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Nanomaterials (Basel, Switzerland) Sep 2023Many purine derivatives are active pharmaceutical ingredients of significant importance in the therapy of autoimmune diseases, cancers, and viral infections. In many... (Review)
Review
Many purine derivatives are active pharmaceutical ingredients of significant importance in the therapy of autoimmune diseases, cancers, and viral infections. In many cases, their medical use is limited due to unfavorable physicochemical and pharmacokinetic properties. These problems can be overcome by the preparation of the prodrugs of purines or by combining these compounds with nanoparticles. Herein, we aim to review the scientific progress and perspectives for polymer-based nanoparticles as drug delivery systems for purines. Polymeric nanoparticles turned out to have the potential to augment antiviral and antiproliferative effects of purine derivatives by specific binding to receptors (ASGR1-liver, macrophage mannose receptor), increase in drug retention (in eye, intestines, and vagina), and permeation (intranasal to brain delivery, PEPT1 transport of acyclovir). The most significant achievements of polymer-based nanoparticles as drug delivery systems for purines were found for tenofovir disoproxil in protection against HIV, for acyclovir against HSV, for 6-mercaptopurine in prolongation of mice ALL model life, as well as for 6-thioguanine for increased efficacy of adoptively transferred T cells. Moreover, nanocarriers were able to diminish the toxic effects of acyclovir, didanosine, cladribine, tenofovir, 6-mercaptopurine, and 6-thioguanine.
PubMed: 37836288
DOI: 10.3390/nano13192647 -
Molecules (Basel, Switzerland) Jun 2022An improved protocol for the transformation of ribonucleosides into 2',3'-dideoxynucleoside and 2',3'-didehydro-2',3'-dideoxynucleoside derivatives, including the...
An improved protocol for the transformation of ribonucleosides into 2',3'-dideoxynucleoside and 2',3'-didehydro-2',3'-dideoxynucleoside derivatives, including the anti-HIV drugs stavudine (d4T), zalcitabine (ddC) and didanosine (ddI), was established. The process involves radical deoxygenation of xanthate using environmentally friendly and low-cost reagents. Bromoethane or 3-bromopropanenitrile was the alkylating agent of choice to prepare the ribonucleoside 2',3'-bisxanthates. In the subsequent radical deoxygenation reaction, tris(trimethylsilyl)silane and 1,1'-azobis(cyclohexanecarbonitrile) were used to replace hazardous BuSnH and AIBN, respectively. In addition, TBAF was substituted for camphorsulfonic acid in the deprotection step of the 5'--silyl ether group, and an enzyme (adenosine deaminase) was used to transform 2',3'-dideoxyadenosine into 2',3'-dideoxyinosine (ddI) in excellent yield.
Topics: Anti-HIV Agents; Didanosine; Dideoxynucleosides; Stavudine; Zalcitabine; Zidovudine
PubMed: 35807233
DOI: 10.3390/molecules27133993 -
Viruses Dec 2021At Bristol-Myers (BM) (1985-1990), John C. Martin started his HIV career with directing the clinical development of didanosine (ddI) and stavudine (d4T). During this... (Review)
Review
At Bristol-Myers (BM) (1985-1990), John C. Martin started his HIV career with directing the clinical development of didanosine (ddI) and stavudine (d4T). During this period, he became aware of the acyclic nucleoside phosphonates (ANPs), such as ()-HPMPA and PMEA, as potential antiviral drugs. Under his impulse, BM got involved in the evaluation of these ANPs, but the merger of BM with Squibb (to become BMS) incited John to leave BM and join Gilead Sciences, and the portfolio of the ANPs followed the transition. At Gilead, John succeeded in obtaining the approval from the US FDA for the use of cidofovir in the treatment of cytomegalovirus (CMV) retinitis in AIDS patients, which was reminiscent of John's first experience with ganciclovir (at Syntex) as an anti-CMV agent. At Gilead, John would then engineer the development of tenofovir, first as TDF (tenofovir disoproxil fumarate) and then as TAF (tenofovir alafenamide) and various combinations thereof, for the treatment of HIV infections (), TDF and TAF for the treatment of hepatitis B (HBV) infections (), and TDF and TAF in combination with emtricitabine for the prophylaxis of HIV infections ().
Topics: Alanine; Anti-HIV Agents; Drug Therapy, Combination; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; HIV; HIV Infections; Hepatitis B; History, 20th Century; History, 21st Century; Humans; Pre-Exposure Prophylaxis; Reverse Transcriptase Inhibitors; Tenofovir
PubMed: 34960679
DOI: 10.3390/v13122410 -
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 -
BMC Infectious Diseases May 2022As people living with HIV (PLWH) are growing older, there is increased incidence of metabolic diseases, including type 2 diabetes mellitus, for which insulin resistance...
