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Scientia Pharmaceutica 2015The aim of this study was to formulate and evaluate stavudine floating microballoons for controlled drug release. Initially, the drug-loaded low-density granular pellets...
The aim of this study was to formulate and evaluate stavudine floating microballoons for controlled drug release. Initially, the drug-loaded low-density granular pellets were prepared with hydroxypropyl methylcellulose E5 grade and by using isopropyl alcohol as a granulating fluid. Further, the low-density granular pellets were subjected to microencapsulation by an emulsion evaporation technique using ethyl cellulose 7 cps and Eudragit S 100 as coating polymers and 1% w/v polyethylene glycol 400 as aqueous phase. The prepared microballoons were characterized for their particle size analysis, angle of repose, and compressibility index. The in vitro release studies were performed in 0.1 N HCl as medium. The prepared microballoons were free-flowing and spherical in shape. From all the formulations, F5E and F5F can be considered as promising controlled release floating microballoons of stavudine providing first-order release over a period of 12 hours, with a minimum floating lag time of 1 minute. It was found that the ratio of the drug & polymer, stirring speed, and concentration of surfactant were the most significant variables which influenced the size of the stavudine microballoons under the applied experimental conditions.
PubMed: 26839847
DOI: 10.3797/scipharm.1501-07 -
Indian Pediatrics Mar 2014To determine the trough and two hour plasma levels of nevirapine, stavudine, and lamivudine when administered in fixed dose combinations (FDC).
OBJECTIVE
To determine the trough and two hour plasma levels of nevirapine, stavudine, and lamivudine when administered in fixed dose combinations (FDC).
DESIGN
Cross sectional.
SETTING
Tertiary care hospital in Northern India.
PARTICIPANTS
79 HIV-infected children receiving antiretroviral therapy with FDCs for more than month.
INTERVENTION
Two-point sampling (0 and 2 hours after the morning dose).
OUTCOME MEASURES
Plasma concentrations of all three drugs were simultaneously assayed by liquid chromatography/mass spectroscopy.
RESULTS
Majority (77%) of children were receiving fixed dose combination of stavudine, lamivudine, nevirapine in the ratio of 6:30:50 mg. The median (IQR) trough and 2-hour plasma levels (µg/mL) of nevirapine, stavudine and lamivudine were 5.2 (4.0, 6.3) and 7.9 (6.0, 9.7); 0.1 (0.06, 0.16) and 1.1 (0.59, 1.6); 0.1 (0.02, 0.2) and 2.5 (1.4, 3.1), respectively. Very few children had sub-therapeutic plasma drug levels of stavudine (2.5%), lamivudine (7.6%) and nevirapine (10%). Inadequate viral suppression at 6 months follow up was significantly associated with initial high viral load, low CD4 percentage at the time of enrolment in study, and lower doses of lamivudine and stavudine.
CONCLUSIONS
The currently available generic pediatric fixed dose antiretroviral combinations in India provide adequate drug exposure in majority of children.
Topics: Adolescent; Anti-HIV Agents; Child; Child, Preschool; Cross-Sectional Studies; Drugs, Generic; Female; HIV Infections; Humans; Infant; Lamivudine; Male; Nevirapine; Stavudine
PubMed: 24736906
DOI: 10.1007/s13312-014-0382-3 -
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 -
Journal of Medicinal Chemistry Feb 2024We report on the synthesis and characterization of three types of nucleoside tetraphosphate derivatives - acting as potential prodrugs of d4T nucleotides: (i) the...
We report on the synthesis and characterization of three types of nucleoside tetraphosphate derivatives - acting as potential prodrugs of d4T nucleotides: (i) the δ-phosph(on)ate is modified by two alkyl residues and ; (ii) the δ-phosph(on)ate is esterified covalently by one acyloxybenzyl moiety and a moiety and ; or (iii) the δ-phosphate of nucleoside tetraphosphate is masked by two prodrug groups and . We were able to prove the efficient release of d4T triphosphate (d4TTP, (i)), δ-monoalkylated d4T tetraphosphates ( and , (ii)), and d4T tetraphosphate (d4T4P, (iii)), respectively, by chemical or enzymatic processes. Surprisingly, δ-dialkylated d4T tetraphosphates, δ-monoalkylated d4T tetraphosphates, and d4T4P were substrates for HIV-RT. Remarkably, the antiviral activity of Tetraro-prodrug was improved by 7700-fold (SI 5700) as compared to the parent d4T in CEM/TK cells, denoting a successful cell membrane passage of these lipophilic prodrugs and an intracellular delivery of the nucleotide metabolites.
