Molecules. 2023 May 15;28(10):4100. doi: 10.3390/molecules28104100.

ABSTRACT

Asthma is a common chronic disease that is characterized by respiratory symptoms including cough, wheeze, shortness of breath, and chest tightness. The underlying mechanisms of this disease are not fully elucidated, so more research is needed to identify better therapeutic compounds and biomarkers to improve disease outcomes. In this present study, we used bioinformatics to analyze the gene expression of adult asthma in publicly available microarray datasets to identify putative therapeutic molecules for this disease. We first compared gene expression in healthy volunteers and adult asthma patients to obtain differentially expressed genes (DEGs) for further analysis. A final gene expression signature of 49 genes, including 34 upregulated and 15 downregulated genes, was obtained. Protein-protein interaction and hub analyses showed that 10 genes, including POSTN, CPA3, CCL26, SERPINB2, CLCA1, TPSAB1, TPSB2, MUC5B, BPIFA1, and CST1, may be hub genes. Then, the L1000CDS2 search engine was used for drug repurposing studies. The top approved drug candidate predicted to reverse the asthma gene signature was lovastatin. Clustergram results showed that lovastatin may perturb MUC5B expression. Moreover, molecular docking, molecular dynamics simulation, and computational alanine scanning results supported the notion that lovastatin may interact with MUC5B via key residues such as Thr80, Thr91, Leu93, and Gln105. In summary, by analyzing gene expression signatures, hub genes, and therapeutic perturbation, we show that lovastatin is an approved drug candidate that may have potential for treating adult asthma.

PMID:37241840 | DOI:10.3390/molecules28104100

Molecules. 2023 May 12;28(10):4045. doi: 10.3390/molecules28104045.

ABSTRACT

Respiratory viral diseases are among the most important causes of disability, morbidity, and death worldwide. Due to the limited efficacy or side effects of many current therapies and the increase in antiviral-resistant viral strains, the need to find new compounds to counteract these infections is growing. Since the development of new drugs is a time-consuming and expensive process, numerous studies have focused on the reuse of commercially available compounds, such as natural molecules with therapeutic properties. This phenomenon is generally called drug repurposing or repositioning and represents a valid emerging strategy in the drug discovery field. Unfortunately, the use of natural compounds in therapy has some limitations, due to their poor kinetic performance and consequently reduced therapeutic effect. The advent of nanotechnology in biomedicine has allowed this limitation to be overcome, showing that natural compounds in nanoform may represent a promising strategy against respiratory viral infections. In this narrative review, the beneficial effects of some promising natural molecules, curcumin, resveratrol, quercetin, and vitamin C, which have been already studied both in native form and in nanoform, against respiratory viral infections are presented and discussed. The review focuses on the ability of these natural compounds, analyzed in in vitro and in vivo studies, to counteract inflammation and cellular damage induced by viral infection and provide scientific evidence of the benefits of nanoformulations in increasing the therapeutic potential of these molecules.

PMID:37241786 | DOI:10.3390/molecules28104045

Life (Basel). 2023 Apr 27;13(5):1095. doi: 10.3390/life13051095.

ABSTRACT

Alzheimer's disease (AD) is a progressive neurodegenerative disease and is the most common type of dementia. Although a considerably large amount of money has been invested in drug development for AD, no disease modifying treatment has been detected so far. In our previous work, we developed a computational method to highlight stage-specific candidate repurposed drugs against AD. In this study, we tested the effect of the top 13 candidate repurposed drugs that we proposed in our previous work in a severity stage-specific manner using an in vitro BACE1 assay and the effect of a top-ranked drug from the list of our previous work, tetrabenazine (TBZ), in the 5XFAD as an AD mouse model. From our in vitro screening, we detected 2 compounds (clomiphene citrate and Pik-90) that showed statistically significant inhibition against the activity of the BACE1 enzyme. The administration of TBZ at the selected dose and therapeutic regimen in 5XFAD in male and female mice showed no significant effect in behavioral tests using the Y-maze and the ELISA immunoassay of Aβ40. To our knowledge, this is the first time the drug tetrabenazine has been tested in the 5XFAD mouse model of AD in a sex-stratified manner. Our results highlight 2 drugs (clomiphene citrate and Pik-90) from our previous computational work for further investigation.

PMID:37240740 | DOI:10.3390/life13051095

J Clin Med. 2023 May 16;12(10):3485. doi: 10.3390/jcm12103485.

