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Expert Opinion on Therapeutic Targets Feb 2020: The purpose of the present study was to examine the chemopreventive effect of stampidine, an aryl phosphate derivative of stavudine, in side by side comparison with... (Comparative Study)
Comparative Study
: The purpose of the present study was to examine the chemopreventive effect of stampidine, an aryl phosphate derivative of stavudine, in side by side comparison with the standard anti-breast cancer drug paclitaxel in the well-established 7,12-dimethylbenz(a)anthracene (DMBA)-induced murine breast cancer model.: Groups of 20 female mice were challenged with the DMBA. DMBA-challenged mice were assigned to various chemoprevention treatments, including stampidine, paclitaxel, and stampidine plus paclitaxel according to the same treatment schedules for 25 weeks.: Stampidine resulted in substantially reduced numbers of tumors, tumor weight as well as tumor size in DMBA-treated mice. Stampidine was as effective as paclitaxel in the model and their combination exhibited greater chemopreventive activity, as measured by reduced tumor incidence and improved tumor-free survival as well as overall survival of DMBA-treated mice. The length of time for the initial tumor to appear in DMBA-challenged mice treated with stampidine was longer than that of mice treated DMBA-challenged control mice. Tumors from mice treated with stampidine or stampidine plus paclitaxel displayed unique changes of a signature protein cassette comprised BRCA1, p21, Bax, and Bcl-2.: Stampidine has potent chemopreventive activity and is as effective as the standard chemotherapy drug paclitaxel in the chemical carcinogenesis.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Breast Neoplasms; Dideoxynucleotides; Disease Models, Animal; Disease-Free Survival; Female; Mice; Mice, Inbred BALB C; Paclitaxel; Stavudine; Survival Rate; Thymidine Monophosphate; Time Factors
PubMed: 32005098
DOI: 10.1080/14728222.2020.1724961 -
Interdisciplinary Perspectives on... 2018The objective was to study the adverse drug reaction (ADR) profile in HIV patients receiving first-line antiretroviral therapy.
BACKGROUND AND OBJECTIVES
The objective was to study the adverse drug reaction (ADR) profile in HIV patients receiving first-line antiretroviral therapy.
METHODS
This was a prospective, observational study that included 171 HIV patients with a follow-up at six months. Demographic details, medical history, details of HIV infection including most recent CD4 count, details of antiretroviral therapy, and other concomitant medication were recorded. Adverse drug reactions were elicited by reviewing patient records and also by interviewing the patient/attendants directly.
RESULTS
171 patients completed the study out of which 88 (51.5%) were males and 83 (48.5%) were females. The study subjects included HIV-positive, treatment naïve patients who were started on treatment regimens recommended by the NACO guidelines. The ADRs observed were a fall in haemoglobin or absolute anaemia in response to zidovudine, nonspecific symptoms like headache, and a nonspecific feeling of being unwell in response to tenofovir, stavudine, and efavirenz; dyslipidaemia, pancreatitis, peripheral neuropathy, and lactic acidosis in response to stavudine; generalised rash in response to nevirapine and one case of nephrotoxicity to efavirenz. Majority of the ADRs satisfied the 'probable' category (60.1%), and the rest were "possible". ADRs to zidovudine and nevirapine superseded all others.
INTERPRETATION AND CONCLUSION
Gastrointestinal effects were the most commonly observed group of ADRs, with nausea being the most common ADR, the others being gastritis and diarrhoea. The other ADRs included rash, hepatotoxicity, blood dyscrasias like anaemia, neutropenia, and thrombocytopenia, and fatigue. Few cases of lactic acidosis, peripheral neuropathy, headache, lipoatrophy, and pancreatitis were reported.
PubMed: 30174689
DOI: 10.1155/2018/8095609 -
Neurology Jan 2009The frequency of HIV dementia in a recent study of HIV+ individuals at the Infectious Disease Institute in Kampala, Uganda, was 31%. Coformulated generic drugs, which... (Clinical Trial)
Clinical Trial
BACKGROUND
The frequency of HIV dementia in a recent study of HIV+ individuals at the Infectious Disease Institute in Kampala, Uganda, was 31%. Coformulated generic drugs, which include stavudine, are the most common regimens to treat HIV infection in Uganda and many other parts of Africa.
