Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.906
Filtrar
1.
Medicine (Baltimore) ; 99(11): e19520, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176102

RESUMO

Proton pump inhibitors (PPIs) have been the first line treatment for gastroesophageal reflux disease (GERD). The aim of this study was to evaluate the efficacy of vonoprazan (VPZ), a potassium-competitive acid blocker for reflux esophagitis (RE), nonerosive reflux disease (NERD), and PPI-resistant GERD patients.An open-label, single-center, observational study in our hospital was performed from August 2016 to August 2017. All patients diagnosed with GERD were asked to self-report a questionnaire of frequency scale for the symptoms of GERD (FSSG) and rate their degree of satisfaction with the treatment of GERD during outpatient visit. A total of 200 (RE 47, NERD 49, PPI-resistant GERD 104) patients were included in the present study. The primary endpoint was the change of FSSG and the proportion of degree of satisfaction with the treatment at the end of the initial therapy. A percentage of improvement (improvement rate) and resolution (resolution rate) at the end of the initial therapy were evaluated. Secondary endpoint included the proportion of patients with symptomatic relapse in the 24-week maintenance phase.FSSG and the degree of satisfaction were significantly improved after the initial therapy in every group. Improvement and resolution rate after the initial therapy were 83.0% and 67.0% in RE, 66.7% and 60.4% in NERD, and 76.0% and 60.4% in PPI-resistant group. There was no significance between after the initial therapy and 24 weeks in improvement and resolution rate. Thirty-two of the total 48 patients did not take VPZ at 24 weeks. Total FSSG score in each group was 1.67 ±â€Š1.97, 2.71 ±â€Š4.91, and 4.0 ±â€Š4.93. The nonrelapse rate at 24 weeks in each group was 66.7%, 60.0%, and 50.0%. The resolution rate at 24 weeks in each group was 38.9%, 45.0%, and 30.0%.The VPZ therapy is effective for initial and maintenance therapy and improves heartburn and patient's satisfaction significantly in all 3 groups. Among patients who stopped taking VPZ during the maintenance period, 42.0% of RE and NERD group and 30% of PPI-resistant group experience complete remission from GERD at 24 weeks by introduction of VPZ.


Assuntos
Refluxo Gastroesofágico/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Feminino , Refluxo Gastroesofágico/fisiopatologia , Humanos , Masculino , Inibidores da Bomba de Prótons/administração & dosagem , Pirróis/administração & dosagem , Índice de Gravidade de Doença , Sulfonamidas/administração & dosagem , Inquéritos e Questionários , Resultado do Tratamento
2.
Gut ; 69(2): 224-230, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31409606

RESUMO

OBJECTIVE: To establish the non-inferior efficacy of vonoprazan versus lansoprazole in the treatment of Asian patients with erosive oesophagitis (EO). DESIGN: In this phase III, double-blind, multicentre study, patients with endoscopically confirmed EO were randomised 1:1 to receive vonoprazan 20 mg or lansoprazole 30 mg, once daily for up to 8 weeks. The primary endpoint was EO healing rate at 8 weeks. The secondary endpoints were EO healing rates at 2 and 4 weeks. Safety endpoints included treatment-emergent adverse events (TEAEs). RESULTS: In the vonoprazan (n=238) and lansoprazole (n=230) arms, 8-week EO healing rates were 92.4% and 91.3%, respectively (difference 1.1% (95% CI -3.822% to 6.087%)). The respective 2-week EO healing rates were 75.0% and 67.8% (difference 7.2% (95% CI -1.054% to 15.371%)), and the respective 4-week EO healing rates were 85.3% and 83.5% (difference 1.8% (95% CI -4.763% to 8.395%)). In patients with baseline Los Angeles classification grade C/D, 2-week, 4-week and 8-week EO healing rates were higher with vonoprazan versus lansoprazole (2 weeks: 62.2% vs 51.5%, difference 10.6% (95% CI -5.708% to 27.002%); 4 weeks: 73.3% vs 67.2%, difference 6.2% (95% CI -8.884 to 21.223); and 8 weeks: 84.0% vs 80.6%, difference 3.4% (95% CI -9.187% to 15.993%)). Overall, EO healing rates appeared higher with vonoprazan versus lansoprazole. TEAE rates were 38.1% and 36.6% in the vonoprazan and lansoprazole group, respectively. CONCLUSION: Our findings demonstrate the non-inferior efficacy of vonoprazan versus lansoprazole in terms of EO healing rate at 8 weeks in this population. Safety outcomes were similar in the two treatment arms. TRIAL REGISTRATION NUMBER: NCT02388724.


