Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 12.151
Filtrar
1.
Am J Gastroenterol ; 116(9): 1896-1904, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34465693

RESUMO

INTRODUCTION: Pangenotypic, all-oral direct-acting antivirals, such as glecaprevir/pibrentasvir (G/P), are recommended for treatment of hepatitis C virus (HCV) infection. Concerns exist about the impact on efficacy in patients with suboptimal adherence, particularly with shorter treatment durations. These post hoc analyses evaluated adherence (based on pill count) in patients prescribed 8- or 12-week G/P, the impact of nonadherence on sustained virologic response at post-treatment week 12 (SVR12), factors associated with nonadherence, and efficacy in patients interrupting G/P treatment. METHODS: Data were pooled from 10 phase 3 clinical trials of treatment-naive patients with HCV genotype 1-6 without cirrhosis/with compensated cirrhosis (treatment adherence analysis) and 13 phase 3 clinical trials of all patients with HCV (interruption analysis). RESULTS: Among 2,149 patients included, overall mean adherence was 99.4%. Over the treatment duration, adherence decreased (weeks 0-4: 100%; weeks 5-8: 98.3%; and weeks 9-12: 97.1%) and the percentage of patients with ≥80% or ≥90% adherence declined. SVR12 rate in the intention-to-treat (ITT) population was 97.7% (modified ITT SVR12 99.3%) and remained high in nonadherent patients in the modified ITT population (<90%: 94.4%-100%; <80%: 83.3%-100%). Psychiatric disorders were associated with <80% adherence, and shorter treatment duration was associated with ≥80% adherence. Among 2,902 patients in the interruption analysis, 33 (1.1%) had a G/P treatment interruption of ≥1 day, with an SVR12 rate of 93.9% (31/33). No virologic failures occurred. DISCUSSION: These findings support the impact of treatment duration on adherence rates and further reinforce the concept of "treatment forgiveness" with direct-acting antivirals.


Assuntos
Ácidos Aminoisobutíricos/uso terapêutico , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Ciclopropanos/uso terapêutico , Hepatite C/tratamento farmacológico , Lactamas Macrocíclicas/uso terapêutico , Leucina/análogos & derivados , Adesão à Medicação , Prolina/análogos & derivados , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Feminino , Humanos , Leucina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prolina/uso terapêutico , Resposta Viral Sustentada , Resultado do Tratamento
2.
Biomolecules ; 11(7)2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34356673

RESUMO

Cyclooxygenase-2 (COX-2) is an important enzyme involved in prostaglandins biosynthesis from arachidonic acid. COX-2 is frequently overexpressed in human cancers and plays a major tumor promoting function. Accordingly, many efforts have been devoted to efficiently target the catalytic site of this enzyme in cancer cells, by using COX-2 specific inhibitors such as celecoxib. However, despite their potent anti-tumor properties, the myriad of detrimental effects associated to the chronic inhibition of COX-2 in healthy tissues, has considerably limited their use in clinic. In addition, increasing evidence indicate that these anti-cancerous properties are not strictly dependent on the inhibition of the catalytic site. These findings have led to the development of non-active COX-2 inhibitors analogues aiming at preserving the antitumor effects of COX-2 inhibitors without their side effects. Among them, two celecoxib derivatives, 2,5-Dimethyl-Celecoxib and OSU-03012, have been developed and suggested for the treatment of viral (e.g., recently SARS-CoV-2), inflammatory, metabolic diseases and cancers. These molecules display stronger anti-tumor properties than celecoxib and thus may represent promising anti-cancer molecules. In this review, we discuss the impact of these two analogues on cancerous processes but also their potential for cancer treatment alone or in combination with existing approaches.


Assuntos
Antineoplásicos/uso terapêutico , Celecoxib/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/farmacologia , Celecoxib/efeitos adversos , Celecoxib/análogos & derivados , Celecoxib/farmacologia , Ciclo Celular/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Humanos , Pirazóis/efeitos adversos , Pirazóis/química , Pirazóis/farmacologia , Sulfonamidas/efeitos adversos , Sulfonamidas/química , Sulfonamidas/farmacologia
3.
Medicine (Baltimore) ; 100(30): e26739, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34397713