ABSTRACT

Spiral ganglion neurons (SGNs) connect cochlear hair cells with higher auditory pathways and their degeneration due to drug toxicity (ototoxicity) contributes to hearing loss. This study aimed to identify drug classes that are negatively correlated with the transcriptome of regenerating SGNs. Human orthologs of differentially expressed genes within the regenerating neonatal mouse SGN transcriptome were entered into CMap and the LINCS unified environment and perturbation-driven gene expression was analyzed. The CMap connectivity scores ranged from 100 (positive correlation) to -100 (negative correlation). Insulin-like growth factor 1/receptor (IGF-1/R) inhibitors were highly negatively correlated with the regenerating SGN transcriptome (connectivity score: -98.87). A systematic literature review of clinical trials and observational studies reporting otologic adverse events (AEs) with IGF-1/R inhibitors identified 108 reports (6141 treated patients). Overall, 16.9% of the treated patients experienced any otologic AE; the rate was highest for teprotumumab (42.9%). In a meta-analysis of two randomized placebo-controlled trials of teprotumumab, there was a significantly higher risk of hearing-related (pooled Peto OR [95% CI]: 7.95 [1.57, 40.17]) and of any otologic AEs (3.56 [1.35, 9.43]) with teprotumumab vs. a placebo, whether or not dizziness/vertigo AEs were included. These results call for close audiological monitoring during IGF-1-targeted treatment, with prompt referral to an otolaryngologist should otologic AEs develop.

PMID:37240591 | DOI:10.3390/jcm12103485

Int J Mol Sci. 2023 May 17;24(10):8896. doi: 10.3390/ijms24108896.

ABSTRACT

Mpox (monkeypox) is a zoonotic viral disease caused by the mpox virus (MPXV). Recently in 2022, a multi-country Mpox outbreak has determined great concern as the disease rapidly spreads. The majority of cases are being noticed in European regions and are unrelated to endemic travel or known contact with infected individuals. In this outbreak, close sexual contact appears to be important for MPXV transmission, and an increasing prevalence in people with multiple sexual partners and in men who have sex with men has been observed. Although Vaccinia virus (VACV)-based vaccines have been shown to induce a cross-reactive and protective immune response against MPXV, limited data support their efficacy against the 2022 Mpox outbreak. Furthermore, there are no specific antiviral drugs for Mpox. Host-cell lipid rafts are small, highly dynamic plasma-membrane microdomains enriched in cholesterol, glycosphingolipids and phospholipids that have emerged as crucial surface-entry platforms for several viruses. We previously demonstrated that the antifungal drug Amphotericin B (AmphB) inhibits fungal, bacterial and viral infection of host cells through its capacity to sequester host-cell cholesterol and disrupt lipid raft architecture. In this context, we discuss the hypothesis that AmphB could inhibit MPXV infection of host cells through disruption of lipid rafts and eventually through redistribution of receptors/co-receptors mediating virus entry, thus representing an alternative or additional therapeutic tool for human Mpox.

PMID:37240241 | DOI:10.3390/ijms24108896

Life Sci. 2023 May 24:121798. doi: 10.1016/j.lfs.2023.121798. Online ahead of print.

ABSTRACT

AIMS: Breast cancer incidence keeps on growing and emerging as one of the major global challenges, therefore, the introduction of new approaches is of great demand. Drug repurposing is crucial to faster and cheaper discovery of anti-cancer drugs. The antiviral tenofovir disproxil fumarate (TF) was reported to decrease hepatocellular carcinoma risk by interfering with cell cycle and proliferation. This study aimed to scrutinize the role of TF alone or combined with doxorubicin (DOX) in 7,12-dimethylbenz (a) anthracene (DMBA)-induced breast carcinoma rat model.

MATERIALS AND METHODS: Breast carcinoma was induced by DMBA (7.5 mg/kg, twice/week, SC into mammary gland) for 4 successive weeks. TF (25 and 50 mg/kg/day) was given orally and DOX (2 mg/kg) was injected once/week by tail vein starting from day 1.

