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Narra J Apr 2024Numerous prior studies have identified therapeutic targets that could effectively combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection,...
Numerous prior studies have identified therapeutic targets that could effectively combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, including the angiotensin-converting enzyme 2 (ACE2) receptor, RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro). In parallel, antiviral compounds like abacavir, acyclovir, adefovir, amantadine, amprenavir, darunavir, didanosine, oseltamivir, penciclovir, and tenofovir are under investigation for their potential in drug repurposing to address this infection. The aim of the study was to determine the effect of modifying the functional groups of the aforementioned antivirals in silico. Using the genetic optimization for ligand docking algorithm on software Maestro (version 11.1), the modified antivirals were docked onto ACE2 receptor, RdRp, and Mpro. Using QuickProp (Maestro v11.1), PASS (prediction of activity spectra for the substances), and altogether with SwissADME, the ADMET (absorption, distribution, metabolism, excretion, and toxicity) of the modified antivirals, as well as their bioavailability and the predicted activity spectra, were determined. Discovery studio software was used to undertake post-docking analysis. Among the 10 antivirals, N(CH) derivative of darunavir, N(CH) derivative of amprenavir and NCH derivative of darunavir exhibited best binding affinities with ACE2 receptor (docking scores: -10.333, -9.527 and -9.695 kJ/mol, respectively). Moreover, NCH derivative of abacavir (-6.506 kJ/mol), NO derivative of didanosine (-6.877 kJ/mol), NCH derivative of darunavir (-7.618 kJ/mol) exerted promising affinity to Mpro. In conclusion, the results of the in silico screenings can serve as a useful information for future experimental works.
Topics: Antiviral Agents; Humans; Molecular Docking Simulation; SARS-CoV-2; Drug Repositioning; COVID-19 Drug Treatment; Models, Molecular; COVID-19; Angiotensin-Converting Enzyme 2; Pneumonia, Viral; Pandemics
PubMed: 38798846
DOI: 10.52225/narra.v4i1.319 -
BMC Infectious Diseases Aug 2019Thymidine analogues (TA) and didanosine (ddI) are associated with long-lasting adipose tissue redistribution. Adiponectin is a widely used marker of adipocyte activity,... (Observational Study)
Observational Study
BACKGROUND
Thymidine analogues (TA) and didanosine (ddI) are associated with long-lasting adipose tissue redistribution. Adiponectin is a widely used marker of adipocyte activity, and adipose tissue density assessed by CT-scan is associated with adipocyte size and function. We hypothesized that prior exposure to TA and ddI was associated with long-lasting adipose tissue dysfunction in people living with HIV (PLWH). Thus, we tested possible associations between markers of adipose tissue dysfunction (adipose tissue density and adiponectin) and prior exposure to TA and/or ddI, years after treatment discontinuation.
METHODS
Eight hundred forty-eight PLWH from the COCOMO study were included and stratified according to prior exposure to TA and/or ddI (with, n = 451; without n = 397). Visceral (VAT) and subcutaneous (SAT) adipose tissue area and density were determined by single slice abdominal CT-scan at lumbar 4th level. Venous blood was collected and analyzed for adiponectin. Multivariable linear and logistic regression analyses were used to test our hypotheses. Multivariable models were adjusted for age, sex, smoking, origin, physical activity, BMI, and adipose tissue area (VAT or SAT area, accordingly to the outcome).
RESULTS
prior exposure to TA and/or ddI was associated with excess risk of low VAT (adjusted OR (aOR) 1.74 [1.14; 2.67]) and SAT density (aOR 1.74 [1.18; 2.58]), for a given VAT and SAT area, respectively. No association between VAT and SAT density with time since TA and/or ddI discontinuation was found. 10 HU increase in VAT density was associated with higher adiponectin plasma level and this association was not modified by prior exposure to TA and/or ddI. Prior exposure to TA and/or ddI was associated with 9% lower [- 17;-2] plasma adiponectin levels and with excess risk of low adiponectin (aOR 1.74 [1.10; 2.76]).
CONCLUSIONS
We described low adipose tissue density and impaired adiponectin production to be associated with prior exposure to TA and/or ddI even years after treatment discontinuation and independently of adipose tissue area. These findings suggest that prior TA and ddI exposure may have long-lasting detrimental effects on adipose tissue function and, consequently, on cardiometabolic health in PLWH.
Topics: Adiponectin; Adipose Tissue; Adult; Anti-HIV Agents; Biomarkers; Cross-Sectional Studies; Didanosine; Female; HIV Infections; Humans; Intra-Abdominal Fat; Longitudinal Studies; Male; Middle Aged; Subcutaneous Fat; Thymidine
PubMed: 31399063
DOI: 10.1186/s12879-019-4347-y -
PloS One 2023Pharmacotherapy is necessary for many people with psychiatric disorders and polypharmacy is common. The psychotropic drug-drug interaction (DDI) should be concerned and...
