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1.
AAPS PharmSciTech ; 21(1): 1, 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712905

RESUMO

The SeDeM diagram expert system has been applied to study Zidovudine and some excipients. From the obtained diagrams, a pharmaceutical formula has been designed. SeDeM diagram ascertains the critical parameters that are suitable for a direct compression. The formula is compressed using a rotary tablet press simulator which emulates rotary tablet press' compression profiles. From these compressions, we study the formula behavior under different industrial production conditions but saving a huge amount of material. The study is done at different compression forces and compression speeds and taking into account the influence of the pre-compression force. The differences observed between the compression profiles are hereby described. The results indicate that the formulation is able to be compressed adequately with the emulated compression profiles and no differences are observed between the final products. Therefore, we can assure that the SeDeM diagram expert system is accurate and robust. Moreover, its results are comparable with the compression results in a rotary tablet press, which has never been described in the pharmaceutical literature before. From the obtained results, it is possible to select the best rotary press to scale-up this formulation.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Composição de Medicamentos/instrumentação , Composição de Medicamentos/métodos , Sistemas Especialistas , Comprimidos , Zidovudina/administração & dosagem , Composição de Medicamentos/normas , Indústria Farmacêutica , Excipientes , Testes de Dureza , Pós
2.
Int J Pharm ; 568: 118558, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31352046

RESUMO

In order to improve efficacy and accessibility of vaginal microbicides, development of smart polymer-based delivery carriers appears essential. In scope of this study, the potential of chitosan glutamate in technology of microbicide multiunit formulations containing zidovudine-loaded microbeads was investigated. Spray-drying optimization was supported by statistical design of experiments. As polymer properties may alter upon processing, particularly important was to examine the influence of product composition and process variables on final microbeads characteristic. Data from ATR-FTIR, Raman, and DSC analysis confirmed drug compatibility with chitosan glutamate after spray-drying. Formulations with polymer:drug ratio 5:1 (w/w) prepared from azeotropic ethanol-water mixture were found to spread easily upon dilution with simulant vaginal fluid, forming viscous, shear-thinning barrier, which could impede direct contact of virus with mucus cells. Furthermore, the presence of ethanol was found crucial to overcome stickiness phenomenon by interrupting hydrogen bonding between drug and polymer. In vitro dissolution studies displayed an initial burst effect followed with prolonged (up to 4 h) drug release stage. By modifying spray-drying temperature, alterations in microbeads' swelling capacity and drug release were observed. Cytotoxicity studies using human vaginal cell line VK2/E6E7 revealed that drug-free formulations exerted no significant impact on mucosal cells, suggesting they are safe for vaginal delivery.


Assuntos
Anti-Infecciosos/administração & dosagem , Quitosana/administração & dosagem , Portadores de Fármacos/administração & dosagem , Glutamatos/administração & dosagem , Zidovudina/administração & dosagem , Administração Intravaginal , Anti-Infecciosos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Dessecação , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Feminino , Glutamatos/química , Humanos , Microesferas , Vagina , Zidovudina/química
3.
Int J Antimicrob Agents ; 54(1): 55-61, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31034939

RESUMO

A phase 1 clinical study was performed to assess the pharmacokinetics and safety of intravenous (i.v.) administration of colistin methanesulfonate (CMS) and azidothymidine (AZT) alone and in combination. Seven healthy subjects received three (every 12 h) 1-h i.v. infusions of 4, 2 and 2 million international units (MIU) of CMS co-administered with 200, 100 and 100 mg of AZT, respectively. In an ex vivo study, urinary bactericidal titres (UBTs) and time-kill curve determinations were performed in artificial urine spiked with colistin sulfate and AZT according to median and minimum peak concentrations in urine measured after the first and third dose using four mcr-1-positive colistin-resistant and five colistin-susceptible Gram-negative isolates. Reciprocal UBTs for the different colistin concentrations obtained in urine ranged from 1-128 and 0-2 for colistin-susceptible and colistin-resistant isolates, respectively. Combination with AZT could increase UBTs up to two dilution steps each for the Enterobacteriaceae and Acinetobacter strains tested. In contrast, the combination had no activity against Pseudomonas strains. In time-kill curves, the combination showed bactericidal activity against colistin-resistant strains even when the substances alone were not bactericidal. Thus, combination of CMS with AZT shows promising synergistic activity against Gram-negative uropathogens, including colistin-resistant Enterobacteriaceae. According to the urinary bactericidal activity, a maintenance dosage of 2 MIU of CMS combined with 100 mg of AZT twice daily may be sufficient for the treatment of urinary tract infections (UTIs) caused by colistin-susceptible strains. However, the dosage requires optimisation for efficient treatment of UTIs caused by colistin-resistant strains.


