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1.
Arch Microbiol ; 206(4): 134, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38433145

RESUMO

Acanthamoeba castellanii are opportunistic pathogens known to cause infection of the central nervous system termed: granulomatous amoebic encephalitis, that mostly effects immunocompromised individuals, and a sight threatening keratitis, known as Acanthamoeba keratitis, which mostly affects contact lens wearers. The current treatment available is problematic, and is toxic. Herein, an amphiphilic star polymer with AB2 miktoarms [A = hydrophobic poly(ℇ-Caprolacton) and B = hydrophilic poly (ethylene glycol)] was synthesized by ring opening polymerization and CuI catalyzed azide-alkyne cycloaddition. Characterization by 1H and 13C NMR spectroscopy, size-exclusion chromatography and fluorescence spectroscopy was accomplished. The hydrophobic drug itraconazole (ITZ) was incorporated in self-assembled micellar structure of AB2 miktoarms through co-solvent evaporation. The properties of ITZ loaded (ITZ-PCL-PEG2) and blank micelles (PCL-PEG2) were investigated through zeta sizer, scanning electron microscopy and Fourier-transform infrared spectroscopy. Itraconazole alone (ITZ), polymer (DPB-PCL), empty polymeric micelles (PCL-PEG2) alone, and itraconazole loaded in polymeric micelles (ITZ-PCL-PEG2) were tested for anti-amoebic potential against Acanthamoeba, and the cytotoxicity on human cells were determined. The polymer was able to self-assemble in aqueous conditions and exhibited low value for critical micelle concentration (CMC) 0.05-0.06 µg/mL. The maximum entrapment efficiency of ITZ was 68%. Of note, ITZ, DPB, PCL-PEG2 and ITZ-PCL-PEG2 inhibited amoebae trophozoites by 37.34%, 36.30%, 35.77%, and 68.24%, respectively, as compared to controls. Moreover, ITZ-PCL-PEG2 revealed limited cytotoxicity against human keratinocyte cells. These results are indicative that ITZ-PCL-PEG2 micelle show significantly better anti-amoebic effects as compared to ITZ alone and thus should be investigated further in vivo to determine its clinical potential.


Assuntos
Acanthamoeba castellanii , Micelas , Humanos , Itraconazol/farmacologia , Alcinos , Polímeros
2.
Bioconjug Chem ; 35(3): 286-299, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38451202

RESUMO

Chemoselective protein modification plays extremely important roles in various biological, medical, and pharmaceutical investigations. Mimicking the mechanism of the chemoselective reaction between natural azaphilones and primary amines, this work successfully simplified the azaphilone scaffold into much simpler 3-acyl-4-pyranones. Examinations confirmed that these slim-size mimics perfectly kept the unique reactivity for selective conjugation with the primary amines including lysine residues of peptides and proteins. The newly developed pyranone tool presents remarkably increased aqueous solubility and compatible second-order rate constant by comparison with the original azaphilone. Additional advantages also include the ease of biorthogonal combinative use with a copper-catalyzed azide-alkyne Click reaction, which was conveniently applied to decorate lysozyme with neutral-, positive- and negative-charged functionalities in parallel. Moderate-degree modification of lysozyme with positively charged quaternary ammoniums was revealed to increase the enzymatic activities.


Assuntos
Lisina , Muramidase , Lisina/química , Indicadores e Reagentes , Peptídeos/química , Aminas , Azidas/química , Química Click , Alcinos/química
3.
Angew Chem Int Ed Engl ; 63(14): e202314786, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38438780

RESUMO

Due to the variety of roles served by the cell membrane, its composition and structure are complex, making it difficult to study. Bioorthogonal reactions, such as the strain promoted azide-alkyne cycloaddition (SPAAC), are powerful tools for exploring the function of biomolecules in their native environment but have been largely unexplored within the context of lipid bilayers. Here, we developed a new approach to study the SPAAC reaction in liposomal membranes using azide- and strained alkyne-functionalized Förster resonance energy transfer (FRET) dye pairs. This study represents the first characterization of the SPAAC reaction between diffusing molecules inside liposomal membranes. Potential applications of this work include in situ bioorthogonal labeling of membrane proteins, improved understanding of membrane dynamics and fluidity, and the generation of new probes for biosensing assays.


