- Hollow mesoporous structured molecularly imprinted polymer as adsorbent in pipette-tip solid-phase extraction for the determination of antiretrovirals from plasma of HIV-infected patients. [Journal Article]
- EElectrophoresis 2018 May 17
- In this work a hollow mesoporous structured molecularly imprinted polymer was synthetized and used as adsorbent in pipette-tip solid-phase extraction for the determination of lamivudine (3TC), zidovu...
In this work a hollow mesoporous structured molecularly imprinted polymer was synthetized and used as adsorbent in pipette-tip solid-phase extraction for the determination of lamivudine (3TC), zidovudine (AZT) and efavirenz (EFZ) from plasma of human immunodeficiency virus (HIV) infected patients by high-performance liquid chromatography (HPLC). All parameters that influence the recovery of the pipette tip based on hollow mesoporous molecularly imprinted polymer solid-phase extraction (PT-HM-MIP-SPE) method were systematically studied and discussed in detail. The adsorbent material was prepared using methacrylic acid and 4-vinylpyridine as functional monomers, ethylene glycol dimethacrylate as crosslinker, acetonitrile as solvent, 4,4'-azobis(4-cyanovaleric acid) as radical initiator, benzalkonium chloride as surfactant), 3TC, and AZT as templates. The simultaneous separation of 3TC, AZT and EFZ by HPLC-UV was performed using a Gemini C18 Phenomenexࣨ column (250 mm × 4.6 mm, 5 μm) and mobile phase consisting of acetonitrile: water pH 3.2 (68:32, v/v), flow rate of 1.0 mL min-1 and λ = 260 nm. The method was linear over the concentration range from 0.25 to 10 μg mL-1 for 3TC and EFZ, and 0.05 to 2.0 μg mL-1 for AZT, with correlation coefficients larger than 0.99 for all analytes. Recovery ± relative standard deviations (RSDs %) were 41.99±2.38 %, 82.29±1.63 %, and 83.72±7.52 % for 3TC, AZT, and EFZ, respectively. The RSDs and relative errors (REs) were lower than 15 % for intra and interday assays. The method has been successfully applied for monitoring HIV-infected patients outside the therapeutic dosage.2 This article is protected by copyright. All rights reserved.
- Anemia and thrombocytopenia in the cohort of HIV-infected adults in northwest Ethiopia: a facility-based cross-sectional study. [Journal Article]
- EEJIFCC 2018; 29(1):36-47
- CONCLUSIONS: We found an overall high prevalence of anemia in the cohort of HIV-infected adults in northwest Ethiopia. HAART naïve subjects and those with CD4 count less than 200 cells/µl were found to be at higher risk for developing anemia. This data has an important implication for management of hematological abnormalities in HIV patients and highlights the need for early initiation of HAART to reduce the burden of anemia.
- Engineered mixed oxide-based polymeric composites for enhanced antimicrobial activity and sustained release of antiretroviral drug. [Journal Article]
- IJInt J Biol Macromol 2018 May 12
- Here, pH-responsive engineered polymeric composites were fabricated from sodium alginate and mixed Cu/Zn oxides. The resulting alginate-CuxZn1-xO composites were characterized by FTIR, SEM and XRD, t...
Here, pH-responsive engineered polymeric composites were fabricated from sodium alginate and mixed Cu/Zn oxides. The resulting alginate-CuxZn1-xO composites were characterized by FTIR, SEM and XRD, then used as an efficient carrier for the antiretroviral drug (zidovudine, AZT) and exhibited remarkable antibacterial properties. The resulting polymeric composites had specific surface areas of 185.2-198.6 m2/g as confirmed by the Brunauer-Emmett-Teller analysis. The metal oxide distribution within the alginate matrix was confirmed from the X-ray diffraction and scanning electron microscopy analyses. The zidovudine, an antiretroviral drug was encapsulated in 30 mg of alginate-Cu0.7Zn0.3O with 68% encapsulation efficiency. The release of AZT in simulated intestinal fluid (pH 7.4) was studied, a slow and sustained release of AZT (~96.2%) was observed. The AZT release kinetics is sufficiently described by the Korsmeyer-Peppas model and follows the Fickian transport profile. Results herein demonstrated that A-Cu0.7Zn0.3O, A-Cu0.3Zn0.7O and Cu0.5Zn0.5O exhibited excellent bacterial devastation property. A dose of 8 μg/mL A-Cu0.7Zn0.3O and 13 μg/mL A-Cu0.3Zn0.7O are sufficient to completely killed E. coli DH5a and S. aureus NSUHS-151 within 24 h.
- Innovation and trends in the development and approval of antiviral medicines: 1987-2017 and beyond. [Review]
- ARAntiviral Res 2018 May 15; 155:76-88
- 2017 marked the 30th anniversary of the approval of zidovudine (AZT) as the first HIV/AIDS therapy. Since then, more than eighty antiviral drugs have received FDA approval, half of which treat HIV in...