Assuntos
Antibacterianos/farmacologia , Colistina/farmacologia , Proteínas de Escherichia coli/genética , Escherichia coli/efeitos dos fármacos , Viabilidade Microbiana/efeitos dos fármacos , Urina/microbiologia , Zidovudina/farmacologia , Acinetobacter/efeitos dos fármacos , Acinetobacter/crescimento & desenvolvimento , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Colistina/administração & dosagem , Colistina/efeitos adversos , Colistina/farmacocinética , Sinergismo Farmacológico , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Humanos , Pseudomonas/efeitos dos fármacos , Zidovudina/administração & dosagem , Zidovudina/efeitos adversos , Zidovudina/farmacocinética
4.
BMC Infect Dis ; 19(1): 246, 2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30871487

RESUMO

BACKGROUND: With the phase-out of stavudine (d4T), change to first-line regimens with zidovudine (AZT) or tenofovir (TDF) in resource-limited settings (RLS) might increase risks of cross-resistance to nucleos(t) ide reverse transcriptase inhibitors (NRTI). This would restrict the scope of switching to the World Health Organisation (WHO)-recommended standard second-line combinations (SLC) without HIV drug resistance (HIVDR)-testing in routine clinical practice. METHODS: An observational study was conducted among 101 Cameroonian patients (55.4% male, median [IQR] age 34 [10-41] years) failing first-line antiretroviral therapy (ART) in 2016, and stratified into three groups according to NRTIs exposure: exposure to both thymidine analogues AZT "and" D4T (group-A, n = 55); exposure to both TDF and AZT "or" D4T (group-B, n = 22); exposure solely to D4T (group-C, n = 24). Protease-reverse transcriptase HIVDR was interpreted using the HIVdb penalty scores (≥60: high-resistance; 20-59: intermediate-resistance; < 20: susceptible). The acceptable threshold for potential-efficacy was set at 80%. RESULTS: The median [IQR] CD4, viral RNA, and time on ART, were respectively 129 [29-466] cells/µl, 71,630 [19,041-368,000] copies/ml, and 4 [2-5] years. Overall HIVDR-level was 89.11% (90/101), with 83.2% harbouring M184 V (high-level 3TC/FTC-resistance) and only 1.98% (2/101) major HIVDR-mutations to ritonavir-boosted protease-inhibitors (PI/r). Thymidine-analogue mutations (TAMs)-1 [T215FY (46.53%), M41 L (22.77%), L210 W (8.91%)], with cross-resistance to AZT and TDF, were higher compared to TAMs-2 [D67N (21.78%), K70R (19.80%), K219QE (18.81%)]. As expected, K65R was related with TDF-exposure: 0% (0/55) in group-A, 22.72% (5/22) group-B, 4.17% (1/24) group-C (p = 0.0013). The potential-efficacy of AZT vs. TDF was respectively 43.64% (24/55) vs. 70.91% (39/55) in group-A (p = 0.0038); 63.64% (14/22) vs. 68.28% (15/22) in group-B (p = 1.0000); and 37.50% (9/24) vs. 83.33% (20/24) in group-C (p = 0.0032). CRF02_AG was the prevailing subtype (63.40%), followed by CRF11.cpx (8.91%), A1 (7.92%), G (5.94%); without any significant effect of the subtype-distribution on HIVDR (92.2% in CRF02_AG vs. 83.8% in non-AG; p = 0.204). CONCLUSION: First-line ART-failure exhibits high-level NRTI-resistance, with potential lower-efficacy of AZT compared to TDF. Significantly, using our 80% efficacy-threshold, only patients without NRTI-substitution on first-line could effectively switch to SLC following the WHO-approach. Patients with multiple NRTI-substitutions (exposed to both thymidine-analogues and TDF) on first-line ART would require HIVDR-testing to select active NRTIs for SLC.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Adolescente , Adulto , Camarões , Criança , Farmacorresistência Viral , Feminino , Infecções por HIV/virologia , Transcriptase Reversa do HIV , HIV-1/genética , HIV-1/fisiologia , Humanos , Masculino , Inibidores da Transcriptase Reversa/administração & dosagem , Ritonavir/administração & dosagem , Estavudina/administração & dosagem , Tenofovir/administração & dosagem , Adulto Jovem , Zidovudina/administração & dosagem
5.
J Pharm Pract ; 32(1): 9-18, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29017426