KEY FINDINGS: The anti-cancerous effect of TF was mediated by suppression of oxidative stress markers and Notch signaling proteins (Notch1, JAG1, and HES1), attenuation of tumor proliferation markers (cyclin-D1 and Ki67), and boosting of apoptosis (P53 and Caspase3) and autophagy biomarkers (Beclin1 and LC3). In parallel, histopathological assessment displayed that mammary glands from animals treated with TF alone or combined with DOX showed better histopathological scores. Interestingly, TF and DOX co-treatment markedly decreased myocardial injury markers (AST, LDH, and CK-MB), restored the balance between GSH and ROS, prohibited lipid peroxidation, and preserved microscopic myocardial architecture.

SIGNIFICANCE: TF elicited antitumor activity via multiple molecular mechanisms. Moreover, combining TF with DOX might be a potential novel strategy to enhance DOX-anticancer activity and decrease its cardiac side effects.

PMID:37236603 | DOI:10.1016/j.lfs.2023.121798

Drug Discov Today. 2023 May 24:103639. doi: 10.1016/j.drudis.2023.103639. Online ahead of print.

ABSTRACT

DrugRepurposing Online is a database of well-curated literature examples of drug repurposing, structured by reference to compounds and indications, via a generalisation layer (within specific datasets) of mechanism. References are categorised by level of relevance to human application to assist users in prioritising repurposing hypotheses. Users can search freely between any two of the three categories in either direction; results can then be extended to the third category. The concatenation of two (or more) direct relationships to create an indirect, hypothetical new repurposing relationship is intended to offer novel and non-obvious opportunities that can be both patented and efficiently developed. A natural language processing (NLP) powered search capability extends the opportunities from the hand-curated foundation to identify further opportunities.

PMID:37236525 | DOI:10.1016/j.drudis.2023.103639

Ther Adv Infect Dis. 2023 May 22;10:20499361231174289. doi: 10.1177/20499361231174289. eCollection 2023 Jan-Dec.

ABSTRACT

BACKGROUND AND AIM: Donepezil is a front-line treatment for Alzheimer's disease. Donepezil treatment is associated with decreased risk of all-cause mortality. Specific protection is observed in pneumonia and cardiovascular disease. We hypothesized that donepezil treatment would improve mortality among Alzheimer's patients following infection with COVID-19. The objective of this study is to assess the influence of ongoing donepezil treatment on survival in Alzheimer's disease patients after polymerase chain reaction (PCR)-confirmed COVID-19 infection.

METHODS: This is a retrospective cohort study. We conducted a national survey of Veterans with Alzheimer's disease to assess the influence of ongoing donepezil treatment on survival in Alzheimer's disease patients after PCR-confirmed COVID-19 infection. We assessed all-cause 30-day mortality stratified by COVID-19 infection and donepezil use, estimating odds ratios using multivariate logistic regression.

RESULTS: Among people with Alzheimer's disease and COVID-19, all-cause 30-day mortality was 29% (47/163) for people taking donepezil compared with 38% (159/419) for those who were not. Among people with Alzheimer's disease without COVID-19, all-cause 30-day mortality was 5% (189/4189) for people taking donepezil compared with 7% (712/10,241) for those who were not. Adjusting for covariates, the decrease in mortality associated with donepezil did not differ between people with and without COVID-19 (interaction p = 0.710).

CONCLUSION: The known survival benefits of donepezil were retained but not found to be specific to COVID-19 among people with Alzheimer's disease.

PMID:37234745 | PMC:PMC10203853 | DOI:10.1177/20499361231174289

Curr Pharm Biotechnol. 2023 May 25. doi: 10.2174/1389201024666230525161432. Online ahead of print.

ABSTRACT

Currently, there are no approved treatments for the fatal infectious coronavirus disease. The process of identifying new applications for approved pharmaceuticals is called drug repurposing. It is a very successful strategy for drug development as it takes less time and cost to uncover a therapeutic agent than the de novo procedure. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the seventh coronavirus that has been identified as a causative agent in humans. SARS-CoV-2 has been recorded in 213 countries, with over 31 million confirmed cases and an estimated death rate of 3%. Medication repositioning may indeed be regarded as a unique therapeutic option for COVID-19 in the present situation. There are various drugs and techniques, which are being used to treat the symptoms of COVID-19. These agents are directed against the viral replication cycle, viral entrance, and viral translocation to the nucleus. Additionally, some can boost the innate antiviral immune response. Drug repurposing is a sensible method and could be a vital approach to treating COVID-19. Combining some of the drugs or supplements with an immunomodulatory diet, psychological assistance, and adherence to standards can ultimately act against COVID-19. A better knowledge of the virus itself and its enzymes will enable the development of more precise and efficient direct-acting antivirals. The primary aim of this review is to present the various aspects of this disease, including various strategies against COVID-19.