BACKGROUND
As people living with HIV (PLWH) are growing older, there is increased incidence of metabolic diseases, including type 2 diabetes mellitus, for which insulin resistance is a key determinant. In this study, we aimed to investigate risk factors associated with insulin resistance in PLWH.
METHODS
We included well-treated PLWH without hepatitis co-infection, and with available fasting serum insulin and plasma glucose (n = 643) from the Copenhagen Comorbidity in HIV Infection Study. Insulin resistance was calculated using the homeostasis model assessment of insulin resistance (HOMA-IR). We investigated the association between risk factors and high HOMA-IR in a logistic regression model adjusted for age, sex, abdominal obesity, smoking status, and origin. When including use of thymidine analogues and/or didanosine in the model, we also adjusted for time with HIV.
RESULTS
Median (IQR) age of PLWH was 52 years (46-61), and 87% (n = 557) were male. Median (IQR) HOMA-IR was 1.86 (1.23-3.14) mmol/L × mU/L. Risk factors significantly associated with high HOMA-IR included older age, BMI ≥ 25, abdominal obesity, waist circumference, use of thymidine analogues and/or didanosine, time with HIV, and CD4 nadir < 200 cells/µL.
CONCLUSIONS
Insulin resistance in PLWH is associated with both use of thymidine analogues and/or didanosine and prior immunodeficiency suggesting that increased attention on blood glucose in these patients could be beneficial.
Topics: Diabetes Mellitus, Type 2; Didanosine; Female; HIV Infections; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Obesity, Abdominal; Thymidine
PubMed: 35643429
DOI: 10.1186/s12879-022-07485-1 -
Antibiotics (Basel, Switzerland) Sep 2023Acute pancreatitis (AP) is an acute inflammation of the pancreas caused by the activation of digestive enzymes in the pancreatic tissue. The main causes of AP are... (Review)
Review
Acute pancreatitis (AP) is an acute inflammation of the pancreas caused by the activation of digestive enzymes in the pancreatic tissue. The main causes of AP are cholelithiasis and alcohol abuse; less commonly, it can be caused by drugs, with a prevalence of up to 5%. Causal associations between drugs and pancreatitis are largely based on case reports or case series with limited evidence. We reviewed the available data on drug-induced AP, focusing on antimicrobial drugs and antivirals, and discussed the current evidence in relation to the classification systems available in the literature. We found 51 suspected associations between antimicrobial and antiviral drugs and AP. The drugs with the most evidence of correlation are didanosine, protease inhibitors, and metronidazole. In addition, other drugs have been described in case reports demonstrating positive rechallenge. However, there are major differences between the various classifications available, where the same drug being assigned to different probability classes. It is likely that the presence in multiple case reports of an association between acute pancreatitis and a drug should serve as a basis for conducting prospective randomized controlled trials to improve the quality of the evidence.
PubMed: 37887196
DOI: 10.3390/antibiotics12101495 -
Viruses Apr 2020Previous studies reported that Angiotensin converting enzyme 2 (ACE2) is the main cell receptor of SARS-CoV and SARS-CoV-2. It plays a key role in the access of the...
Previous studies reported that Angiotensin converting enzyme 2 (ACE2) is the main cell receptor of SARS-CoV and SARS-CoV-2. It plays a key role in the access of the virus into the cell to produce the final infection. In the present study we investigated in silico the basic mechanism of in the lung and provided evidences for new potentially effective drugs for Covid-19. Specifically, we used the gene expression profiles from public datasets including The Cancer Genome Atlas, Gene Expression Omnibus and Genotype-Tissue Expression, Gene Ontology and pathway enrichment analysis to investigate the main functions of -correlated genes. We constructed a protein-protein interaction network containing the genes co-expressed with . Finally, we focused on the genes in the network that are already associated with known drugs and evaluated their role for a potential treatment of Covid-19. Our results demonstrate that the genes correlated with are mainly enriched in the sterol biosynthetic process, Aryldialkylphosphatase activity, adenosylhomocysteinase activity, trialkylsulfonium hydrolase activity, acetate-CoA and CoA ligase activity. We identified a network of 193 genes, 222 interactions and 36 potential drugs that could have a crucial role. Among possible interesting drugs for Covid-19 treatment, we found Nimesulide, Fluticasone Propionate, Thiabendazole, Photofrin, Didanosine and Flutamide.
Topics: Angiotensin-Converting Enzyme 2; Anti-Inflammatory Agents; Antiviral Agents; Betacoronavirus; COVID-19; Computational Biology; Computer Simulation; Coronavirus Infections; Databases, Genetic; Drug Discovery; Gene Expression Profiling; Gene Regulatory Networks; Humans; Lung; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protein Interaction Mapping; Receptors, Coronavirus; Receptors, Virus; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 32268515
DOI: 10.3390/v12040404 -
AIDS (London, England) Jul 2020To evaluate whether there is an increased risk of neurologic diagnoses in children who are HIV-exposed but uninfected (CHEU) exposed in utero to specific antiretroviral...
