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Molecules (Basel, Switzerland) Aug 2023The behavior of four drugs from the family of nucleoside analog reverse-transcriptase inhibitors (zalcitabine, stavudine, didanosine, and apricitabine) in a membrane...
The behavior of four drugs from the family of nucleoside analog reverse-transcriptase inhibitors (zalcitabine, stavudine, didanosine, and apricitabine) in a membrane environment was traced using molecular dynamics simulations. The simulation models included bilayers and monolayers composed of POPC and POPG phospholipids. It was demonstrated that the drugs have a higher affinity towards POPG membranes than POPC membranes due to attractive long-range electrostatic interactions. The results obtained for monolayers were consistent with those obtained for bilayers. The drugs accumulated in the phospholipid polar headgroup region. Two adsorption modes were distinguished. They differed in the degree of penetration of the hydrophilic headgroup region. Hydrogen bonds between drug molecules and phospholipid heads were responsible for adsorption. It was shown that apricitabine penetrated the hydrophilic part of the POPC and POPG membranes more effectively than the other drugs. Van der Waals interactions between S atoms and lipids were responsible for this.
Topics: Molecular Dynamics Simulation; Reverse Transcriptase Inhibitors; Stavudine; Phospholipids; DNA-Directed RNA Polymerases
PubMed: 37687102
DOI: 10.3390/molecules28176273 -
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 -
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 -
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 -
Cureus Mar 2023Noncirrhotic portal hypertension (NCPH) has recently been found in human immunodeficiency virus (HIV)-infected patients taking didanosine. Here, we describe an...
Noncirrhotic portal hypertension (NCPH) has recently been found in human immunodeficiency virus (HIV)-infected patients taking didanosine. Here, we describe an HIV-infected patient with portal hypertension due to hepatoportal sclerosis who presented with hematemesis at the emergency department (ED). CT angiography of the abdomen and pelvis with and without contrast revealed a diminutive portal vein with corresponding massive lower esophageal varices and superior mesenteric vein to the right gonadal vein varices. Esophagogastroduodenoscopy (EGD) revealed grade II varices were found in the lower third of the esophagus, for which the patient's symptoms improved with emergency endoscopic band ligation, octreotide and didanosine discontinuation. Our case demonstrates a rare complication that can occur with continued didanosine use in an HIV-positive patient. We highlight the need for a standard diagnostic upper gastrointestinal endoscopy to screen for portal hypertension and high-risk esophageal varices in patients with long-term didanosine use as seen in our patient.
PubMed: 37082489
DOI: 10.7759/cureus.36364 -
Cell Reports Jan 2023The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) is growing. Repurposing...
The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) is growing. Repurposing compounds already used clinically, usually at modified doses, allows rapid implementation of geroprotective pharmaceuticals. Here we find the anti-retroviral nucleoside reverse transcriptase inhibitor (NRTI) zidovudine robustly extends lifespan and health span in C. elegans, independent of electron transport chain impairment or ROS accumulation. Rather, zidovudine treatment modifies pyrimidine metabolism and transcripts related to proteostasis. Testing regulators of mitochondrial stress and proteostasis shows that lifespan extension is dependent on activating transcription factor 4 (ATF-4). ATF-4 regulates longevity induced by mitochondrial stress, specifically communication between mitochondrial and cytosolic translation. Translation is reduced in zidovudine-treated worms, also dependent on ATF-4. Finally, we show ATF-4-dependent lifespan extension induced by didanosine, another NRTI. Altogether, our work elucidates the geroprotective effects of NRTIs such as zidovudine in vivo, via reduction of translation and ATF-4.
Topics: Animals; Humans; Zidovudine; Longevity; Activating Transcription Factor 4; Caenorhabditis elegans; Reverse Transcriptase Inhibitors; Retroviridae; HIV Infections
PubMed: 36640360
DOI: 10.1016/j.celrep.2022.111928 -
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 -
AIDS and Behavior May 2023Multiple factors may affect combined antiretroviral therapy (cART). We investigated the impact of food, beverages, dietary supplements, and alcohol on the... (Meta-Analysis)
Meta-Analysis Review
Multiple factors may affect combined antiretroviral therapy (cART). We investigated the impact of food, beverages, dietary supplements, and alcohol on the pharmacokinetic and pharmacodynamic parameters of 33 antiretroviral drugs. Systematic review in adherence to PRISMA guidelines was performed, with 109 reports of 120 studies included. For each drug, meta-analyses or qualitative analyses were conducted. We have found clinically significant interactions with food for more than half of antiretroviral agents. The following drugs should be taken with or immediately after the meal: tenofovir disoproxil, etravirine, rilpivirine, dolutegravir, elvitegravir, atazanavir, darunavir, lopinavir, nelfinavir, ritonavir, saquinavir. Didanosine, zalcitabine, zidovudine, efavirenz, amprenavir, fosamprenavir, and indinavir should be taken on an empty stomach for maximum patient benefit. Antiretroviral agents not mentioned above can be administered regardless of food. There is insufficient evidence available to make recommendations about consuming juice or alcohol with antiretroviral drugs. Resolving drug-food interactions may contribute to maximized cART effectiveness and safety.
Topics: Humans; HIV Infections; Ritonavir; Ethanol; Anti-Retroviral Agents; Beverages; Dietary Supplements; Anti-HIV Agents
PubMed: 36318429
DOI: 10.1007/s10461-022-03880-6