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1.
Acta Trop ; 201: 105226, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31634454

RESUMO

Trichinellosis is a zoonotic parasitic disease caused by Trichinella spiralis, and it is also a widely prevalent foodborne parasitic disease. At present, albendazole and benzimidazole are the most commonly used therapeutic drugs for the clinical treatment of trichinellosis, but they have many side effects. Sanguinarine is a benzophenanthridine alkaloid that has biological activity, such as antibacterial, antitumour and antiparasitic activities. Therefore, the present study aimed to evaluate the anti-Trichinella effect of sanguinarine in vivo and in vitro. The results showed that sanguinarine had a lethal effect on muscle larvae, adults and new-borne larvae in vitro. The damage to adults treated with sanguinarine was observed by scanning electron microscopy. Sanguinarine could significantly reduce the burden of worms in mice during the pre-adult, migrating larva and encysted larva stages. The ratio of intestinal villus to crypt (V/C) in mice treated with sanguinarine was significantly higher than that in non-treated control mice. Compared with the non-treated control group, the sanguinarine-treated group exhibited a significantly increased number of small intestine goblet cells. The level of reactive oxygen species (ROS) in the serum of mice treated with sanguinarine was significantly higher than that of the control group mice in the pre-adult and encysted larva stages. This study suggests that sanguinarine is a potential drug against trichinellosis.


Assuntos
Anti-Helmínticos/uso terapêutico , Benzofenantridinas/uso terapêutico , Intestino Delgado/parasitologia , Isoquinolinas/uso terapêutico , Larva/efeitos dos fármacos , Trichinella spiralis/efeitos dos fármacos , Triquinelose/tratamento farmacológico , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos
2.
Ann Hematol ; 98(11): 2569-2578, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31628518

RESUMO

Treatment results for multiple myeloma and plasma cell leukemia have considerably improved, but cure remains elusive and establishing new therapeutic approaches constitutes a major unmet clinical need. We analyzed the anti-myeloma properties of the aza-anthracenedione pixantrone which has been successfully used in a phase III study for the treatment of patients with aggressive non-Hodgkin's lymphoma as monotherapy as well as in combination regimes in vitro and in an adapted in vivo model (ex ovo chicken chorioallantoic membrane (CAM) assay). Pixantrone significantly inhibited proliferation and metabolic activity of all investigated myeloma cell lines. Importantly, anti-myeloma effects were more pronounced in tumor cell lines than in stromal cells, mesenchymal stem cells, and peripheral blood mononuclear cells of healthy controls. Apoptosis of myeloma cell lines was observed only after a 7-day incubation period, indicating a fast cytostatic and a slower cytotoxic effect of this drug. Pixantrone reduced the viability of primary plasma cells of patients and induced downregulation of myeloma-cell growth in the CAM assay. Additionally, we demonstrate in vitro synergism between pixantrone and the histone deacetylase inhibitor panobinostat with respect to its anti-proliferative features. From these data, we conclude that systematic investigations of the clinical usefulness of pixantrone in the framework of controlled clinical trials are clearly indicated (e.g., in penta-refractory patients).


Assuntos
Antineoplásicos/uso terapêutico , Isoquinolinas/uso terapêutico , Leucemia Plasmocitária/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Embrião de Galinha , Membrana Corioalantoide/efeitos dos fármacos , Ensaios Clínicos como Assunto , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Metabolismo Energético/efeitos dos fármacos , Feminino , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Panobinostat/farmacologia , Estudos Retrospectivos
3.
Blood ; 134(19): 1573-1577, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31554637

RESUMO

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (FL) represent indolent malignancies characterized by multiple episodes of relapse. Therapy has centered on agents that largely target the B-cell receptor pathway. Duvelisib is a second-generation oral inhibitor of phosphoinositide-3 kinase, downstream of the B-cell receptor pathway, approved in the United States for relapsed CLL/SLL and FL. Duvelisib represents a highly active agent, and ongoing investigations, including fixed-duration drug combinations and alternative dosing schedules, are aimed at reducing immune-mediated toxicities.


Assuntos
Antineoplásicos/uso terapêutico , Isoquinolinas/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Purinas/uso terapêutico , Humanos
4.
Expert Opin Investig Drugs ; 28(10): 827-833, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31474120

RESUMO

Introduction: A compound that simultaneously inhibits PDE3 and PDE4 should increase airway caliber by relaxing the smooth muscle and, simultaneously, suppress airway inflammatory responses. Ensifentrine (RPL554) is considered a PDE3/4 inhibitor, although its affinity for PDE3 is 3,440 times higher than that for PDE4, that is under clinical development for the treatment of asthma and COPD and, potentially, cystic fibrosis. Areas covered: We analyze the development of this molecule from its basic pharmacology to the present clinical Phase II studies. Expert opinion: Ensifentrine is an interesting drug but there is a lack of solid studies that still does not allow us to correctly allocate this molecule in the current COPD and even asthma therapeutic armamentarium. Furthermore, apparently ensifentrine has not yet entered Phase III clinical development and, in any case, there is no reliable evidence of its ability to elicit an anti-inflammatory activity in patients with COPD or asthma. Therefore, the real anti-inflammatory profile of ensifentrine must be clarified with new studies of basic pharmacology and adequate clinical studies specifically designed. However, at present the most intriguing perspective is linked to its possible use in the treatment of cystic fibrosis, also considering the lack of valid therapeutic options for this disease.