RESUMO

The HIV-infected patients are co-infected with many bacterial infections in which tuberculosis is most common found worldwide. These patients are often administered with combined therapy of anti-retroviral and anti-tubercular drugs which leads to several complications including hepatotoxicity or adverse drug interactions. The drug-drug interactions between the anti-retroviral and anti-tubercular drugs are not clearly defined and hence, this study was conducted to evaluate the pharmacokinetic drug-drug interactions of Zidovudine (AZT) with Isoniazid (INH) and its hepatotoxic metabolites. Seventy two rats were randomly divided into two major groups with their sub-groups each comprising 6 animals. The Group I received INH alone at a dose of 25 mg/kg; b.w and Group II received AZT (50 mg/kg; b.w) along with INH orally. Pharmacokinetic studies of INH and its metabolites i.e., acetyl hydrazine (ACHY) and hydrazine (HYD) shows that INH and ACHY attains maximum plasma concentration ( Cmax) within 30 minutes and HYD attains Cmax at 1 hour after INH administration and all these analytes disappear from plasma within 4 hours. Pharmacokinetic studies also revealed that AZT treatment did not showed any drug-drug interactions and have no effect on the T1/2, plasma clearance, AUC, Cmax and Tmax of INH and its hepatotoxic metabolites.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Antituberculosos/administração & dosagem , Isoniazida/administração & dosagem , Zidovudina/administração & dosagem , Animais , Fármacos Anti-HIV/farmacologia , Antituberculosos/farmacocinética , Área Sob a Curva , Interações de Medicamentos , Meia-Vida , Humanos , Hidrazinas/farmacocinética , Isoniazida/farmacocinética , Ratos , Ratos Wistar , Zidovudina/farmacologia
6.
Indian J Pharmacol ; 50(4): 212-214, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30505059

RESUMO

Highly active antiretroviral therapy (HAART) is nowadays universally available to patients with HIV/AIDS. This has led to increased longevity in people living with HIV/AIDS. However, these patients frequently face chronic and rarely acute life-threatening complications of HAART. Herein, we report the case of a patient who was on HAART and developed zidovudine-induced lactic acidosis, acute pancreatitis, and myopathy. Although these acute complications are rare, a high index of suspicion is required for early diagnosis and to reduce significant morbidity and mortality.


Assuntos
Acidose Láctica/induzido quimicamente , Doenças Musculares/induzido quimicamente , Pancreatite/induzido quimicamente , Zidovudina/efeitos adversos , Acidose Láctica/diagnóstico , Doença Aguda , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Doenças Musculares/diagnóstico , Pancreatite/diagnóstico , Zidovudina/administração & dosagem
7.
Biomater Sci ; 7(1): 178-186, 2018 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-30507990

RESUMO

A novel chemical approach integrating the benefits of nanoparticles with versatility of coordination chemistry is reported herein to increase the effectiveness of well-known HIV antiretroviral drugs. The novelty of our approach is illustrated using a catechol ligand tethered to the known antiretroviral azidothymidine (AZT) as a constitutive building block of the nanoparticles. The resulting nanoscale coordination polymers (NCPs) ensure good encapsulation yields and equivalent antiretroviral activity while significantly diminishing its cytotoxicity. Moreover, this novel family of nanoparticles also offers (i) long-lasting drug release that is dissimilar inside and outside the cells depending on pH, (ii) triggered release in the presence of esterases, activating the antiviral activity in an on-off manner due to a proper chemical design of the ligand and (iii) improved colloidal stabilities and cellular uptakes (up to 50-fold increase). The presence of iron nodes also adds multifunctionality as possible contrast agents. The present study demonstrates the suitability of NCPs bearing pharmacologically active ligands as an alternative to conventional antiretroviral treatments.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Catecóis/química , Portadores de Fármacos/química , Nanopartículas/química , Polímeros/química , Zidovudina/administração & dosagem , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Ligantes , Nanopartículas/ultraestrutura , Zidovudina/química , Zidovudina/farmacocinética , Zidovudina/farmacologia
8.
Vopr Virusol ; 63(5): 212-217, 2018.
Artigo em Russo | MEDLINE | ID: mdl-30550097