Assuntos
Bicamadas Lipídicas , Lipossomos , Lipossomos/química , Reação de Cicloadição , Azidas/química , Alcinos/química
5.
J Am Chem Soc ; 146(10): 6817-6829, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38427023

RESUMO

N-Acetyl muramic acid (NAM) probes containing alkyne or azide groups are commonly used to investigate aspects of cell wall synthesis because of their small size and ability to incorporate into bacterial peptidoglycan (PG). However, copper-catalyzed alkyne-azide cycloaddition (CuAAC) reactions are not compatible with live cells, and strain-promoted alkyne-azide cycloaddition (SPAAC) reaction rates are modest and, therefore, not as desirable for tracking the temporal alterations of bacterial cell growth, remodeling, and division. Alternatively, the tetrazine-trans-cyclooctene ligation (Tz-TCO), which is the fastest known bioorthogonal reaction and not cytotoxic, allows for rapid live-cell labeling of PG at biologically relevant time scales and concentrations. Previous work to increase reaction kinetics on the PG surface by using tetrazine probes was limited because of low incorporation of the probe. Described here are new approaches to construct a minimalist tetrazine (Tz)-NAM probe utilizing recent advancements in asymmetric tetrazine synthesis. This minimalist Tz-NAM probe was successfully incorporated into pathogenic and commensal bacterial PG where fixed and rapid live-cell, no-wash labeling was successful in both free bacterial cultures and in coculture with human macrophages. Overall, this probe allows for expeditious labeling of bacterial PG, thereby making it an exceptional tool for monitoring PG biosynthesis for the development of new antibiotic screens. The versatility and selectivity of this probe will allow for real-time interrogation of the interactions of bacterial pathogens in a human host and will serve a broader utility for studying glycans in multiple complex biological systems.


Assuntos
Compostos Heterocíclicos , Peptidoglicano , Humanos , Azidas , Ácidos Murâmicos , Reação de Cicloadição , Alcinos
6.
Sci Rep ; 14(1): 5265, 2024 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-38438418

RESUMO

Nutritional status is considered a major diagnostic and prognostic indicator of HIV/AIDS in adults. In this aspect, current HIV-treatment guidelines, particularly in low-income countries, recommend the regular monitoring of body mass index (BMI) to determine patients' clinical response to antiretroviral therapy (ART). However, data regarding the change in BMI status of HIV-positive adults on ART following the implementation of the test and treat strategy were limited in Ethiopia. Hence, this study is aimed at investigating the trends of BMI change over time and its associated factors among HIV-positive adults in Northwest Ethiopia. A retrospective longitudinal study was conducted among 404 randomly selected HIV-positive adults receiving ART in Felegehiwot Comprehensive Specialized Hospital (FHCSH), Northern Ethiopia. Data were extracted from the medical record charts of study participants, entered into Epi-data 4.6 software, and exported to Stata 14.2 software for analysis. A generalized estimating equation (GEE) model was fitted to determine the change in BMI status over time and its predictors in HIV-positive adults. The level of significance was declared at a p-value of < 0.05. More than half (201, or 51.73%) of the total 404 participants were female. In the cohort, both the baseline and follow-up mean body mass index levels of the participants fell in the normal range and increased from 20.34 (standard deviation/SD ± 2.8) to 21.41 (SD ± 3.13). The individual profile plots of 50 participants indicated that there is considerable variability in weight change across individuals. Duration of ART follow-up (ß = 0.203, 95% confidence interval (CI) 0.16 to 0.24), unemployment (ß = - 0.96, 95% CI 1.67 to - 0.25), WHO stage III/IV HIV disease (ß = - 0.92, 95% CI - 1.57 to - 0.35),and Tenofovir/Lamivudine/Dolutegravir (TDF/3TC/DTG)ART regimen (ß = 0.95, 95% CI 0.32 to 1.57) were identified as significant predictors of change in the BMI status of participants. Likewise, the interaction of TDF/3TC/DTG ART regimen * follow-up duration (ß = 2.16, 95% CI 1.84 to 2.84), WHO stage III/IV clinical disease * follow-up duration (ß = - 1.43, 95% CI - 1.71 to - 1.15) and TB/HIV co-infection * follow-up duration (ß = 1.89, 95% CI 1.57 to 2.87) significantly affects the trend in BMI change status of HIV-positive adults. In this study, the BMI status of HIV-positive adults receiving ART increased with a linear trend. Unemployment, stage III/IV HIV diseases, and Tenofovir/Lamivudine/Efavirenz (TDF/3TC/EFV) ART-drug regimen decreases the mean BMI status of HIV-positive adults. Special consideration and strict follow-up need to be given to those individuals with advanced HIV/AIDS diseases and other identified risk group.


