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1.
Am J Nephrol ; 53(10): 701-710, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36450264

RESUMO

INTRODUCTION: Anemia frequently occurs in chronic kidney disease (CKD), is associated with poor quality of life and cardiovascular outcomes, and its treatment represents a considerable economic burden to the healthcare system. Although effective, the current standard of care for the treatment of anemia in chronic kidney disease patients with erythropoiesis-stimulating agents requires chronic/ongoing injections, making the treatment less accessible or desirable to patients not treated by in-center maintenance hemodialysis. Furthermore, safety concerns, including an increased risk of cardiovascular events and mortality, have emerged from their use in studies targeting hemoglobin concentrations in the normal or near-normal range. The orally active hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat may offer advantages over erythropoiesis-stimulating agents by correcting anemia via pathways activating endogenous erythropoietin production. METHODS: To comprehensively analyze the safety profile of vadadustat in patients with dialysis-dependent and non-dialysis-dependent CKD-related anemia, we pooled the safety populations from each of the four trials in the phase 3 clinical program (n = 7,373) and compared the risk of treatment-emergent adverse events (TEAEs) for each treatment arm. RESULTS: In patients randomized to vadadustat versus darbepoetin alfa, rates of TEAEs (88.9% vs. 89.3%), treatment-emergent serious adverse events (58.0% vs. 59.3%), and TEAEs leading to death (16.1% vs. 16.2%) were similar, as were rates of adverse events of special interest, including cardiovascular-, hepatic-, and neoplasm-related adverse events. DISCUSSION/CONCLUSION: Among patients with CKD-related anemia treated with vadadustat, we observed similar rates of adverse events relative to those treated with darbepoetin alfa.


Assuntos
Anemia , Eritropoetina , Hematínicos , Insuficiência Renal Crônica , Humanos , Darbepoetina alfa/efeitos adversos , Qualidade de Vida , Anemia/tratamento farmacológico , Anemia/etiologia , Eritropoetina/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Hematínicos/efeitos adversos , Diálise Renal/efeitos adversos , Hemoglobinas/análise
2.
Alzheimers Dement (N Y) ; 6(1): e12107, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33344752

RESUMO

INTRODUCTION: Allopregnanolone is an endogenous neurosteroid with the potential to be a novel regenerative therapeutic for Alzheimer's disease (AD). Foundations of mechanistic understanding and well-established preclinical safety efficacy make it a viable candidate. METHODS: A randomized, double-blinded, placebo-controlled, single and multiple ascending dose trial was conducted. Intravenous allopregnanolone or placebo was administered once-per-week for 12 weeks with a 1-month follow-up. Participants with early AD (mild cognitive impairment due to AD or mild AD), a Mini-Mental State Examination score of 20-26 inclusive, and age ≥55 years were randomized (6:2 to three allopregnanolone dosing cohorts or one placebo cohort). Primary endpoint was safety and tolerability. Secondary endpoints included pharmacokinetic (PK) parameters and maximally tolerated dose (MTD). Exploratory endpoints included cognitive and imaging biomarkers. RESULTS: A total of 24 participants completed the trial. Allopregnanolone was safe and well tolerated in all study participants. No differences were observed between treatment arms in the occurrence and severity of adverse events (AE). Most common AE were mild to moderate in severity and included rash (n = 4 [22%]) and fatigue (n = 3 [17%]). A single non-serious AE, dizziness, was attributable to treatment. There was one serious AE not related to treatment. Pharmacokinetics indicated a predictable linear dose-response in plasma concentration of allopregnanolone after intravenous administration over 30 minutes. The maximum plasma concentrations for the 2 mg, 4 mg, 6 mg, and 10 mg dosages were 14.53 ng/mL (+/-7.31), 42.05 ng/mL (+/-14.55), 60.07 ng/mL (+/-12.8), and 137.48 ng/mL (+/-38.69), respectively. The MTD was established based on evidence of allopregnanolone-induced mild sedation at the highest doses; a sex difference in the threshold for sedation was observed (males 10 mg; females 14 mg). No adverse outcomes on cognition or magnetic resonance imaging-based imaging outcomes were evident. CONCLUSIONS: Allopregnanolone was well tolerated and safe across all doses in persons with early AD. Safety, MTD, and PK profiles support advancement of allopregnanolone as a regenerative therapeutic for AD to a phase 2 efficacy trial. TRIAL REGISTRATION: ClinicalTrials.gov-NCT02221622.