RESUMO

OBJECTIVES: The goal of this work was to study the immunological and virological efficacy of the domestic antiretroviral drug nicavir (at the optimal dose, as proven by previous clinical studies) with lamivudine, in comparison with other drugs of the group of nucleoside reverse transcriptase inhibitors in combination with kaletra in perinatal HIV chemoprophylaxis regimens. METHODS: 658 pregnant women aged 16-39 years and children born to them were examined. The first group (281 people) and the third group (66 people) received the nicavir (manufactured by AZT PHARMA KB LLC) with lamivudine in combination with calyx; the second (281 people) and the fourth (30 people) of the comparison group, stag and zidovudine, respectively, with lamivudine in combination with calyx. The effectiveness of CP was assessed from the increase in the number of CD4 lymphocytes, reduction of the viral load, and the number of children born without HIV DNA in the blood. RESULTS: Against the backdrop of the therapy, the viral load below the detectable level and the positive dynamics of CD4 lymphocytes were registered in all examined women prior to childbirth. When applying the scheme of niacavir + lamivudine + kaletra, a more rapid decrease in the level of BH, most pronounced by week 4 of therapy, was found, as compared with the rate of decline of the same index in pregnant comparison groups. CONCLUSIONS: The obtained results allow us to consider ART with the inclusion of nicavir effective and recommend its priority use in perinatal prevention of mother-to-child transmission of HIV.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Organofosfonatos/administração & dosagem , Zidovudina/análogos & derivados , Adolescente , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Quimioprevenção/métodos , Combinação de Medicamentos , Feminino , Infecções por HIV/patologia , Infecções por HIV/transmissão , Infecções por HIV/virologia , HIV-1/patogenicidade , Humanos , Lactente , Recém-Nascido , Transmissão Vertical de Doença Infecciosa , Lamivudina/administração & dosagem , Lopinavir/administração & dosagem , Assistência Perinatal , Ritonavir/administração & dosagem , Carga Viral/efeitos dos fármacos , Adulto Jovem , Zidovudina/administração & dosagem
9.
Indian J Med Res ; 148(2): 207-214, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30381544

RESUMO

Background & objectives: Nucleoside reverse transcriptase inhibitors (NRTIs) are known to cause mitochondrial toxicity. This study was done to estimate mitochondrial DNA (mtDNA) content of peripheral blood mononuclear cells (PBMCs) among human immunodeficiency virus (HIV) infected, NRTI treated and antiretroviral therapy (ART)-naïve patients and evaluate the utility of mtDNA content as a biomarker of mitochondrial toxicity. Methods: mtDNA content in PBMCs of 57 HIV-infected ART untreated and 30 ART treated with stavudine (d4T) or zidovudine (AZT) containing regimen were compared against 24 low-risk healthy controls (LoRHC). Results: There was a significant (P=0.01) reduction in mtDNA content among HIV-infected (104; 80-135) compared to LoRHC (127; 110-167), and it was the same in both the treated (104.8; 88-130) and untreated patients (104.7; 78-142). mtDNA significantly (P=0.014) declined in ART treated patients symptomatic for toxicity (97; 74-111) than the asymptomatic patients (128; 103- 153). Interpretation & conclusions: mtDNA depletion in PBMCs was evident among HIV-infected individuals on ART. Moreover, as mtDNA content was reduced among the patients symptomatic for toxicity than the asymptomatic in both the HIV-infected groups, the current study supports mtDNA content of PBMCs to serve as a biomarker of mitochondrial dysfunction induced by NRTI and HIV. Longitudinal studies with a large sample need to be done to confirm these findings.


Assuntos
DNA Mitocondrial/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/administração & dosagem , Adulto , Terapia Antirretroviral de Alta Atividade , Feminino , Infecções por HIV/complicações , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/patogenicidade , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Masculino , Pessoa de Meia-Idade , Estavudina/administração & dosagem , Estavudina/efeitos adversos , Zidovudina/administração & dosagem
10.
Molecules ; 23(10)2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30347696