BACKGROUND
Pharmacotherapy is necessary for many people with psychiatric disorders and polypharmacy is common. The psychotropic drug-drug interaction (DDI) should be concerned and efficiently monitored by a proper instrument.
OBJECTIVES
This study aimed to investigate the prevalence and associated factors of psychotropic DDI and to compare the identification utility from three databases: Drugs.com®, Lexicomp®, and Epocrates®.
METHODS
This was a retrospective cohort design. We collected demographic and clinical data of all patients hospitalised in the psychiatric inpatient unit in 2020. Psychotropic DDI profiles were examined through three databases. Descriptive statistics were used to report comprehensiveness of each database and prevalence of psychotropic DDI. The Fleiss' kappa index would be analysed to indicate agreement strength of DDI severity classification among three databases.
RESULTS
From 149 total admissions, the psychotropic DDIs were found in 148 admissions (99.3%). Thorough the study, there were 182 of both psychotropic and other agents prescribed under 1,357 prescriptions. In total, 2,825 psychotropic DDIs were identified by using Drugs.com® 2,500 times, Epocrates® 2,269 times, and Lexicomp® 2,265 times. Interactions with clonazepam was the three most frequent agents when co-administrated with quetiapine (n = 56), risperidone (n = 36), and valproic acid and derivatives (n = 36). Serious DDIs were comparatively lower in incidence and there was no evidence of its association with reported clinical adverse consequences. The study revealed slight and fair agreement regarding severity classification among the three databases was found. DDI events detected by Drugs.com® were greatest in number, but Lexicomp® provided the broadest list of medications prescribed in our study.
CONCLUSION
Among three databases, interactions detected by Drugs.com® were greatest in number, whereas Lexicomp® provided the broadest list of medications. Development of such databases, based on both theoretical and clinical conceptions, should be focused to balance safety of patients and weariness of healthcare providers.
Topics: Humans; Retrospective Studies; Databases, Factual; Didanosine; Fatigue; Drug Interactions
PubMed: 37347788
DOI: 10.1371/journal.pone.0287575 -
Medicina (Kaunas, Lithuania) May 2022This article aims to describe a unique case of didanosine-induced retinal degeneration that was discovered 11 years after the drug withdrawal. The patient is a...
This article aims to describe a unique case of didanosine-induced retinal degeneration that was discovered 11 years after the drug withdrawal. The patient is a 42-year-old woman with a medical history of HIV and hepatitis C virus since 2004. She has been prescribed antiretroviral therapy since then. For the first seven years (2004-2011), the patient was prescribed a combination therapy consisting of didanosine, efavirenz, and lamivudine. The protocol was changed to atripla (efavirenz, emtricitabine, and tenofovir) from 2011 to 2021. Recently (October 2021-January 2021), the patient was prescribed eviplera (rilpivirin, emtricitabine, and tenofovir). In addition, her past medical history revealed Gougerot-Sjogren syndrome and rheumatoid arthritis. She was prescribed hydroxychloroquine (HCQ) (2009-2021) at a dose of 400 mg daily. She had no vision complaint. During her routine HCQ screening at the eye clinic, University Hospital Bretonneau, Tours, France, the widefield colour fundus photograph showed well-defined symmetric mid-peripheral areas of chorioretinal atrophy sparing the posterior pole of both eyes. Furthermore, the widefield fundus autofluorescence illustrated mid-peripheral round well-demarcation hypoautofluorescent areas of chorioretinal atrophy of both eyes. Conversely, the macular optical coherence tomography (OCT) was normal. Many of her drugs are known to be associated with retinopathy such as HCQ, tenofovir, efavirenz, and didanosine. Because our data corroborate peripheral retinal damage rather than posterior pole damage, this case report is compatible with didanosine-induced retinopathy rather than HCQ, efavirenz, or tenofovir retinal toxicity. All HIV patients who are presently or were previously on didanosine therapy should have their fundus examined utilising widefield fundus autofluorescence and photography.
Topics: Adult; Atrophy; Choroid Diseases; Didanosine; Emtricitabine; Female; HIV Infections; Humans; Hydroxychloroquine; Retinal Degeneration; Tenofovir; Tomography, Optical Coherence
PubMed: 35743998
DOI: 10.3390/medicina58060735 -
PloS One 2020Cellular immunometabolism among people living with HIV (PLWH) on antiretroviral therapy (ART) remains under investigated. We assessed the relationships between...
BACKGROUND
Cellular immunometabolism among people living with HIV (PLWH) on antiretroviral therapy (ART) remains under investigated. We assessed the relationships between mitochondrial oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) and blood parameters associated with HIV immune dysregulation.