OBJECTIVE
To evaluate whether there is an increased risk of neurologic diagnoses in children who are HIV-exposed but uninfected (CHEU) exposed in utero to specific antiretroviral medications.
DESIGN
Prospective cohort study of CHEU enrolled from 2007 to 2017.
METHODS
We evaluated children for neurologic case status, including microcephaly, febrile seizures, seizure disorders, ophthalmologic disorders, and other neurologic disorders. Adjusted relative risks (aRRs) were estimated for the association between in-utero antiretroviral exposure and neurologic case using log-binomial regression, accounting for potential confounders. Sensitivity analyses were conducted to evaluate robustness of findings.
RESULTS
Among 3747 eligible CHEU, 231 (6.2%) met neurologic case criteria (95% CI 5.4--7%). Most eligible children (86%) were exposed in utero to combination antiretroviral regimens. In adjusted models, children exposed to efavirenz at any time during pregnancy had higher risk of neurologic case status (aRR = 1.53, 95% CI 0.94--2.51). This association was stronger when comparing efavirenz exposure at conception to no exposure during pregnancy (aRR = 1.92, 95% CI 1.09--3.36) and considering follow-up and case diagnosis only through age 2 (aRR = 2.14, 95% CI 1.11--4.12). Children exposed to didanosine at conception and during the first trimester had increased risk of neurologic case status (aRR = 2.28, 95% CI 1.07--4.87 and aRR = 2.02, 95% CI 1.01--4.04, respectively), compared with didanosine-unexposed children. Children with dolutegravir exposure had some suggestion of increased risk of neurologic case (aRR = 2.43, 95% CI 0.75--7.84), which was observed consistently across several sensitivity analyses.
CONCLUSION
Efavirenz and didanosine exposure during pregnancy were associated with higher risk of neurologic abnormalities in CHEU, and dolutegravir exposure showed some suggestive associations, which warrant further monitoring.
Topics: Abnormalities, Drug-Induced; Adult; Anti-HIV Agents; Child; Child, Preschool; Didanosine; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Male; Microcephaly; Pregnancy; Pregnancy Complications, Infectious; Prenatal Exposure Delayed Effects; Prospective Studies; Treatment Outcome
PubMed: 32310900
DOI: 10.1097/QAD.0000000000002550 -
ACS Omega Jun 2022Analogues and derivatives of natural nucleosides/nucleotides are considered among the most successful bioactive species of drug-like compounds in modern medicinal...
Analogues and derivatives of natural nucleosides/nucleotides are considered among the most successful bioactive species of drug-like compounds in modern medicinal chemistry, as they are well recognized for their diverse and efficient pharmacological activities in humans, especially as antivirals and antitumors. Coronavirus disease 2019 (COVID-19) is still almost incurable, with its infectious viral microbe, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continuing to wreak devastation around the world. This global crisis pushed all involved scientists, including drug discoverers and clinical researchers, to try to find an effective and broad-spectrum anti-COVID-19 drug. Didanosine (2',3'-dideoxyinosine, DDI) is a synthetic inosine/adenosine/guanosine analogue and highly active antiretroviral therapeutic agent used for the treatment of human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS). This potent reverse-transcriptase inhibitor is characterized by proven strong pharmacological effects against the viral genome, which may successfully take part in the effective treatment of SARS-CoV-2/COVID-19. Additionally, targeting the pivotal SARS-CoV-2 replication enzyme, RNA-dependent RNA polymerase (RdRp), is a very successful tactic to combat COVID-19 irrespective of the SARS-CoV-2 variant type because RdRps are broadly conserved among all SARS-CoV-2 strains. Herein, the current study proved for the first time, using the antiviral evaluation, that DDI is capable of potently inhibiting the replication of the novel virulent progenies of SARS-CoV-2 with quite tiny anti-SARS-CoV-2 and anti-RdRp EC values of around 3.1 and 0.19 μM, respectively, surpassing remdesivir together with its active metabolite (GS-441524). Thereafter, the computational interpretation of the biological results supported that DDI strongly targets the key pocket of the SARS-CoV-2 RdRp main catalytic active site. The ideal pharmacophoric characteristics of the ligand DDI make it a typical inhibiting agent of SARS-CoV-2 multiplication processes (including high-fidelity proofreading), with its elastic structure open for many kinds of derivatization. In brief, the present results further uphold and propose the repurposing potentials of DDI against the different types of COVID-19 and convincingly motivate us to quickly launch its extensive preclinical/clinical pharmacological evaluations, hoping to combine it in the COVID-19 therapeutic protocols soon.
PubMed: 35785294
DOI: 10.1021/acsomega.1c07095 -
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