PMID:37231727 | DOI:10.2174/1389201024666230525161432

Mol Biol Rep. 2023 May 25. doi: 10.1007/s11033-023-08490-6. Online ahead of print.

ABSTRACT

Cell death is a natural mechanism for biological clearance for the maintenance of homeostasis in a dynamic microenvironment of the central nervous system. Stress and various factors can lead to imbalance between cellular genesis and cell death leading to dysfunctionality and a number of neuropathological disorders. Drug repurposing can help bypass development time and cost. A complete understanding of drug actions and neuroinflammatory pathways can lead to effective control of neurodegenerative disorders. This review covers recent advances in various neuroinflammatory pathways understanding, biomarkers, and drug repurposing for neuroprotection.

PMID:37231215 | DOI:10.1007/s11033-023-08490-6

Assay Drug Dev Technol. 2023 May 25. doi: 10.1089/adt.2023.013. Online ahead of print.

ABSTRACT

Candidosis is one of the most frequent opportunistic infections and exhibits variable clinical presentations, including oral localized forms. Drugs affecting the renin-angiotensin system targets inhibit secreted aspartic proteases from Candida albicans. The objective of the study was to evaluate whether losartan has antimicrobial action against C. albicans biofilms. Biofilms were treated with losartan or aliskiren (for comparison) for 24 h. Metabolic activity of viable cells and growth inhibition of C. albicans biofilms were assessed using XTT [2,3-Bis(2-Methoxy-4-Nitro-5-Sulfophenyl)-5-[(Phenyl-Amino)Carbonyl]-2H-Tetrazolium Hydroxide] and colony-forming unit assays, respectively. In addition, the cytotoxicity of the drugs on human cells was evaluated using the AlamarBlue assay. Both drugs decreased fungal viability at all concentrations. In addition, all concentrations of losartan inhibited the growth of C. albicans biofilm, ranging from 47% to 88.5%, whereas aliskiren showed inhibition from 1 to 10 mg/mL, which ranged from 16% to 97.6%. Furthermore, at certain concentrations, these drugs maintained the viability of human cells. Losartan and aliskiren have fungistatic and fungicidal action against C. albicans biofilms and are compatible with human cells. Therefore, these antihypertensive drugs can be repurposed to interfere with the metabolism and development of Candida biofilms, which are widely associated with clinical forms of candidosis, including oral localized forms such as denture stomatitis.

PMID:37229625 | DOI:10.1089/adt.2023.013

J Chem Inf Model. 2023 May 25. doi: 10.1021/acs.jcim.3c00282. Online ahead of print.

ABSTRACT

The SARS-CoV-2 main protease (Mpro) is a crucial enzyme for viral replication and has been considered an attractive drug target for the treatment of COVID-19. In this study, virtual screening techniques and in vitro assays were combined to identify novel Mpro inhibitors starting from around 8000 FDA-approved drugs. The docking analysis highlighted 17 promising best hits, biologically characterized in terms of their Mpro inhibitory activity. Among them, 7 cephalosporins and the oral anticoagulant betrixaban were able to block the enzyme activity in the micromolar range with no cytotoxic effect at the highest concentration tested. After the evaluation of the degree of conservation of Mpro residues involved in the binding with the studied ligands, the ligands' activity on SARS-CoV-2 replication was assessed. The ability of betrixaban to affect SARS-CoV-2 replication associated to its antithrombotic effect could pave the way for its possible use in the treatment of hospitalized COVID-19 patients.

PMID:37227780 | DOI:10.1021/acs.jcim.3c00282

BMC Bioinformatics. 2023 May 24;24(1):215. doi: 10.1186/s12859-023-05343-8.

ABSTRACT

BACKGROUND: There is a pressing need for improved methods to identify effective therapeutics for diseases. Many computational approaches have been developed to repurpose existing drugs to meet this need. However, these tools often output long lists of candidate drugs that are difficult to interpret, and individual drug candidates may suffer from unknown off-target effects. We reasoned that an approach which aggregates information from multiple drugs that share a common mechanism of action (MOA) would increase on-target signal compared to evaluating drugs on an individual basis. In this study, we present drug mechanism enrichment analysis (DMEA), an adaptation of gene set enrichment analysis (GSEA), which groups drugs with shared MOAs to improve the prioritization of drug repurposing candidates.

