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1.
N Engl J Med ; 381(10): 933-944, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31483964

RESUMO

BACKGROUND: Pyruvate kinase deficiency is caused by mutations in PKLR and leads to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase in red cells. METHODS: In this uncontrolled, phase 2 study, we evaluated the safety and efficacy of mitapivat in 52 adults with pyruvate kinase deficiency who were not receiving red-cell transfusions. The patients were randomly assigned to receive either 50 mg or 300 mg of mitapivat twice daily for a 24-week core period; eligible patients could continue treatment in an ongoing extension phase. RESULTS: Common adverse events, including headache and insomnia, occurred at the time of drug initiation and were transient; 92% of the episodes of headache and 47% of the episodes of insomnia resolved within 7 days. The most common serious adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients (4%). A total of 26 patients (50%) had an increase of more than 1.0 g per deciliter in the hemoglobin level. Among these patients, the mean maximum increase was 3.4 g per deciliter (range, 1.1 to 5.8), and the median time until the first increase of more than 1.0 g per deciliter was 10 days (range, 7 to 187); 20 patients (77%) had an increase of more than 1.0 g per deciliter in the hemoglobin level at more than 50% of visits during the core study period, with improvement in markers of hemolysis. The response was sustained in all 19 patients remaining in the extension phase, with a median follow-up of 29 months (range, 22 to 35). Hemoglobin responses were observed only in patients who had at least one missense PKLR mutation and were associated with the red-cell pyruvate kinase protein level at baseline. CONCLUSIONS: The administration of mitapivat was associated with a rapid increase in the hemoglobin level in 50% of adults with pyruvate kinase deficiency, with a sustained response during a median follow-up of 29 months during the extension phase. Adverse effects were mainly low-grade and transient. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02476916.).


Assuntos
Anemia Hemolítica Congênita não Esferocítica/tratamento farmacológico , Hemoglobinas/metabolismo , Piperazinas/administração & dosagem , Piruvato Quinase/deficiência , Erros Inatos do Metabolismo dos Piruvatos/tratamento farmacológico , Quinolinas/administração & dosagem , Administração Oral , Adolescente , Adulto , Anemia Hemolítica Congênita não Esferocítica/sangue , Anemia Hemolítica Congênita não Esferocítica/genética , Catecóis , Esquema de Medicação , Feminino , Seguimentos , Cefaleia/induzido quimicamente , Humanos , Masculino , Mutação , Piperazinas/efeitos adversos , Piruvato Quinase/sangue , Piruvato Quinase/genética , Erros Inatos do Metabolismo dos Piruvatos/sangue , Erros Inatos do Metabolismo dos Piruvatos/genética , Quinolinas/efeitos adversos , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Tirfostinas , Adulto Jovem
2.
Genet Med ; 18(1): 73-81, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25834948

RESUMO

PURPOSE: Approximately two-thirds of patients with the lysosomal storage disease mucopolysaccharidosis II have progressive cognitive impairment. Intravenous (i.v.) enzyme replacement therapy does not affect cognitive impairment because recombinant iduronate-2-sulfatase (idursulfase) does not penetrate the blood-brain barrier at therapeutic concentrations. We examined the safety of idursulfase formulated for intrathecal administration (idursulfase-IT) via intrathecal drug delivery device (IDDD). A secondary endpoint was change in concentration of glycosaminoglycans in cerebrospinal fluid. METHODS: Sixteen cognitively impaired males with mucopolysaccharidosis II who were previously treated with weekly i.v. idursulfase 0.5 mg/kg for ≥6 months were enrolled. Patients were randomized to no treatment or 10-mg, 30-mg, or 1-mg idursulfase-IT monthly for 6 months (four patients per group) while continuing i.v. idursulfase weekly. RESULTS: No serious adverse events related to idursulfase-IT were observed. Surgical revision/removal of the IDDD was required in 6 of 12 patients. Twelve total doses were administrated by lumbar puncture. Mean cerebrospinal fluid glycosaminoglycan concentration was reduced by approximately 90% in the 10-mg and 30-mg groups and approximately 80% in the 1-mg group after 6 months. CONCLUSIONS: These preliminary data support further development of investigational idursulfase-IT in MPS II patients with the severe phenotype who have progressed only to a mild-to-moderate level of cognitive impairment.Genet Med 18 1, 73-81.