RESUMO

The co-use of conventional drug and herbal medicines may lead to herb-drug interaction via modulation of drug-metabolizing enzymes (DMEs) by herbal constituents. UDP-glucuronosyltransferases (UGTs) catalyzing glucuronidation are the major metabolic enzymes of Phase II DMEs. The in vitro inhibitory effect of several herbal constituents on one of the most important UGT isoforms, UGT2B7, in human liver microsomes (HLM) and rat liver microsomes (RLM) was investigated. Zidovudine (ZDV) was used as the probe substrate to determine UGT2B7 activity. The intrinsic clearance (Vmax/Km) of ZDV in HLM is 1.65 µL/mg/min which is ten times greater than in RLM, which is 0.16 µL/mg/min. Andrographolide, kaempferol-3-rutinoside, mitragynine and zerumbone inhibited ZDV glucuronidation in HLM with IC50 values of 6.18 ± 1.27, 18.56 ± 8.62, 8.11 ± 4.48 and 4.57 ± 0.23 µM, respectively, hence, herb-drug interactions are possible if andrographolide, kaempferol-3-rutinoside, mitragynine and zerumbone are taken together with drugs that are highly metabolized by UGT2B7. Meanwhile, only mitragynine and zerumbone inhibited ZDV glucuronidation in RLM with IC50 values of 51.20 ± 5.95 µM and 8.14 ± 2.12 µM, respectively, indicating a difference between the human and rat microsomal model so caution must be exercised when extrapolating inhibitory metabolic data from rats to humans.


Assuntos
Glucuronosiltransferase/antagonistas & inibidores , Interações Ervas-Drogas , Microssomos Hepáticos/efeitos dos fármacos , Zidovudina/administração & dosagem , Animais , Diterpenos/administração & dosagem , Glucuronídeos/antagonistas & inibidores , Glucuronosiltransferase/química , Glucuronosiltransferase/isolamento & purificação , Glucuronosiltransferase/metabolismo , Medicina Herbária , Humanos , Microssomos Hepáticos/enzimologia , Ratos , Alcaloides de Triptamina e Secologanina/administração & dosagem , Sesquiterpenos/administração & dosagem , Zidovudina/antagonistas & inibidores , Zidovudina/química
11.
AAPS PharmSciTech ; 19(7): 3219-3227, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30187445

RESUMO

This study aimed to examine the influence of the combination of chemical enhancers and a microemulsion on the transdermal permeation of zidovudine (AZT). Ethanol, 1,8-cineole, and geraniol were incorporated in a microemulsion. The droplet size, zeta potential, rheology, and SAXS analysis were performed. The permeation enhancer effect was evaluated using pig ear skin. Snake skin (Boa constrictor) treated with the formulations was also used as a stratum corneum model and studied by attenuated total reflectance-infrared spectroscopy. As a result, it was observed that the incorporation of the chemical enhancers promoted a decrease of the droplet size and some rheological modifications. The 1,8-cineole associated with the microemulsion significantly increased the permeated amount of AZT. Conversely, ethanol significantly increased the quantity of the drug retained in the skin. The probable mechanism for the cineole and ethanol effects was respectively: fluidization and increasing of the diffusion coefficient, and increasing of the partition coefficient. Surprising, geraniol + microemulsion drastically decreased both the permeated and the retained amount of AZT into the skin. Thus, the adequate association of microemulsion and chemical enhancers showed to be a crucial step to enable the topical or transdermal use of drugs.


Assuntos
Sistemas de Liberação de Medicamentos , Zidovudina/administração & dosagem , Administração Cutânea , Animais , Emulsões , Permeabilidade , Pele/metabolismo , Suínos , Zidovudina/química , Zidovudina/farmacocinética
13.
Eur J Pharm Sci ; 122: 22-30, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-29933076

RESUMO

An adapted methodology for obtaining lipid nanoparticles that only uses the microwave reactor in the synthesis process was developed. The method has the following features: one-pot, one-step, fast, practical, economical, safe, readiness of scaling-up, lack of organic solvents and production of nanoparticles with low polydispersity index (PDI) (below 0.3). This new method was applied for the development of nanostructured lipid carriers (NLC) loaded with a hydrophilic drug, the antiretroviral agent zidovudine (AZT). The aim of the present work was to develop, evaluate and compare optimized NLC formulations produced by two different methods - hot ultrasonication and microwave-assisted method. The development and optimization of the NLC formulations were supported by a Quality by Design (QbD) approach. All formulations were physicochemically characterized by the same parameters. The optimized formulations presented a suitable profile for oral administration (particle size between 100 and 300 nm, PDI < 0.3 and negative zeta potential >-20 mV). Furthermore, the morphologies assessed by TEM showed spherical shape and confirmed the results obtained by DLS. Both AZT loaded formulations were physically stable for at least 45 days and non-toxic on Jurkat T cells. Drug release studies showed a controlled release of AZT under gastric and plasma-simulated conditions.