RESULTS: First, we tested DMEA on simulated data and showed that it can sensitively and robustly identify an enriched drug MOA. Next, we used DMEA on three types of rank-ordered drug lists: (1) perturbagen signatures based on gene expression data, (2) drug sensitivity scores based on high-throughput cancer cell line screening, and (3) molecular classification scores of intrinsic and acquired drug resistance. In each case, DMEA detected the expected MOA as well as other relevant MOAs. Furthermore, the rankings of MOAs generated by DMEA were better than the original single-drug rankings in all tested data sets. Finally, in a drug discovery experiment, we identified potential senescence-inducing and senolytic drug MOAs for primary human mammary epithelial cells and then experimentally validated the senolytic effects of EGFR inhibitors.

CONCLUSIONS: DMEA is a versatile bioinformatic tool that can improve the prioritization of candidates for drug repurposing. By grouping drugs with a shared MOA, DMEA increases on-target signal and reduces off-target effects compared to analysis of individual drugs. DMEA is publicly available as both a web application and an R package at https://belindabgarana.github.io/DMEA .

PMID:37226094 | DOI:10.1186/s12859-023-05343-8

Front Oncol. 2023 May 8;13:1106667. doi: 10.3389/fonc.2023.1106667. eCollection 2023.

ABSTRACT

INTRODUCTION: Cervical cancer is a worldwide health problem due to the number of deaths caused by this neoplasm. In particular, in 2020, 30,000 deaths of this type of tumor were reported in Latin America. Treatments used to manage patients diagnosed in the early stages have excellent results as measured by different clinical outcomes. Existing first-line treatments are not enough to avoid cancer recurrence, progression, or metastasis in locally advanced and advanced stages. Therefore, there is a need to continue with the proposal of new therapies. Drug repositioning is a strategy to explore known medicines as treatments for other diseases. In this scenario, drugs used in other pathologies that have antitumor activity, such as metformin and sodium oxamate, are analyzed.

METHODS: In this research, we combined the drugs metformin and sodium oxamate with doxorubicin (named triple therapy or TT) based on their mechanism of action and previous investigation of our group against three CC cell lines.

RESULTS: Through flow cytometry, Western blot, and protein microarray experiments, we found TT-induced apoptosis on HeLa, CaSki, and SiHa through the caspase 3 intrinsic pathway, including the critical proapoptotic proteins BAD, BAX, cytochrome-C, and p21. In addition, mTOR and S6K phosphorylated proteins were inhibited in the three cell lines. Also, we show an anti-migratory activity of the TT, suggesting other targets of the drug combination in the late CC stages.

DISCUSSION: These results, together with our former studies, conclude that TT inhibits the mTOR pathway leading to cell death by apoptosis. Our work provides new evidence of TT against cervical cancer as a promising antineoplastic therapy.

PMID:37223676 | PMC:PMC10200932 | DOI:10.3389/fonc.2023.1106667

Genes Dis. 2022 Mar 28;10(2):340-343. doi: 10.1016/j.gendis.2022.02.015. eCollection 2023 Mar.

NO ABSTRACT

PMID:37223537 | PMC:PMC10201598 | DOI:10.1016/j.gendis.2022.02.015

J Biomol Struct Dyn. 2023 May 22:1-15. doi: 10.1080/07391102.2023.2214232. Online ahead of print.

ABSTRACT

The Small Multidrug Resistance efflux pump protein KpnE, plays a pivotal role in multi-drug resistance in Klebsiella pneumoniae. Despite well-documented study of its close homolog, EmrE, from Escherichia coli, the mechanism of drug binding to KpnE remains obscure due to the absence of a high-resolution experimental structure. Herein, we exclusively elucidate its structure-function mechanism and report some of the potent inhibitors through drug repurposing. We used molecular dynamics simulation to develop a dimeric structure of KpnE and explore its dynamics in lipid-mimetic bilayers. Our study identified both semi-open and open conformations of KpnE, highlighting its importance in transport process. Electrostatic surface potential map suggests a considerable degree of similarity between KpnE and EmrE at the binding cleft, mostly occupied by negatively charged residues. We identify key amino acids Glu14, Trp63 and Tyr44, indispensable for ligand recognition. Molecular docking and binding free energy calculations recognizes potential inhibitors like acarbose, rutin and labetalol. Further validations are needed to confirm the therapeutic role of these compounds. Altogether, our membrane dynamics study uncovers the crucial charged patches, lipid-binding sites and flexible loop that could potentiate substrate recognition, transport mechanism and pave the way for development of novel inhibitors against K. pneumoniae.Communicated by Ramaswamy H. Sarma.