Assuntos
Iduronato Sulfatase/administração & dosagem , Mucopolissacaridose II/tratamento farmacológico , Criança , Pré-Escolar , Terapia de Reposição de Enzimas , Feminino , Glicosaminoglicanos/líquido cefalorraquidiano , Humanos , Iduronato Sulfatase/efeitos adversos , Iduronato Sulfatase/líquido cefalorraquidiano , Iduronato Sulfatase/farmacocinética , Injeções Espinhais , Masculino , Mucopolissacaridose II/sangue , Mucopolissacaridose II/líquido cefalorraquidiano , Mucopolissacaridose II/metabolismo
3.
Mol Genet Metab ; 118(2): 65-9, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27132782

RESUMO

Well-defined and reliable clinical outcome assessments are essential for determining whether a drug provides clinically meaningful treatment benefit for patients. In 2015, FDA convened a workshop, "Assessing Neurocognitive Outcomes in Inborn Errors of Metabolism." Topics covered included special challenges of clinical studies of inborn errors of metabolism (IEMs) and other rare diseases; complexities of identifying treatment effects in the context of the dynamic processes of child development and disease progression; and the importance of natural history studies. Clinicians, parents/caregivers, and participants from industry, academia, and government discussed factors to consider when developing measures to assess treatment outcomes, as well as tools and methods that may contribute to standardizing measures. Many issues examined are relevant to the broader field of rare diseases in addition to specifics of IEMs.


Assuntos
Testes de Estado Mental e Demência/normas , Erros Inatos do Metabolismo/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Doenças Raras/tratamento farmacológico , Cuidadores , Criança , Desenvolvimento Infantil , Ensaios Clínicos como Assunto , Progressão da Doença , Humanos , National Institutes of Health (U.S.) , Pais , Tecnologia de Sensoriamento Remoto , Estados Unidos , United States Food and Drug Administration
4.
Mol Genet Metab ; 118(3): 198-205, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27211612

RESUMO

OBJECTIVE: This was an open-label, phase 1/2 dose-escalation, safety trial of intrathecal recombinant human heparan-N-sulfatase (rhHNS) administered via intrathecal drug delivery device (IDDD) for treating mucopolysaccharidosis IIIA (NCT01155778). STUDY DESIGN: Twelve patients received 10, 45, or 90mg of rhHNS via IDDD once monthly for a total of 6 doses. Primary endpoints included adverse events (AEs) and anti-rhHNS antibodies. Secondary endpoints included standardized neurocognitive assessments, cortical gray matter volume, and pharmacokinetic/pharmacodynamic analyses. RESULTS: All patients experienced treatment-emergent AEs; most of mild-to-moderate severity. Seven patients reported a total of 10 serious AEs (SAEs), all but one due to hospitalization to revise a nonfunctioning IDDD. No SAEs were considered related to rhHNS. Anti-rhHNS antibodies were detected in the serum of 6 patients and in the cerebrospinal fluid (CSF) of 2 of these. CSF heparan sulfate levels were elevated at baseline and there were sustained declines in all tested patients following the first rhHNS dose. No impact of anti-rhHNS antibodies on any pharmacodynamic or safety parameters was evident. 4 of 12 patients showed a decline in developmental quotient, 6 were stable, and 2 patients had only a single data point. No dose group showed a clearly different response pattern. CONCLUSIONS: rhHNS administration via IDDD appeared generally safe and well tolerated. Treatment resulted in consistent declines in CSF heparan sulfate, suggesting in vivo activity in the relevant anatomical compartment. Results of this small study should be interpreted with caution. Future studies are required to assess the potential clinical benefits of rhHNS and to test improved IDDD models.


Assuntos
Heparitina Sulfato/líquido cefalorraquidiano , Mucopolissacaridose III/tratamento farmacológico , Sulfatases/administração & dosagem , Adolescente , Anticorpos/sangue , Anticorpos/líquido cefalorraquidiano , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Espinhais/instrumentação , Masculino , Mucopolissacaridose III/líquido cefalorraquidiano , Sulfatases/efeitos adversos , Sulfatases/imunologia , Resultado do Tratamento , Adulto Jovem
5.
Nat Biotechnol ; 40(6): 840-854, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35534554

RESUMO

The emergency use authorizations (EUAs) of two mRNA-based severe acute respiratory syndrome coronavirus (SARS-CoV)-2 vaccines approximately 11 months after publication of the viral sequence highlights the transformative potential of this nucleic acid technology. Most clinical applications of mRNA to date have focused on vaccines for infectious disease and cancer for which low doses, low protein expression and local delivery can be effective because of the inherent immunostimulatory properties of some mRNA species and formulations. In addition, work on mRNA-encoded protein or cellular immunotherapies has also begun, for which minimal immune stimulation, high protein expression in target cells and tissues, and the need for repeated administration have led to additional manufacturing and formulation challenges for clinical translation. Building on this momentum, the past year has seen clinical progress with second-generation coronavirus disease 2019 (COVID-19) vaccines, Omicron-specific boosters and vaccines against seasonal influenza, Epstein-Barr virus, human immunodeficiency virus (HIV) and cancer. Here we review the clinical progress of mRNA therapy as well as provide an overview and future outlook of the transformative technology behind these mRNA-based drugs.