OBJECTIVE
To evaluate the benefits and risks of stavudine-based highly active antiretroviral therapy (HAART) for HIV-associated cognitive impairment and distal sensory neuropathy. The study compared neuropsychological performance changes in HIV+ individuals initiating HAART for 6 months and HIV- individuals receiving no treatment for 6 months. The risk of antiretroviral toxic neuropathy as a result of the initiation of stavudine-based HAART was also examined.
METHODS
At baseline, 102 HIV+ individuals in Uganda received neurologic, neuropsychological, and functional assessments; began HAART; and were followed up for 6 months. Twenty-five HIV- individuals received identical clinical assessments and were followed up for 6 months.
RESULTS
In HIV+ individuals, there was improvement in verbal memory, motor and psychomotor speed, executive thinking, and verbal fluency. After adjusting for differences in sex, HIV+ individuals demonstrated significant improvement in the Color Trails 2 test (p = 0.025) compared with HIV- individuals. Symptoms of neuropathy developed in 38% of previously asymptomatic HIV+ patients after initiation of the stavudine-based HAART.
CONCLUSIONS
After the initiation of highly active antiretroviral therapy (HAART) including stavudine, HIV+ individuals with cognitive impairment improve significantly as demonstrated by improved performance on a test of executive function. However, peripheral neurotoxicity occurred in 30 patients, presumably because of stavudine-based HAART, suggesting the need for less toxic therapy.
Topics: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cognition Disorders; Developing Countries; Disability Evaluation; Female; Humans; Male; Neuropsychological Tests; Outcome Assessment, Health Care; Risk Assessment; Stavudine; Treatment Outcome; Uganda
PubMed: 19139369
DOI: 10.1212/01.wnl.0000339042.96109.86 -
The Lancet. Infectious Diseases Feb 2016WHO 2013 guidelines recommend universal treatment for HIV-infected children younger than 5 years. No paediatric trials have compared nucleoside reverse-transcriptase... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND
WHO 2013 guidelines recommend universal treatment for HIV-infected children younger than 5 years. No paediatric trials have compared nucleoside reverse-transcriptase inhibitors (NRTIs) in first-line antiretroviral therapy (ART) in Africa, where most HIV-infected children live. We aimed to compare stavudine, zidovudine, or abacavir as dual or triple fixed-dose-combination paediatric tablets with lamivudine and nevirapine or efavirenz.
METHODS
In this open-label, parallel-group, randomised trial (CHAPAS-3), we enrolled children from one centre in Zambia and three in Uganda who were previously untreated (ART naive) or on stavudine for more than 2 years with viral load less than 50 copies per mL (ART experienced). Computer-generated randomisation tables were incorporated securely within the database. The primary endpoint was grade 2-4 clinical or grade 3/4 laboratory adverse events. Analysis was intention to treat. This trial is registered with the ISRCTN Registry number, 69078957.
FINDINGS
Between Nov 8, 2010, and Dec 28, 2011, 480 children were randomised: 156 to stavudine, 159 to zidovudine, and 165 to abacavir. After two were excluded due to randomisation error, 156 children were analysed in the stavudine group, 158 in the zidovudine group, and 164 in the abacavir group, and followed for median 2·3 years (5% lost to follow-up). 365 (76%) were ART naive (median age 2·6 years vs 6·2 years in ART experienced). 917 grade 2-4 clinical or grade 3/4 laboratory adverse events (835 clinical [634 grade 2]; 40 laboratory) occurred in 104 (67%) children on stavudine, 103 (65%) on zidovudine, and 105 (64%), on abacavir (p=0·63; zidovudine vs stavudine: hazard ratio [HR] 0·99 [95% CI 0·75-1·29]; abacavir vs stavudine: HR 0·88 [0·67-1·15]). At 48 weeks, 98 (85%), 81 (80%) and 95 (81%) ART-naive children in the stavudine, zidovudine, and abacavir groups, respectively, had viral load less than 400 copies per mL (p=0·58); most ART-experienced children maintained suppression (p=1·00).