Assuntos
Asma/tratamento farmacológico , Isoquinolinas/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Pirimidinonas/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Asma/fisiopatologia , Fibrose Cística/tratamento farmacológico , Fibrose Cística/fisiopatologia , Desenvolvimento de Medicamentos/métodos , Humanos , Isoquinolinas/farmacologia , Inibidores da Fosfodiesterase 3/farmacologia , Inibidores da Fosfodiesterase 3/uso terapêutico , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Pirimidinonas/farmacologia
5.
Hepatol Int ; 13(5): 587-598, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31463665

RESUMO

BACKGROUND AND AIMS: One-third of the global hepatitis C virus (HCV) burden is found in Asia. Real-world data from diverse East Asian cohorts remain limited. This study addressed the real-world status of direct-acting antiviral (DAA) therapy among patients from East Asia. METHODS: Chronic hepatitis C (CHC) patients from clinical sites in Japan, Taiwan, South Korea, and Hong Kong were recruited in the REAL-C registry, an observational chart review registry. The primary outcome was sustained virologic response (SVR12, HCV RNA PCR < 25 IU/mL 12 week post-therapy). RESULTS: A total of 6287 CHC patients were enrolled. Compared to other East Asian patients, patients from Japan were older (66.3 vs. 61.5 years, p < 0.0001), had lower body mass indices (22.9 kg/m2 vs. 24.6 kg/m2, p < 0.001), and were more likely to have non-liver malignancy history (12.2% vs. 5.0%, p < 0.001).The overall SVR12 rate was 96.4%, similar to patients both inside and outside Japan (96.6% vs. 96%, p = 0.21). The SVR12 rate ranged from 91.1 to 99.4% except treatment-experienced cirrhotic HCV genotype-1 patients who received daclatasvir/asunaprevir (85.9%) and the treatment-experienced cirrhotic HCV genotype-2 patients treated with sofosbuvir/ribavirin (87%). The overall rate of drug discontinuation was 1.9%, also similar across regions. On multivariate regression analyses, there was no significant association between geographic region and SVR outcomes. CONCLUSIONS: In this large multinational CHC cohort from the East Asia, oral DAAs were highly effective and well tolerated across the region. Policies should encourage treatment for all CHC patients with DAAs in Asia with its heavy burden of HCV.


Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Idoso , Quimioterapia Combinada , Feminino , Hong Kong , Humanos , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Isoquinolinas/administração & dosagem , Isoquinolinas/uso terapêutico , Japão , Masculino , Pessoa de Meia-Idade , República da Coreia , Ribavirina/administração & dosagem , Ribavirina/uso terapêutico , Sofosbuvir/administração & dosagem , Sofosbuvir/uso terapêutico , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Taiwan , Resultado do Tratamento
6.
N Engl J Med ; 381(11): 1001-1010, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31340089

RESUMO

BACKGROUND: Roxadustat (FG-4592) is an oral inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase that stimulates erythropoiesis and regulates iron metabolism. In phase 2 studies involving patients with chronic kidney disease, roxadustat increased levels of endogenous erythropoietin to within or near the physiologic range, along with increasing hemoglobin levels and improving iron homeostasis. Additional data are needed regarding the efficacy and safety of roxadustat for the treatment of anemia in patients with chronic kidney disease who are not undergoing dialysis. METHODS: In this phase 3 trial conducted at 29 sites in China, we randomly assigned 154 patients with chronic kidney disease in a 2:1 ratio to receive roxadustat or placebo three times a week for 8 weeks in a double-blind manner. All the patients had a hemoglobin level of 7.0 to 10.0 g per deciliter at baseline. The randomized phase of the trial was followed by an 18-week open-label period in which all the patients received roxadustat; parenteral iron was withheld. The primary end point was the mean change from baseline in the hemoglobin level, averaged over weeks 7 through 9. RESULTS: During the primary-analysis period, the mean (±SD) change from baseline in the hemoglobin level was an increase of 1.9±1.2 g per deciliter in the roxadustat group and a decrease of 0.4±0.8 g per deciliter in the placebo group (P<0.001). The mean reduction from baseline in the hepcidin level (associated with greater iron availability) was 56.14±63.40 ng per milliliter in the roxadustat group and 15.10±48.06 ng per milliliter in the placebo group. The reduction from baseline in the total cholesterol level was 40.6 mg per deciliter in the roxadustat group and 7.7 mg per deciliter in the placebo group. Hyperkalemia and metabolic acidosis occurred more frequently in the roxadustat group than in the placebo group. The efficacy of roxadustat in hemoglobin correction and maintenance was maintained during the 18-week open-label period. CONCLUSIONS: In Chinese patients with chronic kidney disease who were not undergoing dialysis, those in the roxadustat group had a higher mean hemoglobin level than those in the placebo group after 8 weeks. During the 18-week open-label phase of the trial, roxadustat was associated with continued efficacy. (Funded by FibroGen and FibroGen [China] Medical Technology Development; ClinicalTrials.gov number, NCT02652819.).


Assuntos
Anemia/tratamento farmacológico , Glicina/análogos & derivados , Hemoglobinas/análise , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Isoquinolinas/uso terapêutico , Insuficiência Renal Crônica/complicações , Acidose/induzido quimicamente , Adulto , Idoso , Anemia/etiologia , Colesterol/sangue , Método Duplo-Cego , Feminino , Glicina/efeitos adversos , Glicina/uso terapêutico , Hematínicos/efeitos adversos , Hematínicos/uso terapêutico , Humanos , Hiperpotassemia/induzido quimicamente , Isoquinolinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue
7.
N Engl J Med ; 381(11): 1011-1022, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31340116

RESUMO

BACKGROUND: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. Additional data are needed regarding the effectiveness and safety of roxadustat as compared with standard therapy (epoetin alfa) for the treatment of anemia in patients undergoing dialysis. METHODS: In a trial conducted in China, we randomly assigned (in a 2:1 ratio) patients who had been undergoing dialysis and erythropoiesis-stimulating agent therapy with epoetin alfa for at least 6 weeks to receive roxadustat or epoetin alfa three times per week for 26 weeks. Parenteral iron was withheld except as rescue therapy. The primary end point was the mean change in hemoglobin level from baseline to the average level during weeks 23 through 27. Noninferiority of roxadustat would be established if the lower boundary of the two-sided 95% confidence interval for the difference between the values in the roxadustat group and epoetin alfa group was greater than or equal to -1.0 g per deciliter. Patients in each group had doses adjusted to reach a hemoglobin level of 10.0 to 12.0 g per deciliter. Safety was assessed by analysis of adverse events and clinical laboratory values. RESULTS: A total of 305 patients underwent randomization (204 in the roxadustat group and 101 in the epoetin alfa group), and 256 patients (162 and 94, respectively) completed the 26-week treatment period. The mean baseline hemoglobin level was 10.4 g per deciliter. Roxadustat led to a numerically greater mean (±SD) change in hemoglobin level from baseline to weeks 23 through 27 (0.7±1.1 g per deciliter) than epoetin alfa (0.5±1.0 g per deciliter) and was statistically noninferior (difference, 0.2±1.2 g per deciliter; 95% confidence interval [CI], -0.02 to 0.5). As compared with epoetin alfa, roxadustat increased the transferrin level (difference, 0.43 g per liter; 95% CI, 0.32 to 0.53), maintained the serum iron level (difference, 25 µg per deciliter; 95% CI, 17 to 33), and attenuated decreases in the transferrin saturation (difference, 4.2 percentage points; 95% CI, 1.5 to 6.9). At week 27, the decrease in total cholesterol was greater with roxadustat than with epoetin alfa (difference, -22 mg per deciliter; 95% CI, -29 to -16), as was the decrease in low-density lipoprotein cholesterol (difference, -18 mg per deciliter; 95% CI, -23 to -13). Roxadustat was associated with a mean reduction in hepcidin of 30.2 ng per milliliter (95% CI, -64.8 to -13.6), as compared with 2.3 ng per milliliter (95% CI, -51.6 to 6.2) in the epoetin alfa group. Hyperkalemia and upper respiratory infection occurred at a higher frequency in the roxadustat group, and hypertension occurred at a higher frequency in the epoetin alfa group. CONCLUSIONS: Oral roxadustat was noninferior to parenteral epoetin alfa as therapy for anemia in Chinese patients undergoing dialysis. (Funded by FibroGen and FibroGen [China] Medical Technology Development; ClinicalTrials.gov number, NCT02652806.).


Assuntos
Anemia/tratamento farmacológico , Epoetina alfa/uso terapêutico , Glicina/análogos & derivados , Hematínicos/uso terapêutico , Hemoglobinas/análise , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Isoquinolinas/uso terapêutico , Insuficiência Renal Crônica/complicações , Adulto , Idoso , Análise de Variância , Anemia/etiologia , Colesterol/sangue , Método Duplo-Cego , Epoetina alfa/efeitos adversos , Feminino , Glicina/efeitos adversos , Glicina/uso terapêutico , Hematínicos/efeitos adversos , Humanos , Hiperpotassemia/induzido quimicamente , Hipertensão/induzido quimicamente , Isoquinolinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Diálise Renal , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/terapia
8.
Medicine (Baltimore) ; 98(30): e16524, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348267

RESUMO

Anti-hepatitis C virus (HCV) treatment for human immunodeficiency virus (HIV)/HCV co-positive patients with hemophilia A presents numerous problems in terms of safety and effectiveness. The emergence of direct-acting antiviral (DAA) regimens has led to tremendous changes in the management of HIV/HCV co-infection over the past few years, but the application of DAA in patients with hemophilia complicated with HIV/HCV co-infection has rarely been reported.We retrospectively analyzed the clinical course and outcome of hemophilia A patients with HIV/HCV co-infection receiving DAA with a focus on the virological response, changes in cluster of differentiation 4 lymphocyte (CD4) count, side effects, and impact on bleeding before and after DAA therapy.A total of 12 hemophilia A patients with HIV/HCV co-infection were included, 9 of which were severe. All the patients were in stable states with CD4 counts >200/mm and plasma HIV ribonucleic acid (RNA) suppressed (<40 IU/mL) while taking the antiretroviral regimen. Majority of the patients (n = 9, 75.0%) were infected with HCV genotype (GT) 1b, while 2 and 1 was infected with HCV GT 2i and HCV GT 3, respectively.After 12 weeks of DAA treatment, 11 patients (91.7%) obtained sustained virologic response within 24 weeks of discontinuation of treatment (SVR24), except 1 patient who was treated with sofosbuvir (SOF) + pegylated interferon + ribavirin (PR), which was then switched to daclatasvir (DCV) + asunaprevir (ASV) for 12 weeks; this patient then achieved SVR24. During DAA treatment, HIV RNA in all the patients was constantly suppressed, while CD4 counts showed no obvious change.The most common treatment-emergent adverse events were weakness and loss of appetite (generally mild). There was no evidence of an increased tendency of bleeding, and changes in response to replacement.DAA therapy offered a safe and well-tolerated management strategy for HIV/HCV co-infected patients with hemophilia A. An awareness of the potential drug-drug interactions (DDI) between DAA and combination antiretroviral therapy (cART) by clinicians is important for optimal management of co-infected patients.


Assuntos
Antivirais/uso terapêutico , Coinfecção/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Hemofilia A/tratamento farmacológico , Hepatite C/tratamento farmacológico , Adulto , Contagem de Linfócito CD4 , Coinfecção/imunologia , Coinfecção/virologia , Quimioterapia Combinada , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1 , Hemofilia A/imunologia , Hemofilia A/virologia , Hepacivirus , Hepatite C/imunologia , Hepatite C/virologia , Humanos , Imidazóis/uso terapêutico , Interferons/uso terapêutico , Isoquinolinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Resposta Viral Sustentada
9.
Ann Hematol ; 98(9): 2025-2033, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31312929

RESUMO

Outcomes for patients with non-Hodgkin's lymphoma (NHL) that proves refractory to treatment remain poor. Treatment of such patients is individualized and can include enrolment in a clinical trial of novel agents or use of one of a wide array of drug regimens. Initial treatment with anthracyclines such as doxorubicin limits options at later stages of treatment because of anthracycline-related cumulative cardiotoxicity. The aza-anthracenedione pixantrone was developed to reduce the likelihood of cardiotoxicity without compromising efficacy and is currently conditionally approved for use as monotherapy in patients with multiply-relapsed or refractory aggressive B cell NHL. The use of pixantrone in combination therapy, often to replace doxorubicin or mitoxantrone, has or is currently being investigated in numerous studies in patients with aggressive or indolent NHL and is the focus of this review. These include the R-CPOP regimen (rituximab, cyclophosphamide, pixantrone, vincristine, prednisone) for aggressive NHL in the first-line setting, including a study in elderly patients with limited cardiac function, and for patients with relapsed NHL with prior anthracycline exposure; the PSHAP regimen (pixantrone, cytarabine, prednisone, cisplatin), also in the latter setting; the PREBen/PEBen regimen (pixantrone, bendamustine and etoposide with or without rituximab) as salvage therapy; and pixantrone in combination with fludarabine, dexamethasone, and rituximab (FPD-R) for relapsed indolent NHL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Isoquinolinas/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Mitoxantrona/uso terapêutico , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Terapia de Salvação/métodos , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Vincristina/uso terapêutico
10.
Curr Opin Ophthalmol ; 30(4): 275-285, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31033737

RESUMO

PURPOSE OF REVIEW: To summarize the recent literature regarding descemetorhexis stripping without endothelial keratoplasty (DWEK), increasingly referred to as Descemet's stripping only (DSO). To report the characteristic clinical, confocal and histologic findings associated with this procedure. RECENT FINDINGS: Reported clearance rates following DSO range from 63 to 100% in recent series, with variation between surgical techniques. Topical Rho-kinase inhibitor has been reported as successfully salvaging failing cases. Its use as an adjuvant to the surgery is gaining widespread adoption with the results of early series now arriving. Apart from a phenotype of central guttata with clear periphery, patient characteristics which determine success remain elusive. Surgical factors affecting success are increasingly well understood, with stromal injury felt to be a retardant to healing. Characteristic clinical signs have been observed and are described herein. Clinical, confocal and light microscopic images are obtained from patients in clinical trials of DSO with ripasudil. SUMMARY: DSO is gaining acceptance as a surgical option for a subset of patients with Fuchs' Dystrophy. The addition of Rho-associated kinase inhibitor appears to improve predictability but further results to this effect must be published and scrutinized.


Assuntos
Lâmina Limitante Posterior/cirurgia , Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior/métodos , Distrofia Endotelial de Fuchs/cirurgia , Epitélio Posterior/cirurgia , Distrofia Endotelial de Fuchs/fisiopatologia , Humanos , Isoquinolinas/uso terapêutico , Sulfonamidas/uso terapêutico , Acuidade Visual/fisiologia , Quinases Associadas a rho/antagonistas & inibidores
11.
Pharmacol Rep ; 71(3): 473-477, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31003160

RESUMO

BACKGROUND: Despite a significant improvement in treatment outcomes, 30-40% of aggressive non-Hodgkin lymphomas (NHL) patients are refractory or relapse after the first line therapy. Half of them are not eligible to autologous stem cell transplantation (ASCT) due to failure of platinum-based salvage regimens. Pixantrone is conditionally approved in Europe in patients with R/R aggressive NHL failing at least 2 previous lines of therapy. Polish Lymphoma Research Group (PLRG) evaluated the efficacy and tolerability of P[R]EBEN combining pixantrone, etoposide, bendamustine with or without rituximab), a new regimen developed recently by Francesco d'Amore, in real-life experience. METHODS: In this retrospective audit, we analyzed the data of consecutive 25 R/R NHL cases, treated with P[R]EBEN regimen in 9 PLRG centers. Safety and efficacy data, including adverse reactions (AE), response rates, progression-free and overall survival (PFS and OS) were collected. RESULTS: Overall response rate (ORR) to P[R]EBEN regimen was 68% (40% CR and 28% PR). Most patients responded, relatively early, by second cycle of therapy. P[R]EBEN was effective in 8 out of 15 patients (53%) refractory to previous platinum-based salvage regimens. In 4 patients (16%) stabilization of disease (SD) during therapy was observed and further 4 patients (16%) progressed during the treatment (PD). Response rates were higher in patients, chemosensitive to their prior regimen (ORR - 87.5%, including 50% CR). At the median follow-up of 7.5 months (range 1-16) the median PFS and OS were not reached. Projected PFS and OS at 12 months are 68% and 78% respectively. The P[R]EBEN regimen was well tolerated and most of patients received it as out-patients. AEs grade ≥3 occurred in 17 patients (68%). Most common grade 3-4 AEs were due to hematological toxicity with febrile neutropenia observed in 5 patients (20%). There were no episodes of septic deaths. Six patients (24%) died during treatment and follow-up period, all of them due to lymphoma progression. CONCLUSION: Our data suggest good efficiency and tolerability of P[R]EBEN regimen as a rescue therapy in patients with R/R aggressive NHL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/uso terapêutico , Etoposídeo/uso terapêutico , Isoquinolinas/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Rituximab/uso terapêutico , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Polônia , Recidiva , Estudos Retrospectivos , Terapia de Salvação/métodos , Transplante Autólogo/métodos
12.
J Am Soc Nephrol ; 30(4): 641-652, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30846557

RESUMO

BACKGROUND: Guidelines recommend reducing elevated serum phosphate in patients with CKD. Tenapanor, a minimally absorbed inhibitor of gastrointestinal sodium/hydrogen exchanger 3 (NHE3), reduces paracellular phosphate transport. METHODS: In this phase 3 randomized, double-blind trial, we randomly assigned patients with hyperphosphatemia receiving maintenance hemodialysis to receive twice-daily oral tenapanor (3, 10, or 30 mg [the latter down-titrated, if needed]) for 8 weeks. Patients were then rerandomized 1:1 to receive either their previously assigned dose or placebo for a 4-week 'withdrawal' period. We measured serum phosphate levels over the course of the trial. The primary end point was mean change in serum phosphate over the 4-week withdrawal period for the tenapanor group (using pooled data) versus the placebo group. RESULTS: Of 219 patients randomized, 152 completed both study phases. During the initial 8-week treatment period, all three treatment groups experienced significant decreases in mean serum phosphate (reductions of 1.00, 1.02, and 1.19 mg/dl, corresponding to the 3, 10, and 30 mg [down-titrated] dose groups, respectively). Tenapanor also showed a significant benefit over placebo during the withdrawal period, with a mean increase of 0.85 mg/dl in the placebo group versus a mean increase of 0.02 mg/dl in the pooled tenapanor group. Adverse events were largely limited to softened stool and a modest increase in bowel movement frequency, resulting from increased stool sodium and water content, stemming from tenapanor's mechanism of action. CONCLUSIONS: Tenapanor significantly reduced elevated serum phosphate in patients with hyperphosphatemia receiving maintenance hemodialysis. Adverse effects were limited to those induced by its known mechanism of action, which increases stool sodium and water content.


Assuntos
Hiperfosfatemia/tratamento farmacológico , Isoquinolinas/uso terapêutico , Falência Renal Crônica/terapia , Fosfatos/sangue , Sulfonamidas/uso terapêutico , Adulto , Idoso , Diarreia/induzido quimicamente , Método Duplo-Cego , Feminino , Humanos , Hiperfosfatemia/sangue , Isoquinolinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Diálise Renal , Trocador 3 de Sódio-Hidrogênio/antagonistas & inibidores , Sulfonamidas/efeitos adversos
13.
J Clin Oncol ; 37(11): 912-922, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30742566

RESUMO

PURPOSE: Indolent non-Hodgkin lymphoma (iNHL) remains largely incurable and often requires multiple lines of treatment after becoming refractory to standard therapies. Duvelisib was approved by the Food and Drug Administration for relapsed or refractory (RR) chronic lymphocytic leukemia or small lymphocytic lymphoma (SLL) and RR follicular lymphoma (FL) after two or more prior systemic therapies. On the basis of the activity of duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase-δ,-γ, in RR iNHL in a phase I study, the safety and efficacy of duvelisib monotherapy was evaluated in iNHL refractory to rituximab and either chemotherapy or radioimmunotherapy. PATIENTS AND METHODS: Eligible patients had measurable iNHL (FL, SLL, or marginal zone B-cell lymphoma) double refractory to rituximab (monotherapy or in combination) and to either chemotherapy or radioimmunotherapy. All were treated with duvelisib 25 mg orally twice daily in 28-day cycles until progression, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) using the revised International Working Group criteria for malignant lymphoma. RESULTS: This open-label, global phase II trial enrolled 129 patients (median age, 65 years; median of three prior lines of therapy) with an ORR of 47.3% (SLL, 67.9%; FL, 42.2%; MZL, 38.9%). The estimated median duration of response was 10 months, and the estimated median progression-free survival was 9.5 months. The most frequent any-grade treatment-emergent adverse events (TEAEs) were diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%). Among the 88.4% of patients with at least one grade 3 or greater TEAE, the most common TEAEs were neutropenia (24.8%), diarrhea (14.7%), anemia (14.7%), and thrombocytopenia (11.6%). CONCLUSION: In the DYNAMO study, oral duvelisib monotherapy demonstrated clinically meaningful activity and a manageable safety profile in heavily pretreated, double-refractory iNHL, consistent with previous observations. Duvelisib may provide a new oral treatment option for this patient population of which many are elderly and in need of additional therapies.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Isoquinolinas/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Purinas/uso terapêutico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Diarreia/induzido quimicamente , Esquema de Medicação , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Estimativa de Kaplan-Meier , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Fosfatidilinositol 3-Quinases/metabolismo , Purinas/administração & dosagem , Purinas/efeitos adversos , Rituximab/administração & dosagem
14.
Cornea ; 38(5): 529-534, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30720541

RESUMO

PURPOSE: Fuchs corneal dystrophy (FD) is a common cause of endothelial keratoplasty. Recently, a series of FD cases treated with Descemet stripping only (DSO) demonstrated recovery of the central endothelium without transplantation of donor cells. Ripasudil, a rho kinase inhibitor, has been shown to promote corneal endothelial wound healing in animal models. This study prospectively evaluated the use of ripasudil in patients undergoing DSO for FD. METHODS: Enrolled patients underwent DSO with or without cataract surgery, performed by 1 surgeon. On the first postoperative day, patients were assigned to topical ripasudil 0.4% (Glanatec) 4 times a day for 2 months or no ripasudil and followed up monthly for the first 6 months and then at 9 and 12 months after surgery. Endothelial cell density (ECD) and pachymetry were evaluated at each postoperative visit. RESULTS: Eighteen patients were enrolled, including 8 women and 1 man in each group. Overall, patients who underwent DSO with ripasudil recovered vision more quickly (4.6 vs. 6.5 weeks, P < 0.01). In addition, the ripasudil group had a statistically significantly higher average ECD at 3, 6, and 12 months. The patients in the DSO observation group had a 10% decrease in peripheral ECD when comparing counts before surgery with counts 12 months after surgery (P < 0.05). In the DSO ripasudil group, there was no significant difference between peripheral ECD at preoperative baseline versus 12 months after surgery. CONCLUSIONS: DSO with topical rho kinase inhibitors may be an alternative treatment for patients with FD and a peripheral ECD greater than 1000 cells/mm.


Assuntos
Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior , Distrofia Endotelial de Fuchs/tratamento farmacológico , Distrofia Endotelial de Fuchs/cirurgia , Isoquinolinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Sulfonamidas/uso terapêutico , Quinases Associadas a rho/antagonistas & inibidores , Idoso , Contagem de Células , Terapia Combinada , Epitélio Posterior/patologia , Feminino , Humanos , Masculino , Estudos Prospectivos , Acuidade Visual
15.
Drugs ; 79(5): 563-572, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30805897

RESUMO

Roxadustat (Ai Rui Zhuo® in China) is an orally administered, small molecule hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that is being developed by FibroGen, in collaboration with Astellas and AstraZeneca, for the treatment of anaemia in patients with dialysis-dependent chronic kidney disease (CKD), non-dialysis-dependent CKD and in patients with myelodysplastic syndromes. The drug reversibly binds to and inhibits HIF-prolyl hydroxylase enzymes that are responsible for the degradation of transcription factors in the HIF family under normal oxygen conditions. Inhibition of these enzymes reduces HIF breakdown and promotes HIF activity, leading to an increase in endogenous erythropoietin production, thereby enhancing erythropoiesis. It also reduces the expression of the peptide hormone hepcidin, improves iron availability and increases haemoglobin levels. HIF regulates the expression of genes in response to reduced oxygen levels, including genes required for erythropoiesis and iron metabolism. Roxadustat is approved in China and is under regulatory review in Japan for the treatment of anaemia in patients with dialysis-dependent CKD. Studies are underway to investigate long-term cardiovascular outcomes with roxadustat versus placebo (for non-dialysis-dependent CKD) or standard of care (for dialysis-dependent CKD). This article summarizes the milestones in the development of roxadustat leading to this first approval.


Assuntos
Anemia/tratamento farmacológico , Glicina/análogos & derivados , Isoquinolinas/farmacocinética , Inibidores de Prolil-Hidrolase/farmacocinética , Anemia/metabolismo , China , Aprovação de Drogas , Eritropoese/efeitos dos fármacos , Eritropoetina/metabolismo , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Glicina/uso terapêutico , Hepcidinas/metabolismo , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Isoquinolinas/uso terapêutico , Inibidores de Prolil-Hidrolase/administração & dosagem , Inibidores de Prolil-Hidrolase/efeitos adversos , Inibidores de Prolil-Hidrolase/uso terapêutico , Diálise Renal
16.
Support Care Cancer ; 27(9): 3593-3597, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30762142

RESUMO

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is one of the most feared and disturbing adverse events of cancer treatment associated with decreased adherence to effective chemotherapy regimens. For high-risk soft tissue sarcoma patients, receiving multiple-day chemotherapy (MD-CT), antiemetic guidelines recommend a combination of an NK1 receptor antagonist (NK1-RA), a 5-HT3 receptor antagonist (5HT3-RA), and dexamethasone on each day of the antineoplastic treatment. NEPA is the first oral fixed-dose combination of a highly selective NK1-RA, netupitant, and second-generation 5HT3-RA, palonosetron. So far, no data has been published in literature about the efficacy of a single dose of NEPA in MD-CT. METHODS: We performed a prospective, non-comparative study to assess the efficacy of one shot of NEPA plus dexamethasone in sarcoma patients receiving MD-CT. The primary efficacy endpoint was a complete response (CR: no emesis, no rescue medication) during the overall phase (0-120 h) in cycle 1. The main secondary endpoints were CR during the overall phase of cycles 2 and 3. RESULTS: The primary endpoint was reached in 88.9% of patients. Cycles 2 and 3 overall CR rates were 88.9% and 82.4%, respectively. The antiemetic regimen was well tolerated. CONCLUSIONS: This pilot study showed the benefit of one shot of NEPA to prevent CINV in sarcoma patients receiving MD-chemotherapy.


Assuntos
Antieméticos/uso terapêutico , Dexametasona/uso terapêutico , Náusea/prevenção & controle , Antagonistas do Receptor de Neuroquinina-1/uso terapêutico , Antagonistas do Receptor 5-HT3 de Serotonina/uso terapêutico , Vômito/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Feminino , Humanos , Isoquinolinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Palonossetrom/uso terapêutico , Projetos Piloto , Estudos Prospectivos , Piridinas/uso terapêutico , Quinuclidinas/uso terapêutico , Receptores da Neurocinina-1/efeitos dos fármacos , Sarcoma/tratamento farmacológico , Vômito/induzido quimicamente
17.
PLoS One ; 14(1): e0210608, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30625226

RESUMO

Standard treatment, unfortunately, yields a poor prognosis for patients with primary or metastatic cancers in the central nervous system, indicating a necessity for novel therapeutic agents. Immunotoxins (ITs) are a class of promising therapeutic candidates produced by fusing antibody fragments with toxin moieties. In this study, we investigated if inherent resistance to IT cytotoxicity can be overcome by rational combination with pro-apoptotic enhancers. Therefore, we combined ITs (9.2.27-PE38KDEL or Mel-14-PE38KDEL) targeting chondroitin sulfate proteoglycan 4 (CSPG4) with a panel of Bcl-2 family inhibitors (ABT-737, ABT-263, ABT-199 [Venetoclax], A-1155463, and S63845) against patient-derived glioblastoma, melanoma, and breast cancer cells/cell lines. In vitro cytotoxicity assays demonstrated that the addition of the ABT compounds, specifically ABT-737, sensitized the different tumors to IT treatment, and improved the IC50 values of 9.2.27-PE38KDEL up to >1,000-fold. Mechanistic studies using 9.2.27-PE38KDEL and ABT-737 revealed that increased levels of intracellular IT, processed (active) exotoxin, and PARP cleavage correlated with the enhanced sensitivity to the combination treatment. Furthermore, we confirmed the synergistic effect of 9.2.27-PE38KDEL and ABT-737 combination therapy in orthotopic GBM xenograft and cerebral melanoma metastasis models in nude mice. Our study defines strategies for overcoming IT resistance and enhancing specific antitumor cytotoxicity in primary and metastatic brain tumors.


Assuntos
Antineoplásicos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Imunotoxinas/uso terapêutico , Nitrofenóis/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzotiazóis/farmacologia , Benzotiazóis/uso terapêutico , Compostos de Bifenilo/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Sinergismo Farmacológico , Endocitose/efeitos dos fármacos , Exotoxinas/farmacologia , Furina/farmacologia , Humanos , Imunotoxinas/farmacologia , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Proteínas de Membrana/metabolismo , Camundongos Nus , Modelos Biológicos , Nitrofenóis/farmacologia , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Análise de Sobrevida , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Fatores de Tempo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Mol Cells ; 42(2): 143-150, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30622226

RESUMO

Chronic neuropathic pain is one of the primary causes of disability subsequent to spinal cord injury. Patients experiencing neuropathic pain after spinal cord injury suffer from poor quality of life, so complementary therapy is seriously needed. Dehydrocorybulbine is an alkaloid extracted from Corydalis yanhusuo. It effectively alleviates neuropathic pain. In the present study, we explored the effect of dehydrocorybulbine on neuropathic pain after spinal cord injury and delineated its possible mechanism. Experiments were performed in rats to evaluate the contribution of dehydrocorybulbine to P2X4 signaling in the modulation of pain-related behaviors and the levels of pronociceptive interleukins and proteins after spinal cord injury. In a rat contusion injury model, we confirmed that chronic neuropathic pain is present on day 7 after spinal cord injury and P2X4R expression is exacerbated after spinal cord injury. We also found that administration of dehydrocorybulbine by tail vein injection relieved pain behaviors in rat contusion injury models without affecting motor functions. The elevation in the levels of pronociceptive interleukins (IL-1ß, IL-18, MMP-9) after spinal cord injury was mitigated by dehydrocorybulbine. Dehydrocorybulbine significantly mitigated the upregulation of P2X4 receptor and reduced ATP-evoked intracellular Ca2+ concentration. Both P2XR and dopamine receptor2 agonists antagonized dehydrocorybulbine's antinociceptive effects. In conclusion, we propose that dehydrocorybulbine produces antinociceptive effects in spinal cord injury models by inhibiting P2X4R.


Assuntos
Isoquinolinas/uso terapêutico , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Receptores Purinérgicos P2X4/metabolismo , Traumatismos da Medula Espinal/complicações , Animais , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Interleucinas/metabolismo , Isoquinolinas/farmacologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Neuralgia/fisiopatologia , Nociceptividade/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores de Dopamina D2/metabolismo , Traumatismos da Medula Espinal/fisiopatologia
19.
Adv Ther ; 36(2): 333-343, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30610614

RESUMO

INTRODUCTION: To evaluate the safety and intraocular pressure (IOP)-lowering effects of a ripasudil 0.4% ophthalmic solution in Japanese patients with glaucoma and ocular hypertension (OH) as a post-marketing surveillance. METHODS: This was a 2-year prospective observational study in patients with glaucoma or OH who had not previously received ripasudil. Patients registered in the study using a central internet-based system from June 1, 2015 to April 30, 2017. Data on adverse drug reactions (ADRs) and IOP were collected and analysed from the first 3 months of ripasudil treatment. RESULTS: Of the 3058 patients in the safety analysis set, 3016 had IOP data and were included in the efficacy analysis. ADRs were seen in 244 (8.0%) of the 3058 patients. IOP decreased significantly in patients with primary open-angle glaucoma (- 2.9 ± 4.2 mmHg; p < 0.001), normal tension glaucoma (- 1.7 ± 2.4 mmHg; p < 0.001), primary angle-closure glaucoma (- 3.9 ± 5.3 mmHg; p < 0.001), and OH (- 3.8 ± 5.8 mmHg; p < 0.001). Significant IOP reduction was also noted in exfoliation glaucoma (- 3.0 ± 5.5 mmHg; p < 0.001), uveitis-associated glaucoma (- 4.7 ± 7.2 mmHg; p < 0.001) and steroid glaucoma (- 5.5 ± 6.0 mmHg; p < 0.001), but not for neovascular glaucoma (- 2.8 ± 12.1 mmHg; p = 0.669). CONCLUSION: Ripasudil was safe and effective in the treatment of glaucoma and OH in Japanese patients, with a low incidence of ADRs or treatment discontinuation, and reduced IOP after 3 months of treatment. FUNDING: Kowa Company, Ltd., Tokyo, Japan.


Assuntos
Glaucoma/tratamento farmacológico , Isoquinolinas/uso terapêutico , Hipertensão Ocular/tratamento farmacológico , Soluções Oftálmicas/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Relação Dose-Resposta a Droga , Feminino , Glaucoma de Ângulo Aberto/tratamento farmacológico , Humanos , Incidência , Pressão Intraocular , Isoquinolinas/efeitos adversos , Japão , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas/efeitos adversos , Vigilância de Produtos Comercializados , Estudos Prospectivos , Sulfonamidas/efeitos adversos , Tonometria Ocular , Resultado do Tratamento
20.
Nephrol Dial Transplant ; 34(2): 339-346, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29617976

RESUMO

Background: Elevated serum fibroblast growth factor 23 (FGF23) is strongly associated with cardiovascular risk and mortality. Tenapanor, an inhibitor of gastrointestinal sodium/hydrogen exchanger isoform 3, decreased serum phosphate in a randomized, double-blind, placebo-controlled Phase 2 trial (ClinicalTrials.gov identifier NCT02081534) of patients receiving hemodialysis with hyperphosphatemia. Here, we report a secondary analysis of effects on serum FGF23 during that study. Methods: After 1-3 weeks of washout of phosphate binders, 162 patients were randomized to receive 4 weeks of treatment with placebo or one of six tenapanor regimens (3 or 30 mg once daily, or 1, 3, 10 or 30 mg twice daily). Intact FGF23 concentrations were determined from serum samples collected at screening, post-washout and end of treatment, assayed in duplicate in a single batch at the end of the study. Results: After phosphate-binder washout, serum FGF23 concentrations increased in all groups [range of geometric means: 1430-2605 pg/mL before, to 2601-6294 pg/mL after washout (P < 0.001 for all patients analyzed as a single group)]. Serum FGF23 concentrations subsequently decreased in tenapanor-treated patients (2030-3563 pg/mL), whereas they increased further in placebo-treated patients (6930 pg/mL). In an analysis of covariance, FGF23 decreased by 9.1-27.9% in tenapanor-treated patients and increased by 21.9% in placebo-treated patients (P ≤ 0.001-0.04). Conclusions: Following a marked increase in serum FGF23 in response to withdrawal of phosphate binders, tenapanor significantly decreased serum FGF23 in patients receiving hemodialysis with hyperphosphatemia. Further studies are required to explore the long-term effects of controlling FGF23 with tenapanor.


Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Hiperfosfatemia/tratamento farmacológico , Isoquinolinas/uso terapêutico , Falência Renal Crônica/tratamento farmacológico , Diálise Renal/métodos , Sulfonamidas/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Hiperfosfatemia/complicações , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Fosfatos/sangue , Diálise Renal/efeitos adversos
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