Assuntos
COVID-19 , Infecções por Vírus Epstein-Barr , Vacinas contra Influenza , COVID-19/prevenção & controle , Vacinas contra COVID-19/uso terapêutico , Herpesvirus Humano 4 , Humanos , Imunização Secundária , RNA Mensageiro/genética , Vacinas Sintéticas , Vacinas de mRNA
6.
Clin Pharmacol Drug Dev ; 8(2): 246-259, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30091852

RESUMO

Pyruvate kinase deficiency is a chronic hemolytic anemia caused by mutations in PK-R, a key glycolytic enzyme in erythrocytes. These 2 phase 1 randomized, placebo-controlled, double-blind healthy-volunteer studies assessed the safety, tolerability, and pharmacokinetics/pharmacodynamics of AG-348, a first-in-class allosteric PK-R activator. Twelve sequential cohorts were randomized 2:6 to receive oral placebo or AG-348, respectively, as a single dose (30-2500 mg) in the single-ascending-dose (SAD) study (ClinicalTrials.gov: NCT02108106) or 15-700 mg every 12 hours or 120 mg every 24 hours, for 14 days in the multiple-ascending-dose (MAD) study (ClinicalTrials.gov: NCT02149966). All 48 subjects completed the fasted SAD part; 44 of 48 completed the MAD (2 discontinued because of adverse events [AEs], 2 withdrew consent). The most common treatment-related AEs in AG-348-treated subjects were headache (16.7% [SAD] and 13.9% [MAD]) and nausea (13.9%, both studies). AE frequency increased at AG-348 doses ≥ 700 mg (SAD) and at 700 mg every 12 hours (MAD); 1 grade ≥ 3 AE occurred in the latter cohort. Pharmacokinetics were favorable with low variability. Dose-dependent changes in blood glycolytic intermediates consistent with glycolytic pathway activation were observed at all MAD doses, supporting future trials investigating the potential of AG-348 for treating PK deficiency or other anemias.


Assuntos
Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Quinolinas/administração & dosagem , Quinolinas/farmacocinética , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Glicólise , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Quinolinas/efeitos adversos
7.
Eur J Pharmacol ; 587(1-3): 141-6, 2008 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-18499098

RESUMO

Triple reuptake inhibitors, which block the serotonin transporter (SERT), norepinephrine transporter (NET) and dopamine transporter (DAT) in the central nervous system have been described as therapeutic alternatives for classical selective serotonin reuptake inhibitors, with advantages due to their multiple mechanisms of action. JNJ-7925476 (trans-6-(4-ethynylphenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline) is a selective and potent inhibitor of the SERT, NET, and DAT (K(i)=0.9, 17 and 5.2 nM, respectively). Following subcutaneous dosing in rat, JNJ-7925476 was rapidly absorbed into the plasma, and drug concentrations in the brain tracked with those in the plasma but were 7-fold higher. The ED(50) values for JNJ-7925476 occupancy of the SERT, NET, and DAT in rat brain were 0.18, 0.09 and 2.4 mg/kg, respectively. JNJ-7925476 (0.1-10 mg/kg, s.c.) rapidly induced a robust, dose-dependent increase in extracellular serotonin, dopamine, and norepinephrine levels in rat cerebral cortex. The compound also showed potent antidepressant-like activity in the mouse tail suspension test (ED(50)=0.3 mg/kg, i.p.). These results demonstrate that JNJ-7925476 is a triple reuptake inhibitor with in-vivo efficacy in biochemical and behavioral models of depression.


Assuntos
Isoquinolinas/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Pirróis/farmacologia , Animais , Área Sob a Curva , Autorradiografia , Barreira Hematoencefálica/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Linhagem Celular Tumoral , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Elevação dos Membros Posteriores , Humanos , Isoquinolinas/química , Isoquinolinas/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microdiálise , Atividade Motora/efeitos dos fármacos , Inibidores da Captação de Neurotransmissores/química , Inibidores da Captação de Neurotransmissores/farmacocinética , Pirróis/química , Pirróis/farmacocinética , Ratos , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Estereoisomerismo
9.
Bioorg Med Chem ; 16(6): 2968-73, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18249544