Topics: Anti-HIV Agents; Nucleosides; Stavudine; HIV-1; Nucleotides; Prodrugs
PubMed: 38345794
DOI: 10.1021/acs.jmedchem.3c02022 -
Antiviral Therapy 2010The aim of this study was to evaluate the pharmacokinetics of lamivudine (3TC), stavudine (d4T) and nevirapine (NVP) in HIV-infected Malawian children receiving... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The aim of this study was to evaluate the pharmacokinetics of lamivudine (3TC), stavudine (d4T) and nevirapine (NVP) in HIV-infected Malawian children receiving quartered tablet multiples of Triomune 40 (generic tablet [GT]) compared with individual generic liquid (GL) and trade liquid (TL).
METHODS
This was a prospective randomized three-way crossover study. Patients (8-<12 kg, 18-<22 kg or 28-<32 kg body weight) taking Triomune 40 were recruited and randomized to receive GT twice daily (one-quarter, one-half or three-quarter tablets using Malawi treatment guidelines), GL twice daily (in the equivalent dose of GT) or TL twice daily (dosed using weight and age from US Department of Health and Human Services paediatric treatment guidelines). After 10 days of one formulation, 6-h pharmacokinetic sampling was performed, and patients were crossed over to subsequent formulations. Baseline concentration (C(0 h)), area under the curve (AUC)(0-6 h), maximum plasma concentration (C(max)) and time to C(max) were generated for each antiretroviral treatment.
RESULTS
A total of 7 males and 11 females (6 in each GT dosing group) with a median (range) age of 7.2 years (1.3-13.6), weight of 19 kg (9.0-30.5) and height of 109 cm (75-132) were recruited. Combining all patients, no difference in pharmacokinetics was noted among the formulations for all drugs. However, patients in the one-quarter GT dosing group (8-<12 kg) had lower 3TC exposures than with the GL or TL (3TC AUC(0-6 h) 1,102, 1,720 and 2,060 h*ng/ml, respectively; P<0.005) and had more subtherapeutic NVP C(0 h) (10 of 13 occasions versus the one-half and three-quarter tablet groups). Compared with Western paediatric cohorts, Malawians had concentrations 30-40% lower for 3TC and d4T and 50% higher for NVP.
CONCLUSIONS
Quartered multiples of Triomune 40 are appropriate for children 18-<22 kg and 28-<32 kg in weight; however, alternative formulations are suggested in children weighing 8-<12 kg.
Topics: Adolescent; Anti-HIV Agents; Body Weight; Child; Child, Preschool; Cross-Over Studies; Dosage Forms; Drug Administration Schedule; Drugs, Generic; Female; HIV; HIV Infections; Humans; Infant; Lamivudine; Malawi; Male; Nevirapine; Prospective Studies; Stavudine
PubMed: 20167994
DOI: 10.3851/IMP1488 -
HIV Medicine Jan 2014Low-dose stavudine therapy may have a lower toxicity profile compared with standard dose. A randomized controlled trial comparing these two doses of stavudine with... (Randomized Controlled Trial)
Randomized Controlled Trial
A randomized clinical trial comparing metabolic parameters after 48 weeks of standard- and low-dose stavudine therapy and tenofovir disoproxil fumarate therapy in HIV-infected South African patients.
OBJECTIVES
Low-dose stavudine therapy may have a lower toxicity profile compared with standard dose. A randomized controlled trial comparing these two doses of stavudine with tenofovir disoproxil fumarate (tenofovir DF) was performed to assess the effects on anthropometry, markers of inflammation, and lipid and glucose metabolism in Black South African patients.
METHODS
Sixty patients were randomized 1:1:1 to either standard-dose (30-40 mg) or low-dose (20-30 mg) stavudine or tenofovir DF (300 mg), each combined with lamivudine and efavirenz, for 48 weeks. Anthropometry, markers of inflammation, and lipid and glucose metabolism were assessed using standard techniques.
RESULTS
In all three treatment arms, there was a significant increase in lipid levels over the study period. At 48 weeks, fasting glucose level (P < 0.005) and homeostasis model assessment (HOMA) score (P < 0.05) increased significantly in the standard-dose stavudine arm, as did insulin and C-peptide levels in both the standard- and low-dose stavudine arms. At week 48, a significant decrease (P < 0.05) in adiponectin was noted in the standard-dose stavudine arm, but there was an increase (P < 0.005) in the tenofovir DF arm. In both the stavudine arms, significant increases in anthropometric measures occurred at 24 weeks but these decreased by week 48. Mitochondrial toxicities occurred in both the stavudine arms. Immunological and virological outcomes were similar for all three arms.