METHODS
PLWH ≥40 years old and on stable ART ≥3 months were enrolled (N = 149). OXPHOS complex I (CI, NADH dehydrogenase) and complex IV (CIV, cytochrome c oxidase) protein levels in PBMCs were quantified using immunoassays. Monocyte subsets and markers of T-cell activation, senescence, and exhaustion were measured on PBMC by flow cytometry. Plasma inflammatory mediators were quantified using a multiplex assay. HIV-uninfected group (N = 44) of similar age, gender, and ethnicity had available OXPHOS levels.
RESULTS
PLWH had a median age of 51 years. Majority were male (88.6%), Caucasian (57.7%), and with undetectable plasma HIV RNA <50 copies/mL (84.6%). Median CI level was lower in PLWH compared with the HIV-seronegative group (65.5 vs 155.0 optical density/μg protein x 103, p <0.0001). There was no significant difference in median CIV levels. Lower OXPHOS levels correlated with lower CD4% and CD4/CD8 ratio. On multivariable linear regression adjusted for age, current use of zidovudine/didanosine, and HIV RNA (detectable versus undetectable), lower OXPHOS levels were significantly associated with higher MPO, SAA, SAP, and sVCAM, and higher frequencies of intermediate (CD14++CD16+) monocytes and TIGIT+TIM3+ CD4 T-cell (p<0.01).
CONCLUSION
CI PBMC protein levels were decreased in PLWH on ART. Decreased OXPHOS correlated with disease severity and inflammation. Further studies on the relationship between immunometabolism and immune dysregulation in HIV are warranted.
Topics: Anti-HIV Agents; CD4-CD8 Ratio; Cross-Sectional Studies; Female; HIV Infections; HIV-1; Hawaii; Host-Pathogen Interactions; Humans; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Middle Aged; Mitochondria; Oxidative Phosphorylation; RNA, Viral; Severity of Illness Index
PubMed: 32353005
DOI: 10.1371/journal.pone.0231761 -
The Science of the Total Environment Sep 2023The use of urine-derived fertilizers has several economic and environmental advantages. However, there is concern that pharmaceutical residues present in urine could...
Uptake of selected antiretrovirals by pepper (Capsicum annum), radish (Raphanus sativus), and ryegrass (Lolium perenne) grown on two contrasting soils and fertilized with human urine-derived fertilizers.
The use of urine-derived fertilizers has several economic and environmental advantages. However, there is concern that pharmaceutical residues present in urine could enter the food chain after plant uptake and pose potential risks to human and animal health. A pot experiment was conducted to evaluate the uptake of nine target antiretroviral drugs (ARVDs) by pepper (Capsicum annum), ryegrass (Lolium perenne) and radish (Raphanus sativus) grown in two soils of contrasting texture and organic matter content and fertilized with stored urine, nitrified urine concentrate (NUC), and struvite. Nevirapine was the only ARVD detected in crops grown with NUC and struvite on both soils, but the concentrations were below the limit of quantification. Plants fertilized with stored urine absorbed lamivudine, ritonavir, stavudine, emtricitabine, nevirapine, and didanosine, while abacavir, efavirenz and zidovudine were not detected. The ARVDs detected in the soils after harvest were significantly higher in the soil with high organic matter and clay content. To assess direct human exposure the estimated daily dietary intake (DDI) of ARVDs by consumption of the pepper and radish fertilized with stored urine was compared with the Threshold of Toxicological Concern (TTC) values based on the Cramer classification tree. The calculated DDI values for all ARVDs were about 300-3000 times lower than the TTC values for class III compounds. Therefore, daily consumption of these crops fertilized with stored urine does not pose a health risk to the consumer. Future research is required to assess the impact of ARVD metabolites, which may be more harmful to human health than the parent compounds.
Topics: Animals; Humans; Soil; Raphanus; Lolium; Fertilizers; Capsicum; Nevirapine; Struvite; Vegetables; Crops, Agricultural; HIV Infections; Soil Pollutants
PubMed: 37269997
DOI: 10.1016/j.scitotenv.2023.164551 -
AIDS (London, England) Mar 2023In utero exposure to didanosine was associated with increased risk of brain cancer in a French study. We used United States health department records to assess cancer...
In utero exposure to didanosine was associated with increased risk of brain cancer in a French study. We used United States health department records to assess cancer risk among 13 617 children exposed to HIV in utero , who remained HIV-uninfected after birth (1990-2017). Risk of brain tumors was borderline elevated among these children (standardized incidence ratio 2.2, 95% confidence interval 0.8-4.8, P = 0.12, based on six cases). Risk was not significantly increased for leukemia or other cancers.
Topics: Pregnancy; Female; Child; Humans; United States; Infant; Anti-HIV Agents; Pregnancy Complications, Infectious; HIV Infections; Prenatal Exposure Delayed Effects; Prospective Studies; Neoplasms
PubMed: 36544264
DOI: 10.1097/QAD.0000000000003458 -
Frontiers in Cardiovascular Medicine 2023Previous studies have reported impairment in systolic and diastolic function in people with HIV (PWHIV). Our aim was to determine if echocardiographically measured left...
