Efficacy, safety, and pharmacokinetics of isoniazid affected by NAT2 polymorphisms in patients with tuberculosis: A systematic review.

N-acetyltransferase 2 (NAT2) genetic polymorphisms might alter isoniazid metabolism leading to toxicity. We reviewed the impact of NAT2 genotype status on the pharmacokinetics, efficacy, and safety of isoniazid, a treatment for tuberculosis (TB). A systematic search for research articles published in Scopus, PubMed, and Embase until August 31, 2023, was conducted without filters or limits on the following search terms and Boolean operators: "isoniazid" AND "NAT2." Studies were selected if NAT2 phenotypes with pharmacokinetics or efficacy or safety of isoniazid in patients with TB were reported. Patient characteristics, NAT2 status, isoniazid pharmacokinetic parameters, early treatment failure, and the prevalence of drug-induced liver injury were extracted. If the data were given as a median, these values were standardized to the mean. Forty-one pharmacokinetics and 53 safety studies were included, but only one efficacy study was identified. The average maximum concentrations of isoniazid were expressed as supratherapeutic concentrations in adults (7.16 ± 4.85 µg/mL) and children (6.43 ± 3.87 µg/mL) in slow acetylators. The mean prevalence of drug-induced liver injury was 36.23 ± 19.84 in slow acetylators, which was significantly different from the intermediate (19.49 ± 18.20) and rapid (20.47 ± 20.68) acetylators. Subgroup analysis by continent showed that the highest mean drug-induced liver injury prevalence was in Asian slow acetylators (42.83 ± 27.61). The incidence of early treatment failure was decreased by genotype-guided isoniazid dosing in one study. Traditional weight-based dosing of isoniazid in most children and adults yielded therapeutic isoniazid levels (except for slow acetylators). Drug-induced liver injury was more commonly observed in slow acetylators. Genotype-guided dosing may prevent early treatment failure.

Synergistic Effects of Taurine and Temozolomide Via Cell Proliferation Inhibition and Apoptotic Induction on U-251 MG Human Glioblastoma Cells.

OBJECTIVE: The combination treatment is a way to improve the therapeutic strategy of temozolomide (TMZ) -resistant glioblastoma (GBM). Taurine (TAU) has the potential to inhibit growth in various cancer cells. The aim of this study was to examine the combined effects of TMZ and TAU on cultured human GBM, U-251 MG cells. METHODS: The cells were incubated with TMZ, TAU, and the combination of both in various ratios. MTT assay was performed to measure the cell viability of the treatments and then the synergistic interactions were evaluated by the Chou-Talalay method. The cell cycle and apoptotic properties of the combined treatment on U-251 MG cells were examined by flow cytometry. The Hoechst 33342 stainings were applied to visualize the morphologic change in the apoptotic process. RESULTS: The combined treatment with a dose reduction of each expressed synergistic effect on the decrease of cell viability. The study on the cell cycle resulted in G2/M phase arrest with increasing apoptotic cells in the SubG1 phase. Moreover, the apoptotic effects of the combinations on U-251 MG cells were explained by the increase of apoptotic cells in both early and late stages and illustrated by some characteristics of the apoptotic process including condensed chromatin and fragmented nuclei. CONCLUSION: The study showed that the combination between TMZ and TAU has a potential in anticancer properties against U-251 MG manifested by the induction of G2/M arrest and apoptosis. These results suggest that this combination may be useful to enhance the efficacy and reduce some adverse events of GBM treatment in the future.

Antitumor Effects of Fucoidan Via Apoptotic and Autophagic Induction on HSC-3 Oral Squamous CellCarcinoma.

OBJECTIVE: Many studies suggested that fucoidan has anticancer potential. The objective of the present study was to determine the cytotoxic effects and mechanism of cell death induced by fucoidan extracted from Fucus vesiculosus on HSC-3 oral squamous cell carcinoma. METHODS: HSC-3 cells were treated with 0, 100, 200, and 400 µg/mL of fucoidan. Cell viability was measured using MTT assay. Apoptosis and cell cycle were measured with a flow cytometry-based assay. Chromatin condensation and nuclear fragmentation were determined using Hoechst 33342 staining. Mitochondrial membrane potential (ΔΨm) was determined using the JC-1 kit. The apoptotic, anti-apoptotic, and autophagic markers study were done by western blot analysis. RESULTS: the viable cell number of treated HSC-3 cells was decreased. Moreover, treated cells were arrested in the G0/G1 phase. Annexin V/PI staining revealed that fucoidan could induce apoptosis in HSC-3 cells. Western blot analysis suggested the up-regulation of apoptotic markers including cleaved caspase-3, cleaved PARP, Bax, and autophagic markers including LC3-II and Beclin-1 but down-regulation of anti-apoptotic markers, Bcl-2. Fucoidan could disturb ΔΨm and induce chromatin condensation with nuclear fragmentation. CONCLUSION: fucoidan has potential in anticancer properties against HSC-3 cells manifested by the induction of apoptosis, cell cycle arrest, and autophagy.
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