CONCLUSIONS
This study highlights the occurrence of metabolic abnormalities with both stavudine and tenofovir DF treatment. Awareness of the potential increased cardiovascular risk should be of concern with the use of both these therapies.
Topics: Adenine; Adult; Alkynes; Analysis of Variance; Anthropometry; Anti-HIV Agents; Benzoxazines; Biomarkers; Body Composition; Cyclopropanes; DNA, Mitochondrial; Dose-Response Relationship, Drug; Drug Substitution; Female; Glucose; HIV Infections; Humans; Inflammation; Lamivudine; Lipid Metabolism; Male; Middle Aged; Phosphorous Acids; South Africa; Stavudine
PubMed: 23980620
DOI: 10.1111/hiv.12074 -
PloS One 2018Following widespread use of stavudine, a thymidine analogue, in antiretroviral therapy (ART) over the past three decades, up to a third of children developed lipoatrophy...
BACKGROUND
Following widespread use of stavudine, a thymidine analogue, in antiretroviral therapy (ART) over the past three decades, up to a third of children developed lipoatrophy (LA) and/or lipohypertrophy (LH). Following phasing-out of stavudine, incidence of newly-diagnosed LA and LH declined dramatically. However, the natural history of existing cases should be explored, particularly with prolonged protease inhibitor exposure.
METHODS
The Collaborative HIV Paediatric Study (CHIPS) is a multicentre cohort study of most HIV-infected children in the United Kingdom and Ireland. Those on ART with a LA/LH assessment recorded in 2003-2011 were included. Assessments were completed annually by consultant physicians. Using the 0-3 grading system, LA or LH was defined as grade 2 or 3. Resolution was defined as return to grade 1 or 0 in all body regions.
RESULTS
Of 1345 children followed for median (IQR) 5.5 (2.9, 8.2) years after ART initiation, 30 developed LA and 27 developed LH, all at least 2 years after ART initiation. Median age at LA diagnosis was 11 (10, 13) years and at LH diagnosis was 13 (11, 15) years. Children with LA were more likely white (p<0.0001); lower height-for-age z-score at ART initiation (p = 0.02); initiated ART earlier (p = 0.04), with longer ART exposure (p = 0.04). Children with LH were similar to those without. Analysis of individual drugs revealed that LA was associated with greater duration of exposure to stavudine and didanosine; while LH was associated with greater duration of exposure to stavudine and ritonavir (given alone or in combination with another protease inhibitor). Median time in follow-up following ART switch was 2.8 (1.9, 4.9) and 2.5 (1.6, 4.7) years respectively. Resolution occurred in 10 (30%) of LA cases (median time to resolution 2.3 [1.8, 3.6] years) and 3 (11%) of LH cases (median time to resolution 2.0 [1.7, 2.1] years).
CONCLUSIONS
Prevalence of LA and LH were low, with some resolution noted, especially for LA. More long-term data are needed.
Topics: Adolescent; Child; Female; HIV Infections; Humans; Incidence; Ireland; Lipodystrophy; Longitudinal Studies; Male; Reverse Transcriptase Inhibitors; Stavudine; Treatment Outcome; United Kingdom
PubMed: 29617438
DOI: 10.1371/journal.pone.0194132 -
MedGenMed : Medscape General Medicine Oct 2007To study the effectiveness and tolerance of an antiretroviral therapy (ART) regimen composed of the antiretroviral agents (ARVs) stavudine (d4T) plus didanosine (ddI)... (Clinical Trial)
Clinical Trial
OBJECTIVE
To study the effectiveness and tolerance of an antiretroviral therapy (ART) regimen composed of the antiretroviral agents (ARVs) stavudine (d4T) plus didanosine (ddI) plus efavirenz (EFV) in patients with advanced HIV infection in Senegal.
DESIGN AND METHODS
This was an open-label, single-arm, 18-month trial in treatment-naive patients. The primary virologic end point was the percentage of patients with plasma HIV RNA < 500 copies/mL at months 6 (M6), 12 (M12) and 18 (M18). The primary analysis was done as intent-to-treat.