Assuntos
Síndrome de Imunodeficiência Adquirida , Alcinos , Ciclopropanos , Infecções por HIV , Adulto , Humanos , Feminino , Masculino , Índice de Massa Corporal , Lamivudina , Etiópia/epidemiologia , Estudos Longitudinais , Estudos Retrospectivos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Tenofovir , Benzoxazinas , Análise de Dados
7.
J Antimicrob Chemother ; 79(3): 526-530, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38300833

RESUMO

BACKGROUND: HIV-1 drug resistance is a huge challenge in the era of ART. OBJECTIVES: To investigate the prevalence and characteristics of acquired HIV-1 drug resistance (ADR) in Shanghai, China. METHODS: An epidemiological study was performed among people living with human immunodeficiency virus (PLWH) receiving ART in Shanghai from January 2017 to December 2021. A total of 8669 PLWH were tested for drug resistance by genotypic resistance testing. Drug resistance mutations (DRMs) were identified using the Stanford University HIV Drug Resistance Database program. RESULTS: Ten HIV-1 subtypes/circulating recombinant forms (CRFs) were identified, mainly including CRF01_AE (46.8%), CRF07_BC (35.7%), B (6.4%), CRF55_01B (2.8%) and CRF08_BC (2.4%). The prevalence of ADR was 48% (389/811). Three NRTI-associated mutations (M184V/I/L, S68G/N/R and K65R/N) and four NNRTI-associated mutations (V179D/E/T/L, K103N/R/S/T, V106M/I/A and G190A/S/T/C/D/E/Q) were the most common DRMs. These DRMs caused high-level resistance to lamivudine, emtricitabine, efavirenz and nevirapine. The DRM profiles appeared to be significantly different among different subtypes. CONCLUSIONS: We revealed HIV-1 subtype characteristics and the DRM profile in Shanghai, which provide crucial guidance for clinical treatment and management of PLWH.


Assuntos
Soropositividade para HIV , HIV-1 , Humanos , HIV-1/genética , Estudos Retrospectivos , China/epidemiologia , Alcinos
8.
J Org Chem ; 89(5): 2895-2903, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38344977

RESUMO

The synthesis of phosphorodiamidate morpholino oligonucleotides (PMOs) incorporating single or double triazole rings in the backbone has been achieved via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The synthetic approach implemented is fundamentally convergent, involving the ligation of a 5'-azide PMO fragment to a 3'-alkyne fragment both in solution and on solid support. To access the 3'-alkyne PMO fragment, we synthesized 3'-N-propargyl chlorophosphoramidate morpholino monomers for all four nucleobases. The resulting triazole-incorporated PMOs (TzPMOs) have exhibited comparable or improved binding affinity toward complementary deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) strands compared to its regular analogues. Finally, a full-length TzPMO was designed to target the Nanog gene, demonstrating almost identical hybridization properties when compared to its regular version. Circular dichroism studies revealed a B-type helical conformation for the duplexes formed by TzPMOs.


Assuntos
Alcinos , Azidas , Morfolinos , Dicroísmo Circular , Triazóis
9.
J Org Chem ; 89(5): 3390-3402, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38377557

RESUMO

The introduction of alkyne moieties into peptides remains in demand as it represents a promising approach for further structural diversification of peptides. Herein, we describe the Pd(II)-catalyzed C(sp3)-H alkynylation of Ala-Asn-embedded di- and tripeptides using Asn as the endogenous lead group. In addition, a key building block for the glycopeptide Tyc4PG-14 and Tyc4PG-15 was produced by our methodology.