RESUMO

ABSTRACT: Baricitinib is a Janus kinase (JAK) inhibitor that selectively blocks against JAK1 and JAK2 signaling. This study aimed to determine the effect of baricitinib on disease activity based on musculoskeletal ultrasound in patients with rheumatoid arthritis (RA).A total of 20 patients with RA receiving baricitinib for 24 weeks were assessed. Ultrasound scores of gray scale and power Doppler synovitis, joint effusion, and bone erosion in each patient were assessed between baseline and 24 weeks for 27 affected joints. Disease activity in RA was evaluated using the disease activity score for 28-joint count with erythrocyte sediment rate (DAS28-ESR), simplified disease activity index (SDAI), and clinical disease activity index (CDAI).Treatment with baricitinib for 12 weeks and 24 weeks significantly decreased disease activity composites such as DAS28-ESR, SDAI, and CDAI (P < .001 for all). Treatment with baricitinib for 24 weeks improved ultrasound-detected gray-scale and power Doppler synovitis and joint effusion compared to baseline (P = .002, P = .030, and P = .002, respectively). Bone erosion scores were not different between baseline and 24 weeks (P = .317). There were no differences in ultrasound abnormalities for improvement based on DAS28-ESR. Changes in power Doppler score were significantly associated with changes in DAS28-ESR (ß = 0.590, P = .044), but not SDAI and CDAI.This study demonstrates that baricitinib treatment has a favorable effect on ultrasound-detected abnormalities including synovitis and bone erosion in patients with RA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Azetidinas/uso terapêutico , Osso e Ossos/efeitos dos fármacos , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Sinovite/tratamento farmacológico , Artrite Reumatoide/diagnóstico por imagem , Azetidinas/farmacologia , Osso e Ossos/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Purinas/farmacologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Sinovite/diagnóstico por imagem , Ultrassonografia
4.
Anticancer Res ; 41(8): 4127-4131, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281883

RESUMO

BACKGROUND/AIM: Direct-acting antiviral (DAA) therapies for patients with hepatitis C virus (HCV) infection deliver higher cure rates and lower frequencies of adverse events than existing therapies, though DAA treatment costs $45,000-64,000 in Japan. The prognosis of patients who require new long-term care insurance (LTCI) certification is inferior to that of patients who do not. Here, we clarify the factors associated with new LTCI certification in elderly patients with HCV infection who undergo DAA therapy. PATIENTS AND METHODS: We retrospectively surveyed 53 patients aged ≥70 years who were treated with DAAs, and evaluated the factors associated with new LTCI certification. RESULTS: Of 53 patients, 10 required new LTCI certification. Age ≥85 years and a modified Japanese Cardiovascular Health Study index ≥2 were independently associated with new LTCI certification. CONCLUSION: In elderly HCV patients, poor frailty status strongly predicted new LTCI certification after DAA therapy.


Assuntos
Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Fragilidade , Hepatite C/tratamento farmacológico , Imidazóis/uso terapêutico , Seguro de Assistência de Longo Prazo , Isoquinolinas/uso terapêutico , Pirrolidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Valina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Definição da Elegibilidade , Feminino , Hepatite C/mortalidade , Humanos , Japão , Masculino , Valina/uso terapêutico
6.
Int Braz J Urol ; 47(5): 982-988, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34260175

RESUMO

PURPOSE: To compare the effects of tadalafil, tamsulosin, and placebo as a medical expulsive therapy (MET) for distal ureteral calculi. MATERIALS AND METHODS: This prospective randomized double-blind clinical trial was conducted on 132 renal colic patients with distal ureteric stones (≤10mm) over a period of 12 months. Patients were randomly divided into three groups. Patients in group A received tamsulosin 0.4mg, in group B received tadalafil 10mg, and in group C received placebo. Therapy was given for a maximum of 4 weeks. The rate of stone expulsion, duration of stone expulsion, the dose and the duration of nonsteroidal anti-inflammatory drugs (NSAIDs), analgesic use, and adverse effects of drugs were recorded. RESULTS: Demographic profiles were comparable between the 3 groups. Although the stone expulsion rate in group A (72.7%) was higher in comparison to group B(63.6%) and group C(56.8%), it was not considered statistically significant (P=0.294). Shorter mean time to stone expulsion was significantly observed in group A (17.75±75), than group B(21.13±1.17) and group C(22.25±1.18) (P=0.47). The mean number of analgesic use was 9.8±5.09 days in group A, 14.6±7.9 days in group B, and 12.6±22.25 days in group C, this difference was significant (P=0.004). The analgesic requirement (doses of NSAIDs and pethidine) in group A was significantly lower than other groups (P< 0.05). Also, patients in group A reported fewer headaches compared to other groups (P=0.011). CONCLUSION: Tamsulosin as medical expulsive therapy is more effective for distal ureteric stones with less need for analgesics and less stone expulsion time than tadalafil.


Assuntos
Cálculos Ureterais , Humanos , Estudos Prospectivos , Sulfonamidas/uso terapêutico , Tadalafila/uso terapêutico , Tansulosina/uso terapêutico , Resultado do Tratamento , Cálculos Ureterais/tratamento farmacológico
7.
Nat Immunol ; 22(8): 1020-1029, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34312547

RESUMO

T cell exhaustion is an induced state of dysfunction that arises in response to chronic infection and cancer. Exhausted CD8+ T cells acquire a distinct epigenetic state, but it is not known whether that chromatin landscape is fixed or plastic following the resolution of a chronic infection. Here we show that the epigenetic state of exhaustion is largely irreversible, even after curative therapy. Analysis of chromatin accessibility in HCV- and HIV-specific responses identifies a core epigenetic program of exhaustion in CD8+ T cells, which undergoes only limited remodeling before and after resolution of infection. Moreover, canonical features of exhaustion, including super-enhancers near the genes TOX and HIF1A, remain 'epigenetically scarred.' T cell exhaustion is therefore a conserved epigenetic state that becomes fixed and persists independent of chronic antigen stimulation and inflammation. Therapeutic efforts to reverse T cell exhaustion may require new approaches that increase the epigenetic plasticity of exhausted T cells.


Assuntos
Antígenos Virais/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Memória Imunológica/imunologia , 2-Naftilamina/uso terapêutico , Anilidas/uso terapêutico , Antivirais/uso terapêutico , Cromatina/metabolismo , Ciclopropanos/uso terapêutico , Epigênese Genética/genética , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Proteínas de Grupo de Alta Mobilidade/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Lactamas Macrocíclicas/uso terapêutico , Prolina/análogos & derivados , Prolina/uso terapêutico , Ribavirina/uso terapêutico , Ritonavir/uso terapêutico , Sulfonamidas/uso terapêutico , Uracila/análogos & derivados , Uracila/uso terapêutico , Valina/uso terapêutico
8.
Blood ; 138(3): 234-245, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34292323

RESUMO

Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent azacytidine, achieves complete remission with or without count recovery in ∼70% of treatment-naive elderly patients unfit for conventional intensive chemotherapy. However, the mechanism of action of this drug combination is not fully understood. We discovered that venetoclax directly activated T cells to increase their cytotoxicity against acute myeloid leukemia (AML) in vitro and in vivo. Venetoclax enhanced T-cell effector function by increasing reactive oxygen species generation through inhibition of respiratory chain supercomplexes formation. In addition, azacytidine induced a viral mimicry response in AML cells by activating the STING/cGAS pathway, thereby rendering the AML cells more susceptible to T cell-mediated cytotoxicity. Similar findings were seen in patients treated with venetoclax, as this treatment increased reactive oxygen species generation and activated T cells. Collectively, this study presents a new immune-mediated mechanism of action for venetoclax and azacytidine in the treatment of AML and highlights a potential combination of venetoclax and adoptive cell therapy for patients with AML.


Assuntos
Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Sulfonamidas/farmacologia , Linfócitos T/efeitos dos fármacos , Adulto , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Células Cultivadas , Humanos , Imunidade Celular/efeitos dos fármacos , Leucemia Mieloide Aguda/imunologia , Espécies Reativas de Oxigênio/imunologia , Sulfonamidas/uso terapêutico , Linfócitos T/imunologia , Células Tumorais Cultivadas
10.
Cancer Sci ; 112(9): 3645-3654, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34288263

RESUMO

CD38 expression on myeloma cells is a critical factor affecting the early response to the anti-CD38 antibody daratumumab. However, factors affecting CD38 expression in untreated multiple myeloma are not fully elucidated. In this study, we found that CD38 expression was significantly lower in myeloma patients with the translocation t(11;14)-associated immature plasma cell phenotype, and particularly in those expressing B-cell-associated genes such as PAX5 and CD79A. CD138, a representative marker of plasmacytic differentiation, was also significantly lower in these patients, suggesting that CD38 expression may be associated with the differentiation and maturation stages of myeloma cells. Furthermore, the BCL2/BCL2L1 ratio, a response marker of the BCL2 inhibitor venetoclax, was significantly higher in patients with the immature phenotype expressing B-cell-associated genes. The BCL2/BCL2L1 ratio and CD38 expression were significantly negatively correlated. We also confirmed that patients with translocation t(11;14) expressing B-cell-associated genes were indeed less sensitive to daratumumab-mediated direct cytotoxicity but highly sensitive to venetoclax treatment in ex vivo assays. Moreover, all-trans-retinoic acid, which enhances CD38 expression and induces cell differentiation in myeloma cells, reduced B-cell marker expression and the BCL2/BCL2L1 ratio in myeloma cell lines, leading to reduced efficacy of venetoclax. Venetoclax specifically induces cell death in myeloma with t(11;14), although why patients with translocation t(11;14) show BCL2 dependence is unclear. These results suggest that BCL2 dependence, as well as CD38 expression, are deeply associated with the differentiation and maturation stages of myeloma cells. This study highlights the importance of examining t(11;14) and considering cell maturity in myeloma treatment strategies.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Glicoproteínas de Membrana/metabolismo , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Translocação Genética/genética , ADP-Ribosil Ciclase 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linfócitos B/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Tretinoína/farmacologia
11.
Vet Dermatol ; 32(4): 363-e100, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34250688

RESUMO

BACKGROUND: Ear tip ulcerative dermatitis (ETUD) is an uncommon clinical reaction pattern in canine dermatology. The lesions are suggestive of vascular damage which may be caused by inflammatory or noninflammatory diseases, and often are idiopathic. Therapeutic options for ETUD include topical glucocorticoids or tacrolimus, pentoxifylline, vitamin E, doxycycline, tetracycline and niacinamide, sulfonamides, glucocorticoids, ciclosporin and surgical correction. HYPOTHESIS/OBJECTIVES: The aims of this retrospective case series were to describe the clinical features and report response to treatment with oclacitinib in dogs with idiopathic, chronic ETUD. ANIMALS: Twenty-five privately owned dogs with unilateral or bilateral ETUD. METHODS AND MATERIALS: Cases of ETUD which were poorly responsive to conventional therapy and subsequently treated with oclacitinib, are summarised. All cases were tested for leishmaniosis by serological examination [indirect fluorescent antibody test (IFAT) or enzyme-linked immunosorbent assay (ELISA)]. Histopathological examination was performed in two cases. RESULTS: Serological results were negative for leishmaniosis in all dogs. Histopathological changes consistent with proliferative thrombovascular necrosis of the pinnae were documented in two cases. Oclacitinib, used at the standard dose range recommended for the treatment of canine atopic dermatitis, effectively resolved ETUD in 22 of 25 dogs within one to three months. Several of the dogs required prolonged use of twice daily dosing. CONCLUSIONS AND CLINICAL RELEVANCE: Oclacitinib should be included among the therapeutic options for ETUD, once infectious diseases have been ruled out.


Assuntos
Dermatite Atópica , Doenças do Cão , Úlcera Cutânea , Animais , Dermatite Atópica/veterinária , Doenças do Cão/tratamento farmacológico , Cães , Pirimidinas , Estudos Retrospectivos , Úlcera Cutânea/veterinária , Sulfonamidas/uso terapêutico
12.
J Coll Physicians Surg Pak ; 31(8): 947-952, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34320713

RESUMO

OBJECTIVE: To assess the effectiveness of the use of dexketoprofen, tamsulosin, silodosin, and tadalafil in medical expulsive therapy for distal ureteral stones in male patients. STUDY DESIGN: Cohort study. PLACE AND DURATION OF STUDY: Department of Urology, Gazi Hospital, Samsun, Turkey, from March 2020 to March 2021. METHODOLOGY: Adult males satisfying the inclusion criteria were randomly assigned into dexketoprofen (Group 1), tamsulosin (Group 2), silodosin (Group 3), or tadalafil (Group 4) treatment arms. The primary endpoint consisted of the stone expulsion rate at the end of four weeks, while the secondary endpoints were the expulsion rate after two weeks and the occurrence of adverse events. Clinical findings were then compared among the study groups. RESULTS: Altogether 193 patients, 50 (25.9%) in group 1, 48 (24.9%) in group 2, 49 (25.4%) in group 3, and 46 (23.8%) in group 4, were enrolled in the study. No significant difference was determined in terms of age, body mass index, stone characteristics, expulsion time, pain episodes, or total analgesic consumption among the four groups. Expulsion rates in the fourth week were 48%, 79.2%, 81.6%, and 78.3% in groups 1, 2, 3, and 4, respectively. Stone expulsion rates were significantly greater in groups 2, 3, and 4 compared to group 1 (p <0.001), but no significant differences were determined between groups 2, 3, and 4. No severe adverse effects occurred throughout the study period. CONCLUSION:   Tamsulosin, silodosin and tadalafil exhibited higher expulsion rates for distal ureteral stones in male patients, although none was significantly superior to the others. All three are safe, efficacious, and well-tolerated, with only very minor side-effects. Key Words: Dexketoprofen, Distal ureteral stones, Medical expulsive therapy, Silodosin, Tadalafil, Tamsulosin.


Assuntos
Cálculos Ureterais , Adulto , Estudos de Coortes , Humanos , Indóis , Cetoprofeno/análogos & derivados , Masculino , Sulfonamidas/uso terapêutico , Tadalafila/uso terapêutico , Tansulosina , Resultado do Tratamento , Trometamina , Turquia , Cálculos Ureterais/tratamento farmacológico
14.
J Clin Neurosci ; 90: 225-232, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34275554

RESUMO

BACKGROUND: The therapeutic efficacy and safety of argatroban for stroke patients remain controversial. The purpose of this study was to collect all evidence and perform a meta-analysis to comprehensively evaluate the effects of argatroban for stroke patients compared with no-argatroban regimens. METHODS: The databases of PubMed, EMBASE and the Cochrane library were searched from their inception up to December 2020. Categorical outcomes were summarized as odds ratio (OR) and 95% confidence interval (CI); while continuous data were pooled as standardized mean difference (SMD) and 95%CI. RESULTS: A total of 11 studies were enrolled. Overall meta-analysis showed infusion of argatroban significantly improved neurological functions of stroke patients compared with control treatment, showing increased National Institutes of Health Stroke Scale (NIHSS) score change (SMD = 1.02; 95% CI, 0.58-1.46, p < 0.001), modified Barthel Index (SMD = 3.81; 95% CI, 2.72-4.89, p < 0.001) as well as a decreased incidence of early neurological deterioration (OR = 0.48; 95% CI: 0.28-0.84, p = 0.01). Argatroban treatment did not increase the risk of symptomatic intracerebral hemorrhage (p = 0.733), asymptomatic intracranial hemorrhage (p = 0.608), gastrointestinal bleeding (p = 0.601), major systemic hemorrhage (p = 0.582) and mortality (p = 0.797), except minor systemic hemorrhage (OR = 2.40; 95% CI: 1.15-5.02, p = 0.020). Subgroup analyses for NIHSS score change and complications obtained the similar conclusions. CONCLUSION: Argatroban infusion may be an effective and safe therapeutic option to improve functional outcomes of stroke patients.


Assuntos
Arginina/análogos & derivados , Ácidos Pipecólicos/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Sulfonamidas/uso terapêutico , Arginina/uso terapêutico , Humanos
15.
J Antimicrob Chemother ; 76(12 Suppl 2): ii45-ii59, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312660

RESUMO

OBJECTIVES: Data on consumption of tetracyclines, sulphonamides and trimethoprim, and other antibacterials were collected from 30 EU/European Economic Area (EEA) countries over two decades. This article reviews temporal trends, seasonal variation, presence of change-points and changes in the composition of main subgroups of tetracyclines, sulphonamides and trimethoprim and other antibacterials. METHODS: For the period 1997-2017, data on consumption of tetracyclines (ATC group J01A), sulphonamides and trimethoprim (ATC group J01E), and other antibacterials (ATC group J01X) in the community and aggregated at the level of the active substance, were collected using the WHO ATC/DDD methodology (ATC/DDD index 2019). Consumption was expressed in DDD per 1000 inhabitants per day and in packages per 1000 inhabitants per day. Consumption of tetracyclines, sulphonamides and trimethoprim, and other antibacterials was analysed based on ATC-4 subgroups and presented as trends, seasonal variation, presence of change-points and compositional changes. RESULTS: In 2017, consumption of tetracyclines, sulphonamides and trimethoprim, and other antibacterials in the community expressed in DDD per 1000 inhabitants per day varied considerably between countries. Between 1997 and 2017, consumption of tetracyclines did not change significantly, while its seasonal variation significantly decreased over time. Consumption of sulphonamides and trimethoprim significantly decreased until 2006, and its seasonal variation significantly decreased over time. The consumption of other antibacterials showed no significant change over time or in seasonal variation. CONCLUSIONS: Consumption and composition of tetracyclines, sulphonamides and trimethoprim, and other antibacterials showed wide variations between EU/EEA countries and over time. This represents an opportunity to further reduce consumption of these groups in some countries and improve the quality of their prescription.


