of awareness of generic drugs and their effective use.MethodsWe conducted a population survey using a structured questionnaire, administered to a sample of 8 outpatient clinics of general practitioners located in different districts of Genoa (Liguria, Italy). Multivariate logistic modeling was adopted to study the relationship between awareness/use of generic drugs and characteristics of subjects.ResultsOut of 2,000 outpatients surveyed, 95% were aware of generic drugs: these were mostly females (OR =2.2, 95% CI: 1.4-3.6), >35 years old (OR >6.0 vs 18-35 years), with a high level of education (OR >4.4 vs "elementary sch"), living in the west side of the city (OR =1.9 vs center); of these, only 59% declared that they effectively use generic drugs. Users were younger (OR =3.1, 18-35 years vs >65 years), with a high level of education (high school/university degree vs no title/elementary/secondary school OR =1.7), and were aware of the lower cost compared with branded drugs, and were mainly informed by pharmacists and physicians.ConclusionsAlthough subjects were substantially aware of the existence of generic drugs, ~40% still did not use them; doubts about their efficacy seem to be mainly driven by the idea that cheaper drugs lead to lower product quality, in terms of efficacy, safety and tolerability. New education policies on generic drugs are needed.
| S-EPMC5572951 | biostudies-literature
Project description:With the escalating costs in drug development, discovering new uses of approved drugs, i.e., drug repurposing, has attracted increasing interest. Spermidine and spermine are important polyamines for most cells and their biosynthesis are strictly regulated by the polyamine metabolic network. In cancerous cells and tumor environments, the concentrations of polyamines are much higher than in normal cells. During the synthesis of spermidine and spermine, an amino-propyl group is provided by decarboxylated S-adenosylmethionine, and the latter is generated from S-adenosylmethionine by AdoMetDC (AdoMet decarboxylase). Therefore, as a rate-limiting enzyme in the biosynthesis of spermidine and spermine, AdoMetDC has been an attractive drug target in cancer studies. In the last decades, many AdoMetDC inhibitors have been discovered, and several AdoMetDC inhibitors are under clinical trials, but unfortunately, none of them have been approved yet. To overcome the high costs in time and money for discovering de novo inhibitors, we set out to repurpose clinic drugs as AdoMetDC inhibitors. We used steric-clashes alleviating receptors (SCAR), a computer-aided drug discovery strategy developed by us recently for in silico screening. By combining computational screening and experimental validation, we successfully identified two approved drugs that have inhibitory potency on AdoMetDC's enzymatic activity. SCAR was previously shown to be suitable for the discovery of both covalent and non-covalent inhibitors, and this work further demonstrated the value of the SCAR strategy in drug repurposing.
| S-EPMC7078168 | biostudies-literature
Project description:Real-world drug repurposing-the immediate "off-label" prescribing of drugs to address urgent clinical needs-is a widely overlooked opportunity. Off-label prescribing (ie, for a nonapproved indication) is legal in most countries and tends to shift the burden of liability and cost to physicians and patients, respectively. Nevertheless, health crises may mean that real-world repurposing is the only realistic source for solutions. Optimal real-world repurposing requires a track record of safety, affordability, and access for drug candidates. Although thousands of such drugs are already available, there is no central repository of off-label uses to facilitate immediate identification and selection of potentially useful interventions during public health crises. Using the current coronavirus disease (COVID-19) pandemic as an example, we provide a glimpse of the extensive literature that supports the rationale behind six generic drugs, in four classes, all of which are affordable, supported by decades of safety data, and targeted toward the underlying pathophysiology that makes COVID-19 so deadly. This paper briefly summarizes why cimetidine or famotidine, dipyridamole, fenofibrate or bezafibrate, and sildenafil citrate are worth considering for patients with COVID-19. Clinical trials to assess efficacy are already underway for famotidine, dipyridamole, and sildenafil, and further trials of all these agents will be important in due course. These examples also reveal the unlimited opportunity to future-proof our health care systems by proactively mining, synthesizing, cataloging, and evaluating the off-label treatment opportunities of thousands of safe, well-established, and affordable generic drugs.