INTERPRETATION
All NRTIs had low toxicity and good clinical, immunological, and virological responses. Clinical and subclinical lipodystrophy was not noted in those younger than 5 years and anaemia was no more frequent with zidovudine than with the other drugs. Absence of hypersensitivity reactions, superior resistance profile and once-daily dosing favours abacavir for African children, supporting WHO 2013 guidelines.
FUNDING
European Developing Countries Clinical Trials Partnership.
Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Child; Child, Preschool; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Infant; Lamivudine; Male; Nevirapine; Stavudine; Tablets; Uganda; Zambia; Zidovudine
PubMed: 26481928
DOI: 10.1016/S1473-3099(15)00319-9 -
The Pediatric Infectious Disease Journal Apr 2015
Topics: Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Utilization; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; HIV-1; Humans; Male; Organophosphonates; Stavudine; Zidovudine
PubMed: 25599283
DOI: 10.1097/INF.0000000000000650 -
Environment International Dec 2019Electrochemical degradation of trace antiretroviral drug stavudine was investigated by using a reactive electrochemical membrane (REM) with Ti/SnO-Sb anode. From the...
Electrochemical degradation of trace antiretroviral drug stavudine was investigated by using a reactive electrochemical membrane (REM) with Ti/SnO-Sb anode. From the results it was evident that the stavudine degradation followed pseudo-first-order kinetics, with the values of the degradation rate constant and half-life being 0.24 min and 2.9 min, respectively, at a current density of 8 mA cm. The degradation rate was obviously decreased under alkaline condition (pH = 11.0) and the degradation was also inhibited in the presence of NO and Cl. Five intermediates were identified in the electrochemical degradation of stavudine, and the degradation pathways were proposed. Density functional theory calculation revealed that the double bond carbon atom nearby hydroxymethyl group was the site attacked by OH and the cleavage of CN bond was the rate-determining step in the electrochemical degradation of stavudine. The nitrogen in stavudine was mainly converted to nitrate and ammonium. Quantitative structure-activity relationship model indicated that the toxicity of some intermediates was higher than the parent compound stavudine. The electric energy consumption for 90% stavudine degradation ranged from 0.87 to 2.29 Wh L at the experimental conditions, indicating that stavudine can be degraded efficiently by the REM with Ti/SnO-Sb anode.
Topics: Antimony; Antiviral Agents; Electrodes; Oxidation-Reduction; Porosity; Stavudine; Tin Compounds; Titanium; Wastewater; Water Pollutants, Chemical; Water Purification
PubMed: 31520959
DOI: 10.1016/j.envint.2019.105157 -
Saudi Pharmaceutical Journal : SPJ :... Oct 2009A simple chemometrics-assisted spectrophotometric method for the simultaneous determination of lamivudine and stavudine in pharmaceutical tablets is described. The UV...
A simple chemometrics-assisted spectrophotometric method for the simultaneous determination of lamivudine and stavudine in pharmaceutical tablets is described. The UV absorption spectra of the studied drugs, in the range of 200-310 nm, showed a considerable degree of spectral overlapping ([Di ](0.5) = 94.9%). Resolution of the mixture has been accomplished by using classical least-squares regression analysis (CLS) and principle components regression analysis methods (PCR). Beer's law was obeyed for both drugs in the general concentration ranges of 2-12 and 3-15 μg ml(-1) for lamivudine and stavudine, respectively. The proposed methods were successfully applied for the determination of the two drugs in laboratory prepared mixtures. The overall recoveries percent were found 98.58 ± 1.53-101.30 ± 1.35 (CLS) and 98.62 ± 1.65-101.13 ± 1.04 (PCR) for lamivudine and 98.43 ± 1.62-99.42 ± 1.55 (CLS) and 98.23 ± 1.97-101.20 ± 1.79 (PCR) for stavudine, respectively. The commercial tablets percentage content was found 98.10 ± 2.5-102.47 ± 2.94 (CLS) and 99.12 ± 1.71-100.92 ± 1.54 (PCR) for lamivudine and 96.00 ± 2.94-98.17 ± 1.72 (CLS) and 97.40 ± 1.55-97.80 ± 1.92 (PCR) for stavudine, respectively. Good percentage recoveries and proper statistical data obtained with both the laboratory prepared mixtures and the commercial tablets proved the suitability and efficiency of the proposed procedures for routine analysis and quality control purposes with quite satisfactory precision. A comparison of the obtained results from CLS and PCR were also performed with those obtained from reported method. The obtained F- and t-values obtained indicating no significant differences between the results of the proposed and reported methods.