2017 marked the 30th anniversary of the approval of zidovudine (AZT) as the first HIV/AIDS therapy. Since then, more than eighty antiviral drugs have received FDA approval, half of which treat HIV infection. Here, we provide a retrospective analysis of approved antiviral drugs, including therapeutics against other major chronic infections such as hepatitis B and C, and herpes viruses, over the last thirty years. During this time, only a few drugs were approved to treat acute viral infections, mainly influenza. Analysis of these approved antiviral drugs based on molecular class and mode of action shows that a large majority are small molecules and direct-acting agents as opposed to proteins, peptides, or oligonucleotides and host-targeting therapies. In addition, approvals of combination therapies accelerated over the last five years. We also provide a prospective study of future potential antiviral therapies, based on current clinical research pipelines across the pharmaceutical industry. Comparing past drug approvals with current clinical candidates hints at the future evolution in antiviral therapies and reveals how antiviral medicines are often discovered. Overall, this work helps forecast future trends and innovation in the field of antiviral research and development.
- Adverse effects in children exposed to maternal HIV and antiretroviral therapy during pregnancy in Brazil: a cohort study. [Journal Article]
- RHReprod Health 2018 May 10; 15(1):76
- CONCLUSIONS: Highly active antiretroviral treatment in pregnant women and viral load control were the main factors associated with MTCT reduction. Antiretroviral use is associated with a high frequency but mainly low severity adverse effects in newborns.
- A genetic IFN/STAT1/FAS axis determines CD4 T stem cell memory levels and apoptosis in healthy controls and Adult T-cell Leukemia patients. [Journal Article]
- OOncoimmunology 2018; 7(5):e1426423
- Adult T-cell leukemia (ATL) is an aggressive, chemotherapy-resistant CD4+CD25+ leukemia caused by HTLV-1 infection, which usually develops in a minority of patients several decades after infection. I...
Adult T-cell leukemia (ATL) is an aggressive, chemotherapy-resistant CD4+CD25+ leukemia caused by HTLV-1 infection, which usually develops in a minority of patients several decades after infection. IFN + AZT combination therapy has shown clinical benefit in ATL, although its mechanism of action remains unclear. We have previously shown that an IFN-responsive FAS promoter polymorphism in a STAT1 binding site (rs1800682) is associated to ATL susceptibility and survival. Recently, CD4 T stem cell memory (TSCM) Fashi cells have been identified as the hierarchical cellular apex of ATL, but a possible link between FAS, apoptosis, proliferation and IFN response in ATL has not been studied. In this study, we found significant ex vivo antiproliferative, antiviral and immunomodulatory effects of IFN-α treatment in short-term culture of primary mononuclear cells from ATL patients (n = 25). Bayesian Network analysis allowed us to integrate ex vivo IFN-α response with clinical, genetic and immunological data from ATL patients, thereby revealing a central role for FAS -670 polymorphism and apoptosis in the coordinated mechanism of action of IFN-α. FAS genotype-dependence of IFN-induced apoptosis was experimentally validated in an independent cohort of healthy controls (n = 20). The same FAS -670 polymorphism also determined CD4 TSCM levels in a genome-wide twin study (p = 7 × 10-11, n = 460), confirming a genetic link between apoptosis and TSCM levels. Transcriptomic analysis and cell type deconvolution confirmed the FAS genotype/TSCM link and IFN-α-induced downregulation of CD4 TSCM-specific genes in ATL patient cells. In conclusion, ex vivo IFN-α treatment exerts a pleiotropic effect on primary ATL cells, with a genetic IFN/STAT1/Fas axis determining apoptosis vs. proliferation and underscoring the CD4 TSCM model of ATL leukemogenesis.
- MPEG-PCL Copolymeric Micelles for Encapsulation of Azithromycin. [Journal Article]
- APAAPS PharmSciTech 2018 Apr 19
- Macrolide antibiotics are lipophilic drugs with some limitations including low solubility, limited cellular permeation, patients discomfort, etc. With amphiphilic methoxy poly(ethylene glycol)-b-poly...
Macrolide antibiotics are lipophilic drugs with some limitations including low solubility, limited cellular permeation, patients discomfort, etc. With amphiphilic methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) (MPEG-PCL) copolymer and azithromycin (AZT) as drug carrier and model drug, AZT-loaded micelles were prepared via thin-membrane hydration method in order to overcome these limitations. Encapsulation efficiency of AZT-loaded micelles was 94.40% with good storage stability for 28 days, and AZT's water solubility was enhanced to 944 μg/mL. Fourier transform infrared spectrum and x-ray diffraction analysis indicated that AZT was enveloped into the micelles in amorphous form due to its interaction with the copolymer. AZT's in vitro release from the AZT-loaded micelles demonstrated a slow and continuous behavior when compared with raw AZT. The release dynamics was accorded with Weibull equation, meaning that release amount of AZT lowered with time and was proportional to remaining amount of drug in the AZT-loaded micelles. Korsmeyer-Peppas fitting result suggested that drug release process was a classical Fickian diffusion-controlled manner. With Staphylococcus aureus as bacterial strain, antibacterial activity of the AZT-loaded micelles displayed was comparable with raw AZT. In conclusion, MPEG-PCL should be a promising carrier for macrolide antibiotic delivery in treatment of bacterial infections.