Assuntos
Esofagite Péptica/tratamento farmacológico , Lansoprazol/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Lansoprazol/administração & dosagem , Lansoprazol/efeitos adversos , Masculino , Pessoa de Meia-Idade , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Índice de Gravidade de Doença , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Cicatrização
3.
Eur J Med Chem ; 185: 111828, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31727471

RESUMO

Novel 3-aroyl-1,4-diarylpyrrole derivatives were synthesized to explore structure-activity relationships at the phenyls at positions 1 and 4 of the pyrrole. The presence of amino phenyl rings at positions 1 and 4 of the pyrrole ring were found to be a crucial requirement for potent antitumor activity. Several compounds strongly inhibited tubulin assembly through binding to the colchicine site. Compounds 42, 44, 48, 62 and 69 showed antitumor activity with low nanomolar IC50 values in several cancer cell lines. Compound 48 was generally more effective as an inhibitor of glioblastoma, colorectal and urinary bladder cancer cell lines; 69 consistently inhibited CML cell lines and demonstrated superiority in nilotinib and imatinib resistant LAMA84-R and KBM5-T315I cells. In animal models, compound 48 exhibited significant inhibition of the growth of T24 bladder carcinoma and ES-2 ovarian clear cell carcinoma tumors. Compounds 48 and 69 represent robust lead compounds for the design of new broad-spectrum anticancer agents active in different types of solid and hematological tumors.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Neoplasias Hematológicas/tratamento farmacológico , Pirróis/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glioblastoma/patologia , Neoplasias Hematológicas/patologia , Humanos , Injeções Intraperitoneais , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Imagem Óptica , Pirróis/administração & dosagem , Pirróis/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
4.
PLoS One ; 14(12): e0226255, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31851711

RESUMO

BACKGROUND: Confounding by disease severity is an issue in pharmacoepidemiology studies of rheumatoid arthritis (RA), due to channeling of sicker patients to certain therapies. To address the issue of limited clinical data for confounder adjustment, a patient-level prediction model to differentiate between patients prescribed and not prescribed advanced therapies was developed as a surrogate for disease severity, using all available data from a US claims database. METHODS: Data from adult RA patients were used to build regularized logistic regression models to predict current and future disease severity using a biologic or tofacitinib prescription claim as a surrogate for moderate-to-severe disease. Model discrimination was assessed using the area under the receiver (AUC) operating characteristic curve, tested and trained in Optum Clinformatics® Extended DataMart (Optum) and additionally validated in three external IBM MarketScan® databases. The model was further validated in the Optum database across a range of patient cohorts. RESULTS: In the Optum database (n = 68,608), the AUC for discriminating RA patients with a prescription claim for a biologic or tofacitinib versus those without in the 90 days following index diagnosis was 0.80. Model AUCs were 0.77 in IBM CCAE (n = 75,579) and IBM MDCD (n = 7,537) and 0.75 in IBM MDCR (n = 36,090). There was little change in the prediction model assessing discrimination 730 days following index diagnosis (prediction model AUC in Optum was 0.79). CONCLUSIONS: A prediction model demonstrated good discrimination across multiple claims databases to identify RA patients with a prescription claim for advanced therapies during different time-at-risk periods as proxy for current and future moderate-to-severe disease. This work provides a robust model-derived risk score that can be used as a potential covariate and proxy measure to adjust for confounding by severity in multivariable models in the RA population. An R package to develop the prediction model and risk score are available in an open source platform for researchers.