| S-EPMC7224168 | biostudies-literature
Project description:Phytopathogenic bacteria are a major cause of crop mortality and yield reduction, especially in field cultivation. The lack of effective chemistry agri-bactericides is responsible for challenging field prevention and treatment, prompting the development of long-lasting solutions to prevent, reduce, or manage some of the most devastating plant diseases facing modern agriculture today and in the future. Therefore, there is an urgent need to find lead drugs preventing and treating phytopathogenic bacterial infection. Drug repurposing, a strategy used to identify novel uses for existing approved drugs outside of their original indication, takes less time and investment than Traditional R&D Strategies in the process of drug development. Based on this method, we conduct a screen of 700 chemically diverse and potentially safe drugs against Xanthomonas oryzae PV. oryzae ACCC 11602 (Xoo), Xanthomonas axonopodis PV. citri (Xac), and Pectobacterium atrosepticum ACCC 19901 (Pa). Furthermore, the structure-activity relationship and structural similarity analysis of active drugs classify potent agri-bactericides into 8 lead series: salicylanilides, cationic nitrogen-containing drugs, azole antifungals, N-containing group, hydroxyquinolines, piperazine, kinase inhibitor and miscellaneous groups. MIC values were evaluated as antibacterial activities in this study. Identifying highly active lead compounds from the screening of approved drugs and comparison with the currently applied plant pathogenic bactericide to validate the bactericidal activity of the best candidates and assess if selected molecules or scaffolds lead to develop new antibacterial agents in the future. In conclusion, this study provides a possibility for the development of potent and highly selective agri-bactericides leads.
| S-EPMC9569004 | biostudies-literature
Project description:Peer mentors have been proven to improve diabetes outcomes, especially among diverse patients. Delivering peer mentoring via remote strategies (phone, text, mobile applications) is critical, especially in light of the recent pandemic. We conducted a real-world evaluation of a remote diabetes intervention in a safety-net delivery system in New York. We summarized the uptake, content, and pre-post clinical effectiveness for English- and Spanish-speaking participants. Of patients who could be reached, 71% (n = 690/974) were enrolled, and 90% of those (n = 618/690) participated in coaching. Patients and mentors had a mean of 32 check-ins, and each patient set an average of 10 goals. 29% of the participants accessed the program via the smartphone application. Among participants with complete hemoglobin A1c data (n = 179), there was an absolute 1.71% reduction (P < .01). There are multiple lessons for successful implementation of remote peer coaching into settings serving diverse patients, including meaningful patient-mentor matching and addressing social determinants.
| S-EPMC7883966 | biostudies-literature
Project description:BackgroundThiopurines remain recommended as maintenance therapy in patients with inflammatory bowel disease (IBD). Despite their widespread use, long-term effectiveness data are sparse and safety is an increasingly debated topic which thwarts proper delineation in the current IBD treatment algorithm.AimsTo document effectiveness and safety of thiopurine monotherapy in patients with IBD, using the population-based IBD South-Limburg (IBDSL) cohort METHODS: All patients starting thiopurine monotherapy as maintenance between 1991 and 2014 were included. Therapy was defined as effective if there was no escalation to biologicals, no course of corticosteroids, no surgery and no hospitalisation for active disease during treatment. Long-term effectiveness was assessed by adjusting for differences in follow-up using Kaplan-Meier analyses. Mid- to long-term safety regarding cancer incidence and clinically relevant liver disease was documented.ResultsIn total, 1016 patients (643 Crohn's disease [CD]; 373 ulcerative colitis [UC]) received thiopurine monotherapy at a median of 15.2 (Q1-Q3 4.2-48.5) months after diagnosis. During follow-up, effectiveness rates at 1, 5 and 10 years were 64%, 45%, 32%, respectively, in CD and and 66%, 41%, 36%, respectively in UC. No statistically significant differences in effectiveness were observed after stratification for era of initiation (pre-biological vs biological, CD: p = 0.56; UC: p = 0.43). Sixteen non-melanoma skin cancers (incidence rate [IR] 3.33/1000 PY), five lymphomas (IR 1.04/1000 PY) and one urinary tract cancer (IR 0.21/1000 PY) were recorded. Two cases of portal hypertension were identified.ConclusionIn real-world practice, thiopurine monotherapy remains effective, safe and durable for patients with CD or UC, including in the era of biologics.