- Quercetin attenuates AZT-induced neuroinflammation in the CNS. [Journal Article]
- SRSci Rep 2018 Apr 18; 8(1):6194
- Highly active anti-retroviral therapy (HAART) is very effective in suppressing HIV-1 replication in patients. However, continuous HAART is required to prevent viral rebound, which may have detrimenta...
Highly active anti-retroviral therapy (HAART) is very effective in suppressing HIV-1 replication in patients. However, continuous HAART is required to prevent viral rebound, which may have detrimental effects in various tissues, including persistent neuroinflammation in the central nervous system (CNS). Here, we show that quercetin (3,5,7,3',4'-pentahydroxy flavones), a natural antioxidant used in Chinese traditional medicines, suppresses the neuroinflammation that is induced by chronic exposure to Zidovudine (azidothymidine, AZT), a nucleoside reverse transcriptase inhibitor (NRTI) that is commonly part of HAART regimens. We found that the up-regulation of pro-inflammatory cytokines and microglial and astrocytic markers induced by AZT (100 mg/kg/day; 8 days) was significantly inhibited by co-administration of quercetin (50 mg/kg/day) in the mouse cortex, hippocampus and spinal cord. We further showed that quercetin attenuated AZT-induced up-regulation of Wnt5a, a key regulator of neuroinflammation. These results suggest that quercetin has an inhibitory effect on AZT-induced neuroinflammation in the CNS, and Wnt5a signaling may play an important role in this process. Our results may further our understanding of the mechanisms of HAART-related neurotoxicity and help in the development of effective adjuvant therapy.
- Zidovudine ameliorates pathology in the mouse model of Duchenne muscular dystrophy via P2RX7 purinoceptor antagonism. [Journal Article]
- ANActa Neuropathol Commun 2018 Apr 11; 6(1):27
- Duchenne muscular dystrophy (DMD) is the most common inherited muscle disorder that causes severe disability and death of young men. This disease is characterized by progressive muscle degeneration a...
Duchenne muscular dystrophy (DMD) is the most common inherited muscle disorder that causes severe disability and death of young men. This disease is characterized by progressive muscle degeneration aggravated by sterile inflammation and is also associated with cognitive impairment and low bone density. Given that no current treatment can improve the long-term outcome, approaches with a strong translational potential are urgently needed. Duchenne muscular dystrophy (DMD) alters P2RX7 signaling in both muscle and inflammatory cells and inhibition of this receptor resulted in a significant attenuation of muscle and non-muscle symptoms in DMDmdx mouse model. As P2RX7 is an attractive target in a range of human diseases, specific antagonists have been developed. Yet, these will require lengthy safety testing in the pediatric population of Duchenne muscular dystrophy (DMD) patients. In contrast, Nucleoside Reverse Transcriptase Inhibitors (NRTIs) can act as P2RX7 antagonists and are drugs with an established safety record, including in children. We demonstrate here that AZT (Zidovudine) inhibits P2RX7 functions acting via the same allosteric site as other antagonists. Moreover, short-term AZT treatment at the peak of disease in DMDmdx mice attenuated the phenotype without any detectable side effects. Recovery was evident in the key parameters such as reduced sarcolemma permeability confirmed by lower serum creatine kinase levels and IgG influx into myofibres, decreased inflammatory cell numbers and inflammation markers in leg and heart muscles of treated mice. Moreover, this short-term therapy had some positive impact on muscle strength in vivo and no detrimental effect on mitochondria, which is the main side-effect of Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Given these results, we postulate that AZT could be quickly re-purposed for the treatment of this highly debilitating and lethal disease. This approach is not constrained by causative DMD mutations and may be effective in alleviating both muscle and non-muscle abnormalities.
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- Complete and durable responses in Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder with Zidovudine, Ganciclovir, Rituximab and Dexamethasone. [Journal Article]
- CCClin Cancer Res 2018 Apr 09
- CONCLUSIONS: EBV+ PCNS-PTLD expressed lytic kinases and therapy with AZT, GCV, rituximab and dexamethasone provided durable responses. Induction of the lytic protein expression and increased cellular sensitivity to antiviral therapy after transfection with viral kinase cDNA provides a mechanistic rationale for our approach.