PMID:37218086 | DOI:10.1080/07391102.2023.2214232

Mol Med. 2023 May 22;29(1):67. doi: 10.1186/s10020-023-00664-z.

ABSTRACT

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most prevalent monogenic human diseases. It is mostly caused by pathogenic variants in PKD1 or PKD2 genes that encode interacting transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). Among many pathogenic processes described in ADPKD, those associated with cAMP signaling, inflammation, and metabolic reprogramming appear to regulate the disease manifestations. Tolvaptan, a vasopressin receptor-2 antagonist that regulates cAMP pathway, is the only FDA-approved ADPKD therapeutic. Tolvaptan reduces renal cyst growth and kidney function loss, but it is not tolerated by many patients and is associated with idiosyncratic liver toxicity. Therefore, additional therapeutic options for ADPKD treatment are needed.

METHODS: As drug repurposing of FDA-approved drug candidates can significantly decrease the time and cost associated with traditional drug discovery, we used the computational approach signature reversion to detect inversely related drug response gene expression signatures from the Library of Integrated Network-Based Cellular Signatures (LINCS) database and identified compounds predicted to reverse disease-associated transcriptomic signatures in three publicly available Pkd2 kidney transcriptomic data sets of mouse ADPKD models. We focused on a pre-cystic model for signature reversion, as it was less impacted by confounding secondary disease mechanisms in ADPKD, and then compared the resulting candidates' target differential expression in the two cystic mouse models. We further prioritized these drug candidates based on their known mechanism of action, FDA status, targets, and by functional enrichment analysis.

RESULTS: With this in-silico approach, we prioritized 29 unique drug targets differentially expressed in Pkd2 ADPKD cystic models and 16 prioritized drug repurposing candidates that target them, including bromocriptine and mirtazapine, which can be further tested in-vitro and in-vivo.

CONCLUSION: Collectively, these results indicate drug targets and repurposing candidates that may effectively treat pre-cystic as well as cystic ADPKD.

PMID:37217845 | DOI:10.1186/s10020-023-00664-z

Drug Dev Ind Pharm. 2023 May 22:1-21. doi: 10.1080/03639045.2023.2216785. Online ahead of print.

ABSTRACT

OBJECTIVE: Present study aimed to identify a safe and effective non-oncology drug cocktail as an alternative to toxic chemotherapeutics for hepatocellular carcinoma treatment. The assessment of cytotoxicity of cocktail (as co-adjuvant) in combination with chemotherapeutic docetaxel (DTX) is also aimed. Further, we aimed to develop an oral solid self-emulsifying drug delivery system (S-SEDDS) for the simultaneous delivery of identified drugs.

SIGNIFICANCE: The identified non-oncology drug cocktail could overcome the shortage of anticancer therapeutics and help to reduce cancer-related mortality. Moreover, the developed S-SEDDS could be an ideal system for concurrent oral delivery of non-oncology drug combinations.

METHODS: The non-oncology drugs (alone and in combinations) were screened in vitro for anticancer effect (against HepG2 cells) using (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide; MTT) dye assay, and cell cycle arresting and apoptotic behaviors using the fluorescence-activated cell sorting (FACS) technique. The S-SEDDS is composed of drugs such as Ketoconazole (KCZ), Disulfiram (DSR), Tadalafil (TLF), and excipients like span-80, tween-80, soybean oil, Leciva S-95, Poloxamer F108 (PF-108), and Neusilin® US2 (adsorbent carrier) was developed and characterized.