Assuntos
Artrite Reumatoide/fisiopatologia , Bases de Dados Factuais , Revisão da Utilização de Seguros , Antirreumáticos/administração & dosagem , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Piperidinas/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Índice de Gravidade de Doença
5.
JAMA ; 322(19): 1887-1898, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31742631

RESUMO

Importance: Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist under investigation for acute treatment of migraine. Objective: To evaluate the efficacy and tolerability of ubrogepant compared with placebo for acute treatment of a single migraine attack. Design, Setting, and Participants: Phase 3, multicenter, randomized, double-blind, placebo-controlled, single-attack, clinical trial (ACHIEVE II) conducted in the United States (99 primary care and research clinics; August 26, 2016-February 26, 2018). Participants were adults with migraine with or without aura experiencing 2 to 8 migraine attacks per month. Interventions: Ubrogepant 50 mg (n = 562), ubrogepant 25 mg (n = 561), or placebo (n = 563) for a migraine attack of moderate or severe pain intensity. Main Outcomes and Measures: Co-primary efficacy outcomes were pain freedom and absence of the participant-designated most bothersome migraine-associated symptom (among photophobia, phonophobia, and nausea) at 2 hours after taking the medication. Results: Among 1686 randomized participants, 1465 received study treatment (safety population; mean age, 41.5 years; 90% female); 1355 of 1465 (92.5%) were evaluable for efficacy. Pain freedom at 2 hours was reported by 101 of 464 participants (21.8%) in the ubrogepant 50-mg group, 90 of 435 (20.7%) in the ubrogepant 25-mg group, and 65 of 456 (14.3%) in the placebo group (absolute difference for 50 mg vs placebo, 7.5%; 95% CI, 2.6%-12.5%; P = .01; 25 mg vs placebo, 6.4%; 95% CI, 1.5%-11.5%; P = .03). Absence of the most bothersome associated symptom at 2 hours was reported by 180 of 463 participants (38.9%) in the ubrogepant 50-mg group, 148 of 434 (34.1%) in the ubrogepant 25-mg group, and 125 of 456 (27.4%) in the placebo group (absolute difference for 50 mg vs placebo, 11.5%; 95% CI, 5.4%-17.5%; P = .01; 25 mg vs placebo, 6.7%; 95% CI, 0.6%-12.7%; P = .07). The most common adverse events within 48 hours of any dose were nausea (50 mg, 10 of 488 [2.0%]; 25 mg, 12 of 478 [2.5%]; and placebo, 10 of 499 [2.0%]) and dizziness (50 mg, 7 of 488 [1.4%]; 25 mg, 10 of 478 [2.1%]; placebo, 8 of 499 [1.6%]). Conclusions and Relevance: Among adults with migraine, acute treatment with ubrogepant compared with placebo led to significantly greater rates of pain freedom at 2 hours with 50-mg and 25-mg doses, and absence of the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose. Further research is needed to assess the effectiveness of ubrogepant against other acute treatments for migraine and to evaluate the long-term safety of ubrogepant among unselected patient populations. Trial Registration: ClinicalTrials.gov Identifier: NCT02867709.


Assuntos
Analgésicos/administração & dosagem , Transtornos de Enxaqueca/tratamento farmacológico , Dor/tratamento farmacológico , Piridinas/administração & dosagem , Pirróis/administração & dosagem , Adulto , Idoso , Analgésicos/efeitos adversos , Tontura/induzido quimicamente , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Manejo da Dor , Piridinas/efeitos adversos , Pirróis/efeitos adversos , Adulto Jovem
6.
Expert Opin Drug Saf ; 18(12): 1255-1261, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31646920