Assuntos
Alanina , Alcinos , Glicopeptídeos , Catálise
10.
Biomacromolecules ; 25(3): 1541-1549, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38394608

RESUMO

Amphiphilic Janus dendrimers (JDs), synthetic alternatives to lipids, have the potential to expand the scope of nanocarrier delivery systems. JDs self-assemble into vesicles called dendrimersomes, encapsulate both hydrophobic cargo and nucleic acids, and demonstrate enhanced stability in comparison to lipid nanoparticles (LNPs). Here, we report the ability to enhance the cellular uptake of Janus dendrimersomes using DNA aptamers. Azido-modified JDs were synthesized and conjugated to alkyne-modified DNAs using copper-catalyzed azide alkyne cycloaddition. DNA-functionalized JDs form nanometer-sized dendrimersomes in aqueous solution via thin film hydration. These vesicles, now displaying short DNAs, are then hybridized to transferrin receptor binding DNA aptamers. Aptamer-targeted dendrimersomes show improved cellular uptake as compared to control vesicles via fluorescence microscopy and flow cytometry. This work demonstrates the versatility of using click chemistry to conjugate functionalized JDs with biologically relevant molecules and the feasibility of targeting DNA-modified dendrimersomes for drug delivery applications.


Assuntos
Aptâmeros de Nucleotídeos , Dendrímeros , Dendrímeros/química , Sistemas de Liberação de Medicamentos , DNA , Alcinos
11.
Int J Mol Sci ; 25(4)2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38396919

RESUMO

High dose (S)-efavirenz (EFV) inhibits the HIV reverse transcriptase enzyme and is used to lower HIV load. Low-dose EFV allosterically activates CYP46A1, the key enzyme for cholesterol elimination from the brain, and is investigated as a potential treatment for Alzheimer's disease. Simultaneously, we evaluate EFV dihydroxymetabolites for in vivo brain effects to compare with those of (S)-EFV. We have already tested (rac)-8,14dihydroxy EFV on 5XFAD mice, a model of Alzheimer's disease. Herein, we treated 5XFAD mice with (rac)-7,8dihydroxy EFV. In both sexes, the treatment modestly activated CYP46A1 in the brain and increased brain content of acetyl-CoA and acetylcholine. Male mice also showed a decrease in the brain levels of insoluble amyloid ß40 peptides. However, the treatment had no effect on animal performance in different memory tasks. Thus, the overall brain effects of (rac)-7,8dihydroxy EFV were weaker than those of EFV and (rac)-8,14dihydroxy EFV and did not lead to cognitive improvements as were seen in treatments with EFV and (rac)-8,14dihydroxy EFV. An in vitro study assessing CYP46A1 activation in co-incubations with EFV and (rac)-7,8dihydroxy EFV or (rac)-8,14dihydroxy EFV was carried out and provided insight into the compound doses and ratios that could be used for in vivo co-treatments with EFV and its dihydroxymetabolite.


Assuntos
Doença de Alzheimer , Fármacos Anti-HIV , Infecções por HIV , Feminino , Masculino , Camundongos , Animais , Colesterol 24-Hidroxilase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Benzoxazinas/química , Alcinos/uso terapêutico , Ciclopropanos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/uso terapêutico
12.
Int J Mol Sci ; 25(4)2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38396908

RESUMO

Rosmarinic acid (RA) is a phenolic compound with antiviral properties, often encountered in dietary supplements and herbal drugs. Data on the pharmacokinetics of RA are lacking in cases of the chronic use of supplements containing this compound, and only limited data on the metabolism and distribution of RA are available. The aim of the study was to investigate the plasma levels of RA after 12 weeks of use and determine potential interactions of RA and selected antiretroviral drugs. Patients infected with human immunodeficiency virus took a supplement containing RA for 12 weeks, after which the RA concentrations in the plasma samples were analyzed. A detailed in silico analysis was conducted in order to elucidate the potential interactions between RA and the drugs efavirenz, darunavir and raltegravir. It was found that RA can be detected in patients' plasma samples, mainly in the form of sulphoglucuronide. The potential interactions are suggested on the level of liver metabolizing enzymes and efflux P-glycoprotein, with RA competing with antiretroviral drugs as a substrate in metabolism and distribution systems. The present study suggests that the simultaneous use of RA and antiretroviral therapy (containing efavirenz, darunavir or raltegravir) may affect the plasma levels of RA after prolonged supplementation.