PubMed: 24109202
DOI: 10.1016/j.jsps.2009.10.003 -
The NRTIs lamivudine, stavudine and zidovudine have reduced HIV-1 inhibitory activity in astrocytes.PloS One 2013HIV-1 establishes infection in astrocytes and macroage-lineage cells of the central nervous system (CNS). Certain antiretroviral drugs (ARVs) can penetrate the CNS, and...
HIV-1 establishes infection in astrocytes and macroage-lineage cells of the central nervous system (CNS). Certain antiretroviral drugs (ARVs) can penetrate the CNS, and are therefore often used in neurologically active combined antiretroviral therapy (Neuro-cART) regimens, but their relative activity in the different susceptible CNS cell populations is unknown. Here, we determined the HIV-1 inhibitory activity of CNS-penetrating ARVs in astrocytes and macrophage-lineage cells. Primary human fetal astrocytes (PFA) and the SVG human astrocyte cell line were used as in vitro models for astrocyte infection, and monocyte-derived macrophages (MDM) were used as an in vitro model for infection of macrophage-lineage cells. The CNS-penetrating ARVs tested were the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir (ABC), lamivudine (3TC), stavudine (d4T) and zidovudine (ZDV), the non-NRTIs efavirenz (EFV), etravirine (ETR) and nevirapine (NVP), and the integrase inhibitor raltegravir (RAL). Drug inhibition assays were performed using single-round HIV-1 entry assays with luciferase viruses pseudotyped with HIV-1 YU-2 envelope or vesicular stomatitis virus G protein (VSV-G). All the ARVs tested could effectively inhibit HIV-1 infection in macrophages, with EC90s below concentrations known to be achievable in the cerebral spinal fluid (CSF). Most of the ARVs had similar potency in astrocytes, however the NRTIs 3TC, d4T and ZDV had insufficient HIV-1 inhibitory activity in astrocytes, with EC90s 12-, 187- and 110-fold greater than achievable CSF concentrations, respectively. Our data suggest that 3TC, d4T and ZDV may not adequately target astrocyte infection in vivo, which has potential implications for their inclusion in Neuro-cART regimens.
Topics: Anti-HIV Agents; Astrocytes; Cell Line; HIV-1; Humans; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine
PubMed: 23614033
DOI: 10.1371/journal.pone.0062196 -
Antimicrobial Agents and Chemotherapy Nov 2018Stavudine remains a useful replacement option for treatment for HIV children. WHO reduced the adult dose to 30 mg twice daily, which maintains efficacy and lowers...