BACKGROUND
Previous studies have reported impairment in systolic and diastolic function in people with HIV (PWHIV). Our aim was to determine if echocardiographically measured left ventricular (LV) global longitudinal strain (GLS) is abnormal in asymptomatic PWHIV.
METHODS
A cross-sectional study of PWHIV ( = 98, 89% male, median age 53 years) and HIV-negative people ( = 50, median age 53 years) without known cardiovascular disease were recruited from a single centre. All participants completed a health/lifestyle questionnaire, provided a fasting blood sample, and underwent a comprehensive echocardiogram for assessment of diastolic and systolic LV function, including measurement of GLS.
RESULTS
All PWHIV were receiving antiretroviral therapy (ART) for a median of 12 years (IQR: 6.9, 22.4), the majority with good virological control (87% suppressed) and without immunological compromise (median CD4 598 cells/µl, IQR: 388, 841). Compared with controls of similar age and gender, there was no difference in GLS [mean GLS -20.3% (SD 2.5%) vs. -21.0% (SD 2.5%), = 0.14] or left ventricular ejection fractions [65.3% (SD 6.3) vs. 64.8% (SD 4.8), = 0.62]. Following adjustment for covariates (gender, heart rate, systolic and diastolic blood pressure, and fasting glucose), the difference in GLS remained non-significant. There were no differences in LV diastolic function between the groups. Exposure to at least one mitochondrially toxic ART drug (didanosine, stavudine, zidovudine, or zalcitabine) was not associated with impairment of LV systolic function.
CONCLUSION
No clinically significant impairment of myocardial systolic function, as measured by LV GLS, was detected in this predominantly Caucasian male population of PWHIV on long-term ART, with no history of cardiovascular disease.
PubMed: 37547256
DOI: 10.3389/fcvm.2023.1198387 -
Antimicrobial Agents and Chemotherapy Aug 2019The Prestwick library was screened for antibacterial activity or "antibiotic resistance breaker" (ARB) potential against four species of Gram-negative pathogens....
The Prestwick library was screened for antibacterial activity or "antibiotic resistance breaker" (ARB) potential against four species of Gram-negative pathogens. Discounting known antibacterials, the screen identified very few ARB hits, which were strain/drug specific. These ARB hits included antimetabolites (zidovudine, floxuridine, didanosine, and gemcitabine), anthracyclines (daunorubicin, mitoxantrone, and epirubicin), and psychoactive drugs (gabapentin, fluspirilene, and oxethazaine). These findings suggest that there are few approved drugs that could be directly repositioned as adjunct antibacterials, and these will need robust testing to validate efficacy.
Topics: Anti-Bacterial Agents; Didanosine; Drug Resistance, Multiple, Bacterial; Ethanolamines; Floxuridine; Gram-Negative Bacteria; Microbial Sensitivity Tests; Mitoxantrone; Zidovudine
PubMed: 31160293
DOI: 10.1128/AAC.00769-19 -
Scientific Reports Aug 2021Drug repurposing is one of the modern techniques used in the drug discovery to find out the new targets for existing drugs. Insilico methods have a major role in this...
Drug repurposing is one of the modern techniques used in the drug discovery to find out the new targets for existing drugs. Insilico methods have a major role in this approach. We used 60 FDA approved antiviral drugs reported in the last 50 years to screen against different cancer cell receptors. The thirteen compounds selected after virtual screening are analyzed for their druggability based on ADMET parameters and found the selectivity of guanine derivatives-didanosine, entecavir, acyclovir, valganciclovir, penciclovir, ganciclovir and valacyclovir as suitable candidates. The pharmacophore model, AARR, suggested based on the common feature alignment, shows that the two fused rings as in guanine and two acceptors-one from keto-oxygen (A5) and other from the substituent attached to nitrogen of imidazole ring (A4) give the druggability to the guanine derivatives. The NBO analysis on N9 is indicative of charge distribution from the ring to substituents, which results in delocalization of negative character in most of the ligands. The molecular dynamics simulations also pointed out the importance of guanine scaffold, which stabilizes the ligands inside the binding pocket of the receptor. All these results are indicative of the selectivity of guanine scaffold in anticancer drug development, especially as PARP1 inhibitors in breast, ovarian and prostate cancer. As these seven molecules are already approved by FDA, we can safely go for further preclinical trials.
Topics: Antineoplastic Agents; Computational Biology; Drug Development; Drug Discovery; Drug Repositioning; Guanine; Humans; Molecular Structure; Neoplasms
PubMed: 34376738
DOI: 10.1038/s41598-021-95507-4