Assuntos
Alcinos , Fármacos Anti-HIV , Benzoxazinas , Ciclopropanos , Infecções por HIV , Humanos , Raltegravir Potássico/uso terapêutico , Darunavir/farmacocinética , Darunavir/uso terapêutico , Infecções por HIV/tratamento farmacológico , Antirretrovirais/uso terapêutico , Fármacos Anti-HIV/uso terapêutico
13.
J Int AIDS Soc ; 27(2): e26216, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38332525

RESUMO

INTRODUCTION: Dolutegravir (DTG) is widely used for antiretroviral therapy (ART). We compared weight and blood pressure trends and examined the association between high blood pressure and weight gain among people living with HIV (PLHIV) switching to or starting DTG-based, efavirenz (EFV)-based and ritonavir-boosted atazanavir (ATV/r)-based ART in Zimbabwe. METHODS: PLHIV aged 18 years or older who started or switched to DTG, EFV or ATV/r-based ART between January 2004 and June 2022 at Newlands Clinic in Harare, Zimbabwe, were eligible. Weight was measured at all visits (Seca floor scales); blood pressure only at clinician-led visits (Omron M2 sphygmomanometer). We used Bayesian additive models to estimate trends in weight gain and the proportion with high blood pressure (systolic >140 mmHg or diastolic >90 mmHg) in the first 2 years after starting or switching the regimen. Finally, we examined whether trends in the proportion with high blood pressure were related to weight change. RESULTS: We analysed 99,969 weight and 35,449 blood pressure records from 9487 adults (DTG: 4593; EFV: 3599; ATV/r: 1295). At 24 months after starting or switching to DTG, estimated median weight gains were 4.54 kg (90% credibility interval 3.88-5.28 kg) in women and 3.71 kg (3.07-4.45 kg) in men, around twice that observed for ATV/r and over four-times the gain observed for EFV. Prevalence of high blood pressure among PLHIV receiving DTG-based ART increased from around 5% at baseline to over 20% at 24 months, with no change in PLHIV receiving EFV- or ATV/r-based ART. High blood pressure in PLHIV switching to DTG was associated with weight gain, with stronger increases in the proportion with high blood pressure for larger weight gains. CONCLUSIONS: Among PLHIV starting ART or switching to a new regimen, DTG-based ART was associated with larger weight gains and a substantial increase in the prevalence of high blood pressure. Routine weight and blood pressure measurement and interventions to lower blood pressure could benefit PLHIV on DTG-based ART. Further studies are needed to elucidate the mechanisms and reversibility of these changes after discontinuation of DTG.


Assuntos
Alcinos , Fármacos Anti-HIV , Ciclopropanos , Infecções por HIV , Hipertensão , Oxazinas , Piperazinas , Piridonas , Adulto , Masculino , Humanos , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Estudos Longitudinais , Sulfato de Atazanavir/efeitos adversos , Pressão Sanguínea , Zimbábue/epidemiologia , Teorema de Bayes , Benzoxazinas/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Aumento de Peso , Peso Corporal , Fármacos Anti-HIV/efeitos adversos
14.
J Agric Food Chem ; 72(9): 4737-4746, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38390707

RESUMO

A methodology for the total and modulable synthesis of (4Z)-lachnophyllum lactone (1), on a gram scale, is reported for the first time. The present work started with the design of a retrosynthetic pathway for the target compound, with the key step identified in Pd-Cu bimetallic cascade cross-coupling cyclization. (4Z)-Lachnophyllum lactone (1) is an acetylenic furanone previously isolated, in a low amount, from the organic extract of the autotrophic weedConyza bonariensis. Tested against the stem parasitic weed Cuscuta campestris in a seedling growth bioassay, (4Z)-lachnophyllum lactone (1) showed almost 85% of inhibitory activity up to 0.3 mM in comparison with the control. At the same concentration, the compound displayed radicle growth inhibitory activity of the root parasitic weeds Orobanche minor and Phelipanche ramosa higher than 70 and 40%, respectively. Surprisingly, the compound showed a high percentage of inhibition, up to 0.1 mM, on C. bonariensis seed germination too. This versatile synthetic strategy was also used to obtain two further natural analogues, namely, (4E)-lachnophyllum lactone (8) and (4Z,8Z)-matricaria lactone (9), that showed, in most cases, the same inhibitory trend with slight differences, highlighting the importance of the stereochemistry and unsaturation of the side chain. Furthermore, all of the compounds showed antifungal activity at 1 mM reducing the mycelial growth of the olive pathogen Verticillium dahliae. The design and implementation of scalable and modulable total synthesis on a gram scale of acetylenic furanones allow the production of a large amount of these natural products, overcoming the limit imposed by isolation from natural sources. The results of the present study pave the way for the development of ecofriendly bioinspired pesticides with potential application in agrochemical practices as alternative to synthetic pesticides.