Stavudine remains a useful replacement option for treatment for HIV children. WHO reduced the adult dose to 30 mg twice daily, which maintains efficacy and lowers mitochondrial toxicity. We explored intracellular stavudine triphosphate levels in children receiving a reduced dose of 0.5 to 0.75 mg/kg of body weight twice daily to investigate whether a similar dose optimization can safely be made. A population pharmacokinetic model was developed to describe the pharmacokinetics of intracellular stavudine triphosphate in 23 HIV children and 24 HIV adults who received stavudine at 0.5 mg/kg and 20 mg twice daily for 7 days, respectively. Simulations were employed to optimize the pediatric dosing regimen to match exposures in adults receiving the current WHO-recommended dose of 30 mg twice daily. A biphasic disposition model with first-order appearance and disappearance described the pharmacokinetics of stavudine triphosphate. The use of allometric scaling with fat-free mass characterized well the pharmacokinetics in both adults and children, and no other significant effect could be detected. Simulations of 30 mg twice daily in adults predicted median (interquartile range [IQR]) stavudine triphosphate minimum drug concentration () and maximum drug concentration () values of 13 (10 to 19) and 45 (38 to 53) fmol/10 cells, respectively. Targeting this exposure, simulations in HIV children were used to identify a suitable weight-band dosing approach (0.5 to 0.75 mg/kg), which was predicted to achieve median (IQR) and values of 13 (9 to 18) and 49 (40 to 58) fmol/10 cells, respectively. Weight-band dosing using a stavudine dose of 0.5 to 0.75 mg/kg is proposed, and it shows comparable exposures to adults receiving the current WHO-recommended dose of 30 mg twice daily. Our pharmacokinetic results suggest that the decreased stavudine dose in children >2 years would have a reduced toxic effect while retaining antiretroviral efficacy.
Topics: Adolescent; Adult; Anti-HIV Agents; Child; Child, Preschool; Drug Administration Schedule; Female; HIV Infections; Humans; Male; Middle Aged; Polyphosphates; Stavudine; Young Adult
PubMed: 30104267
DOI: 10.1128/AAC.00761-18 -
Perspectives in Clinical Research Apr 2013This study evaluated the suspected adverse drug reactions (ADR) reported from a spontaneous reporting program in Human Immunodeficiency Virus (HIV) positive patients...
AIM
This study evaluated the suspected adverse drug reactions (ADR) reported from a spontaneous reporting program in Human Immunodeficiency Virus (HIV) positive patients receiving antiretroviral therapy (ART) in Nigeria.
MATERIALS AND METHODS
This descriptive study analyzed individual case safety reports (ICSRs) in HIV-positive patients receiving ART between January 2011 and December 2011 in 38 secondary hospitals. All ICSRs during this period were included. Chi-square was used to test the association between variables at 95% confidence interval.
RESULTS
From 1237 ICSRs collated, only 1119 (90.5%) were valid for analysis. Mean age of patients was 35.3 (95%CI, 35.1-35.5) years; and 67.1% were females. A total of 1679 ADR cases were reported, a mean (± Standard Deviation, SD) of 1.5 (± 0.8) ADR cases per patient. Of reported ADRs, 63.2%, 8.2% and 19.3% occurred in patients on Zidovudine-based, Stavudine-based and Tenofovir-based regimens, respectively. The commonest ADRs included (12.0%) peripheral neuropathy, (11.4%) skin rash, (10.1%) pruritus and (6.5%) dizziness. ADR occurrence was associated with ART regimens, concomitant medicines and age (P < 0.05) unlike gender. Anaemia was associated with Zidovudine (AZT)/ Lamivudine (3TC) /Nevirapine (NEV) regimen [Odds ratio, OR = 6.4 (3.0-13.8); P < 0.0001], and peripheral neuropathy with Stavudine (d4T)/3TC/NEV regimen [OR = 8.7 (5.8-30.0), P < 0.0001] and Tenofovir (TDF)/Emtricitabine (FTC)/Efavirenz (EFV) regimen [OR = 2.1 (1.0-4.1), P = 0.0446]. Skin rash and peripheral neuropathy were associated with patients aged < 15years [OR = 3.0 (1.3-6.6), P = 0.0056] and 45-59years [OR = 1.9 (1.3-2.7), P = 0.0006] respectively. Palpitation and polyuria were associated with Salbutamol [OR = 55.7 (4.9-349.6), P = 0.0000] and Nonsteroidal anti-inflammatory drugs (NSAIDS) [OR = 50.2 (0.9-562.1), P = 0.0040] respectively.
CONCLUSION
ADRs were less likely to occur in patients on stavudine-based and tenofovir-based regimens compared to zidovudine-based regimens. Peripheral neuropathy was also found to be associated with tenofovir-based regimen. This may require further studies and evaluation.
PubMed: 23833736
DOI: 10.4103/2229-3485.111784