Assuntos
Fármacos Anti-HIV/química , Portadores de Fármacos/química , Micro-Ondas , Nanoestruturas/química , Zidovudina/química , Fármacos Anti-HIV/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Diglicerídeos/administração & dosagem , Diglicerídeos/química , Portadores de Fármacos/administração & dosagem , Composição de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Emulsões , Humanos , Células Jurkat , Nanoestruturas/administração & dosagem , Sonicação , Triglicerídeos/administração & dosagem , Triglicerídeos/química , Zidovudina/administração & dosagem
14.
Anal Bioanal Chem ; 410(21): 5245-5253, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29947896

RESUMO

Asymmetric flow field-flow fractionation (AF4) coupled with UV-Vis spectroscopy, multi-angle light scattering (MALS) and refractive index (RI) detection has been applied for the characterization of MIL-100(Fe) nanoMOFs (metal-organic frameworks) loaded with nucleoside reverse transcriptase inhibitor (NRTI) drugs for the first time. Empty nanoMOFs and nanoMOFs loaded with azidothymidine derivatives with three different degrees of phosphorylation were examined: azidothymidine (AZT, native drug), azidothymidine monophosphate (AZT-MP), and azidothymidine triphosphate (AZT-TP). The particle size distribution and the stability of the nanoparticles when interacting with drugs have been determined in a time frame of 24 h. Main achievements include detection of aggregate formation in an early stage and monitoring nanoMOF morphological changes as indicators of their interaction with guest molecules. AF4-MALS proved to be a useful methodology to analyze nanoparticles engineered for drug delivery applications and gave fundamental data on their size distribution and stability. Graphical abstract ᅟ.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Complexos de Coordenação/química , Portadores de Fármacos/química , Estruturas Metalorgânicas/química , Nanopartículas/química , Zidovudina/administração & dosagem , Fármacos Anti-HIV/química , Antimetabólitos/administração & dosagem , Antimetabólitos/química , Didesoxinucleotídeos/administração & dosagem , Didesoxinucleotídeos/química , Difusão Dinâmica da Luz , Fracionamento por Campo e Fluxo , Modelos Moleculares , Tamanho da Partícula , Refratometria , Espectrofotometria Ultravioleta , Nucleotídeos de Timina/administração & dosagem , Nucleotídeos de Timina/química , Zidovudina/análogos & derivados , Zidovudina/química
15.
Clin Cancer Res ; 24(14): 3273-3281, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29632007

RESUMO

Purpose: Primary central nervous system posttransplant lymphoproliferative disorder (PCNS-PTLD) is a complication of solid organ transplantation with a poor prognosis and typically associated with Epstein-Barr virus (EBV). We hypothesized EBV lytic-phase protein expression would allow successful treatment with antiviral therapy.Patients and Methods: Thirteen patients were treated with zidovudine (AZT), ganciclovir (GCV), dexamethasone, and rituximab in EBV+ PCNS-PTLD. Twice-daily, intravenous AZT 1,500 mg, GCV 5 mg/kg, and dexamethasone 10 mg were given for 14 days. Weekly rituximab 375 mg/m2 was delivered for the first 4 weeks. Twice-daily valganciclovir 450 mg and AZT 300 mg started day 15. Lytic and latent protein expression was assessed using in situ hybridization and immunohistochemistry. Immunoblot assay assessed lytic gene activation. Cells transfected with lytic kinase vectors were assessed for sensitivity to our therapy using MTS tetrazolium and flow cytometry.Results: The median time to response was 2 months. Median therapy duration was 26.5 months. Median follow-up was 52 months. The estimated 2-year overall survival (OS) was 76.9% (95% CI, 44.2%-91.9%). Overall response rate (ORR) was 92% (95% CI, 64%-100%). BXLF1/vTK and BGLF4 expression was found in the seven tumor biopsies evaluated. Lytic gene expression was induced in vitro using the four-drug regimen. Transfection with viral kinase cDNA increased cellular sensitivity to antiviral therapy.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. Clin Cancer Res; 24(14); 3273-81. ©2018 AACR.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças do Sistema Nervoso Central/tratamento farmacológico , Transtornos Linfoproliferativos/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biópsia , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/etiologia , Dexametasona/administração & dosagem , Infecções por Vírus Epstein-Barr/complicações , Feminino , Ganciclovir/administração & dosagem , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/etiologia , Masculino , Pessoa de Meia-Idade , Transplante de Órgãos/efeitos adversos , Transplante de Órgãos/métodos , Prognóstico , Rituximab/administração & dosagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Zidovudina/administração & dosagem
16.
Pediatr Infect Dis J ; 37(3): 246-252, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28834955