Assuntos
Alcaloides , Asteraceae , Orobanche , Praguicidas , Antifúngicos/farmacologia , Lactonas/química , Sementes , Plantas Daninhas , Agricultura , Alcaloides/farmacologia , Alcinos , Praguicidas/farmacologia , Germinação
15.
ACS Appl Mater Interfaces ; 16(9): 11315-11323, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38394235

RESUMO

Adenosine triphosphate (ATP) is a central molecule of organisms and is involved in many biological processes. It is also widely used in biocatalytic processes, especially as a substrate and precursor of many cofactors─such as nicotinamide adenine dinucleotide phosphate (NADP(H)), coenzyme A (CoA), and S-adenosylmethionine (SAM). Despite its great scientific interest and pivotal role, its use in industrial processes is impeded by its prohibitory cost. To overcome this limitation, we developed a greener synthesis of adenosine derivatives and efficiently selectively grafted them onto organic nanoparticles. In this study, cellulose nanocrystals were used as a model combined with click chemistry via a copper-catalyzed azide/alkyne cycloaddition reaction (CuAAC). The grafted adenosine triphosphate derivative fully retains its biocatalytic capability, enabling heterobiocatalysis for modern biochemical processes.


Assuntos
Química Click , Nanopartículas , Celulose/química , Biocatálise , Adenosina , Nanopartículas/química , Azidas/química , Trifosfato de Adenosina , Alcinos/química , Cobre/química , NADP , Catálise
16.
Antivir Ther ; 29(1): 13596535241233128, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38375582

RESUMO

BACKGROUND: In British Columbia, antiretrovirals (ARVs) for HIV treatment (HIV-Tx) and pre-exposure prophylaxis (PrEP) are free-of-charge through publicly-funded Drug Treatment Programs (DTPs). When available, less costly generics are substituted for brand-name ARVs. We describe the incidence and type of product substitution issue (PSI) adverse drug reactions (ADRs) attributed to generic ARVs. METHODS: Cohorts included DTP clients ≥19 years who received generic ARVs for HIV-Tx (abacavir-lamivudine, emtricitabine-tenofovir DF, efavirenz-emtricitabine-tenofovir DF, atazanavir or darunavir between 01 Jun 2017 and 30 Jun 2022) or PrEP (emtricitabine-tenofovir DF, 01 Apr 2018 to 30 Jun 2022). Demographic, ARV and ADR data were extracted from DTP databases and summarized by descriptive statistics. PSI incidence was calculated for each product during the year following brand-to-generic and generic-to-generic transitions (first-year-post-rollout), and compared between generic versions using generalized estimating equations. For context, incidence of any ARV product-related ADR was calculated in the same 1-year periods. RESULTS: During first-year-post-rollout periods, 5339 HIV-Tx (83% male, median age 52 years) and 8095 PrEP (99% male, median 33 years) clients received generic ARVs, and reported 78 and 23 generic PSIs, respectively. PSI incidence was <1% for most generic ARVs, with mild-moderate symptoms including gastrointestinal upset, headache, dizziness, fatigue/malaise and skin rash. In HIV-Tx clients, the efavirenz-containing product had higher PSI incidence than other ARVs (2.2%, p = .004), due to more neuropsychiatric adverse reactions. Any ADR incidence was stable across measurement periods, and generic PSIs represented less than one third of all product-related ADRs. CONCLUSIONS: Generic substitution of antiretrovirals for HIV-Tx and PrEP was well tolerated, with ≤2% incidence of mild-moderate PSI ADRs.