RESUMO

Background: The safety and effectiveness of vonoprazan-based Helicobacter pylori (H. pylori) eradication therapy in routine clinical practice, and patient characteristics that influence safety and effectiveness, have not been well investigated.Methods: H. pylori-positive patients with gastric ulcer, duodenal ulcer, idiopathic thrombocytopenic purpura, history of endoscopic treatment of early gastric cancer, and gastritis were enrolled. Patients received vonoprazan 20 mg, amoxicillin (AMPC) 750 mg, and clarithromycin (CAM) 200-400 mg twice daily for 7 days for the first-line eradication. For the second-line eradication, vonoprazan, AMPC, and metronidazole (MTZ) 250 mg were administered. The incidence of adverse drug reactions (ADRs) and eradication rates were evaluated.Results: The incidences of ADRs with vonoprazan/AMPC/CAM and vonoprazan/AMPC/MTZ were 3.22% (16/497) and 1.89% (1/53), respectively. Commonly reported ADRs were diarrhea, nausea, dysgeusia, feces soft, and rash. The eradication rates of the first-line therapy and the second-line therapy were 91.24% (427/468) and 95.45% (42/44), respectively. No notable differences in ADRs and eradication rates were observed when stratified by patient demographic characteristics.Conclusion: No new safety concerns were observed, and the effectiveness of vonoprazan-based triple therapy was confirmed in routine clinical practice.Trial registration: This study is registered at the Japan Pharmaceutical Information Center Clinical Trials Information (JapicCTI-153003).


Assuntos
Antibacterianos/administração & dosagem , Infecções por Helicobacter/tratamento farmacológico , Inibidores da Bomba de Prótons/administração & dosagem , Pirróis/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Amoxicilina/administração & dosagem , Antibacterianos/efeitos adversos , Claritromicina/administração & dosagem , Quimioterapia Combinada , Feminino , Helicobacter pylori/isolamento & purificação , Humanos , Masculino , Metronidazol/administração & dosagem , Pessoa de Meia-Idade , Vigilância de Produtos Comercializados , Estudos Prospectivos , Inibidores da Bomba de Prótons/efeitos adversos , Pirróis/efeitos adversos , Sulfonamidas/efeitos adversos , Adulto Jovem
7.
Immunol Med ; 42(2): 84-93, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31318324

RESUMO

Atopic dermatitis (AD) is the most common inflammatory skin disease driven by both terminal keratinocyte differentiation defects and type 2 immune responses, and this condition causes psychological and social morbidity. Although patients with severe AD require systemic immunotherapy, conventional agents including ciclosporin could not be used for several years due to side effects such as nephrotoxicity, hypertension and long-term risks of malignancy. It is well known that dupilumab, which blocks receptor binding of both IL-4 and IL-13, is remarkably efficacious in the treatment of AD. We have entered a new era when many novel topical and systemic agents that may have great potential in AD treatment are emerging through clinical trials. The purpose of this article is to summarize the efficacy and safety of the current topical and systemic therapies in AD by reviewing recently published papers regarding phase II/III clinical trials. It is revealed that topical phosphodiesterase 4 inhibitors and Janus kinase (JAK) inhibitors are promising treatments for AD. Moreover, systemic therapies such as biologics targeting IL-13 and oral JAK inhibitors show strong efficacy in AD.


Assuntos
Dermatite Atópica/tratamento farmacológico , Inibidores de Janus Quinases/administração & dosagem , Inibidores da Fosfodiesterase 4/administração & dosagem , Acrilamidas/administração & dosagem , Administração Tópica , Anticorpos Monoclonais Humanizados/administração & dosagem , Produtos Biológicos/administração & dosagem , Compostos de Boro/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Dermatite Atópica/etiologia , Dermatite Atópica/imunologia , Humanos , Imunoterapia , Interleucina-13 , Terapia de Alvo Molecular , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Resorcinóis/administração & dosagem , Estilbenos/administração & dosagem , Canais de Cátion TRPV/antagonistas & inibidores
8.
Nat Commun ; 10(1): 2735, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227713

RESUMO

The contribution of mast cells in the microenvironment of solid malignancies remains controversial. Here we functionally assess the impact of tumor-adjacent, submucosal mast cell accumulation in murine and human intestinal-type gastric cancer. We find that genetic ablation or therapeutic inactivation of mast cells suppresses accumulation of tumor-associated macrophages, reduces tumor cell proliferation and angiogenesis, and diminishes tumor burden. Mast cells are activated by interleukin (IL)-33, an alarmin produced by the tumor epithelium in response to the inflammatory cytokine IL-11, which is required for the growth of gastric cancers in mice. Accordingly, ablation of the cognate IL-33 receptor St2 limits tumor growth, and reduces mast cell-dependent production and release of the macrophage-attracting factors Csf2, Ccl3, and Il6. Conversely, genetic or therapeutic macrophage depletion reduces tumor burden without affecting mast cell abundance. Therefore, tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer.


