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Preprint REVIEW | doi:10.20944/preprints202305.1010.v2

Drugs of the Kallikrein-Kinin System: An Overview

François Marceau

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: kallikrein-kinin system; kininogens; bradykinin; B1 receptor; B2 receptor; hereditary angioedema

Online: 6 June 2023 (09:42:29 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202306.0356.v1

JAC4 Enhances Radiotherapy Effect of NSCLC and Reduces Normal Lung Injury Through Differential Regulation of JWA-mediated DNA Repair

Luman Wang, Jie Ni, Kun Ding, Chao Zhang, Aiping Li, Jianwei Zhou

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: NSCLC; JAC4; DNA repair; radiotherapy; bidirectional effect

Online: 5 June 2023 (16:38:38 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202306.0342.v1

A Comparative Study of Tumor-Specificity and Neurotoxicity Between 3-Styrylchromones and Anticancer Drugs

Tomoyuki Abe, Hiroshi Sakagami, Shigeru Amano, Shin Uota, Kenjiro Bandow, Yoshihiro Uesawa, Shiori U, Hiroki Shibata, Yuri Takemura, Yu Kimura, Koichi Takao, Yoshiaki Sugita, Akira Sato, Sei-ichi Tanuma, Hiroshi Takeshima

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: chromone derivatives; oral squamous cell carcinoma; tumor-specificity; keratinocyte toxicity; neurotoxicity; signaling pathway

Online: 5 June 2023 (15:45:48 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202306.0208.v1

Experimental Treatment with Edaravone in a Mouse Model of Spinocerebellar Ataxia 1

Martina Sucha, Simona Benediktova, Filip Tichanek, Jan Jedlicka, Stepan Kapl, Dana Jelinkova, Zdenka Purkartova, Jan Tuma, Jitka Kuncova, Jan Cendelin

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: cerebellum; edaravone; mitochondria; neurodegeneration; spinocerebellar ataxia type 1

Online: 2 June 2023 (14:01:57 CEST)

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Preprint REVIEW | doi:10.20944/preprints202305.1981.v1

Serotonergic Modulation of Neurovascular Transmission: A Focus on Prejunctional 5-Ht Receptors/Mechanisms

Abimael González-Hernández, Bruno A. Marichal-Cancino, Antoinette MaassenVanDenBrink, Carlos M. Villalón

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Serotonin; CGRP; blood pressure; migraine; hypertension

Online: 29 May 2023 (05:42:58 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202305.1844.v1

Neuroprotective Potential of L-glutamate Transporters in Human Induced Pluripotent Stem Cell-Derived Neural Cells against Excitotoxicity

Kanako Takahashi, Yuto Ishibashi, Kaori Chujo, Ikurou Suzuki, Kaoru Sato

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: excitotoxicity; human induced pluripotent stem cell; neuron; astrocyte; L-glutamate transporter; EAAT1; EAAT2

Online: 26 May 2023 (04:22:41 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202305.1179.v1

Determining the Safety of the Tobacco Cembranoid (1S,2E,4R,6R,7E,11E)-Cembratriene-4,6-diol (4R): A Translational Study in Nonhuman Primates

Nadezhda Sabeva, William Castro, Yancy Ferrer-Acosta, Pedro A Ferchmin, Vesna A Eterovic, Demetrio Sierra-Mercado, Naydi Pérez-Rios, Sona Rivas-Tumanyan, Antonio H Martins

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: cembranoids, safety, nonhuman primates, 4R

Online: 17 May 2023 (04:16:16 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202305.1086.v1

Validation of Broth Macrodilution Volatilization Method for Testing of Essential Oils in Liquid and Vapor Phase: Chemical Composition, Cytotoxicity and Antibacterial Effect of Indian Medicinal Plants Against Pneumonia-Causing Pathogens

Aishwarya Chaure, Marketa Houdkova, Julien Antih, Klara Urbanova, Ivo Doskocil, Mukund Lal Naik, Khageshwar Singh Patel, Ladislav Kokoska

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: antimicrobial activity; Cymbopogon citratus; Cyperus scariosus; GC/MS; headspace analysis; macrodilution; MTT assay; respiratory infections; Trachyspermum ammi; vapor phase; volatiles

Online: 16 May 2023 (04:56:04 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202305.1022.v1

In vitro and Reactive Metabolites Investigation of Metabolic Profiling of Tyrosine Kinase Inhibitors Dubermatinib in HLMs by LC–MS/MS

Nasser Salem Al-Shakliah, Rashad Alsalahi, Hatem Abuelizz, Adnan A. Kadi

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: N-methyl piperazine; Dubermatinib; In vitro metabolites; Cyano adducts; GSH conjugate; Xe-nosite reactivity model

Online: 15 May 2023 (10:28:28 CEST)

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Preprint REVIEW | doi:10.20944/preprints202305.1010.v1

Drugs of the Kallikrein-Kinin System: An Overview

François Marceau

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: kallikrein-kinin system; kininogens; bradykinin; B1 receptor; B2 receptor; hereditary angioedema

Online: 15 May 2023 (09:40:56 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202305.1006.v1

Novel Anti-melanoma Leads Are Efficacious in A375 Cell Line Xenograft Melanoma Model in Nude Mice

Sadeeshkumar Velayutham, Ryan Seerattan, Maab Sultan, Trisha Seal, Samaya Danthurthy, Baskaran Chinnapan, Jessica Landi, Kaitlyn Pearl, Aveta Singh, Keiran S.M. Smalley, Julia Zaias, Jun Yong Choi, Dmitriy Minond

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Melanoma; drug discovery; spliceosomal inhibition; BRAF; cell line xenograft; organ histopathology

Online: 15 May 2023 (09:19:54 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202305.0877.v1

Teratogen Potential Evaluation of the Aqueous and Hydroalcoholic Leaf Extracts of Crataegus oxyacantha in Pregnancy Rats

Fany Renata Aguilera-Rodríguez, Ana Lourdes Zamora-Perez, Rosalinda Gutiérrez-Hernández, Sol María Quirarte-Báez, Claudia Araceli Reyes Estrada, Yveth Marlene Ortiz-García, Blanca Patriicia Lazalde-Ramos

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: keyword 1; Crataegus oxyacantha 2; teratogen potential 3; micronuclei 4; Malondialdehyde

Online: 12 May 2023 (04:12:40 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202305.0807.v1

Quinone Pool, a Key Target of Plant Flavonoids Inhibiting Gram-Positive Bacteria

Li Zhang, Yu Yan, Jianping Zhu, Xuexue Xia, Ganjun Yuan, Shimin Li, Beibei Deng, Xinrong Luo

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Flavonoid; Antimicrobial mechanism; Quinone; Menaquinone; Respiratory chain; bacterium; MIC; Staphylococcus aureus; α-Mangostin

Online: 11 May 2023 (05:50:54 CEST)

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Plant flavonoids have increasingly paid a close attention to for new antimicrobial agents or adjuvants. In our previous work, it was confirmed that the cell membrane is the major site of plant flavonoids acting on the gram-positive bacteria, and which likely involves the inhibition of the respiratory chain. Inspired by the similar structural and antioxidant characters of plant flavonoids to MKH₂, we deduced that the quinone pool is probably a key target of plant flavonoids inhibiting gram-positive bacteria. To verify this, twelve plant flavonoids with six structural subtypes were preliminary selected, and their MICs against gram-positive bacteria were predicted from the antimicrobial quantitative relationship of plant flavonoids to gram-positive bacteria. The results showed they have different antimicrobial activities. After their MICs against S. aureus were determined using broth microdilution method, nine compounds with the MICs ranged from 2 to 4,096 μg/mL or more than 1,024 μg/mL were eventually selected, and then their MICs against S. aureus were determined interfered with different concentrations of MK-4 and the MKs extracted from S. aureus. The results showed that the greater the antibacterial activities of plant flavonoids were, the more greatly their antibacterial activities decreased along with the increase of the interfering concentrations of MK-4 (from 2 to 256 μg/mL) and MK extract (from 4 to 512 μg/mL), and while those, with the MICs equal to or more than 512 μg/mL, decreased a little or remained unchanged. Especially, under the interference of MK-4 (256 μg/mL) and MK extract (512 μg/mL), the MICs of α-mangostin, a compound with greatest inhibitory activity to S. aureus in these twelve plant flavonoids, increased by 16 times and 8 to16 times, respectively. Based on these above, it was proposed that the quinone pool is a key target of plant flavonoids inhibiting gram-positive bacteria, and which likely involves multiple mechanisms including some enzyme and non-enzyme inhibitions.

