REVIEW | doi:10.20944/preprints202111.0384.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: Alcohol abuse; cell signaling; FDA-approved drugs; oxidative stress; therapy
Online: 22 November 2021 (11:41:50 CET)
Pancreatitis and alcoholic pancreatitis are serious health concerns, and there is an urgent need for effective treatment strategies. Alcohol is a known etiological factor for pancreatitis, including acute pancreatitis (AP) and chronic pancreatitis (CP). Excessive alcohol consumption induces many pathological stress responses; of particular note is endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR). ER stress results from the accumulation of unfolded/misfolded protein in the ER and is implicated in the pathogenesis of alcoholic pancreatitis. Here we summarize the possible mechanisms by which ER stress contributes to alcoholic pancreatitis. We also discuss potential approaches targeting ER stress and UPR for developing novel therapeutic strategies for the disease.
Subject: Chemistry, Medicinal Chemistry Keywords: cannabis; cannabinergic; drug; FDA-approved; medical conditions; pharmaceutical-grade; phytocannabinoid
Online: 31 August 2020 (10:38:32 CEST)
Despite the surge in the research of cannabis chemistry and its biological and medical activity, only a few cannabis-based pharmaceutical-grade drugs have been developed and marketed to date. Not many of these drugs are Food and Drug Administration (FDA)-approved and some are still going through regulation processes. Active compounds including cannabinergic compounds (i.e., molecules targeted to modulate the endocannabinoid system) or analogs of phytocannabinoids (cannabinoids produced by the plant) may be developed into single-molecule drugs. However, since in many cases treatment with whole plant extract is preferred over treatment with a single purified molecule, some more recently developed cannabis-derived drugs contain several molecules. Different combinations of active plant ingredients (API) from cannabis with proven synergy may be identified and developed as drugs to treat different medical conditions. However, possible negative effects between cannabis compounds should also be considered, as well as the effect of the cannabis treatment on the endocannabinoid system. FDA registration of single, few or multiple molecules as drugs is a challenging process and certain considerations that should be reviewed in this process, including issues of drug-drug interactions, are also discussed here.
Subject: Life Sciences, Virology Keywords: Ebola virus; rhesus macaque; animal model; FDA Animal Rule; natural history
Online: 5 February 2021 (11:34:20 CET)
Ebola virus (EBOV) is a negative-sense RNA virus that can infect humans and nonhuman primates with severe health consequences. Development of countermeasures requires a thorough understanding of the interaction between host and pathogen, and the course of disease. The goal of this study was to further characterize EBOV disease in a uniformly lethal rhesus macaque model, in order to support development of a well-characterized model following rigorous quality standards. Rhesus macaques were intramuscularly exposed to EBOV and one group was euthanized at predetermined time points to characterize progression of disease. A second group was not scheduled for euthanasia in order to analyze survival, changes in physiology, clinical pathology, terminal pathology, and telemetry kinetics. On day 3, sporadic viremia was observed and pathological evidence was noted in lymph nodes. By day 5, viremia was detected in all EBOV exposed animals and pathological evidence was noted in the liver, spleen, and gastrointestinal tissues. These data support the notion that EBOV infection in rhesus macaques is a rapid systemic disease similar to infection in humans, under a compressed time scale. Biomarkers that correlated with disease progression at the earliest stages of infection were observed thereby identifying potential “trigger--to-treat” for use in therapeutic studies.
COMMUNICATION | doi:10.20944/preprints202004.0062.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; FDA approved drugs; High Throughput Virtual Screening; Sincalide; Pentagastrin.
Online: 6 April 2020 (14:09:04 CEST)
In the end of December 2019, a new strain of coronavirus was identified in the Wuhan city of Hubei province in China. Within a shorter period of time, an unprecedented outbreak of this strain was witnessed over the entire Wuhan city. This novel coronavirus strain was later officially renamed as COVID-19 (Coronavirus disease 2019) by the World Health Organization. The mode of transmission had been found to be human-to-human contact and hence resulted in a rapid surge across the globe where more than 1,100,000 people have been infected with COVID-19. In the current scenario, finding potent drug candidates for the treatment of COVID-19 has emerged as the most challenging task for clinicians and researchers worldwide. Identification of new drugs and vaccine development may take from a few months to years based on the clinical trial processes. To overcome the several limitations involved in identifying and bringing out potent drug candidates for treating COVID-19, in the present study attempts were made to screen the FDA approved drugs using High Throughput Virtual Screening (HTVS). The COVID-19 main protease (COVID-19 Mpro) was chosen as the drug target for which the FDA approved drugs were initially screened with HTVS. The drug candidates that exhibited favorable docking score, energy and emodel calculations were further taken for performing Induced Fit Docking (IFD) using Schrodinger’s GLIDE. From the flexible docking results, the following four FDA approved drugs Sincalide, Pentagastrin, Ritonavir and Phytonadione were identified. In particular, Sincalide and Pentagastrin can be considered potential key players for the treatment of COVID-19 disease.
COMMUNICATION | doi:10.20944/preprints202003.0125.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: 2019-nCoV; Darunavir; ACE-2; Receptor Binding Domain; Metastable Conformation; FDA database
Online: 7 March 2020 (16:28:05 CET)
The transnational spread of coronavirus (2019-nCoV) first detected in Wuhan is causing global panic; thus, accelerated research into clinical intervention is of high necessity. The spike glycoprotein structure has been resolved, and its affinity to human angiotensin-converting enzyme 2 (ACE-2) has been experimentally validated. Here, using computational methods, a metastable conformation of 2019-nCoV-RBD/ACE-2 complex has been revealed and FDA-database of approved drugs have been docked into the interface. Darunavir has been discovered as high ligand affinity candidate capable of disrupting communication between 2019-nCoV-RBD and ACE-2. Darunavir, in addition to its previously known anti-HIV protease inhibitor is now repurposeable for the treatment 2019-nCoV disease acting via disruption of cellular recognition, binding and invasion.
REVIEW | doi:10.20944/preprints202208.0194.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: biosimilar; analytical assessment; animal testing; clinical pharmacology; clinical efficacy; FDA; EMA; MHRA; WHO
Online: 10 August 2022 (05:19:49 CEST)
Scientific, technical and bioinformatics advances have made it possible to establish analytics-based molecular biosimilarity for the approval of biosimilars. If the molecular structure and other product- and process-related attributes are comparable within the limits of testing then a biosimilar candidate would have safe safety and efficacy as its reference products. The current model of animal and human testing becomes redundant since all of these studies have much lower sensitivity and reproducibility in confirming biosimilarity. The recent AI-based protein structure prediction model has confirmed that the 3D structure can be predicted from the amino acid sequence, reducing the need for structural analysis; however, the new test methods based on MS are millions of times more sensitive and accurate. While the regulatory agencies have begun waiving animal testing and, in some cases, clinical efficacy testing, removing clinical pharmacology profiling brings a dramatic paradigm shift, reducing development costs without compromising safety and efficacy. Also shared is a list of 160+ products ready to enter as biosimilars. Major actions from regulatory agencies and developers are required to make this paradigm shift.
REVIEW | doi:10.20944/preprints202111.0310.v1
Subject: Mathematics & Computer Science, Probability And Statistics Keywords: Functional Data Analysis (FDA); Hybrid Data; Semi-Functional Partial Linear Regression Model (SFPLR); Partial Functional Linear Regression; Literature Review
Online: 17 November 2021 (15:21:19 CET)
Background: In the functional data analysis (FDA), the hybrid or mixed data are scalar and functional datasets. The semi-functional partial linear regression model (SFPLR) is one of the first semiparametric models for the scalar response with hybrid covariates. Various extensions of this model are explored and summarized. Methods: Two first research articles, including “semi-functional partial linear regression model”, and “Partial functional linear regression” have more than 300 citations in Google Scholar. Finally, only 106 articles remained according to the inclusion and exclusion criteria such as 1) including the published articles in the ISI journals and excluding 2) non-English and 3) preprints, slides, and conference papers. We use the PRISMA standard for systematic review. Results: The articles are categorized into the following main topics: estimation procedures, confidence regions, time series, and panel data, Bayesian, spatial, robust, testing, quantile regression, varying Coefficient Models, Variable Selection, Single-index model, Measurement error, Multiple Functions, Missing values, Rank Method and Others. There are different applications and datasets such as the Tecator dataset, air quality, electricity consumption, and Neuroimaging, among others. Conclusions: SFPLR is one of the most famous regression modeling methods for hybrid data that has a lot of extensions among other models.