Assuntos
Interleucina-33/imunologia , Macrófagos/imunologia , Mastócitos/imunologia , Neoplasias Gástricas/imunologia , Aminopiridinas/administração & dosagem , Animais , Degranulação Celular/efeitos dos fármacos , Degranulação Celular/imunologia , Cromolina Sódica/administração & dosagem , Modelos Animais de Doenças , Epitélio/imunologia , Epitélio/patologia , Feminino , Mucosa Gástrica/citologia , Mucosa Gástrica/imunologia , Mucosa Gástrica/patologia , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Pirróis/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise Serial de Tecidos , Microambiente Tumoral/imunologia
9.
BMC Dermatol ; 19(1): 8, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174539

RESUMO

BACKGROUND: Several different Physician Global Assessment (PGA) versions have been used in clinical studies as a co-primary end point to evaluate psoriasis severity. Tofacitinib is an oral Janus kinase inhibitor. We performed an analysis of the PGA using data from studies of tofacitinib in moderate to severe chronic plaque psoriasis. METHODS: Data from 3641 patients with moderate to severe chronic plaque psoriasis, enrolled in one of four phase III tofacitinib studies (OPT Pivotal 1 and 2, OPT Compare and OPT Retreatment), were used to evaluate a three-item PGA scale. RESULTS: Confirmatory Factor Analyses showed that equal weighting of the three items (erythema, induration and scaling) was appropriate. The PGA demonstrated acceptable test-retest reliability (Intraclass Correlation Coefficient, 0.7) and internal consistency (Cronbach's Coefficient Alpha ≥ 0.9 at primary time points). The Clinically Important Difference was estimated as 0.55 (95% confidence interval: 0.546-0.563). Known-group validity was shown by demonstrating that PGA scores could discriminate between different degrees of disease severity. The PGA was significantly correlated with other clinical end points in the studies (Psoriasis Area and Severity Index, r = 0.75-0.79; Dermatology Life Quality Index, r = 0.44-0.57; Patient Global Assessment, r = 0.66-0.72). CONCLUSIONS: Consistent with previous findings from a phase II study, these results indicate that this PGA is a valid, reliable instrument for evaluating disease severity in clinical studies of psoriasis.


Assuntos
Inibidores de Janus Quinases/administração & dosagem , Piperidinas/administração & dosagem , Psoríase/diagnóstico , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Índice de Gravidade de Doença , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/tratamento farmacológico , Psoríase/patologia , Qualidade de Vida , Reprodutibilidade dos Testes , Pele/efeitos dos fármacos , Pele/patologia , Resultado do Tratamento , Adulto Jovem
10.
Intern Med ; 58(17): 2427-2433, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31178490

RESUMO

Objective Gastroesophageal reflux disease (GERD) is a highly prevalent disorder that negatively affects patients' quality of life and reduces their work productivity. The medical expenses associated with the treatment of GERD are the highest among all digestive diseases. Current guidelines recommend the administration of a standard dose of proton pump inhibitor (PPI) for eight weeks as an initial GERD treatment. However, there is growing concern regarding the safety of PPI treatment. Recently, a novel potassium-competitive acid blocker (P-CAB), vonoprazan (VPZ), was approved for the treatment of reflux esophagitis in Japan and may provide clinical benefits in GERD treatment. This study was conducted to evaluate the cost-effectiveness of a P-CAB, VPZ vs. a PPI, lansoprazole (LPZ), for the acute medical treatment of reflux esophagitis. Methods A clinical decision analysis was performed using a Markov chain approach to compare VPZ to LPZ in the acute treatment of reflux esophagitis in Japan. Results The P-CAB strategy was superior to the PPI strategy in terms of cost-effectiveness (direct cost per patient to achieve clinical success) and the number of days for which medication was required. Sensitivity analyses revealed that this superiority was robust within the plausible range of probabilities. This remained true even when the healing rates in cases of mild esophagitis were applied. Conclusion The P-CAB strategy was consistently superior to the conventional PPI strategy using the original LPZ in terms of cost-effectiveness and the number of days for which medication was required. Thus, VPZ appears to be the drug of choice for the acute medical treatment of reflux esophagitis.