RESULTS: The cocktail composed of KCZ, DSR, and TLF has showed substantial cytotoxicity (at the lowest concentration of 3.3 picomoles), HepG2 cell arrest at G0/G1 and S phases, and substantial cell death via apoptosis. The Docetaxel (DTX) inclusion into this cocktail has further resulted in increased cytotoxicity, cell arrest at the G2/M phase, and cell necrosis. The optimized blank liquid SEDDS that remains transparent without phase separation for more than 6 months is used for the preparation of drug-loaded liquid SEDDS (DL-SEDDS). The optimized DL-SEDDS with low viscosity, good dispersibility, considerable drug retention upon dilution, and smaller particle size is further converted into drug-loaded solid SEDDS (DS-SEDDS). The final DS-SEDDS demonstrated acceptable flowability and compression characteristics, significant drug retention (more than 93%), particle size in nano range (less than 500 nm) and nearly spherical morphology following dilutions. The DS-SEDDS showed substantially increased cytotoxicity and Caco-2 cell permeability than plain drugs. Furthermore, DS-SEDDS containing only non-oncology drugs caused lower in vivo toxicity (only 6% body weight loss) than DS-SEDDS containing non-oncology drugs with DTX (about 10% weight loss).

CONCLUSION: The current study revealed a non-oncology drug combination effective against hepatocellular carcinoma. Further, it is concluded that the developed S-SEDDS containing non-oncology drug combination alone and in combination with DTX could be a promising alternative to toxic chemotherapeutics for the effective oral treatment of hepatic cancer.

PMID:37216496 | DOI:10.1080/03639045.2023.2216785

Health Sci Rep. 2023 May 20;6(5):e1276. doi: 10.1002/hsr2.1276. eCollection 2023 May.

ABSTRACT

Amidst, the global pandemic of antimicrobial resistance (AMR), the rate at which AMR increases overwhelms the increased efforts to discover new effective antimicrobials. There is a persistent need for alternative treatment modalities so as to keep up with the pace. AMR is the leading cause of death in the world and its health and economic consequences suggest the urgent need for sustainable interventions. Vitamins have consistently proven to have antimicrobial activity as well as slowing down the AMR rate by influencing the AMR genes even towards extensive multidrug resistant strains. Evidences suggest that the use of some vitamins on their own or in combination with existing antimicrobial agents could be a breakthrough towards combating AMR. This will widen the antimicrobial agents' options in the treatment arena, preserve the antimicrobial agents susceptible to develop resistant so that they can be used in severe infections only, reduce the tension and burden of the AMR crisis significantly and give enough room for development of new antimicrobial agents. Moreover, almost all viral, fungal, parasitic and bacterial resistant strains of concern as listed by World Health Organization have been found to be sensitive to several vitamins either synergistically with other antimicrobials or independently. Considering their widened spectrum of immunomodulatory and antimicrobial effect, some vitamins can further be repositioned as prophylactic antimicrobial agents in clinical situations like in presurgeries prophylaxis so as to avoid unnecessary use of antimicrobials especially antibiotics. Various relevant AMR stakeholders should invest in clinical trials and systematic reviews with available data to enable quick repositioning of some potential vitamins as antimicrobial agents as an emergency rapid response towards AMR Crisis. This includes the preparation of guidelines containing specificity of which vitamin to be used for treatment of which type of infection.

PMID:37216052 | PMC:PMC10199457 | DOI:10.1002/hsr2.1276

IIC Int Rev Ind Prop Copyr Law. 2023;54(5):732-763. doi: 10.1007/s40319-023-01329-4. Epub 2023 May 4.

ABSTRACT

The benefits of access to clinical trial data are related to their inestimable value from the perspective of clinical trial participants, society as a whole, public health systems and scientific progress. In light of the development of innovative data analysis technologies, access to raw clinical trial data opens up an ever-widening array of possibilities: it can profoundly facilitate machine data analysis for, inter alia, hypothesis generation, risk modelling, counterfactual simulation and - finally - drug repurposing and development. The enactment of the new Clinical Trials Regulation (EU) No. 536/2014 (CTR) and introduction of the Clinical Trials Information System (CTIS) were heralded as ensuring a level of transparency in clinical trials that is sufficient to contribute to protecting public health and fostering the innovation capacity of European medical research, while recognizing the legitimate economic interests of sponsors. This paper presents the hitherto binding rules for the disclosure of clinical trial data and, against this background, their new framework, introduced by the CTR. In addition to assessing whether the CTR's objectives are fulfilled, this paper examines whether the latest changes impact the hitherto existing rules on protection of regulatory data via regulatory exclusivities. Finally, it points out concerns regarding whether data gathered in the CTIS can be efficiently used by innovative data analysis technologies for further processing for both commercial and non-commercial purposes.

PMID:37215361 | PMC:PMC10158712 | DOI:10.1007/s40319-023-01329-4