3.
PLoS One ; 10(6): e0128313, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26039057

RESUMO

To develop allopregnanolone as a therapeutic for Alzheimer's disease, we investigated multiple formulations and routes of administration in translationally relevant animal models of both sexes. Subcutaneous, topical (transdermal and intranasal), intramuscular, and intravenous allopregnanolone were bolus-administered. Pharmacokinetic analyses of intravenous allopregnanolone in rabbit and mouse indicated that peak plasma and brain levels (3-fold brain/plasma ratios) at 5min were sufficient to activate neuroregenerative responses at sub-sedative doses. Slow-release subcutaneous suspension of allopregnanolone displayed 5-fold brain/plasma ratio at Cmax at 30min. At therapeutic doses by either subcutaneous or intravenous routes, allopregnanolone mouse plasma levels ranged between 34-51ng/ml by 30min, comparable to published endogenous human level in the third trimester of pregnancy. Exposure to subcutaneous, topical, intramuscular, and intravenous allopregnanolone, at safe and tolerable doses, increased hippocampal markers of neurogenesis including BrdU and PCNA in young 3xTgAD and aged wildtype mice. Intravenous allopregnanolone transiently and robustly phosphorylated CREB within 5min and increased levels of neuronal differentiation transcription factor NeuroD within 4h. Neurogenic efficacy was achieved with allopregnanolone brain exposure of 300-500hr*ng/g. Formulations were tested to determine the no observable adverse effect level (NOAEL) and maximally tolerated doses (MTD) in male and female rats by sedation behavior time course. Sex differences were apparent, males exhibited ≥40% more sedation time compared to females. Allopregnanolone formulated in sulfobutyl-ether-beta-cyclodextrin at optimized complexation ratio maximized allopregnanolone delivery and neurogenic efficacy. To establish the NOAEL and MTD for Allo-induced sedation using a once-per-week intravenous regenerative treatment regimen: In female rats the NOAEL was 0.5mg/kg and MTD 2mg/kg. The predicted MTD in human female is 0.37mg/kg. In male rats the NOAEL and MTD were less than those determined for female. Outcomes of these PK/PD studies predict a safe and efficacious dose range for initial clinical trials of allopregnanolone for Alzheimer's disease. These findings have translational relevance to multiple neurodegenerative conditions.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Pregnanolona/farmacocinética , Pregnanolona/uso terapêutico , Doença de Alzheimer/patologia , Animais , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Bromodesoxiuridina/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Ciclodextrinas/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/efeitos dos fármacos , Nível de Efeito Adverso não Observado , Fosforilação/efeitos dos fármacos , Pregnanolona/efeitos adversos , Pregnanolona/farmacologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Coelhos , Ratos Sprague-Dawley , Resultado do Tratamento
4.
Alzheimers Dement ; 11(10): 1212-21, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25676387

RESUMO

INTRODUCTION: Data obtained in completed Alzheimer's disease (AD) clinical trials can inform decision making for future trials. Recognizing the importance of sharing these data, the Coalition Against Major Diseases created an Online Data Repository for AD (CODR-AD) with the aim of supporting accelerated drug development. The aim of this study was to build an open access, standardized database from control arm data collected across many clinical trials. METHODS: Comprehensive AD-specific data standards were developed to enable the pooling of data from different sources. Nine member organizations contributed patient-level data from 24 clinical trials of AD treatments. RESULTS: CODR-AD consists of control arm pooled and standardized data from 24 trials currently numbered at 6500 subjects; Alzheimer's Disease Assessment Scale-cognitive subscale 11 is the main outcome and specific covariates are also included. DISCUSSION: CODR-AD represents a unique integrated standardized clinical trials database available to qualified researchers. The pooling of data across studies facilitates a more comprehensive understanding of disease heterogeneity.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ensaios Clínicos como Assunto , Bases de Dados Factuais , Cognição , Tomada de Decisões , Humanos , Internet , Padrões de Referência , Estatística como Assunto
5.
Front Cell Neurosci ; 8: 203, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25126056

RESUMO

Allopregnanolone (Allo), a neurosteroid, has emerged as a promising promoter of endogenous regeneration in brain. In a mouse model of Alzheimer's disease, Allo induced neurogenesis, oligodendrogenesis, white matter generation and cholesterol homeostasis while simultaneously reducing ß-amyloid and neuroinflammatory burden. Allo activates signaling pathways and gene expression required for regeneration of neural stem cells and their differentiation into neurons. In parallel, Allo activates systems to sustain cholesterol homeostasis and reduce ß-amyloid generation. To advance Allo into studies for chronic human neurological conditions, we examined translational and clinical parameters: dose, regimen, route, formulation, outcome measures, and safety regulations. A treatment regimen of once per week at sub-sedative doses of Allo was optimal for regeneration and reduction in Alzheimer's pathology. This regimen had a high safety profile following chronic exposure in aged normal and Alzheimer's mice. Formulation of Allo for multiple routes of administration has been developed for both preclinical and clinical testing. Preclinical evidence for therapeutic efficacy of Allo spans multiple neurological diseases including Alzheimer's, Parkinson's, multiple sclerosis, Niemann-Pick, diabetic neuropathy, status epilepticus, and traumatic brain injury. To successfully translate Allo as a therapeutic for multiple neurological disorders, it will be necessary to tailor dose and regimen to the targeted therapeutic mechanisms and disease etiology. Treatment paradigms conducted in accelerated disease models in young animals have a low probability of successful translation to chronic diseases in adult and aged humans. Gender, genetic risks, stage and burden of disease are critical determinants of efficacy. This review focuses on recent advances in development of Allo for Alzheimer's disease (AD) that have the potential to accelerate therapeutic translation for multiple unmet neurological needs.

6.
J Cereb Blood Flow Metab ; 29(6): 1084-98, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19319146

RESUMO

Our laboratory has shown that peripheral inflammatory pain induced by lambda-carrageenan (CIP) can increase blood-brain barrier (BBB) permeability and alter tight junction (TJ) protein expression leading to changes in BBB functional integrity. However, the intracellular signaling mechanisms involved in this pathophysiologic response have not been elucidated. Transforming growth factor (TGF)-beta signaling pathways are known to regulate vascular integrity and permeability. Therefore, we examined the function of TGF-beta signaling at the BBB in rats subjected to CIP. During CIP, serum TGF-beta1 and protein expression of the TGF-beta receptor activin receptor-like kinase-5 (ALK5) were reduced. Brain permeability to (14)C-sucrose was increased and expression of TJ proteins (i.e., claudin-5, occludin, zonula occluden (ZO-1)) were also altered after 3 h CIP. Pharmacological inhibition of ALK5 with the selective inhibitor SB431542 further enhanced brain uptake of (14)C-sucrose, increased TJ protein expression (i.e., claudin-3, claudin-5, occludin, ZO-1), and decreased nuclear expression of TGF-beta/ALK5 signaling molecules (i.e., Smad2, Smad3), which suggests a role for TGF-beta/ALK5 signaling in the regulation of BBB integrity. Interestingly, administration of exogenous TGF-beta1 before CIP activated the TGF-beta/ALK5 pathway and reduced BBB permeability to (14)C-sucrose. Taken together, our data show that TGF-beta/ALK5 signaling is, in part, involved in the regulation of BBB functional integrity.


Assuntos
Barreira Hematoencefálica/metabolismo , Inflamação/complicações , Dor/etiologia , Dor/metabolismo , Transdução de Sinais , Junções Íntimas/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Receptores de Ativinas/metabolismo , Animais , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Carragenina/farmacologia , Edema/induzido quimicamente , Edema/metabolismo , Feminino , Temperatura Alta , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases , Ratos , Ratos Sprague-Dawley , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta , Proteínas Smad/metabolismo , Especificidade por Substrato , Sacarose/metabolismo
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