Assuntos
Alcinos , Fármacos Anti-HIV , Benzoxazinas , Ciclopropanos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Infecções por HIV , Profilaxia Pré-Exposição , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , HIV , Colúmbia Britânica/epidemiologia , Substituição de Medicamentos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Infecções por HIV/diagnóstico , Antirretrovirais/uso terapêutico , Tenofovir/efeitos adversos , Emtricitabina/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Fármacos Anti-HIV/efeitos adversos
17.
Int J Mol Sci ; 25(3)2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38339215

RESUMO

α-Hydroxy ketones are a class of vital organic skeletons that generally exist in a variety of natural products and high-value chemicals. However, the traditional synthetic route for their production involves toxic Hg salts and corrosive H2SO4 as catalysts, resulting in harsh conditions and the undesired side reaction of Meyer-Schuster rearrangement. In this study, CO2-promoted hydration of propargylic alcohols was achieved for the synthesis of various α-hydroxy ketones. Notably, this process was catalyzed using an environmentally friendly and cost-effective biomass-based ionic liquids/CuCl system, which effectively eliminated the side reaction. The ionic liquids utilized in this system are derived from natural biomass materials, which exhibited recyclability and catalytic activity under 1 bar of CO2 pressure without volatile organic solvents or additives. Evaluation of the green metrics revealed the superiority of this CuCl/ionic liquid system in terms of environmental sustainability. Further mechanistic investigation attributed the excellent performance to the ionic liquid component, which exhibited multifunctionality in activating substrates, CO2 and the Cu component.


Assuntos
Alcinos , Líquidos Iônicos , Propanóis , Cetonas , Dióxido de Carbono , Biomassa , Catálise
18.
STAR Protoc ; 5(1): 102900, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38367230

RESUMO

Alkynes are widely present in natural products and pharmaceutical compounds. Here, we present a protocol for nickel-catalyzed cross-coupling of terminal alkynes with aryl iodides or bromides for constructing a C(sp2)-C(sp) bond. We describe steps for reagent preparation, reaction setup, purification process, and product characterization. We also detail procedures for obtaining a single crystal of 6-(phenylethynyl)-1-(phenylsulfonyl)-1H-indole (3b). The application of this protocol is limited to aryl bromide and iodide. For complete details on the use and execution of this protocol, please refer to Chen et al.1.


Assuntos
Alcinos , Níquel , Níquel/química , Alcinos/química , Catálise
19.
Bioorg Med Chem ; 101: 117636, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38354458

RESUMO

Functionalised tetrahydropyran and spirooxepane scaffolds were prepared utilising an iodoetherification strategy and elaborated to demonstrate their potential use in library synthesis. The iodoetherification products could be readily transformed to the corresponding azides that could be further functionalised via copper-catalysed azide-alkyne cycloaddition or reduction to the amine. The lead-likeness and three-dimensionality of the scaffolds were examined and compared to commercial libraries.


Assuntos
Azidas , Descoberta de Drogas , Reação de Cicloadição , Ciclização , Cobre , Alcinos , Catálise
20.
J Inorg Biochem ; 254: 112504, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38412777

RESUMO

There is considerable interest in using the metalloprotein cofactor vitamin B12 as a vehicle to deliver drugs and diagnostic agents into mammalian or bacterial cells by exploiting the B12-specific active uptake pathways. Conjugation of the cargo via the ß-axial site or the 5'-OH of the ribose of the nucleotide are the most desirable sites, to maximise intracellular uptake. Herein we show the potential of conjugation at the beta-azido ligand of the vitamin B12 derivative azidocobalamin via a click-type azide-alkyne 1,3-dipolar cycloaddition (Huisgen cycloaddition) reaction. Reacting azidocobalamin with dimethyl acetylenedicarboxylate at 40 °C results in essentially stoichiometric conversion of azidocobalamin to the corresponding triazolato complex. The stability of the complex as a function of pH and in the presence of cyanide were investigated. The complex is stable in pD 7.0 phosphate buffer for 24 h. The rate of beta-axial ligand substitution was found to be one order of magnitude slower for the triazolatocobalamin complex compared with azidocobalamin.


Assuntos
Azidas , Vitamina B 12 , Animais , Reação de Cicloadição , Ligantes , Cobre , Alcinos , Vitaminas , Mamíferos
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