RESULTS
The staging of HIV disease, performed using the definitions of the US Centers for Disease Control and Prevention (CDC), was CDC stage B or C for all 40 recruited patients. At baseline, the mean CD4+ cell count was 133 +/- 92/mcL (+/- standard deviation [SD]; range 1-346), and 23% of patients had CD4+ cell counts below 50/mcL. The mean baseline plasma HIV RNA level was 5.5 +/- 0.4 log(10) copies/mL (+/- SD; range 4.6-5.9). The proportion of patients with plasma HIV-1 RNA below 500 copies/mL fell during the study from 73% (95% CI [56; 85]) at M6 to 56% (95% CI [41; 73]) at M12 and 43% (95% CI [27; 59]) at M18. Plasma HIV-RNA was below 50 copies/mL in 50% of study subjects (95% CI [31; 66]) at M6, 43% (95% CI [27; 59]) at M12, and 33% (95% CI [19; 49]) at M18. The mean increase in the CD4+ cell count was 105 +/- 125/mcL (n = 38) at M3 and 186 +/- 122/mcL (n = 21) at M18. Eight patients died, including 6 because of infectious complications. The last viral load (VL) value before death was < 500 copies/mL in all these patients except 1 nonadherent patient. Fifteen patients (37.5%) had peripheral neuropathy that was severe enough in 5 patients (12.5%) to require ddI and d4T discontinuation.
CONCLUSION
Virologic efficacy combination therapy with d4T, ddI, and EFV was measured by the percentage of patients with plasma HIV RNA values below 500 copies/mL and 50 copies/mL; for both parameters, virologic efficacy decreased during the study period. This is explained by the high mortality rate (20%) and treatment modifications due to adverse events (13%). These data strengthen the recently revised World Health Organization (WHO) guidelines advocating initiation of highly active antiretroviral therapy (HAART) before profound CD4 lymphocyte depletion occurs and avoiding HAART regimens containing d4T and ddI because of treatment-limiting side effects.
Topics: Administration, Oral; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Developing Countries; Didanosine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; HIV Infections; Humans; Male; Maximum Tolerated Dose; Patient Compliance; RNA, Viral; Risk Assessment; Senegal; Severity of Illness Index; Stavudine; Survival Rate; Treatment Outcome; Viral Load
PubMed: 18311357
DOI: No ID Found -
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 -
AIDS Research and Human Retroviruses Sep 2022Hypertension (HTN) is a common comorbidity among people with HIV and associated with an increased risk for atherosclerotic cardiovascular disease and chronic kidney... (Randomized Controlled Trial)
Randomized Controlled Trial
Hypertension (HTN) is a common comorbidity among people with HIV and associated with an increased risk for atherosclerotic cardiovascular disease and chronic kidney disease. The relationship of antiretroviral therapy (ART) initiation to incident HTN remains a clinical question. We determined HTN incidence at 48 weeks of follow-up among ART-naive participants without HTN and not taking antihypertensive medications at ART initiation through randomized clinical trials through the AIDS Clinical Trial Group between 1999 and 2011. We assessed the association of baseline characteristics, including randomized ART agents with HTN incidence at 48 weeks using Poisson regression models. Incident HTN was defined as blood pressure ≥130/80 mmHg, or use of antihypertensive medication. Among 2,614 participants, mean age was 37 ± 10 years, 79% male sex, and 36% African American race. After 48 weeks, 839 participants (32%) developed HTN. Receiving a non-nucleoside reverse transcriptase inhibitor (NNRTI) was associated with an increased relative risk (RR) of incident HTN, while the risk was lower for protease inhibitor use. Stavudine and efavirenz were associated with an increased RR of developing HTN, while tenofovir disoproxil fumarate, darunavir/ritonavir, and atazanavir/ritonavir were associated with a decreased risk of developing HTN. Additionally, older age, higher body mass index (BMI), and having hepatitis C were associated with an increased risk for developing HTN, while women and participants with a higher baseline CD4 count were at a decreased risk of developing HTN at 48 weeks. One third of these ART naive participants developed HTN after ART initiation. NNRTIs, notably efavirenz, and stavudine were associated with an increased risk of HTN. Additional factors associated with HTN included traditional factors like older age and higher BMI, and advanced HIV disease (lower CD4 count). (Clinicaltrials.gov: NCT00001137).
Topics: Adult; Alkynes; Anti-HIV Agents; Antihypertensive Agents; Benzoxazines; Cyclopropanes; Female; HIV Infections; Humans; Hypertension; Male; Middle Aged; Risk Factors; Ritonavir; Stavudine
PubMed: 35778856
DOI: 10.1089/AID.2021.0213