RESUMO

BACKGROUND: HIV-1 infection may impair transplacental antibody transfer to infants. The impact of highly active antiretroviral treatment (ART) given during pregnancy on transplacental antibody transport is unknown. METHODS: HIV-1 infected pregnant women with CD4 counts between 200 - 500 were randomized to short-course zidovudine (ZDV) or triple ART at 32 weeks gestation for prevention of mother-to-child HIV-1 transmission. Levels of maternal antibody against measles, pneumococcus and rotavirus at delivery, and antibody transfer to the baby through cord blood, were compared between trial arms. RESULTS: Overall, 141 and 148 women were randomized to triple ART and ZDV, respectively; cord blood was available for a subset (n = 20 in triple ART and n = 22 in ZDV). Maternal antibody levels to all pathogens during pregnancy and at delivery were not significantly different between arms. Within each arm, antibody levels at delivery were lower than at enrolment. For all antibodies, a woman's levels before delivery were an important predictor of amount transferred to her infant. Women on triple ART transferred higher levels of pathogen-specific antibodies when compared with women on short course ZDV. CONCLUSIONS: Women on triple ART transferred higher levels of pathogen-specific antibodies compared with women on ZDV alone.


Assuntos
Anticorpos Anti-HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Imunidade Materno-Adquirida , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/imunologia , Zidovudina/uso terapêutico , Adulto , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Feminino , HIV-1 , Humanos , Imunoglobulina G/imunologia , Quênia , Adesão à Medicação , Gravidez , Resultado do Tratamento , Carga Viral , Adulto Jovem , Zidovudina/administração & dosagem
17.
Expert Opin Pharmacother ; 19(1): 13-25, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28764578

RESUMO

INTRODUCTION: Infants who acquire HIV have an exceptionally high risk of morbidity and mortality if they do not receive antiretroviral therapy (ART). AREAS COVERED: This review aims to summarize the currently available evidence on ART in HIV-infected neonates. Data were obtained from literature searches from PubMed, abstracts from International Conferences (2000-2017), and authors' files EXPERT OPINION: Current evidence favors early diagnosis and prompt ART of HIV infection in newborns. The precise timing of initiation of ART remains undetermined. Very early (close to birth) ART appears to limit the size of the viral reservoir and may restrict replication-competent virus, but the clinical benefit remains unproven. Among the current options for initial therapy, in full term neonates from 2 weeks of life onwards, a lopinavir/ritonavir-based three-drug regimen is preferred. In term infants, younger than 2 weeks a nevirapine-based regimen is recommended, although there are no clinical trial data supporting that initiating treatment before 2 weeks improves outcome compared to starting afterwards. Existing safety information is insufficient to recommend ART in preterm infants, with pharmacokinetic data available for zidovudine only. If ART is considered in this setting, an individual case assessment of the risk/benefit ratio of treatment should be made.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Diagnóstico Precoce , Infecções por HIV/tratamento farmacológico , Infecções por HIV/diagnóstico , Humanos , Recém-Nascido , Transmissão Vertical de Doença Infecciosa , Nevirapina/administração & dosagem , Ritonavir/uso terapêutico , Zidovudina/administração & dosagem
18.
Int J Hematol ; 107(3): 378-382, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29090417

RESUMO

Globally, > 5-10 million people are estimated to be infected with Human T-lymphotropic virus type 1 (HTLV-1), of whom ~ 5% develop adult T-cell leukemia/lymphoma (ATL). Despite advances in chemotherapy, overall survival (OS) has not improved in the 35 years since HTLV-1 was first described. In Europe/USA, combination treatment with zidovudine and interferon-α (ZDV/IFN-α) has substantially changed the management of patients with the leukemic subtypes of ATL (acute or unfavorable chronic ATL) and is under clinical trial evaluation in Japan. However, there is only a single published report of long-term clinical remission on discontinuing ZDV/IFN-α therapy and the optimal duration of treatment is unknown. Anecdotal cases where therapy is discontinued due to side effects or compliance have been associated with rapid disease relapse, and it has been widely accepted that the majority of patients will require life-long therapy. The development of molecular methods to quantify minimal residual disease is essential to potentially guide therapy for individual patients. Here, for the first time, we report molecular evidence that supports long-term clinical remission in a patient who was previously treated with ZDV/IFN-α for 5 years, and who has now been off all therapy for over 6 years.