| S-EPMC9544244 | biostudies-literature
Project description:BackgroundThere are 3 main epileptic conditions in hospital settings that may require intravenous antiepileptic treatment: status epilepticus, acute repetitive convulsive seizures, and postoperative seizures. Generic intravenous levetiracetam (IV LEV) (Focale; Great Eastern Drug Co, Bangkok, Thailand), has been reported to have comparable efficacy to original IV LEV for treating status epilepticus and acute repetitive convulsive seizures in a randomized controlled trial. At present, there are limited data on the efficacy and tolerability of generic intravenous LEV in real-world situations.ObjectiveThis study aimed to evaluate the clinical outcomes of generic IV LEV in a real-world setting.MethodsA retrospective study and analyses were conducted. All adult patients who used IV LEV at University Hospital, Khon Kaen University, Thailand from June 1, 2019, until February 15, 2020, were included. Data were analyzed and reported in terms of the efficacy and tolerability of generic IV LEV.ResultsNinety-three patients received IV LEV by 3 indications: status epilepticus, acute repetitive convulsive seizures, and postoperative seizures. The proportions of these 3 indications were 41.94% (39 patients), 9.67% (9 patients), and 48.39% (45 patients), respectively. The average seizure control rate at 24 hours was 89.25%. The seizure control rate was significantly higher in the acute repetitive convulsive seizures and postoperative seizure groups than in the status epilepticus group when generic IV LEV was given as the first-line treatment (75.00%; 88.37% vs 50.00%; P 0.035). The average length of hospital stay was 18.24 (25.40) days. There was no significant discharge status among the 3 groups (P = 0.348). Moreover, the average mortality rate was 5.38%. Side effects were reported in 14 patients (15.05%). The 2 most common side effects were vomiting and bronchospasm (3 patients; 3.22%). There were 10 patients with uncontrolled seizures at 24 hours (10.75%). The only factor associated with uncontrolled seizures at 24 hours was a history of epilepsy. The uncontrolled seizure group had a higher proportion of epilepsy patients than the seizure-controlled group (70.00% vs 33.73%; P = 0.037). Poor discharge status (not improved/death) was 18.28% (17 patients). There was no significant factor between those with an improved or poor discharge status.ConclusionsGeneric IV LEV was effective and relatively well tolerated in the 3 clinical settings (ie, status epilepticus, acute repetitive convulsive seizures, and postoperative seizures). Further clinical data are still required to confirm the results of this study.(Curr Ther Res Clin Exp. 2022; 83:XXX-XXX).
| S-EPMC8605403 | biostudies-literature
Project description:BackgroundAblation-based treatment has emerged as an alternative rhythm control strategy for symptomatic atrial fibrillation (AF). Recent studies have demonstrated the cost-effectiveness of ablation compared with medical therapy in various circumstances. We assessed the economic comparison between ablation and medical therapy based on a nationwide real-world population.Methods and findingsFor 192,345 patients with new-onset AF (age ≥ 18 years) identified between August 2015 and July 2018 from the Korean Health Insurance Review and Assessment Service (HIRA) database, medical resource use data were collected to compare AF patients that underwent ablation (N = 2,131) and those administered antiarrhythmic drugs (N = 8,048). Subsequently, a Markov chain Monte Carlo model was built. The patients had at least one risk factor for stroke, and the base-case used a 20-year time horizon, discounting at 4.5% annually. Transition probabilities and costs were estimated using the present data, and utilities were derived from literature review. The costs were converted to US $ (2019). Sensitivity analyses were performed using probabilistic and deterministic methods. The net costs and quality-adjusted life years (QALY) for antiarrhythmic drugs and ablation treatments were $37,421 and 8.8 QALYs and $39,820 and 9.3 QALYs, respectively. Compared with antiarrhythmic drugs, incremental cost-effectiveness ratio of ablation was $4,739/QALY, which is lower than the willingness-to-pay (WTP) threshold of $32,000/QALY.ConclusionIn symptomatic AF patients with a stroke risk under the age of 75 years, ablation-based rhythm control is potentially a more economically attractive option compared with antiarrhythmic drug-based rhythm control in Korea.
| S-EPMC9902500 | biostudies-literature
Project description:Grantsmanship is an integral component of surviving and thriving in academic science, especially in the current funding climate. Therefore, any additional opportunities to write, read, and review grants during graduate school may have lasting benefits on one's career. We present here our experience with a small, student-run grant program at Georgetown University Medical Center. Founded in 2010, this program has several goals: 1) to give graduate students an opportunity to conduct small, independent research projects; 2) to encourage graduate students to write grants early and often; and 3) to give graduate students an opportunity to review grants. In the 3 yr since the program's start, 28 applications have been submitted, 13 of which were funded for a total of $40,000. From funded grants, students have produced abstracts and manuscripts, generated data to support subsequent grant proposals, and made new professional contacts with collaborators. Above and beyond financial support, this program provided both applicants and reviewers an opportunity to improve their writing skills, professional development, and understanding of the grants process, as reflected in the outcome measures presented. With a small commitment of time and funding, other institutions could implement a program like this to the benefit of their graduate students.
| S-EPMC3763010 | biostudies-literature