Assuntos
Refluxo Gastroesofágico/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Lansoprazol/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Análise Custo-Benefício , Esquema de Medicação , Feminino , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/economia , Humanos , Japão , Lansoprazol/administração & dosagem , Lansoprazol/economia , Cadeias de Markov , Pirróis/administração & dosagem , Pirróis/economia , Qualidade de Vida , Sulfonamidas/administração & dosagem , Sulfonamidas/economia
11.
PLoS Negl Trop Dis ; 13(5): e0007373, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31120889

RESUMO

Infections of humans and livestock with African trypanosomes are treated with drugs introduced decades ago that are not always fully effective and often have severe side effects. Here, the trypanosome haptoglobin-haemoglobin receptor (HpHbR) has been exploited as a route of uptake for an antibody-drug conjugate (ADC) that is completely effective against Trypanosoma brucei in the standard mouse model of infection. Recombinant human anti-HpHbR monoclonal antibodies were isolated and shown to be internalised in a receptor-dependent manner. Antibodies were conjugated to a pyrrolobenzodiazepine (PBD) toxin and killed T. brucei in vitro at picomolar concentrations. A single therapeutic dose (0.25 mg/kg) of a HpHbR antibody-PBD conjugate completely cured a T. brucei mouse infection within 2 days with no re-emergence of infection over a subsequent time course of 77 days. These experiments provide a demonstration of how ADCs can be exploited to treat protozoal diseases that desperately require new therapeutics.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antiprotozoários/administração & dosagem , Benzodiazepinas/administração & dosagem , Pirróis/administração & dosagem , Tripanossomíase Africana/tratamento farmacológico , Animais , Anticorpos Monoclonais/química , Antiprotozoários/química , Benzodiazepinas/química , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Pirróis/química , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/parasitologia
12.
Med Oncol ; 36(6): 52, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053989

RESUMO

A randomized, phase III trial of orantinib in combination with transcatheter arterial chemoembolization (TACE) did not prolong overall survival (OS) over placebo (ORIENTAL study). A subgroup analysis was conducted to evaluate the efficacy and safety of orantinib in Japanese patients enrolled in the ORIENTAL study. The data of Japanese patients from this study were analyzed. The overall survival (OS), time to progression (TTP), and time to TACE failure (TTTF) were compared between orantinib and placebo arms using stratified log-rank test. Since TTTF in patients with Barcelona Clinic Liver Cancer stage B (BCLC-B) showed favor outcome in this study, the OS and TTTF according to BCLC staging system were also analyzed. The subgroup analysis consisted of 219 and 213 patients in the orantinib and placebo arms. Median OS was 32.5 vs 33.0 months (p = 0.906), median TTP was 4.7 vs 3.1 months (p = 0.011), and median TTTF was 25.3 vs 18.2 months (p = 0.160) in the orantinib and placebo groups, respectively. Patients with BCLC-B in the orantinib and placebo groups showed a median OS of 33.7 and 30.1 months, respectively (p = 0.260), while the corresponding median TTTF were 25.3 and 14.0 months (p = 0.125). The Japanese population safety profile was similar to all over population in the ORIENTAL study. No significant differences were observed in the OS and TTTF though the TTP was significantly improved in the orantinib arm. The OS and TTTF showed a tendency to be prolonged following orantinib treatment of Japanese HCC patients with BCLC-B in the ORIENTAL study.


Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Indóis/administração & dosagem , Neoplasias Hepáticas/terapia , Inibidores de Proteínas Quinases/administração & dosagem , Pirróis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Ensaios Clínicos Fase III como Assunto , Terapia Combinada , Feminino , Humanos , Japão , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Taxa de Sobrevida , Resultado do Tratamento
13.
J Exp Clin Cancer Res ; 38(1): 220, 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31126320

RESUMO

BACKGROUND: Androgen receptor (AR) is expressed in approximately 70% of breast tumors. Recent studies increasingly support AR as a potential therapeutic target of AR-positive breast cancer. We have previously reported that deubiquitinase USP14 stabilizes AR proteins by deubiquitination and USP14 inhibition results in inhibition of cell growth and tumor progression in AR-positive prostate cancer and breast cancer. The current study aims to explore the anticancer effect of a treatment combining AR antagonist enzalutamide with USP14 inhibition on breast cancer cells. METHODS: The combining effects of enzalutamide and USP14 inhibition on breast cancer cell proliferation and apoptosis and associated cell signaling were evaluated in vitro and in vivo. RESULTS: USP14 inhibition via administration of IU1 or USP14-specific siRNA/shRNA enhanced cell growth inhibition and apoptosis induction by enzalutamide in breast cancer cell lines in vitro and in vivo. Additionally, the combination of enzalutamide with USP14 inhibition/knockdown induced significant downregulation of AR proteins and suppression of AR-related signaling pathways, including Wnt/ß-catenin and PI3K/AKT pathways. Moreover, AKT inhibition via MK2206 increased the antiproliferative and proapoptotic effects of enzalutamide+IU1 combined treatment. CONCLUSION: Collectively, our data suggest that USP14 inhibition in combination with enzalutamide represents a potentially new therapeutic strategy for breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feniltioidantoína/análogos & derivados , Pirróis/administração & dosagem , Pirrolidinas/administração & dosagem , Ubiquitina Tiolesterase/metabolismo , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Células MCF-7 , Camundongos , Feniltioidantoína/administração & dosagem , Feniltioidantoína/farmacologia , Pirróis/farmacologia , Pirrolidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ubiquitina Tiolesterase/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Medicine (Baltimore) ; 98(20): e15701, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096515

RESUMO

BACKGROUND: Endoscopic submucosal dissection (ESD) is a standard procedure for treating gastric neoplasms. However, ESD causes larger artificial ulcers other than mucosal resection methods. We conducted this prospective randomized controlled study to evaluate the effect of stronger acid suppression on ESD ulcers caused by doubling the proton pump inhibitor (PPI) dose and compare the effects of 20-mg (standard dose) and 40-mg (double dose) esomeprazole (EswonampTM, Daewon Pharmaceutical Co., Ltd., Seoul, Korea) on ulcer healing. METHODS: One hundred ninety-seven patients who underwent gastric ESD from July 2017 to December 2017 at Pusan National University Yangsan Hospital were enrolled and randomly assigned to the standard or double-dose group. Change in ulcer size from the day of ESD to 4 weeks after ESD and the scar-change rate were compared between the groups. RESULTS: There were no significant differences in ulcer contraction (84.5% in 20 mg group vs 86.3% in 40 mg group, P = .91) or scar-change rate (30.9% vs 30.6%, P > .99) between the groups. In a multivariate analysis, initial ulcer size [odds ratio (OR) 0.24; 95% confidence interval (CI) 0.11-0.50] and early gastric cancer (OR 0.22, 95% CI 0.08-0.58) were significantly associated with delayed ulcer healing. CONCLUSIONS: Both 40 and 20-mg esomeprazole have similar effects on ESD-induced ulcer area reduction, suggesting that strong acid suppression does not necessarily result in rapid artificial ulcer healing. TRIAL REGISTRATION NUMBER: RCT no.: KCT0002885.


Assuntos
Ressecção Endoscópica de Mucosa/efeitos adversos , Esomeprazol/uso terapêutico , Neoplasias Gástricas/cirurgia , Úlcera Gástrica/tratamento farmacológico , Ressecção Endoscópica de Mucosa/métodos , Esomeprazol/administração & dosagem , Feminino , Humanos , Masculino , Estudos Prospectivos , Inibidores da Bomba de Prótons/uso terapêutico , Pirróis/administração & dosagem , Pirróis/uso terapêutico , República da Coreia/epidemiologia , Neoplasias Gástricas/complicações , Neoplasias Gástricas/patologia , Úlcera Gástrica/patologia , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Úlcera/tratamento farmacológico , Úlcera/patologia , Cicatrização/efeitos dos fármacos
15.
J Med Econ ; 22(8): 777-787, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30982378