Assuntos
Antivirais/administração & dosagem , Interferon-alfa/administração & dosagem , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Indução de Remissão , Zidovudina/administração & dosagem , Adulto , Aloenxertos , Transplante de Medula Óssea , Doença Crônica , Terapia Combinada , Quimioterapia Combinada , Vírus Linfotrópico T Tipo 1 Humano , Humanos , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Leucemia-Linfoma de Células T do Adulto/virologia , Masculino , Neoplasia Residual/diagnóstico , Fatores de Tempo
19.
Pan Afr Med J ; 28: 7, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29138653

RESUMO

Introduction: In many settings, several factors including adverse drug reactions and clinical failure can limit treatment choices for combined antiretroviral therapy (cART). The aim of the study was to describe the incidence of first-line cART changes and associated factors in a cohort of Kenyan sex workers. Methods: This was a retrospective review of medical records collected from 2009 to 2013. The review included records of HIV-infected patients aged ≥ 18 years, who received either stavudine or zidovudine or tenofovir disoproxil fumarate-based regimens. Using systematic random sampling, the study selected 1 500 records and censoring targeted the first incident of a drug change from the first-line cART. Results: The overall incidence rate of cART changes was 11.1 per 100 person-years within a total follow-up period of 3 427.9 person-years. Out of 380 patients who changed cART, 370 (97%) had a drug substitution and 10 (3%) switched regimens. The most commonly cited reasons for changing cART were adverse drug reactions (76%). Tenofovir disoproxil fumarate had a lower drug change rate (1.9 per 100 person years) compared to stavudine (27 per 100 person years). Using zidovudine as the reference group, stavudine-based regimens were significantly associated with an increased hazard of drug changes (adjusted hazards ratio 10.2; 95% CI: 6.02-17.2). Conclusion: These findings suggest a moderate incidence of cART changes among sex workers in Nairobi, Kenya. Individuals using stavudine were at a higher risk of experiencing a change in their cART, mostly presenting within 20 months, and primarily due to adverse drug reactions.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Profissionais do Sexo , Adulto , Fármacos Anti-HIV/efeitos adversos , Feminino , Seguimentos , Humanos , Incidência , Quênia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estavudina/administração & dosagem , Tenofovir/administração & dosagem , Fatores de Tempo , Zidovudina/administração & dosagem
20.
BMC Res Notes ; 10(1): 623, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29183354

RESUMO

OBJECTIVE: The rapid scale-up of antiretroviral therapy (ART) coverage in sub-Saharan Africa has encountered the challenge of maintaining international clinical standards of ART utilization and change of ART regimens. In Cameroon, scarce reports have documented the motives for change of ART. This study had as objective to investigate the reasons for switch in ART through a secondary analysis and descriptive synthesis of data from a cross-sectional study at the Limbe Regional Hospital. RESULTS: One hundred participants were included. Their mean age was 40.2 ± 8.0 years and 70% of them were females. The median duration of ART use was 60 months. Zidovudine-Lamivudine-Nevirapine regimen was received by 83% of patients while the Stavudine-Lamivudine-Nevirapine regimen had the highest median duration of use (58 months). Most patients had experienced changes in ART (especially from Stavudine-Lamivudine-Nevirapine regimen) with the chief reason being unavailability of their previous regimens. Four patients had their ART changed due to active tuberculosis, 4 due to pregnancy and 7 due to ART toxicity (4 and 3 for peripheral neuropathy and lipodystrophy respectively). In conclusion, shortages in ART hugely influenced switch in regimens. In such a context, modifications in ART possibly deviate from guidelines with resultant sub-optimal therapy and enhanced drug resistance.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Substituição de Medicamentos , Infecções por HIV/tratamento farmacológico , Lamivudina/uso terapêutico , Nevirapina/uso terapêutico , Estavudina/uso terapêutico , Zidovudina/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Camarões , Estudos de Coortes , Estudos Transversais , Combinação de Medicamentos , Feminino , Humanos , Lamivudina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Nevirapina/administração & dosagem , Encaminhamento e Consulta , Estavudina/administração & dosagem , Zidovudina/administração & dosagem
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