- HIV-1 Drug Resistance and Third-Line Therapy Outcomes in Patients Failing Second-Line Therapy in Zimbabwe. [Journal Article]
- OFOpen Forum Infect Dis 2018; 5(2):ofy005
- CONCLUSIONS: The prevelance of PI mutations was high. Adolescents and young adults had a lower risk of acquiring major PI resistance mutations, possibly due to poor adherence to ART. Third-line treatment with a regimen of Darunavir/r, Raltegravir/Dolutegravir, and optimized nucleoside reverse transcriptase inhibitors was effective.
- Removal of antiretroviral drugs stavudine and zidovudine in water under UV254and UV254/H2O2processes: Quantum yields, kinetics and ecotoxicology assessment. [Journal Article]
- JHJ Hazard Mater 2018 Feb 07; 349:195-204
- The concentration of antiretroviral drugs in wastewater treatment plants (WWTP) effluents and surface waters of many countries has increased significantly due to their widespread use for HIV treatmen...
The concentration of antiretroviral drugs in wastewater treatment plants (WWTP) effluents and surface waters of many countries has increased significantly due to their widespread use for HIV treatment. In this study, the removal of stavudine and zidovudine under UV254photolysis or UV254/H2O2was investigated in a microcapillary film (MCF) photoreactor, using minimal water samples quantities. The UV254quantum yield of zidovudine, (2.357 ± 0.0589)·10-2 mol ein-1(pH 4.0-8.0), was 28-fold higher that the yield of stavudine (8.34 ± 0.334)·10-4 mol ein-1(pH 6.0-8.0). The second-order rate constant kOH,iof reaction of hydroxyl radical with the antiretrovirals (UV254/H2O2process) were determined by kinetics modeling: (9.98 ± 0.68)·108 M-1 s-1(pH 4.0-8.0) for zidovudine and (2.03 ± 0.18)·109 M-1 s-1(pH 6.0-8.0) for stavudine. A battery of ecotoxicological tests (i.e. inhibition growth, bioluminescence, mutagenic and genotoxic activity) using bacteria (Aliivibrio fischeri, Salmonella typhimurium), crustacean (Daphnia magna) and algae (Raphidocelis subcapitata) revealed a marked influence of the UV dose on the ecotoxicological activity. The UV254/H2O2treatment process reduced the ecotoxicological risk associated to direct photolysis of the antiretrovirals aqueous solutions, but required significantly higher UV254doses (≥2000 mJ cm-2) in comparison to common water UV disinfection processes.
- Inclusion body myositis and human immunodeficiency virus type 1: A new case report and literature review. [Journal Article]
- NDNeuromuscul Disord 2018 Jan 10
- Prevalence of muscle disease in human immunodeficiency virus (HIV) infection is less than 1% of patients with acquired immune deficiency syndrome. Sporadic inclusion body myositis (IBM) is observed i...
Prevalence of muscle disease in human immunodeficiency virus (HIV) infection is less than 1% of patients with acquired immune deficiency syndrome. Sporadic inclusion body myositis (IBM) is observed in a few cases of patients infected by retroviruses such as HIV-1. A Caucasian man was diagnosed with HIV when he was 30 years old. The viral load was undetectable and CD4 cell count was 600/mm3when the diagnosis of inclusion body myositis was confirmed. Histological findings were typical of IBM. The treatment consisted of immunoglobulin therapy for three years without effect. Twenty-two patients were found in the English and French literature. They are younger than those who suffer from IBM without HIV (median age = 47, range: 30 to 59), and they are mostly men with considerable serum creatine kinase (CK) elevation (median CK level = 1322 IU/L, range: 465 to 10270), most of them were treated with Zidovudine.
- Lipid-based nanocarrier efficiently delivers highly water soluble drug across the blood-brain barrier into brain. [Journal Article]
- DDDrug Deliv 2018; 25(1):504-516
- Delivering highly water soluble drugs across blood-brain barrier (BBB) is a crucial challenge for the formulation scientists. A successful therapeutic intervention by developing a suitable drug deliv...
Delivering highly water soluble drugs across blood-brain barrier (BBB) is a crucial challenge for the formulation scientists. A successful therapeutic intervention by developing a suitable drug delivery system may revolutionize treatment across BBB. Efforts were given here to unravel the capability of a newly developed fatty acid combination (stearic acid:oleic acid:palmitic acid = 8.08:4.13:1) (ML) as fundamental component of nanocarrier to deliver highly water soluble zidovudine (AZT) as a model drug into brain across BBB. A comparison was made with an experimentally developed standard phospholipid-based nanocarrier containing AZT. Both the formulations had nanosize spherical unilamellar vesicular structure with highly negative zeta potential along with sustained drug release profiles. Gamma scintigraphic images showed both the radiolabeled formulations successfully crossed BBB, but longer retention in brain was observed for ML-based formulation (MGF) as compared to soya lecithin (SL)-based drug carrier (SYF). Plasma and brain pharmacokinetic data showed less clearance, prolonged residence time, more bioavailability and sustained release of AZT from MGF in rats compared to those data of the rats treated with SYF/AZT suspension. Thus, ML may be utilized to successfully develop drug nanocarrier to deliver drug into brain across BBB, in a sustained manner for a prolong period of time and may provide an effective therapeutic strategy for many diseases of brain. Further, many anti-HIV drugs cannot cross BBB sufficiently. Hence, the developed formulation may be a suitable option to carry those drugs into brain for better therapeutic management of HIV.
- Recent updates for designing CCR5 antagonists as anti-retroviral agents. [Review]
- EJEur J Med Chem 2018 Jan 31; 147:115-129
- The healthcare system faces various challenges in human immunodeficiency virus (HIV) therapy due to resistance to Anti-Retroviral Therapy (ART) as a consequence of the evolutionary process. Despite t...
The healthcare system faces various challenges in human immunodeficiency virus (HIV) therapy due to resistance to Anti-Retroviral Therapy (ART) as a consequence of the evolutionary process. Despite the success of antiretroviral drugs like Zidovudine, Zalcitabine, Raltegravir WHO ranks HIV as one of the deadliest diseases with a mortality of one million lives in 2016. Thus, there emerges an urgency of developing a novel anti-retroviral agent that combat resistant HIV strains. The clinical development of ART from a single drug regimen to current triple drug combination is very slow. The progression in the structural biology of the viral envelope prompted the discovery of novel targets, which can be demonstrated a proficient approach for drug design of anti-retroviral agents. The current review enlightens the recent updates in the structural biology of the viral envelope and focuses on CCR5 as a validated target as well as ways to overcome CCR5 resistance. The article also throws light on the SAR studies and most prevalent mutations in the receptor for designing CCR5 antagonists that can combat HIV-1 infection. To conclude, the paper lists diversified scaffolds that are in pipeline by various pharmaceutical companies that could provide an aid for developing novel CCR5 antagonists.
- Inhibitory Effect of Sauchinone on UDP-Glucuronosyltransferase (UGT) 2B7 Activity. [Journal Article]
- MMolecules 2018 Feb 09; 23(2)
- Herb-drug interaction (HDI) limits clinical application of herbs and drugs, and inhibition of herbs towards uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) has gained attention as one of th...
Herb-drug interaction (HDI) limits clinical application of herbs and drugs, and inhibition of herbs towards uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) has gained attention as one of the important reasons to cause HDIs. Sauchinone, an active lignan isolated from aerial parts ofSaururus chinensis(Saururacease), possesses anti-oxidant, anti-inflammatory, and anti-viral activities. In pharmacokinetics of sauchinone, sauchinone is highly distributed to the liver, forming extensive metabolites of sauchinone via UGTs in the liver. Thus, we investigated whether sauchinone inhibited UGTs to explore potential of sauchinone-drug interactions. In human liver microsomes (HLMs), sauchinone inhibited activities of UGT1A1, 1A3, 1A6, and 2B7 with IC50values of 8.83, 43.9, 0.758, and 0.279 μM, respectively. Sauchinone also noncompetitively inhibited UGT1A6 and 2B7 withKivalues of 1.08 and 0.524 μM, respectively. In in vivo interaction study using mice, sauchinone inhibited UGT2B7-mediated zidovudine metabolism, resulting in increased systemic exposure of zidovudine when sauchinone and zidovudine were co-administered together. Our results indicated that there is potential HDI between sauchinone and drugs undergoing UGT2B7-mediated metabolism, possibly contributing to the safe use of sauchinone and drug combinations.
- Nucleoside reverse transcriptase inhibitor-induced rat oocyte dysfunction and low fertility mediated by autophagy. [Journal Article]
- OOncotarget 2018 Jan 09; 9(3):3895-3907
- Low fertility is one of the most common side effects caused by nucleoside reverse transcriptase inhibitors (NRTIs), whereas the molecular mechanism underlying this process were largely unclear. This ...
Low fertility is one of the most common side effects caused by nucleoside reverse transcriptase inhibitors (NRTIs), whereas the molecular mechanism underlying this process were largely unclear. This study was conducted to investigate whether autophagy plays a role in NRTIs-induced oocyte dysfunction and low fertility in female rat. Both in vivo and in vitro experiments were conducted. For the in vivo experiment, female adult Sprague-Dawley rats were subjected to zidovudine (AZT) and lamivudine (3TC) intragastric treatment for 3, 6, 9, and 12 weeks; a control was also set. Oocytes were collected for maturation evaluation, in vitro fertilization and mitochondrial function assays, and apoptosis and autophagy analysis. For the in vitro experiment, oocytes were collected and assigned to the control, 3-methyladenine (3-MA, an effective autophagy inhibitor), AZT, AZT+3-MA, 3TC, and 3TC+3-MA groups. The oocytes were cultured with the abovementioned drugs for 24, 48, and 72 h and then, subjected to the same assays as in the in vivo study. The results showed a significant time-dependent decrease in oocyte maturation-related maker levels, oocyte cleavage rate, blastocyst formation rate, mitochondrial DNA copy number and adenosine triphosphate level, and apoptosis, and a significant increase in the reactive oxygen species levels (all P-values < 0.05), in both the in vivo and the in vitro experiments. These changes, except for the changes in the oocyte maturation-related markers, were partially attenuated by 3-MA. In conclusion, we demonstrated that NRTIs can cause rat oocyte dysfunction and low fertility, and this damage was, at least partially, mediated by autophagy.
- A stability-indicating LC-MS/MS method for zidovudine: Identification, characterization and toxicity prediction of two major acid degradation products. [Journal Article]
- JPJ Pharm Anal 2017; 7(4):231-236
- Zidvovudine (AZT) is a nucleoside analogue reverse transcriptase inhibitor (NRTI), a class of anti-retroviral drug. A stability-indicating assay method for AZT was developed in line with ICH guidelin...
Zidvovudine (AZT) is a nucleoside analogue reverse transcriptase inhibitor (NRTI), a class of anti-retroviral drug. A stability-indicating assay method for AZT was developed in line with ICH guideline. Successful separation of AZT and its degradation products was achieved by gradient elution mode on reverse phase C18 column using 10 mM ammonium acetate: acetonitrile as the mobile phase at 0.8 mL/min flow rate, 25 µL injection volume, 30 °C column temperature and 285 nm detection wavelength. Two major acid degradation products were identified and characterized by liquid chromatography-electrospray ionization mass spectrometry (LC-ESI/MS/MS) and accurate mass measurements. The probable mechanisms for the formation of degradation products were identified based on a comparison of the fragmentation pattern of the [M + H] + ions of AZT and its degradation products. One of the degradation products, DP-1, was isolated by semi-preparative high performance liquid chromatography (HPLC) using Waters XBridge Prep C18 (250 mm×10 mm, 5 µm). Degradation products showed higher toxicity compared to the drug in some models assessed by TOPKAT software. The method validation was performed with respect to robustness, specificity, linearity, precision and accuracy as per ICH guideline Q2 (R1).
- Hematological parameters of human immunodeficiency virus positive pregnant women on antiretroviral therapy in Aminu Kano Teaching Hospital Kano, North Western Nigeria. [Journal Article]
- JLJ Lab Physicians 2018 Jan-Mar; 10(1):60-63
- CONCLUSIONS: There is a significant difference in terms of hematological parameters between HIV-positive and HIV-negative pregnant women in this environment.
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- Impact of Timing of Antiretroviral Treatment and Birth Weight on Mother-to-Child Human Immunodeficiency Virus Transmission: Findings From an 18-Month Prospective Cohort of a Nationally Representative Sample of Mother-Infant Pairs During the Transition From Option A to Option B+ in Zimbabwe. [Journal Article]
- CIClin Infect Dis 2018 Feb 01; 66(4):576-585
- CONCLUSIONS: ART preconception has the highest impact on reducing MTCT, indicating that HIV-infected, reproductive-age women should be prioritized in "treat-all" strategies. HIV-infected mothers without ART use should be identified at the first immunization visit and treatment initiated to reduce postdelivery MTCT. MTCT risk is higher in mothers with low-birth-weight deliveries.