Assuntos
Tetraciclinas , Trimetoprima , Antibacterianos/uso terapêutico , Uso de Medicamentos , União Europeia , Humanos , Sulfonamidas/uso terapêutico , Tetraciclinas/uso terapêutico , Trimetoprima/uso terapêutico
18.
J Enzyme Inhib Med Chem ; 36(1): 1029-1047, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34107837

RESUMO

Thirty seven N-(5-methoxyphenyl)-4-methoxybenzenesulphonamide with methoxy or/and bromo substitutions (series 1-4) and with different substituents on the sulphonamide nitrogen have been synthesised. 21 showed sub-micromolar cytotoxicity against HeLa and HT-29 human tumour cell lines, and were particularly effective against MCF7. The most potent series has 2,5-dimethoxyanilines, especially the 4-brominated compounds 23-25. The active compounds inhibit microtubular protein polymerisation at micromolar concentrations, thus pointing at tubulin as the target. Co-treatment with the MDR inhibitor verapamil suggests that they are not MDR substrates. Compound 25 showed nanomolar antiproliferative potency. It severely disrupts the microtubule network in cells and arrests cells at the G2/M cell-cycle phase, thus confirming tubulin targeting. 25 triggered apoptotic cell death, and induced autophagy. Docking studies suggest binding in a distinct way to the colchicine site. These compounds are promising new antitumor agents acting on tubulin.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adenocarcinoma/patologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7
19.
Infez Med ; 29(2): 242-251, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34061790

RESUMO

Despite the high efficacy of direct-acting antivirals (DAAs), the selection of resistance-associated substitutions (RASs) after virological failure of hepatitis C virus (HCV) DAAs can impair the cure of chronic HCV. The aim of the study was to characterize RASs after virological failure of DAAs in Italy over the years. Within the Italian network VIRONET-C, the change in prevalence of NS3/4A-NS5A-NS5B RASs was retrospectively evaluated in patients who failed a DAA regimen over the years 2015-2019. NS3, NS5A and NS5B Sanger sequencing was performed using homemade protocols and the geno2pheno system was used to define HCV-genotype/subtype and predict drug resistance. The changes in the prevalence of RASs over time were evaluated using the chi-square test for trend. Predictors of RASs at failure were analysed by logistic regression. Among 468 HCV-infected patients, HCV genotype 1 was the most prevalent (1b in 154, 33% and 1a in 109, 23%). DAA regimens were: ledipasvir (LDV)/sofosbuvir (SOF) in 131 patients (28%), daclatasvir (DCV)/SOF in 109 (23%), ombitasvir/paritaprevir/ritonavir+dasabuvir (3D) in 89 (19%), elbasvir (EBR)/grazoprevir (GRZ) in 52 (10.5%), velpatasvir (VEL)/SOF in 53 (11%), glecaprevir (GLE)/pibrentasvir (PIB) in 27 (6%) and ombitasvir/paritaprevir/ritonavir (2D) in 7 (1.5%); ribavirin was administered in 133 (28%). The NS5A fasta sequence was available for all patients, NS5B and NS3/4A both for 93%. The prevalence of NS5A and NS3/4A RASs significantly declined from 2015 to 2019; NS5B RAS remained stable. Independent predictors of any RASs included older age and genotype 1a (vs G2 and vs G4). Notably, at least partial susceptibility to all the agents included in the GLE/PIB and VEL/SOF/Voxilaprevir (VOX) combinations was predicted in >95% of cases. As RASs remain common at the failure of DAAs, their identification could play a crucial role in optimizing re-treatment strategies. In Italy RAS prevalence has been decreasing over the years and susceptibility to the latest developed drug combinations is maintained in most cases.


Assuntos
Antivirais , Hepatite C Crônica , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Carbamatos/uso terapêutico , Combinação de Medicamentos , Fluorenos/uso terapêutico , Genótipo , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Itália , Compostos Macrocíclicos/uso terapêutico , Prevalência , Estudos Retrospectivos , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...