RESUMO

Aims: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This analysis investigated the cost-effectiveness of the second-line treatment with tofacitinib, compared with adalimumab, both plus methotrexate (MTX), in patients with moderate-to-severe RA and an inadequate response to the first-line MTX, from a Taiwan National Health Insurance Administration perspective. Materials and methods: A patient-level simulation model was used to project lifetime costs and quality-adjusted life-years (QALYs). Base-case analysis compared second-line treatment with tofacitinib 5 mg twice daily plus MTX vs adalimumab 40 mg every 2 weeks plus MTX. Patients switched or discontinued treatment due to a lack or loss of effectiveness or a serious adverse event. Efficacy was measured by change in Health Assessment Questionnaire-Disability Index (HAQ-DI) score. HAQ-DI scores were used to predict mortality and resource utilization, and were mapped onto utility values to estimate QALYs. Efficacy and safety data were derived from clinical trials and other secondary sources. Uncertainty in model parameters was explored using one-way deterministic and probabilistic sensitivity analyses. Results: Patients gained 0.09 more QALYs with second-line tofacitinib plus MTX compared with adalimumab plus MTX (5.13 vs 5.04, respectively) at an additional cost of New Taiwan Dollars (NT$) 12,881. The incremental cost-effectiveness ratio was NT$143,122/QALY. One-way sensitivity analysis confirmed the base-case result was robust. Limitations: The lack of available clinical data, particularly for HAQ-DI scores, may introduce some bias in the analysis. No patients were in an early stage of RA, which may limit the generalizability of these results. Base-case results from our study are not necessarily generalizable to countries with healthcare systems that differ considerably from Taiwan. Conclusions: From a payer perspective, second-line treatment with tofacitinib plus MTX is a cost-effective treatment strategy, compared with adalimumab plus MTX, in patients with moderate-to-severe RA in Taiwan.


Assuntos
Adalimumab/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Adalimumab/administração & dosagem , Adalimumab/economia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/administração & dosagem , Antirreumáticos/economia , Análise Custo-Benefício , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Modelos Econômicos , Piperidinas/administração & dosagem , Piperidinas/economia , Pirimidinas/administração & dosagem , Pirimidinas/economia , Pirróis/administração & dosagem , Pirróis/economia , Anos de Vida Ajustados por Qualidade de Vida , Índice de Gravidade de Doença , Taiwan , Adulto Jovem
17.
AAPS PharmSciTech ; 20(5): 167, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30993508

RESUMO

Preformulation studies on tofacitinib citrate, a small molecule JAK3 specific inhibitor, have not been previously reported in literature. We therefore conducted several preformulation studies on tofacitinib citrate, and its free base, to better understand factors that affect its solubility, stability, and solid-state characteristics. Further, the results of the preformulation studies helped facilitate the development of a nebulized formulation of tofacitinib citrate for inhalational delivery to house dust mite allergen-challenged, BALB/c mice as a potential treatment for eosinophilic asthma. The preformulation results indicated tofacitinib having a basic pKa of 5.2, with its stability dependent on pH, ionic strength, and temperature. Degradation of tofacitinib follows apparent first-order kinetics. In order to maximize stability of the drug, ionic strength and temperature should be minimized, with an optimal range pH between 2.0 and 5.0. Additionally, our findings demonstrate that tofacitinib citrate can successfully be nebulized at a suitable droplet size for inhalation (1.2 ± 0.2 µm MMAD) through a nose-only chamber. Animals dosed with tofacitinib citrate demonstrated marked reductions in BAL eosinophils and total protein concentrations following HDM challenge. These data suggest that tofacitinib citrate represents the potential to be an effective therapy for eosinophilic asthma.


Assuntos
Antiasmáticos/administração & dosagem , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirróis/administração & dosagem , Pirróis/uso terapêutico , Administração por Inalação , Alérgenos , Animais , Composição de Medicamentos , Estabilidade de Medicamentos , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Pyroglyphidae
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA