RESUMO
INTRODUCTION: The breakthrough in erythropoietin-stimulating agents in the 1990s improved the prognosis and treatment of complications in chronic kidney disease patients and renal anemia. Discovery of the novel molecular mechanisms for hypoxia-inducible factor (HIF) transcription factor under hypoxic conditions has led to the development of oral drugs, HIF-Prolyl Hydroxylase inhibitors (HIF-PHIs), that constantly activate erythropoietin by inhibiting prolyl hydroxylase. HIF-PHIs have gained rapid approval in Asian countries, including Japan, with six distinct types entering clinical application. AREAS COVERED: This article provides a comprehensive review of the latest literature, with a particular focus on the effectiveness and safety of vadadustat. EXPERT OPINION: A phase 3, randomized, open-label, clinical trial (PRO2TECT) demonstrated that vadadustat had the prespecified non-inferiority for hematologic efficacy as compared with darbepoetin alfa in non-dialysis-dependent patients not previously treated with ESA. However, vadadustat did not show non-inferiority in major adverse cardiovascular events in the non-US/non-Europe patients. It may partly because of imbalances of the baseline eGFR level in those countries. In dialysis-dependent patients, a phase 3 clinical trial (INNO2VATE) showed vadadustat was non-inferior to darbepoetin alfa in cardiovascular safety and maintenance of hemoglobin levels. Adverse events including cancer, retinopathy, thrombosis, and vascular calcification should be evaluated in future clinical studies.
Assuntos
Anemia , Hematínicos , Insuficiência Renal Crônica , Humanos , Anemia/tratamento farmacológico , Anemia/etiologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Hematínicos/uso terapêutico , Hematínicos/efeitos adversos , Glicina/análogos & derivados , Glicina/uso terapêutico , Glicina/efeitos adversos , Inibidores de Prolil-Hidrolase/uso terapêutico , Inibidores de Prolil-Hidrolase/efeitos adversos , Inibidores de Prolil-Hidrolase/farmacologia , Inibidores de Prolil-Hidrolase/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Eritropoetina/uso terapêutico , Eritropoetina/efeitos adversos , Ácidos Picolínicos/uso terapêutico , Ácidos Picolínicos/efeitos adversos , Ácidos Picolínicos/farmacologiaRESUMO
BACKGROUND: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production. METHODS: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter). RESULTS: A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively. CONCLUSIONS: Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO2VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).
Assuntos
Anemia/tratamento farmacológico , Darbepoetina alfa/uso terapêutico , Glicina/análogos & derivados , Hematínicos/uso terapêutico , Ácidos Picolínicos/uso terapêutico , Inibidores de Prolil-Hidrolase/uso terapêutico , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/complicações , Idoso , Anemia/sangue , Anemia/etiologia , Doenças Cardiovasculares/induzido quimicamente , Darbepoetina alfa/efeitos adversos , Feminino , Glicina/efeitos adversos , Glicina/uso terapêutico , Hematínicos/efeitos adversos , Hemoglobinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Ácidos Picolínicos/efeitos adversos , Inibidores de Prolil-Hidrolase/efeitos adversos , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/terapiaRESUMO
BACKGROUND: Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production. METHODS: In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52. RESULTS: A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter. CONCLUSIONS: Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PRO2TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).
Assuntos
Anemia/tratamento farmacológico , Darbepoetina alfa/uso terapêutico , Glicina/análogos & derivados , Hematínicos/uso terapêutico , Ácidos Picolínicos/uso terapêutico , Inibidores de Prolil-Hidrolase/uso terapêutico , Insuficiência Renal Crônica/complicações , Administração Oral , Idoso , Anemia/sangue , Anemia/etiologia , Doenças Cardiovasculares/induzido quimicamente , Darbepoetina alfa/efeitos adversos , Feminino , Glicina/efeitos adversos , Glicina/uso terapêutico , Hematínicos/efeitos adversos , Hemoglobinas/análise , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Ácidos Picolínicos/efeitos adversos , Inibidores de Prolil-Hidrolase/efeitos adversos , Insuficiência Renal Crônica/mortalidadeRESUMO
N-(2-(diethylamino)-ethyl)-18F-5-fluoropicolinamide (18F-P3BZA) is a radiotracer that demonstrates high binding selectivity and affinity in melanoma. The aim of the present study was to estimate the biodistribution and clinical radiation dosimetry of 18F-P3BZA in healthy volunteers and perform a preliminary clinical application for PET/CT imaging in melanoma patients. Methods:18F-P3BZA was produced efficiently with a radiosynthesizer. Six healthy volunteers were injected with 18F-P3BZA (211.7 ± 15.4 MBq) followed by serial whole-body PET/CT scans and blood tests to assess biodistribution, pharmacokinetic, and radiation dosimetry at 10 min, 1 h, 2 h, and 4 h after injection. The vital signs of volunteers were recorded in regular intervals during the imaging sessions. The effective dose for each subject after the medical internal radiation dosimetry schema was calculated with OLINDA/EXM software. For the preliminary clinical application, 5 patients with suspected melanomas underwent 18F-P3BZA PET/CT imaging at 10 min and 1 h after injection. All patients also underwent 18F-FDG PET/CT scans on the third day to compare the potential diagnostic ability of 18F-P3BZA with 18F-FDG. Results: The radiochemistry yield of 18F-P3BZA labeling was 12.3% ± 3.9%, and the purity of 18F-P3BZA after purification and formulation was higher than 99.5%. The highest uptake of 18F-P3BZA was in the liver with an SUVmean of 8.3 ± 1.0 at 10 min after injection. The resultant whole-body effective dose was 0.0193 mSv/MBq. 18F-P3BZA showed high uptake and suggested an ability for specific imaging of melanoma and its metastasis in patients. The average SUVmean of 18F-P3BZA and 18F-FDG in tumors was 19.7 ± 5.3 and 10.8 ± 2.7 at 60 min after injection. Conclusion: Our study suggests that 18F-P3BZA is safe and compatible for clinical use. The first-in-human clinical application to melanoma showed favorable delineated tumors in patients, demonstrating the potential of 18F-P3BZA for diagnostic PET imaging of melanoma.
Assuntos
Melaninas/metabolismo , Ácidos Picolínicos/farmacocinética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Adulto , Feminino , Voluntários Saudáveis , Humanos , Masculino , Melanoma/diagnóstico por imagem , Melanoma/metabolismo , Pessoa de Meia-Idade , Ácidos Picolínicos/efeitos adversos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/efeitos adversos , Radiometria , Segurança , Distribuição Tecidual , Imagem Corporal TotalRESUMO
Five Ru(II)(η6-toluene) complexes formed with 2-picolinic acid and its various derivatives have been synthesized and characterized. X-ray structures of four complexes are also reported. Complex formation processes of [Ru(II)(η6-toluene)(H2O)3]2+ organometallic cation with the metal-free ligands were studied in aqueous solution in the presence of chloride ions by the combined use of 1H NMR spectroscopy, UV-visible spectrophotometry and pH-potentiometry. Solution stability, chloride ion affinity and lipophilicity of the complexes were characterized together with in vitro cytotoxic and antiproliferative activity in cancer cell lines being sensitive and resistant to classic chemotherapy and in normal cells as well. Formation of mono complexes such as [Ru(η6-toluene)(L)(Z)]+/0 (L: completely deprotonated ligand; Zâ¯=â¯H2O/Cl-) with high stability and [Ru(η6-toluene)(L)(OH)] was found in solution. The pKa values (8.3-8.7) reflect the formation of low amount of mixed hydroxido species at pHâ¯7.4 at 0.2â¯M KCl ionic strength. The complexes are fairly hydrophilic and show moderate chloride ion affinity and fast chloride-water exchange processes. The studied complexes exhibit no cytotoxic activity in human cancer cells (IC50â¯>â¯100⯵M), only complexes formed with 2-picolinic acid (1) and its 3-methyl derivative (2) represented a moderate antiproliferative effect (IC50â¯=â¯84.8 (1), 79.2⯵M (2)) on a multidrug resistant colon adenocarcinoma cell line revealing considerable multidrug resistant selectivity. Complexes 1 and 2 bind to human serum albumin covalently and relatively slowly with moderate strength at multiple binding sites without ligand cleavage.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Complexos de Coordenação/farmacologia , Ácidos Picolínicos/farmacologia , Rutênio/farmacologia , Tolueno/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/efeitos adversos , Complexos de Coordenação/química , Cristalografia por Raios X , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Estabilidade de Medicamentos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Cinética , Conformação Molecular , Ácidos Picolínicos/efeitos adversos , Ácidos Picolínicos/química , Rutênio/efeitos adversos , Rutênio/química , Solubilidade , Tolueno/efeitos adversos , Tolueno/químicaRESUMO
A classic response to systemic hypoxia is the increase in red blood cell production. This response is controlled by the prolyl hydroxylase domain/hypoxia-inducible factor (HIF) pathway, which regulates a broad spectrum of cellular functions. The discovery of this pathway as a key regulator of erythropoiesis has led to the development of small molecules that stimulate the production of endogenous erythropoietin and enhance iron metabolism. This review provides a concise overview of the cellular and molecular mechanisms that govern HIF-induced erythropoietic responses and provides an update on clinical experience with compounds that target HIF-prolyl hydroxylases for anemia therapy.
Assuntos
Eritropoese/efeitos dos fármacos , Prolina Dioxigenases do Fator Induzível por Hipóxia/fisiologia , Ferro/metabolismo , Inibidores de Prolil-Hidrolase/uso terapêutico , Anemia/tratamento farmacológico , Barbitúricos/efeitos adversos , Barbitúricos/uso terapêutico , Ensaios Clínicos como Assunto , Eritropoetina/biossíntese , Glicina/efeitos adversos , Glicina/análogos & derivados , Glicina/uso terapêutico , Humanos , Isoquinolinas/efeitos adversos , Isoquinolinas/uso terapêutico , Ácidos Picolínicos/efeitos adversos , Ácidos Picolínicos/uso terapêutico , Diálise Renal/efeitos adversosRESUMO
OBJECTIVE: To report a case of acute tubular necrosis associated with the use of a chromium picolinate-containing dietary supplement. CASE SUMMARY: A 24-year-old white male who had been ingesting a dietary supplement (Arsenal X) for 2 weeks during his workout sessions developed acute renal failure. Radiologic investigation showed the presence of a solitary right kidney, and an open renal biopsy confirmed features of acute tubular necrosis. He developed significant renal impairment that required hemodialysis. He was also treated with plasmapheresis and steroids, as a diagnosis of pulmonary-renal syndrome was entertained early in the disease course, which was subsequently ruled out. The patient ultimately recovered and, on outpatient visits, was noted to have normal renal function. DISCUSSION: The use of dietary supplements has become increasingly popular in the US, and these supplements are not subject to stringent premarketing testing or postmarketing surveillance. The main ingredients in the supplement discussed here were chromium picolinate, Sida cordifolia, synephrine, and guarana. An objective causality assessment using the Naranjo probability scale indicated a probable association between the use of this supplement and the development of acute renal failure in this patient. CONCLUSIONS: Current information regarding the beneficial effects of trivalent chromium is not very robust; therefore, use of this agent cannot be recommended at this time. This report serves as an important reminder to the public, as well as healthcare providers, of potential nephrotoxic reactions to dietary supplements.
Assuntos
Suplementos Nutricionais/efeitos adversos , Necrose Tubular Aguda/induzido quimicamente , Ácidos Picolínicos/efeitos adversos , Adulto , Anti-Inflamatórios/uso terapêutico , Humanos , Necrose Tubular Aguda/patologia , Masculino , Plasmaferese , Diálise Renal , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Previous research has shown that smokers have reduced brain and platelet monoamine oxidase B (MAOB) activity. This is probably due to some components of tobacco smoke. When smokers quit, MAOB activity returns to normal. Reduced MAO activity may increase nicotine's addictive potential. AIMS: To assess whether lazabemide, a reversible selective MAOB inhibitor, promotes smoking cessation. STUDY DESIGN: Double-blind, randomized, placebo-controlled, multicenter phase II study. Placebo, lazabemide 100 mg/day and 200 mg/day were administered for 8 weeks. This was a dose finding, proof-of-concept, exploratory study. SETTING: General practices and anti-smoking clinics in France and Belgium. PARTICIPANTS: Smokers smoking > or=15 cigarettes per day and motivated to quit. MAIN OUTCOME MEASURE: Sustained abstinence during the last 4 weeks of the study. FINDINGS: The study was discontinued prematurely by the sponsor before randomization of the planned 420 smokers because of liver toxicity observed in other indications. Data of 330 randomized subjects could be analysed. Sustained abstinence during the last 4 weeks of treatment was 9%, 11% and 17% in the intent-to-treat population [P for trend: 0.036 (one-sided)]; 11%, 14% and 21% in the intent-to-treat population of smokers without those excluded because of discontinuation of the study [n = 262, P for trend: 0.02 (one-sided)], and 19%, 27% and 35% in completers [P for trend: 0.03 (one-sided)], in the placebo, lazabemide 100 mg/day and lazabemide 200 mg/day groups, respectively. Point prevalence abstinence (intent-to-treat population) at the end of treatment (week 8) was 17%, 19% and 30% in the placebo, lazabemide 100 mg/day and lazabemide 200 mg/day groups, respectively (placebo vs. lazabemide 200 mg/day: P = 0.01, one-sided). No treatment emergent major adverse event occurred. More nausea and insomnia were reported with lazabemide than with placebo. CONCLUSIONS: MAOB inhibitors are promising treatments as an aid in smoking cessation. There may be an interest to develop MAOB inhibitors with an acceptable toxicity profile. Further studies may associate MAOB inhibitors with nicotine replacement therapies to increase therapeutic efficacy.
Assuntos
Inibidores da Monoaminoxidase/uso terapêutico , Ácidos Picolínicos/uso terapêutico , Abandono do Hábito de Fumar/métodos , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Monoaminoxidase/efeitos adversos , Ácidos Picolínicos/efeitos adversosRESUMO
OBJECTIVE: To describe a case of toxicity secondary to chronic ingestion of 6-12 times the recommended daily allowance of over-the-counter (OTC) chromium picolinate. CASE SUMMARY: A 33-year-old white woman presented with weight loss, anemia, thrombocytopenia, hemolysis, liver dysfunction (aminotransferase enzymes 15-20 times normal, total bilirubin 3 times normal), and renal failure (serum creatinine 5.3 mg/dL; blood urea nitrogen 152 mg/dL). She had ingested chromium picolinate 1200-2400 microg/d for the previous 4-5 months to enhance weight loss. The patient had chromium plasma concentrations 2-3 times normal. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome were ruled out by clinical findings, peripheral blood smears, and a bone marrow biopsy. The patient was managed with supportive measures and received blood product transfusions and hemodialysis. Hemolysis stabilized and liver function improved over 6 days. Liver function returned to normal prior to discharge. Renal function began to return on day 12 and her serum creatinine on discharge was 1.3 mg/dL. One year later, all laboratory values were within normal limits. DISCUSSION: Trivalent chromium is an essential trace element that is considered safe when ingested in normal quantities. Trivalent chromium compounds are used by patients to enhance weight loss, increase lean body mass, and/or improve glycemic control. Information regarding the toxicity of chromium picolinate is limited. CONCLUSIONS: Chromium supplements may cause serious renal impairment when ingested in excess. Medication histories should include attention to the use of OTC nutritional supplements often regarded as harmless by the public and lay media.
Assuntos
Quelantes de Ferro/efeitos adversos , Ácidos Picolínicos/efeitos adversos , Injúria Renal Aguda/fisiopatologia , Adulto , Contagem de Células Sanguíneas , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Overdose de Drogas , Feminino , Hemólise/efeitos dos fármacos , Humanos , Medicamentos sem Prescrição , Trombocitopenia/induzido quimicamenteAssuntos
Ácidos Picolínicos/uso terapêutico , Sarcoma/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Ácidos Picolínicos/administração & dosagem , Ácidos Picolínicos/efeitos adversos , Rabdomiossarcoma/tratamento farmacológicoRESUMO
Thirty-seven children with various malignant neoplasms were treated with 1-acetyl-2-picolinoylhydrazine. Complete regressions were documented in one child with embryonal rhabdomyosarcoma, in one child with generalized histiocytosis-X, and in one child with Hodgkin's disease. One patient had renal failure while receiving the drug but no conclusive cause and effect relationship could be established. Toxic effects otherwise were mild and consisted primarily of nausea and vomiting.