Preprint ARTICLE | doi:10.20944/preprints202305.0605.v1

The Pathophysiological Changes and Clinical Effects of Tetramethylpyrazine in ICR Mice with Fluoride-Induced Hepatopathy

Shuai Zhang, Yilei Zheng, Hong Du, Wei Zhang, Haohuan Li, Yangping Ou, Funeng Xu, Juchun Lin, Hualin Fu, Liren Zhang, Gang Shu

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: acute fluorosis; tetramethylpyrazine; liver; oxidative damage; Nrf2

Online: 9 May 2023 (08:34:59 CEST)

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Preprint REVIEW | doi:10.20944/preprints202305.0429.v1

Environmental Pollution by Ozone, Oxidative Stress: the Relationship between the Intestine and Neurodegenerative Disease

Selva Rivas-Arancibia, Alfredo Miranda-Martínez, Erika Rodriguez-Martinez, Eduardo Hernández-Orozco, Marlen Valdés-Fuentes, Roberto De la Rosa-Sierra

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Ozone; Oxidative stress; Bowel; Brain; Degenerative disease

Online: 8 May 2023 (03:21:21 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202305.0269.v1

Murad Tumayhi, David Banji, Ibrahim Khardali, Otilia Banji, Saeed Alshahrani, Saad Alqahtani, Safiah Muqri, Amal Abdullah, Wedad Sherwani, Ibraheem Attafi

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: forensic toxicology; amphetamine-related fatalities; brain; omega-3 fatty acids; docosahexaenoic acid; Comparative Toxicogenomic Database (CTD)

Online: 4 May 2023 (13:28:44 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202305.0255.v1

Ghassan Shaikhain, Mohammed Gaballah, Ahmad Alhazmi, Ibrahim Khardali, Ahmad Hakami, Magbool Oraiby, Sultan Alharbi, Mohammed Tobaigi, Mohammed Ghalibi, Mohsen Fageeh, Mohammed Albeishy, Ibraheem Attafi

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: forensic toxicology; khat; cathinone; cathine; postmortem

Online: 4 May 2023 (10:22:24 CEST)

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Interpreting khat-related fatalities is challenging due to a lack of data on cathinone and cathine reference concentrations in postmortem tissues. This study investigated the autopsy findings and toxicological results of Khat-related fatalities in Saudi Arabia's Jazan region from January 1, 2018 to December 31, 2021. All confirmed cathine and cathinone results in postmortem blood, urine, brain, liver, kidney, and stomach samples were recorded and analyzed. Autopsy findings and the manner and cause of death of the deceased were assessed. Saudi Arabia's Forensic Medicine Center investigated 651 fatality cases over four years. Thirty postmortem samples were positive for khat's active constituents, cathinone and cathine. The percentage of khat-related fatalities was 3% in 2018 and 2019, and increased from 4% in 2020 to 9% in 2021, when compared to all fatal cases. They were all male ranging in age from 23 to 45. Firearm injuries (10 cases), hanging (7 cases), road traffic accident (2 cases), head injury (2 cases), stab wounds (2 cases), poisoning (2 cases), unknown (2 cases), ischemic heart disease (1 case), brain tumor (1 case), and choking (1 case) were responsible for deaths. 57% of postmortem samples tested positive for khat only, while 43% tested positive for khat with other drugs. Amphetamine is the drug most frequently involved. Cathinone and cathine average concentrations were 85 and 486 ng/mL in blood, 69 and 682 ng/mL in brain, 64 and 635 ng/mL in liver, and 43 and 758 ng/mL in kidney. The 10th–90th percentiles of blood concentrations of cathinone and cathine were 18 – 218 ng/mL and 222 – 843 ng/mL, respectively. These findings show that 90% of khat-related fatalities had cathinone concentrations greater than 18 ng/mL and cathine concentrations greater than 222 ng/mL. According to the cause of death, homicidal was most common in fatalities involving khat alone (77%). More research is required, especially toxicological and autopsy findings, to determine the involvement of khat in crimes and fatalities. This study may help forensic scientists and toxicologists investigate khat-related fatalities.

Preprint ARTICLE | doi:10.20944/preprints202305.0222.v1

Inhibitory Potential of Synthetic Amino Acid Derivatives Against Digestive Enzymes–Promising Hypoglycemic and Anti-Obesity Agents

Franciane Campos da Silva, Bruna Celeida Silva Santos, Pedro Pôssa de Castro, Giovanni Wilson Amarante, Orlando Vieira de Sousa

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Amino acid derivatives; Digestive enzymes; Pancreatic lipase; Pancreatic α-Amylase; α-Glucosidase; Metabolic disorders

Online: 4 May 2023 (07:59:29 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202305.0120.v1

Chemical Composition of Essential Oil of Cymbopogon schoenanthus (L.) Spreng From Burkina Faso, and Effects Against Prostate and Cervical Cancer Cell Lines

Bagora Bayala, Laetizia Liz Coulibaly, Florencia Djigma, Julio Bunay, Albert Yonli, Lassina Traore, Silvère Baron, Gilles Figueredo, Jacques Simpore, Jean-Marc A. Lobaccaro

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Cymbopogon schoenanthus; essential oil; antioxidant; cytotoxic; antimigratory; cell cycle; cancer

Online: 3 May 2023 (09:21:43 CEST)

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Preprint REVIEW | doi:10.20944/preprints202305.0031.v1

Mast Cells as a Potential Target of Molecular Hydrogen in Regulating the Local Tissue Microenvironment

Dmitri Atiakshin, Andrey Kostin, Artem Volodkin, Anna Nazarova, Viktoriya Shishkina, Dmitry Esaulenko, Igor Buchwalow, Markus Tiemann, Mami Noda

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: molecular hydrogen; reactive oxygen intermediates; mast cells; secretome; specific mast cell proteases; local tissue microenvironment; inflammation

Online: 1 May 2023 (11:54:37 CEST)

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Preprint REVIEW | doi:10.20944/preprints202304.1141.v1

Functional Biosimilarity to Replace Clinical Efficacy Testing of mAb Biosimilars: Advancing the FDA Perspective

Sarfaraz K. Niazi

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: biosimilarity; biosimilars; pharmacodynamic biomarkers; monoclonal antibodies; FDA; clinical efficacy testing in healthy subjects; clinical efficacy testing in patients; functional assays; receptor binding

Online: 28 April 2023 (08:03:20 CEST)

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Preprint REVIEW | doi:10.20944/preprints202304.1116.v1

Physiological Activity of Trace Element Germanium Including Anticancer Properties

Leonid G. Menchikov, Anatoliy V. Popov

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: germanium compounds; Ge-132; germatrane; biological activity; cancer; Warburg effect

Online: 28 April 2023 (04:53:49 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202304.0625.v1

Clinical Use of Cisplatin Liposomes for Patients With Refractory Advanced Cancer

Yasuo Komura, Shintarou Kimura, Tomoko Katagiri, Yumi Hirasawa, Misaki Hirayama, Tomonori Okuda, Hiromi Muranishi, Koichiro Homma

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: adverse drug reaction; cisplatin liposomes; circulating tumor cells; enhanced permeability and retention effect; nephrotoxicity; pulmonary metastasis of pancreatic cancer; quality of life; recurrent liver metastases from primary nasal cancer

Online: 20 April 2023 (07:52:10 CEST)

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Preprint BRIEF REPORT | doi:10.20944/preprints202303.0532.v1

Genomic analysis of Carbapenem-resistance conferring genes in Klebsiella pneumoniae

Sabbarinath Subramanian

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Carbapenem, Antimicrobial Resistance, Klebsiella pneumoniae, genomic context

Online: 30 March 2023 (13:02:47 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202303.0502.v1

Antituberculosis Propensity of Synthetic Biscoumarin Derivatives: An In Silico and In Vitro Approach

Bashir A Sheikh, Basharat Ahmad Bhat, Humaira Zareen, Masood A Rizvi, Zahoor Ahmad, Mustfa Alkhanani, Abdullah Almilaibary, Suliman A Alsagaby, Manzoor Ahmad Mir

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Tuberculosis; Biscoumarins; Ligand molecules; DprE1; Anti-tuberculosis activity; Molecular docking; MD Simulation; Cytotoxicity

Online: 29 March 2023 (04:21:45 CEST)

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Preprint REVIEW | doi:10.20944/preprints202303.0464.v1

Reinventing Therapeutic Proteins: Optimizing Investments and Meeting Humanitarian Needs

Sarfaraz K. Niazi, Zamara Mariam

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Therapeutic proteins; Recombinant proteins; Repurposing; Reinventing, Drug-antibody combinations, AI/ML, Efficacy improvement, Immunogenicity; Artificial Intelligence; mRNA; High throughput analysis

Online: 27 March 2023 (14:02:03 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202303.0455.v1

Prevalence and Antibiotic Resistance Pattern of Streptococcus, Staphylococcus, Neisseria meningitidis and Enterobacteriaceae in Two Reference Hospitals of Yaoundé: An Overview before and during COVID-19 Pandemic Era

Cecile Ingrid Djuikoue, Willy Yamdeu Djonkouh, Cavin Epie Bekolo, Rodrigue Kamga Wouambo, Raspail Carrel Founou, Paule Dana Djouela Djoulako, Gilder Tonfack Temgoua, Benjamin D. Thumamo Pokam, Nicolas Antoine-Moussiaux, Teke R. Apalata

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: resistant bacteria; COVID-19 pandemic era; antibiotics

Online: 27 March 2023 (08:59:13 CEST)

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Abstract: The overuse of antibiotic prophylaxis during the COVID-19 pandemic would have led to the devel-opment of antibiotic-resistant bacterial strains, thereby increasing the epidemiological burden of antimicrobi-al resistance. The aim of this study was to determine the prevalence and antibiotic resistance pattern of bacte-ria isolated in 02 referral health facilities in Yaoundé before and during the COVID-19 pandemic era. We conducted a retrospective study over a period of 03 years (from 1 January 2019 to 31 December 2021) in the bacteriology units of the Central and General Hospitals of Yaoundé, Cameroon. The review of the services' registers was done to record bacterial isolates (Streptococcus, Staphylococcus, Neisseria meningitidis and Entero-bacteriaceae) as well as their susceptibility to selected, specific and highly potent antibiotics: Cefixime, Azythromycin and Erythromycin. The relationship between each group of resistant bacteria and the antibiotic of interest was determined by simple linear regression; the comparison of the prevalences of before (2019) and during 2 consecutive years of the COVID-19 pandemic onset (2020 and 2021) was done by the Chi2 test of in-dependence. In all, 426 bacterial strains were included. It appeared that the highest number of bacteria iso-lates and lowest rate of bacterial resistance were recorded during the pre-COVID 2019 period in 2019 (160 isolates vs. 58.8% resistance rate). Conversely, lower bacteria stains but greater resistance burden were rec-orded during the pandemic era (2020 and 2021) with the lowest bacteria amount and peak of bacteria re-sistance registered in 2020, the year of COVID-19 onset (120 isolates vs. 70% resistance in 2020 and 146 iso-lates vs.58.9% resistance in 2021). In contrast to almost all others groups of bacteria where the resistance burden was quite constant over years, the Enterobacteriaceae exhibited greater resistance rate during the pandemic period [60%(48/80) in 2019 to 86.9%(60/69) in 2020 and 64.5%(61/95) in 2021)]. Concerning antibiotics, unlike Erythromycin, Azythromycin related resitance increased during the pandemic period and the resistance to Cefixim tends to decrease the year of the pandemic onset (2020) and re-increase one year therafter. A significant association was found between resistant Enterobacteriaceae strains and Cefixime (R= 0.7; P-value= 0.0001) and also, between resistant Staphylococcus strains and Erythromycin (R= 0.8; P-value= 0.0001). It could be that the more frequent use of these antibiotics has increased resistance rate especially in Enterobacteriaceae. Anticromicrobial resistance should be closely monitor during and after COVID pandemic era.

Preprint ARTICLE | doi:10.20944/preprints202303.0411.v1

Stachydrine and Synephrine, a Pair of Bioactive Equilibrists in Four Chinese Herbs from Citrus Genus

Yifei Sun, Xuexue Xia, Ganjun Yuan, Tongke Zhang, Beibei Deng, Xinyu Feng, Qixuan Wang

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Choline; Citrus; method; analysis; decoction; Zhishi; Zhiqiao; effect; cardiovascular protection; uterus

Online: 23 March 2023 (08:36:04 CET)

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Preprint REVIEW | doi:10.20944/preprints202211.0221.v3

Tucaresol: A Unique Oral Candidate Drug Ideally Accessible for Treatment of COVID-19 Disease

Christopher Penney, Boulos Zacharie, Jean-Simon Duceppe

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Tucaresol; COVID-19; SARS-CoV-2; HIV; T helper cell; CD4 receptor

Online: 14 March 2023 (08:51:05 CET)

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Abstract: The SARS-CoV-2 pandemic has significantly impacted world health and economic status. In response, much work has been undertaken to provide effective, safe vaccines, antibodies and antiviral drugs with which to address this pandemic. Treatment of a pandemic population presents multiple challenges in addition to the primary issue of drug efficacy and safety, such as large scale drug manufacture and distribution, drug stability, oral dosing and pharmacoeconomic considerations. Ideally, these factors must be addressed if new candidate drugs are to be advanced for treatment of large (pandemic) populations. Subsequently, new antivirals have reached the market but choices are few. According to the NIH Covid Treatment Guidelines, only three small molecule antiviral drugs are available to treat COVID-19 disease. As such, a significant part of the research towards discovery of new antiviral drugs has focused on screening and evaluation of ‘repurposed drugs’ or previously approved or clinical stage drugs. Yet, in spite of this increased research activity, one promising clinical stage candidate drug has received little attention regarding its potential as a monotherapy or component of combination therapy for treatment of COVID-19 disease. Tucaresol, with documented human safety and pharmacokinetic data, is an orally active, stable, small molecule amenable to large scale manufacture by a proprietary two-step synthesis developed by us. Tucaresol functions as a host-targeted antiviral by selective protection/reconstitution of CD4+ T helper cells as demonstrated in HIV patients and SIV macaques. In view of similarities between HIV and SARS-CoV-2, especially with respect to host CD4+ T helper cells, and the suitability of Tucaresol for facile treatment of pandemic populations, Tucaresol is presented herein for treatment of mild-to-moderate COVID-19 patients but may also be useful for treatment of advanced disease accompanied by lymphopenia.

Preprint ARTICLE | doi:10.20944/preprints202303.0234.v1

The Effects of Antiperspirant Aluminum Chlorohydrate on the Development of Antibiotic Resistance in Staphylococcus epidermidis

Ayse Aras, Suna Sibel Rizvanoglu, Elif Seren Tanriverdi, Basar Karaca, Mujde Eryilmaz

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: aluminum chlorohydrate; antibiotic resistance; minimum inhibitory concentration; quantitative reverse transcriptase-PCR; Staphylococcus epidermidis

Online: 13 March 2023 (14:04:54 CET)

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Preprint ARTICLE | doi:10.20944/preprints202303.0231.v1

Antidotal Effect of Dihydroxyacetone in Aluminum Phosphide-Intoxicated Patients

Reza Heidari, Hossein Niknahad, Ali Jangjoo, Vahidreza Asghari

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Aluminum phosphide; Clinical Toxicology; Dihydroxyacetone; Pharmacotherapy; Phosphine; Suicide; Toxicity

Online: 13 March 2023 (10:37:23 CET)

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Background: Aluminum phosphide (AlP), also known as “rice tablet,” is widely used as an effective pesticide. However, AlP poisoning is a common cause of mortality in many countries, such as Iran. Unfortunately, there is no specific antidote for AlP toxicity to date. AlP releases phosphine gas when it is exposed to moisture and acid. Phosphine is a robust mitochondrial toxin that could significantly inhibit cellular energy metabolism. AlP poisoning is an emergency condition that needs instant and effective intervention. Dihydroxyacetone (DHA) is a simple saccharide used for several pharmacological as well as cosmetic purposes. Previously, we found that DHA could significantly prevent mitochondrial impairment induced by toxic agents such as cyanide and phosphine in various in vitro and in vivo experimental models.Methods: Hospitalized patients (n = 111) were evaluated for eligibility criteria. Among these patients, n = 35 cases were excluded due to incomplete data (n = 11) and suspicion of poisoning rather than AlP (n = 24). Meanwhile, n = 76 cases with confirmed AlP poisoning were included in the study. AlP-poisoned patients who did not receive DHA (n =18) were used as the control group.Patients (n = 58) received at least one dose of DHA (500 ml of 5% DHA solution w/v, i.v.) in addition to routine treatment of AlP poisoning. Arterial blood gas (ABG), blood pH, bicarbonate levels, and other vital signs and biochemical measurements were monitored. Moreover, the mortality rate and time of hospitalization were evaluated in both DHA-treated (n = 58) and AlP-poisoned patients without DHA administration (n = 18). Several biomarkers were assessed before (upon hospitalization) and after DHA treatment. The routine tests for AlP-poisoned patients in this study were the measurement of electrolytes (K+ and Na+), WBC, RBC, hemoglobin, INR, carbonate (HCO3), blood pH, PaCO2, and PaO2 and SGPT, SGOT, BUN, Cr. Results: Upon patients' admission, significant decreases in blood pH (acidosis), blood PaO₂, and HCO₃ levels were the hallmarks of AlP poisoning. It was found that DHA significantly alleviated biomarkers of AlP poisoning and tremendously enhanced patients’ survival rate compared to patients treated based on hospital routine AlP poisoning protocols (no DHA). No significant adverse effects were evident in DHA-treated patients in the current study.Interpretation: These data suggest that parenteral DHA is a novel and effective antidote against AlP poisoning.Trial registration: IR.SUMS.REC.1394.102

Preprint ARTICLE | doi:10.20944/preprints202303.0193.v1

Complex Networks Analyses of Antibiofilm Peptides: An Emerging Tool for Next Generation Antimicrobials Discovery

Guillermin Agüero-Chapin, Agostinho Antunes, José R. Mora, Noel Pérez, Ernesto Contreras‑Torres, José R. Valdes-Martini, Felix Martinez-Rios, Cesar H. Zambrano, Yovani Marrero-Ponce

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Antibiofilm peptide; chemical space; StarPep toolbox; complex network; centrality measure; motif discovery

Online: 10 March 2023 (09:36:30 CET)

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Preprint ARTICLE | doi:10.20944/preprints202303.0151.v1

Trichoderma asperellum Extract Isolated From Brazil Nuts (Bertholletia excelsa. BONPL): In Vivo and In Silico Studies on Melanogenesis in Zebrafish

Adriana Maciel Ferreira, Iracirema da Silva Sena, Jhone Curti, Agerdânio Andrade De Souza, Paulo Cesar dos Santos Lima, Alex Bruno Lobato Rodrigues, Ryan da Silva Ramos, Wandson Braamcamp de Souza Pinheiro, Irlon Maciel Ferreira, José Carlos Tavares Carvalho

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Amazon fungi; Fungus extract; Trichoderma asperellum; Melanogenesis; Zebrafish

Online: 8 March 2023 (08:48:58 CET)

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Preprint ARTICLE | doi:10.20944/preprints202303.0012.v1

Vegetable Oil-Peroxidation Product ‘Hydroxynonenal’ Causes Hepatic Injury and Steatosis by Hsp70.1 and BHMT Disorders

Tetsumori Yamashima, Yurie Mori, Takuya Seike, Sharif Ahmed, Piyakarn Boontem, Shihui Li, Shinji Oikawa, Hatasu Kobayashi, Tatsuya Yamashita, Mitsuru Kikuchi, Shuichi Kaneko, Eishiro Mizukoshi

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: betaine-homocysteine S-methyltransferase; calpain-cathepsin hypothesis; carbonylation; cell death; lysosomal rupture; phosphatidylcholine

Online: 1 March 2023 (07:45:34 CET)

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Hsp70.1 has dual functions as chaperone protein and lysosomal stabilizer. Previously, we reported that calpain-mediated cleavage of carbonylated Hsp70.1 causes ischemic neuronal death by inducing lysosomal rupture. Recently, we found that the consecutive injections of vegetable oil-peroxidation product ‘hydroxynonenal’ induces hepatocyte death via the similar cascade. As Hsp70.1 is related also to fatty acid β-oxidation in the liver, its deficiency is known to cause accumulation of fat. Genetic deletion of betaine-homocysteine S-methyltransferase (BHMT) was reported to perturb choline metabolism, inducing decrease of phosphatidylcholine with the resultant hepatic steatosis. Here, focusing on disorders of Hsp70.1 and BHMT, we studied the mechanism of hepatocyte degeneration and steatosis, using monkeys after the consecutive injections of synthetic hydroxynonenal. As these monkeys showed a significant impairment of liver functions, the liver tissues without and with hydroxynonenal injections were compared by proteomics, immunoblotting, immunohisto-chemical and electron microscopic analyses. Western blotting showed upregulation of neither Hsp70.1 nor BHMT, but an increased cleavage of both proteins. Proteomics showed downregulation of Hsp70.1, while 2-fold increments of carbonylated BHMT. Hsp70.1 carbonylation was negligible, showing a marked contrast to ischemic neurons which were associated with ~10-fold increments. The control liver histologically showed lipid droplets in Ito cells, but lipid depositions within hepatocytes were very little. In contrast, after hydroxynonenal injections, widespread fatty degeneration and focal coagulation necrosis were observed with accumulation of numerous tiny lipid droplets within and around the degenerating/dying hepatocytes. Electron microscopy showed lysosomal membrane permeabilization/rupture, remarkable dissolution of mitochondria and rough ER membrane, and proliferation of abnormal peroxisomes. It is probable that disruptions of rough ER caused impaired synthesis of Hsp70.1 and BHMT proteins, while impairments of mitochondria and peroxisomes presumably contributed to the sustained generation of reactive oxygen species. Since both Hsp70.1 and BHMT are vulnerable to the long-standing oxidative stressor, hydroxynonenal-induced disorders facilitated degeneration and steatosis of hepatocytes, respectively.

Preprint REVIEW | doi:10.20944/preprints202302.0510.v1

Combining Copper and Zinc into a Biosensor for Anti-Chemoresistance and Achieving Osteosarcoma Therapeutic Efficacy

Yan Yik Lim, Ahmad Mujahid Ahmad Zaidi, Azizi Miskon

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Metal-Based Drugs; CuZn; Anti-Chemoresistance; Osteosarcoma Therapy; Ligand Biosensors.

Online: 28 February 2023 (06:51:00 CET)

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Preprint ARTICLE | doi:10.20944/preprints202302.0447.v1

Urinary Excretion Kinetics of Salbutamol and Its Sulfoconjugated Main Metabolite After Oral and Inhalative Administration of Racemic Salbutamol or Levosalbutamol

Annika Lisa Jendretzki, Lukas Corbinian Harps, Yanan Sun, Felix Bredendiek, Matthias Bureik, Ulrich Girreser, Xavier De la Torre, Francesco Botrè, Maria Kristina Parr

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: salbutamol; metabolism; excretion rates; salbutamol-4’-O-sulfate; bioanalysis; biosynthesis; SULT1A3

Online: 27 February 2023 (06:27:43 CET)

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Preprint REVIEW | doi:10.20944/preprints202302.0173.v1

Proposing Intranasal Rifampin for Alzheimer’s Disease and the Other Age-Related Neurodegenerative Proteinopathies

Coad Thomas Dow, Laith Kidess

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: ifampin; proteinopathies; permeability glycoprotein; intranasal; bi-directional; Alzheimer’s; Parkinson’s; Lewy body dementia; multiple system atrophy; huntington’s; amyotrophic lateral sclerosis/frontotemporal dementia spectrum

Online: 10 February 2023 (02:31:56 CET)

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Preprint ARTICLE | doi:10.20944/preprints202302.0152.v1

Frontline Sodium Channel-Blocking Antiseizure Medicine Use Promotes Future Onset of Drug-Resistant Chronic Seizures

Dannielle Zierath, Stephanie Mizuno, Melissa Barker-Haliski

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: carbamazepine; levetiracetam; gabapentin; perampanel; valproic acid; phenobarbital; topiramate; neurogenesis; Ki-67

Online: 9 February 2023 (03:00:09 CET)

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The mechanisms of treatment-resistant epilepsy remain unclear. We have previously shown that frontline administration of therapeutic doses of lamotrigine (LTG), which preferentially inhibits the fast-inactivation state of sodium channels, during corneal kindling of mice promotes cross-resistance to several other antiseizure medicines (ASMs). However, whether this phenomenon extends to monotherapy with ASMs that stabilize the slow inactivation state of sodium channels is unknown. Therefore, this study assessed whether lacosamide (LCM) monotherapy during corneal kindling would promote future development of drug-resistant focal seizures in mice. Male CF-1 mice (n=40/group; 18-25 g) were administered an anticonvulsant dose of LCM (4.5 mg/kg, ip), LTG (8.5 mg/kg, ip), or vehicle (0.5% methylcellulose) twice daily for two weeks during kindling. A subset of mice (n=10/group) were euthanized 1 day after kindling for immunohistochemical assessment of astrogliosis, neurogenesis, and neuropathology. The dose-related antiseizure efficacy of distinct ASMs, LTG, LCM, carbamazepine, levetiracetam, gabapentin, perampanel, valproic acid, phenobarbital, and topiramate was then assessed in remaining kindled mice. Neither LCM nor LTG administration prevented kindling: 29/39 vehicle-exposed mice were kindled; 33/40 LTG-exposed mice were kindled; and 31/40 LCM-exposed mice were kindled. Mice administered LCM or LTG during kindling became resistant to escalating doses of LCM, LTG, and carbamazepine. Perampanel, valproic acid, and phenobarbital were less potent in LTG- and LCM-kindled mice, whereas levetiracetam and gabapentin retained equivalent potency across groups. Notable differences in reactive gliosis and neurogenesis were also appreciated. This study indicates that early, repeated administration of sodium channel blocking ASMs, regardless of inactivation state preference, promotes pharmacoresistant chronic seizures. Inappropriate ASM monotherapy in newly diagnosed epilepsy may thus be one driver of future drug-resistance, with resistance being highly ASM class-specific.

Preprint REVIEW | doi:10.20944/preprints202208.0008.v2

Sidney Ley

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: influenza; antivirals; umifenovir; neuraminidase inhibitors; adamantanes; cap-dependent endo-nuclease inhibitors

Online: 7 February 2023 (06:22:28 CET)

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Preprint ARTICLE | doi:10.20944/preprints202302.0114.v1

Study of Technological Parameters of Antioxim Compound Medicine

Feruza Baxtiyarovna Ismailova, Holida Mannanovna Yunosova

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: dry extract; antioxidant; collection of plant; phytopreparation; antioxidant compound medicine; technological parameters

Online: 7 February 2023 (02:59:51 CET)

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Preprint REVIEW | doi:10.20944/preprints202302.0042.v1

Targeting Matrix Exopolysaccharides to Disrupt Pseudomonas aeruginosa Biofilms in Cystic Fibrosis

Jonathan Chung, Shafinaz Eisha, Subin Park, Amanda Morris, Isaac Martin

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Cystic fibrosis; Pseudomonas aeruginosa; antibiotic adjunct; anti-biofilm; biofilm-degrading enzymes; matrix exopolysaccharides; alginate oligosaccharide

Online: 2 February 2023 (09:38:31 CET)

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Preprint REVIEW | doi:10.20944/preprints202301.0528.v1

Therapeutic Properties of Polyphenols Affect AMPK Molecular Pathway in Hyperlipidemia

Mohammadjavad Sotoudeheian, SeyedAhmad Hoseini, Seyed-Mohamad-Sadegh Mirahmadi

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: AMPK; Polyphenols; Dyslipidemia; Nrf2

Online: 29 January 2023 (10:39:25 CET)

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Preprint REVIEW | doi:10.20944/preprints202212.0574.v2

Mass Spectrometry-Based Techniques Towards OMICS 2.0

Ivan Šoša

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: cost; mass spectrometry; OMICS; OMICS 2.0: Society 5.0;

Online: 27 January 2023 (06:59:30 CET)

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Preprint REVIEW | doi:10.20944/preprints202301.0449.v1

Classification, Perception, Sociological Aspects, and Toxicity of Emerging Flavored Oral Nicotine Pouches

Sadiya Bi Shaikh, Chad Newton, Wai Cheung Tung, Yehao Sun, Dongmei Li, Deborah Ossip, Irfan Rahman

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: ONPs; tobacco; nicotine; flavors; perception; toxicity; menthol

Online: 25 January 2023 (09:33:04 CET)

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Introduction: Oral Nicotine Pouches (ONPs) are the new form of nicotine pouches that have become a type of emerging smokeless tobacco product sold by various tobacco companies. These smokeless tobacco products are being marketed for usage all over as Snus containing tobacco-derived nicotine (Natural) or as tobacco-free nicotine (Synthetic) as substitutes for other tobacco products that are limited in public places. ONPs have become popular tobacco products among adolescents/young adults and over 50% of young adult users of ONP use flavored ONP, such as menthol/mint, tobacco, dessert/candy, and fruity, being the most popular flavors. Various new ONP flavors are currently popular locally as well in the online market. Tobacco, Menthol, and fruit-flavored ONPs could motivate cigarette smokers to alteration to ONPs. Methods: We expanded our knowledge on natural/synthetic ONP flavors wheels to available data on ONPs, describing in detail their flavors and brands (US and Europe) in both natural/Synthetic ONP categories. We classified over 152 snus and 228 synthetic ONPs into the following flavor categories: “Tobacco”, “Menthol/Mint”, “Fruity”, “Candy/Deserts”, “Drink”, “Aroma”, “Spices” and “Mixed Flavors”. Results: Based on total numbers, wefound that the most popular ONPs flavor sold as tobacco and menthol to be among natural ONPs, among synthetic ONPs fruity and menthol as the most prominent flavors with varying concentrations of nicotine and other flavoring chemicals including coolant WS-23. We also illustrated possible molecular targets and toxicities due to exposure to ONPs activating several signaling cascades like AKT and NF-B might possibly lead to apoptosis and epithelial mesenchymal transition (EMT). Conclusions: Considering the marketing of ONP products with various flavor profiles and most of these products containing tobacco/menthol/fruit flavor, it is likely to have regulation and marketing disclaimer on some of these products. Further, it would be logical to determine how the market reacts in terms of compliance and non-compliance with flavor restrictions by the regulatory agencies.

Preprint ARTICLE | doi:10.20944/preprints202301.0440.v1

Safety Profile of Standard and Booster Covid-19 Vaccines in Physicians in Quito-Ecuador. A Cross-Sectional Study

Nancy Jeanneth Flores-Lastra, Josue David Rivadeneira-Dueñas, Luis Ernesto Fuenmayor-González, Glenda Guayasamín-TIpanta, Michelle Jácome-García, Tamara Otzen, Carlos Manterola

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: COVID-19 Vaccines; BNT162 Vaccine; ChAdOx1 nCoV-19; Side Effects and Adverse Reactions; Booster Immunizations; COVID-19; SARS-CoV-2

Online: 25 January 2023 (03:50:52 CET)

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Preprint ARTICLE | doi:10.20944/preprints202301.0371.v1

Network Pharmacological Analysis of a New Herbal Combination Targeting Hyperlipidemia and Efficacy Validation in Vitro

Tae-Hyoung Kim, Ga-Ram Yu, Hyuck Kim, Jai-Eun Kim, Dong-Woo Lim, Won-Hwan Park

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Network pharmacology; GO enrichment analysis; Key target validation; Hyperlipidemia; Hepatic steatosis; herbal combination; combinational effect; Arum ternata; Poria cocos; Zingiber officinale

Online: 20 January 2023 (06:41:44 CET)

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Preprint ARTICLE | doi:10.20944/preprints202301.0359.v1

Preliminary Evidence of Good Safety Profile and Outcomes of Early Treatment With Tixagevimab/Cilgavimab Compared to Previously Employed Monoclonal Antibodies for COVID-19 in Immunocompromised Patients

Andrea Lombardi, Giulia Viero, Simone Villa, Simona Biscarini, Emanuele Palomba, Cecilia Azzara', Nathalie Iannotti, Bianca Mariani, Camilla Genovese, Mara Tomasello, Anna Tonizzo, Marco Fava, Antonia Grazia Valzano, Letizia Morlacchi, Maria Francesca Donato, Giuseppe Castellano, Ramona Cassin, Maria Carrabba, Antonio Muscatello, Andrea Gori, Alessandra Bandera

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: monoclonal antibodies; tixagevimab/cilgavimab; immunocompromised

Online: 19 January 2023 (12:00:57 CET)

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Preprint ARTICLE | doi:10.20944/preprints202301.0305.v1

Molecular Docking and ADMET Prediction of Modified and Derivative Forms of 2-Deoxy-D-glucose against COVID-19 Main Protease Complex: In silico Approach

Rashmi Rekha Samal, Suryasikha Samal, Choudhury Suryakant Mishra, Atala Bihari Jena, Asim K Duttaroy

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Covid-19; Deoxy-D-glucose; molecular docking; ADMET

Online: 17 January 2023 (09:32:43 CET)

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Preprint ARTICLE | doi:10.20944/preprints202212.0244.v2

Metformin Therapy and Breast Cancer Incidence in the Hail Region

Mhdia Osman, Taif Muqbel, Ahad Alenzi, Shuruq Alenzi, Nasrin Kalifa, Weam Khojali, Halima Mustafa Elagib, Weiam Hussein, Marwa H. Abdallah

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: breast cancer; diabetes; metformin

Online: 13 January 2023 (07:29:32 CET)

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Preprint REVIEW | doi:10.20944/preprints202301.0195.v1

Capillary Leak Syndrome after SARS-CoV-2 Infection and COVID-19 Vaccines: A Comparative Review

Zeinab Mohseni Afshar, Hossein Nazari Rostami, Ali Tavakoli Pirzaman, Rezvan Hosseinzadeh, Arefeh Babazadeh, Dariush Hosseinzadeh, Seyed Rouhollah Miri, Terence T. Sio, Mohammad Barary, Soheil Ebrahimpour

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: COVID-19; COVID-19 vaccines; capillary leak syndrome

Online: 11 January 2023 (09:41:36 CET)

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Preprint ARTICLE | doi:10.20944/preprints202301.0170.v1

Self-Micellizing Solid Dispersion of Thymoquinone with Enhanced Biopharmaceutical and Nephroprotective Effects

Shimul Halder, Sanjida Afrose, Manik Chandra Shill, Nahid Sharmin, Patricia Prova Mollick, Madhabi Lata Shuma, Md. Abdul Muhit, S. M. Abdur Rahman

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: biopharmaceutical; nephroprotective; oral absorption; self-micellizing solid dispersion; thymoquinone.

Online: 10 January 2023 (03:09:17 CET)

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Preprint ARTICLE | doi:10.20944/preprints202301.0087.v1

Combination of Farnesol with Common Antifungal Drugs: Inhibitory Effect against Clinical Isolates of Candida Species

Fatemeh Nikoomanesh, Mahsa Falahati, André Luis Souza Dos Santos, Célia Fortuna Rodrigues, Shahla Roudbar Mohammadi, Mitra Rafiee, Lucia Černáková, Maryam Roudbary

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: vulvovaginal candidiasis; farnesol; azoles; resistance

Online: 5 January 2023 (02:03:12 CET)

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Preprint ARTICLE | doi:10.20944/preprints202301.0050.v1

Declining Frequency of Chloroquine-resistant Haplotype of Plasmodium falciparum (CVIET) in an Endemic Area of Southwest Nigeria 17 Years After Withdrawal of Chloroquine

Abiodun I. Amusan, Olugbenga Akinola, Kazeem Akano, Maria A. Hernández-Castañeda, Jenna K. Dick, Akintunde Sowunmi, Geoffrey T. Hart, Grace Olusola Gbotosho

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Plasmodium falciparum chloroquine resistance; mutations; CVINT; malaria; allele frequency

Online: 4 January 2023 (03:04:50 CET)

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Preprint REVIEW | doi:10.20944/preprints202212.0574.v1

Mass Spectrometry-Based Techniques Towards OMICS 2.0

Ivan Šoša

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: cost; mass spectrometry; OMICS; OMICS 2.0: Society 5.0; sustainability

Online: 30 December 2022 (08:31:29 CET)

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Preprint ARTICLE | doi:10.20944/preprints202212.0440.v1

Implementation of Antimicrobial Stewardship in a District Hospital in the Ashanti Region of Ghana Using a Health Partnership Model

Obed Kwabena Offe Amponsah, Aaron J. Courtenay, Ahmed Abuelhana, Nana Kwame Ayisi-Boateng, Douglas Anning Opoku, Lawrence Kobbina Blay, Nana Akua Abruquah, Annabella Bensusan Osafo, Charlotte Boachie Danquah, Phyllis Tawiah, Mercy Naa Aduele Opare-Addo, Alex Owusu-Ofori, Kwame Ohene Buabeng

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Antimicrobial stewardship; Point prevalence survey; Antimicrobial resistance; Ghana; CwPAMS; Antibiotic use; THET

Online: 23 December 2022 (03:53:09 CET)

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Preprint ARTICLE | doi:10.20944/preprints202212.0419.v1

Shallow and Deep-water Ophiura Species Produce a Panel of Chlorin Compounds with Potent Photodynamic Anticancer Activities

Antonina Klimenko, Robin Huber, Laurence Marcourt, Dmitry Tabakaev, Alexey Koval, Salim Sh. Dautov, Tatyana N. Dautova, Jean-Luc Wolfender, Rob Thew, Yuri Khotimchenko, Emerson Ferreira Queiroz, Vladimir L. Katanaev

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: marine organisms; chlorins; photodynamic therapy; brittle stars; Ophiuroidea; phototoxicity; cancer

Online: 22 December 2022 (05:02:21 CET)

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Preprint ARTICLE | doi:10.20944/preprints202212.0320.v1

Efficacy and Effectiveness of the Herbal Medicinal Product BNO 1016 in the Management of Acute Rhinosinusitis in the Context of Antibiotic Stewardship

Claudia B. Bittner, Hubert Steindl, Dimitri Abramov-Sommariva, Michael Plach, Christoph Abels, Claus Bachert

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: BNO 1016; antibiotics; herbal medicine; sinusitis; phytotherapy

Online: 19 December 2022 (04:05:48 CET)

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Preprint REVIEW | doi:10.20944/preprints202212.0276.v1

Rethinking the Paradoxical Increase in Endogenous Glucose Production in Response to Metformin: Should We Retain the Glucagon Antagonistic Effect of the Drug?

Jabeur Methnani, Taieb Ach, Aymen El Hraiech, Imed Latiri, Ali Bouslama, Monia Zaouali, Asma omezzine, Ezdine Bouhlel

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Biguanides; Antihyperglycemic agents; Liver alpha-cell axis; gluconeogenesis; Protein metabolism; insulin sensitivity

Online: 15 December 2022 (08:37:28 CET)

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Preprint REVIEW | doi:10.20944/preprints202212.0175.v1

Dexrazoxane: Exposing the Vulnerability of SARS-CoV-2

Keith McCormack

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: SARS-CoV-2; Poly(A); dexrazoxane; supramolecular self-assembly; base stacking

Online: 9 December 2022 (09:55:12 CET)

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Preprint ARTICLE | doi:10.20944/preprints202212.0170.v1

Low-intensity Pulsed Ultrasound-mediated Blood-brain Barrier Opening Increases Anti-programmed Death-ligand 1 Delivery and Efficacy in Gl261 Mouse Model

Mohammed H Ahmed, Emie Quissac, Nolwenn Lemaire, Isaias Hernández-Verdín, Noël Zahr, Charlotte Schmitt, Guillaume Bouchoux, Michael Canney, M.D. Santin, Alexandra Petiet, Laura Mouton, Coralie Guerin, Lea Guyonnet, Marc Sanson, Maïté Verreault, Alexandre Carpentier, Ahmed Idbaih

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: SonoCloud; GL261 mouse model; ultrasound-mediated drug delivery; glioblastoma; immune checkpoint inhibitors

Online: 9 December 2022 (02:59:28 CET)

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Preprint ARTICLE | doi:10.20944/preprints202212.0162.v1

Stability Study of Temocillin for Outpatient Parenteral Antimicrobial Therapy

Beatriz Fernández-Rubio, Laura Herrera-Hidalgo, María Victoria Gil-Navarro, Luis E López-Cortés, Jesús Rodríguez-Baño, Rafael Luque-Márquez, Arístides De Alarcón, Sonia Luque-Pardos, Autora Fernández-Polo, José María Gutiérrez-Urbón, Alicia Gutiérrez-Valencia

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Temocillin; Stability; Outpatient Parenteral Antimicrobial Therapy; Temperatures; Elastomeric devices; Infusion bags

Online: 8 December 2022 (14:32:52 CET)

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Preprint ARTICLE | doi:10.20944/preprints202212.0140.v1

High-Throughput Drug Screening on Borrelia Garinii and Borrelia Afzelii Identified Hypocrellin A as an Active Drug Candidate against Borrelia Species

Tingting Li, Yuxian Xin, Dongxia Liu, Jingrong Sun, Jingwei Li, Ying Zhang, Jie Feng

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Drug screening; Borrelia afzelii; Borrelia garinii; Persister; Hypocrellin A; biofilm

Online: 8 December 2022 (02:24:04 CET)

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Preprint ARTICLE | doi:10.20944/preprints202212.0084.v1

Relationships between Effects of Ag Nanoparticles and Ag Salt on Behavioral and Cognitive Functions of Mice and Ageing

Anna A. Antsiferova, Marina Yu. Kopaeva, Pavel K. Kashkarov

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: nanoform; nanoparticle; nanoparticles; silver; silver citrate; ageing; behavioral functions; cognitive functions; stress; individual content

Online: 6 December 2022 (01:33:04 CET)

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Preprint REVIEW | doi:10.20944/preprints202212.0022.v1

FABRY DISEASE: Switch from Enzyme Replacement Therapy to Oral Chaperone Migalastat. What Do We Know Today?

Fernando Perretta, Sebastián Jaurretche

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Fabry disease; globotriaosylceramide; α-galactosidase-A; enzyme replacement therapy; chaperone therapy; migalastat

Online: 1 December 2022 (09:50:49 CET)

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Preprint REVIEW | doi:10.20944/preprints202211.0221.v2

Tucaresol: A Unique Oral Candidate Drug Ideally Accessible for Treatment of COVID-19 Disease

Christopher Penney, Boulos Zacharie, Jean-Simon Duceppe

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Tucaresol; COVID-19; SARS-CoV-2; HIV; T helper cell; CD4 receptor

Online: 28 November 2022 (07:29:24 CET)

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Abstract: The SARS-CoV-2 pandemic has significantly impacted world health and economic status. In response, much work has been undertaken to provide effective, safe vaccines, antibodies and antiviral drugs with which to address this pandemic. Treatment of a pandemic population presents multiple challenges in addition to the primary issue of drug efficacy and safety, such as large scale drug manufacture and distribution, drug stability, oral dosing and pharmacoeconomic considerations. Ideally, these factors must be addressed if new candidate drugs are to be advanced for treatment of large (pandemic) populations. Subsequently, new antivirals have reached the market but choices are few. According to the NIH Covid Treatment Guidelines, only three small molecule antiviral drugs are available to treat COVID-19 disease. As such, a significant part of the research towards discovery of new antiviral drugs has focused on screening and evaluation of ‘repurposed drugs’ or previously approved or clinical stage drugs. Yet, in spite of this increased research activity, one promising clinical stage candidate drug has received little attention regarding its potential as a monotherapy or component of combination therapy for treatment of COVID-19 disease. Tucaresol, with documented human safety and pharmacokinetic data, is an orally active, stable, small molecule amenable to large scale manufacture by a proprietary two-step synthesis developed by us. Tucaresol functions as a host-targeted antiviral by selective protection/reconstitution of CD4+ T helper cells as demonstrated in HIV patients and SIV macaques. In view of similarities between HIV and SARS-CoV-2, especially with respect to host CD4+ T helper cells, and the suitability of Tucaresol for facile treatment of pandemic populations, Tucaresol is presented herein for treatment of mild-to-moderate COVID-19 patients but may also be useful for treatment of advanced disease accompanied by lymphopenia.

Preprint ARTICLE | doi:10.20944/preprints202208.0232.v3

Does Cannabidiol (CBD) in Food Supplements Pose a Serious Health Risk? Consequences of the EFSA Clock Stop Regarding Novel Food Authorisation

Dirk W. Lachenmeier, Constanze Sproll, Patricia Golombek, Stephan G. Walch

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: food safety; risk assessment; Cannabis sativa; tetrahydrocannabinol; food supplements; cannabidiol; benchmark dose; health-based guidance value (HBGV); liver toxicity

Online: 24 November 2022 (02:53:03 CET)

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Preprint REVIEW | doi:10.20944/preprints202211.0433.v1

Modification Strategies for Ionic Complementary Self-Assembling Peptides: Taking RADA16-Ⅰ as an Example

Weiwei Guo, Yinping Ma, Lei Hu, Yujie Feng, Yanmiao Liu, Xuedong Yi, Wenzhi Zhang, Fushan Tang

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: hydrogel; active motifs modification; regenerative medicine; Self-assembling peptide

Online: 23 November 2022 (05:11:24 CET)

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Preprint REVIEW | doi:10.20944/preprints202211.0271.v1

Revisiting the Anti-cancer Toxicity of Clinically Approved Platinating Derivatives

Benjamin N. Forgie, Rewati Prakash, Carlos M. Telleria

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: cisplatin; carboplatin; oxaliplatin; cellular uptake; DNA damage; transcription regulation; non-nuclear targets; chemoresistance; mechanisms of action; clinical usages; influx and efflux pumps; ribosome biogenesis; ER stress response; immunogenic cell death; interstrand and intrastrand DNA cross-links.

Online: 15 November 2022 (03:38:06 CET)

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Preprint REVIEW | doi:10.20944/preprints202211.0221.v1

Tucaresol: A Unique Oral Candidate Drug Ideally Accessible for Treatment of COVID-19 Disease

Christopher Penney, Boulos Zacharie, Jean-Simon Duceppe

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Tucaresol; COVID-19; SARS-CoV-2; HIV; T helper cell; CD4 receptor

Online: 11 November 2022 (07:52:38 CET)

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Abstract: The SARS-CoV-2 pandemic has significantly impacted world health and economic status. In response, much work has been undertaken to provide effective, safe vaccines, antibodies and antiviral drugs with which to address this pandemic. Treatment of a pandemic population presents multiple challenges in addition to the primary issue of drug efficacy and safety, such as large scale drug manufacture and distribution, drug stability, oral dosing and pharmacoeconomic considerations. Ideally, these factors must be addressed if new candidate drugs are to be advanced for treatment of large (pandemic) populations. Subsequently, new antivirals have reached the market but choices are few. According to the NIH Covid Treatment Guidelines, only three small molecule antiviral drugs are available to treat COVID-19 disease. As such, a significant part of the research towards discovery of new antiviral drugs has focused on screening and evaluation of ‘repurposed drugs’ or previously approved or clinical stage drugs. Yet, in spite of this increased research activity, one promising clinical stage candidate drug has received little attention regarding its potential as a monotherapy or component of combination therapy for treatment of COVID-19 disease. Tucaresol, with documented human safety and pharmacokinetic data, is an orally active, stable, small molecule amenable to large scale manufacture by a proprietary two-step synthesis developed by us. Tucaresol functions as a host-targeted antiviral by selective protection/reconstitution of CD4+ T helper cells as demonstrated in HIV patients and SIV macaques. In view of similarities between HIV and SARS-CoV-2, especially with respect to host CD4+ T helper cells, and the suitability of Tucaresol for facile treatment of pandemic populations, Tucaresol is presented herein for treatment of mild-to-moderate COVID-19 patients but may also be useful for treatment of advanced disease accompanied by lymphopenia.

Preprint ARTICLE | doi:10.20944/preprints202211.0188.v1

Direct in Vivo Comparison of ^99mTc-labeled Scaffold Proteins, DARPin G3 and ADAPT6, for Visualization of HER2 Expression and Monitoring of Early Response for Trastuzumab Therapy

Vladimir Tolmachev, Vitalina Bodenko, Maryam Oroujeni, Sergey Deyev, Elena Konovalova, Alexey Schulga, Sarah Lindbo, Sophia Hober, Olga Bragina, Anna Orlova, Anzhelika Vorobyeva

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: radionuclide molecular imaging; HER2; scaffold proteins; DARPin; ADAPT6; technetium-99m; preclinical

Online: 10 November 2022 (03:31:20 CET)

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Preprint BRIEF REPORT | doi:10.20944/preprints202211.0154.v1

Aésculus hippocástanum: Phytoscreening, Antiradical Activity, and Anti-Inflammatory Effect

Albina Filatova, Luiza Azimova, Ulugbek Gayibov, Abboskhon Turaev, Takhir Aripov, Sabina Gayibova

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: chestnut; stable radical; phytoconstituents; swelling

Online: 8 November 2022 (10:30:57 CET)

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Preprint REVIEW | doi:10.20944/preprints202211.0122.v1

Endocannabinoid System: Chemical Characteristics and Biological Activity

Guilherme Montes

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Endocannabinoid system; receptor cannabinoid; endocannabinoids ligands; phytocannabinoids; Integrative and Complementary Health Practices

Online: 7 November 2022 (11:36:46 CET)

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Preprint ARTICLE | doi:10.20944/preprints202211.0089.v1

Tibouchina granulosa Leaves Presents Anti-Inflammatory Effect

Carolina Carvalho Guilhon, Alan Silva Minho, Marc Pouliot, Fabio Boylan, Patricia Dias Fernandes

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Tibouchina granulosa; anti-inflammatory activity; hispiduloside; cytokines

Online: 4 November 2022 (07:24:02 CET)

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Preprint BRIEF REPORT | doi:10.20944/preprints202211.0063.v1

In vivo Acute Toxicity Studies of Novel Melanoma Actives

Sadeeshkumar Velayutham, Trisha Seal, Samaya Danthurthy, Julia Zaias, Keiran S.M. Smalley, Dmitriy Minond

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: melanoma; drug discovery; spliceosomal inhibition; acute toxicity; blood chemistry; organ histopathology

Online: 3 November 2022 (01:43:05 CET)

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Preprint REVIEW | doi:10.20944/preprints202210.0484.v1

Use of Intra-Articular Injection Corticosteroid Injections to the First Metatarsophalangeal Joint. First Theme of a Scoping Review

Ian Reilly, Rajesh Botchu

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Steroid injection; synovial joint; first metatarsophalangeal joint; hallux limitus; hallux rigidus; hallux valgus; gout; arthrofibrosis

Online: 31 October 2022 (10:27:07 CET)

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Preprint ARTICLE | doi:10.20944/preprints202210.0459.v1

Phenylbenzohydrazides Obtained from Isatoic Anhydride Present Anti-Inflammatory Activity in Vivo and in Vitro

João Pedro Barros de Paiva, Millena Santos Cordeiro, Patricia Ribeiro de Carvalho França, Luiz Octavio Pereira Branco, Isabela Souza dos Santos, Nanashara Figueiredo Reis, Patrick Pedro Pimentel, Thais Biondino Sardella Giorno, Evanoel Crizanto de Lima, Patricia Dias Fernandes

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Phenylbenzohydrazides; isatoic anhydride; inflammation; anti-inflammatory substance; carrageenan-induced inflammation; nitric oxide

Online: 31 October 2022 (01:02:02 CET)

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Preprint REVIEW | doi:10.20944/preprints202210.0347.v1

Pharmaceutical Treatment of Monkeypox Virus: A Narrative Review and Bibliometric Analysis

Muhammad Aaqib Shamim, Prakisini Satapathy, Bijaya Kumar Padhi, Sai Dutt Veeramachaneni, Naushaba Akhtar, Anindita Pradhan, Abhimanyu Agrawal, Pradeep Dwivedi, Aroop Mohanty, Kreeti Bhusan Pradhan, Russell Kabir, Ali A Rabaan, Jawaher Alotaibi, Zainab A. Al Ismail, Zainab A. Alsoliabi, Ali Al Fraij, Ranjit Sah, Alfonso J. Rodriguez-Morales

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: monkeypox virus; infection; treatment; antiviral; drug; management; public health emergency; tecovirimat; cidofovir; bibliometric analysis

Online: 24 October 2022 (03:38:12 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202210.0281.v1

COVID -19 Pandemic Diseases Effect on Self-Medication Practices Among Community of Bedelle City and Its Surrounding, Buno Bedelle Zone, South West of Oromia, Ethiopia

Wakuma Wakene Jifar, Osman Mohammed Oumer, Ismael Indris Muhammed

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Covid-19; Medicine; Practice; Bedelle city; Self-Medication

Online: 19 October 2022 (10:09:14 CEST)

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Preprint REVIEW | doi:10.20944/preprints202210.0189.v1

Acetaminophen Causes Neurodevelopmental Injury in Susceptible Babies and Children: No Valid Rationale for Controversy

Lisa Zhao, John P. Jones, Lauren G. Anderson, Zacharoula Konsoula, Cynthia D. Nevison, Kathryn J. Reissner, William Parker

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: acetaminophen; autism; paracetamol; neurodevelopment

Online: 13 October 2022 (08:00:33 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202210.0168.v1

Health Risk Assessment of Dermal Exposure to Polycyclic Aromatic Hydrocarbons from the Use of Infant Diapers

Alfred Bernard, Dudler Vincent

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: diaper; polycyclic aromatic hydrocarbons; skin cancer; neurobehavioral changes

Online: 12 October 2022 (09:55:13 CEST)

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Preprint REVIEW | doi:10.20944/preprints202210.0148.v1

Virtual Screening and Zebrafish Models in Tandem, for Drug Discovery and Development

David Hernández-Silva, Francisca Alcaraz-Pérez, Horacio Pérez-Sánchez, María Luisa Cayuela

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: drug development; high throughput screening; in vivo/in silico screening; zebrafish

Online: 11 October 2022 (10:33:33 CEST)

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Preprint REVIEW | doi:10.20944/preprints202210.0142.v1

Employ of Anthocyanins in nanocarriers for Nano Delivery: In Vitro and In Vivo Experimental Approaches for Chronic Diseases

Ana C. Gonçalves, Amícal Falcão, Gilberto Alves, João A. Lopes, Luís R. Silva

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: bioactive compounds; anthocyanins; drug delivery system; nanoparticles; chronic diseases; health benefits

Online: 11 October 2022 (05:04:19 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202210.0104.v1

Polio Eradication or Comeback? Outcome Reporting Bias in the 1954 Poliomyelitis Vaccine Field Trial

Ronald B. Brown

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: polio; paralytic poliomyelitis; Salk vaccine field trial; inactivated polio vaccine; vaccine efficacy; relative risk reduction; absolute risk reduction; number needed to vaccinate; acute flaccid paralysis; polio eradication; mass vaccination

Online: 9 October 2022 (03:16:35 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202210.0058.v1

Advanced Epi-X4 Derivatives Covalently Bind Human Serum Albumin Resulting in Prolonged Plasma Stability

Armando Rodríguez-Alfonso, Astrid Heck, Yasser Ruiz-Blanco, Andrea Gilg, Ludger Ständker, Seah Ling Kuan, Tanja Weil, Elsa Sanchez-Garcia, Sebastian Wiese, Jan Münch, Mirja Harms

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: EPI-X4; albumin carrier; peptide stability; CXCR4 antagonist;

Online: 6 October 2022 (08:50:49 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202210.0050.v1

Comparative Preclinical Evaluation of Peptide-Based Chelators for Labeling of DARPin G3 with 99mTc for Radionuclide Imaging of HER2 Expression in Cancer

Maria Larkina, Evgenii Plotnikov, Ekaterina Bezverkhniaia, Yulia Shabanova, Maria Tretyakova, Feruza Yuldasheva, Roman Zelchan, Alexey Schulga, Elena Konovalova, Anzhelika Vorobyeva, Javad Garousi, Torbjörn Gräslund, Mikhail Belousov, Vladimir Tolmachev, Sergey M. Deyev

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: radionuclide; HER2; DARPin; SPECT; 99mTc; imaging; cancer

Online: 6 October 2022 (08:09:37 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202210.0038.v1

Minimalised Three-Dimensional Human Midbrain In Vitro Model for Neurotoxicity Evaluation of DYRK1 Inhibitors

Xiao Wan, Vincent Fagan, Paul Brennan, Daniel Ebner

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: three-dimensional in vitro model; DYRK1; human midbrain; neural progenitor cells

Online: 5 October 2022 (11:29:38 CEST)

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Preprint REVIEW | doi:10.20944/preprints202209.0458.v1

Potential Inflammatory Biomarker in Patients with Attention Deficit Hyperactivity Disorder

Ji Hyun Park

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: kynurenine pathway; inflammatory biomarkers; inflammation; ADHD; neurobiology; kynurenine

Online: 29 September 2022 (08:11:33 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202209.0371.v1

Bioefficacy of Hydroxytyrosol-Rich Food Supplements on Preventing Lipid Peroxidation in Healthy Men

Cecilia Bender, Ilaria Candi, Eva Rogel

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: olive phenolics; hydroxytyrosol; oxidized LDL; ox-LDL; isoprostanes; F2-isoprostanes

Online: 23 September 2022 (10:23:51 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202209.0310.v1

Systematic Down-Selection of Repurposed Drug Candidates for COVID-19

Christopher A. MacRaild, Muzaffar-Ur-Rehman Mohammed, Faheem Faheem, Sankaranarayanan Murugesan, Ian K. Styles, Amanda L. Peterson, Carl M.J. Kirkpatrick, Matthew A. Cooper, Enzo A. Palombo, Moana M. Simpson, Hardik Ashish Jain, Vinti Agarwal, Alexander J. McAuley, Anupama Kumar, Darren J. Creek, Natalie L. Trevaskis, Seshadri S. Vasan

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: COVID-19; CoviRx.org; database; drugs; pandemic; repurposing; SARS-CoV-2; therapies; treatments; Variants of Concern (VOC)

Online: 20 September 2022 (15:00:48 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202208.0171.v2

Drug Combinations to Prevent Antimicrobial Resistance: Some Correlations and Laws, and their Verifications, thus Proposing Some Principles and a Preliminary Scheme

Houqin Yi, Ganjun Yuan, Shimin Li, Xuejie Xu, Yingying Guan, Li Zhang, Yu Yan

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: combination; antimicrobial resistance; selection index; collateral sensitivity; mutant prevention concentration; minimal inhibitory concentration; fractional inhibitory concentration index; stress factor

Online: 13 September 2022 (07:53:32 CEST)

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Antimicrobial resistance (AMR) has been a serious threat to human health, and combination therapy is proved to be an economic and effective strategy to fight the resistance. However, the abuse of drug combinations would conversely accelerate the spread of AMR. In our previous work, it had been concluded that the mutant selection indexes (SIs) of one agent against a specific bacterial strain are closely related to the proportions of two agents in a drug combination. To discover probable correlations, predictors and laws for further proposing feasible principles and schemes guiding the AMR-preventing practice, here three aspects were further explored. First, the power function (y=ax^b, a > 0) correlation between the SI (y) of one agent and the ratio value (x) of two agents in a drug combination was further established based on the mathematical and statistical analyses for those experimental data, and two rules a₁ × MIC₁ = a₂ × MIC₂ and b₁ + b₂ = -1 were discovered from both equations of y=a₁x^b1 and y=a₂x^b2 respectively for two agents in drug combinations. Simultaneously, it was found that one agent with larger MPC alone for drug combinations show greater potency for narrowing itself MSW and preventing the resistance. Second, a new concept as mutation-preventing selection index (MPSI) was proposed and used for evaluating the mutation-preventing potency difference of two agents in drug combinations, and the positive correlation between the MPSI and the mutant prevention concentration (MPC) or minimal inhibitory concentration (MIC) was subsequently established. Inspired by this, the significantly positive correlation, contrary to previous reports, between the MIC and the corresponding MPC of antimicrobial agents against pathogenic bacteria was established using one hundred and eighty-one of data pairs reported. These results together of above three aspects indicate that the MPCs in alone and combination are very important indexes for drug combinations to predict the mutation-preventing effects and the trajectories of collateral sensitivity, and while the MPC of an agent can be roughly calculated from its corresponding MIC. Subsequently, the former conclusion was further verified and improved by the antibiotic exposure to forty-three groups designed as different drug concentrations and various proportions. The results further proposed that the C/MPC for the agent with larger proportion in drug combinations can be considered as a predictor and is the key to judge whether the resistance and the collateral sensitivity occur to two agents. Based on these above correlations, laws, and their verification experiments, some principles were proposed, and a diagram of the mutation-preventing effects and the resistant trajectories for drug combinations with different concentrations and ratios of two agents was presented. Simultaneously, the reciprocal of MPC alone (1/MPC), proposed as the stress factors of two agents in drug combinations, together with their SI in combination, is the key to predict the mutation-preventing potency and control the trajectories of collateral sensitivity. Finally, a preliminary scheme for antimicrobial combinations preventing the AMR was further proposed for subsequent improvement research and clinic popularization, based on the above analyses and discussion. Moreover, some similar conclusions were speculated for triple or multiple drug combinations.

Preprint ARTICLE | doi:10.20944/preprints202208.0232.v2

Does Cannabidiol (CBD) in Food Supplements Pose a Serious Health Risk? Consequences of the EFSA Clock Stop Regarding Novel Food Authorisation

Dirk W. Lachenmeier, Constanze Sproll, Patricia Golombek, Stephan G. Walch

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: food safety; risk assessment; Cannabis sativa; tetrahydrocannabinol; food supplements; cannabidiol; benchmark dose; reference dose; liver toxicity

Online: 5 September 2022 (04:34:49 CEST)

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Preprint REVIEW | doi:10.20944/preprints202208.0542.v1

The Immunomodulating Properties of Noni Juice

Brett J. West

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Noni juice; Morinda citrifolia; immune system; immunomodulation

Online: 31 August 2022 (09:02:28 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202208.0504.v1

Development and Validation of UPLC-Qtof-MS Method for Blood Analysis of Amphetamine-Related Drug Isomers

Ahmad Alamir, James Watterson, Ibraheem Attafi

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Amphetamine-related drugs; Forensic Toxicology; blood; UPLC-qTOF-MS; MMSPE; Validation; SWGTOX

Online: 30 August 2022 (04:09:57 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202208.0232.v1

Does Cannabidiol (CBD) in Food Supplements Pose a Serious Health Risk? Consequences of the EFSA Clock Stop Regarding Novel Food Authorisation

Dirk W. Lachenmeier, Constanze Sproll, Patricia Golombek, Stephan G. Walch

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: food safety; risk assessment; Cannabis sativa; tetrahydrocannabinol; food supplements; cannabidiol; benchmark dose; reference dose; liver toxicity

Online: 12 August 2022 (09:00:49 CEST)

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Preprint REVIEW | doi:10.20944/preprints202208.0212.v1

Potential Drug Targets and Treatment Options for Covid-19: A Review

Muluken Wubetu

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: COVID-19; Drug targets; Inflammation; Treatment Options; Vaccines

Online: 11 August 2022 (08:07:05 CEST)

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Preprint REVIEW | doi:10.20944/preprints202208.0194.v1

Sarfaraz K. Niazi

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: biosimilar; analytical assessment; animal testing; clinical pharmacology; clinical efficacy; FDA; EMA; MHRA; WHO

Online: 10 August 2022 (05:19:49 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202208.0171.v1

Drug Combinations to Prevent Antimicrobial Resistance: Some Correlations, Rules and Laws, and a Preliminary Scheme

Houqin Yi, Ganjun Yuan, Shimin Li, Xuejie Xu, Yingying Guan, Li Zhang, Yu Yan

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: combination; antimicrobial resistance; selection index; collateral sensitivity; mutant prevention concentration; minimal inhibitory concentration; fractional inhibitory concentration index; stress factor

Online: 9 August 2022 (04:19:53 CEST)

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Antimicrobial resistance (AMR) has been a serious threat to human health, and combination therapy is proved to be an economic and effective strategy to fight the resistance. However, the abuse of drug combinations would conversely accelerate the spread of AMR. To guide the practice, some regularity conclusions had been drawn in our previous work. Based on those experimental data, here the power function (y=ax^b, a>0) correlation between the mutant selection index (SI) (y) of one agent and the ratio value (x) of two agents in a drug combination was established, and two rules a₁ × MIC₁ = a₂ × MIC₂ and b₁ + b₂ = -1 were discovered from both equations of y=a₁x^b1 and y=a₂x^b2 for two agents in drug combinations. Simultaneously, it was found that one agent with larger MPC alone for drug combinations would present a larger |b| and show greater potency for narrowing itself MSW and preventing the resistance. Another, a new concept as mutation-preventing selection index (MPSI) was proposed and used for evaluating the mutation-preventing potency difference of two agents in drug combinations, and the positive correlation between the MPSI and the mutant prevention concentration (MPC) or minimal inhibitory concentration (MIC) was subsequently established. Inspired by this, the significantly positive correlation, contrary to previous reports, between the MIC and the corresponding MPC of antimicrobial agents against pathogenic bacteria was established using one hundred and eighty-one of data pairs reported. These above together indicate that the MPCs in alone and combination are very important indexes for drug combinations to predict the mutation-preventing effects and the trajectories of collateral sensitivity, and the MPC of an agent can be roughly calculated from its corresponding MIC. Subsequently, this was further verified and improved by the antibiotic exposure to forty-three groups designed as different drug concentrations and various proportions. Based on these, the diagram of the mutation-preventing effects and the resistant trajectories of drug combinations with different concentrations and ratio of two agents was presented, and the C/MPC for the agent with larger proportion in drug combinations is the key to judge whether the resistance and the collateral sensitivity occur to two agents. Furthermore, the stress factors 1/MPC alone of two agents, together with their SI in combination, are the key to predict the mutation-preventing effects, and control the trajectories of collateral sensitivity. Combined the discussion and analyses for the above results and previous work, a preliminary scheme for antimicrobial combinations preventing the AMR was further proposed for subsequent improvement research and clinic popularization. Moreover, some other proposals and regularity conclusions related to preventing the AMR, involving fractional inhibitory concentration index (FICI), mutant selection index (SI), and pharmacokinetic parameters (t_1/2, AUC₂₄/MPC, C_max/MPC, and f %T > MPC, etc.), were analyzed and discussed, and finally some similar conclusions were speculated for triple or multiple drug combinations.

Preprint ARTICLE | doi:10.20944/preprints202208.0144.v1

Surface Modification of Biodegradable Microparticles With the Novel Host-Derived Immunostimulant CPDI-02 Significantly Increases Short-Term and Long-Term Mucosal and Systemic Antibodies Against Encapsulated Protein Antigen in Young Naïve Mice After Respi

Jacob E. Parriott, Jason P. Stewart, Derek D. Smith, Stephen M. Curran, Christopher D. Bauer, Todd A. Wyatt, Joy A. Phillips, Elizabeth R. Lyden, Geoffrey M. Thiele, Joseph Anthoney Vetro

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: mucosal immunization; mucosal vaccine; vaccine delivery; administration volume; targeted vaccines; M cell targeting; dendritic cell targeting; C5aR1; C5a1R; CD88; EP54; EP67

Online: 8 August 2022 (10:17:30 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202208.0135.v1

The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups - an Investigation using Physiologically based Pharmacokinetic Modelling

Karel Allegaert, Mohammad Yaseen Abbasi, Robin Michelet, Olusola Olafuyi

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: physiologically based pharmacokinetic modelling; propofol; low cardiac output; pharmacokinetics; neonate; developmental pharmacology; asphyxia; hypothermia; pediatrics; pharmacokinetics

Online: 8 August 2022 (06:12:36 CEST)

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Preprint COMMUNICATION | doi:10.20944/preprints202208.0022.v1

Can Biomarkers of Oxidative Stress in Serum Predict Disease Severity in West Nile Virus Infection? A Pilot Study

Maxim Van Herreweghe, Annelies Breynaert, Tess De Bruyne, Corneliu Petru Popescu, Simin-Aysel Florescu, Yaniv Lustig, Eli Schwartz, Federico Giovanni Gobbi, Nina Hermans, Ralph Huits

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Oxidative stress; West Nile virus; West Nile Fever; West Nile Neuroinvasive disease; Flaviviridae; biomarkers

Online: 1 August 2022 (11:21:20 CEST)

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Medicine and Pharmacology