RESUMO

Currently, the only clinically effective treatment for Alzheimer's disease (AD) is the use of acetylcholinesterase (AChE) inhibitors. These inhibitors have limited efficacy in that they only treat the symptoms and not the disease itself. Additionally, they often have unpleasant side effects. Here we consider the viability of a single molecule having the actions of both an AChE inhibitor and histamine H(3) receptor antagonist. Both histamine H(3) receptor antagonists and AChE inhibitors improve and augment cholinergic neurotransmission in the cortex. However, whereas an AChE inhibitor will impart its effect everywhere, a histamine H(3) antagonist will raise acetylcholine levels mostly in the brain as its mode of action will primarily be on the central nervous system. Therefore, the combination of both activities in a single molecule could be advantageous. Indeed, studies suggest an appropriate dual-acting compound may offer the desired therapeutic effect with fewer unpleasant side effects [CNS Drugs2004, 18, 827]. Further, recent studies(2) indicate the peripheral anionic site (PAS) of AChE interacts with the beta-amyloid (betaA) peptide. Consequently, a molecule capable of disrupting this interaction may have a significant impact on the production of or the aggregation of betaA. This may result in slowing down the progression of the disease rather than only treating the symptoms as current therapies do. Here, we detail how the use of the available crystal structure information, pharmacophore modeling and docking (automated, manual, classical, and QM/MM) lead to the identification of an AChE inhibitor-histamine H(3) receptor antagonist. Further, based on our models we speculate that this dual-acting compound may interact with the PAS. Such a dual-acting compound may be able to affect the pathology of AD in addition to providing symptomatic relief.


Assuntos
Inibidores da Colinesterase/química , Antagonistas dos Receptores Histamínicos H3/química , Modelos Moleculares , Doença de Alzheimer/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Relação Quantitativa Estrutura-Atividade
10.
Eur J Pharmacol ; 576(1-3): 43-54, 2007 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-17765221

RESUMO

Wake-promoting agents such as modafinil are used in the clinic as adjuncts to antidepressant therapy in order to alleviate lethargy. The wake-promoting action of histamine H(3) receptor antagonists has been evidenced in numerous animal studies. They may therefore be a viable strategy for use as an antidepressant therapy in conjunction with selective serotonin reuptake inhibitors. JNJ-28583867 (2-Methyl-4-(4-methylsulfanyl-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline) is a selective and potent histamine H(3) receptor antagonist (K(i)=10.6 nM) and inhibitor of the serotonin transporter (SERT) (K(i)=3.7 nM), with 30-fold selectivity for SERT over the dopamine and norepinephrine transporters. After subcutaneous administration, JNJ-28583867 occupied both the histamine H(3) receptor and the SERT in rat brain at low doses (<1 mg/kg). JNJ-28583867 blocked imetit-induced drinking (3-10 mg/kg i.p.), confirming in vivo functional activity at the histamine H(3) receptor and also significantly increased cortical extracellular levels of serotonin at doses of 0.3 mg/kg (s.c.) and higher. Smaller increases in cortical extracellular levels of norepinephrine and dopamine were also observed. JNJ-28583867 (3-30 mg/kg p.o.) showed antidepressant-like activity in the mouse tail suspension test. JNJ-28583867 (1-3 mg/kg s.c.) caused a dose-dependent increase in the time spent awake mirrored by a decrease in NREM. Concomitantly, JNJ-28583867 produced a potent suppression of REM sleep from the dose of 1 mg/kg onwards. JNJ-28583867 has good oral bioavailability in the rat (32%), a half-life of 6.9 h and a C(max) of 260 ng/ml after 10 mg/kg p.o. In summary, JNJ-28583867 is a combined histamine H(3) receptor antagonist-SERT inhibitor with in vivo efficacy in biochemical and behavioral models of depression and wakefulness.


Assuntos
Antagonistas dos Receptores Histamínicos/farmacologia , Receptores Histamínicos H3/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Cães , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Antagonistas dos Receptores Histamínicos/farmacocinética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Tetra-Hidroisoquinolinas/farmacocinética
11.
Ther Innov Regul Sci ; 51(2): 257-263, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30231724

RESUMO

While planning for a successful clinical trial in a prevalent condition is no trivial orchestration, even more complicated is the coordination of novel, delicate and critical operational components necessary for the successful conduct of clinical trials of rare disease (RD). We highlight some of the inherent and practical challenges to conducting clinical trials and selecting or developing endpoints for RD and the importance of including the patient voice or perspective. These challenges include the lack of regulatory precedent for proposed endpoints, a void of available measures, little or no published literature or natural history information, the practicalities of obtaining access to patients, and the appropriateness of placebo-controlled trials. As part of our review, we include practical considerations for addressing these issues along with a regulatory perspective regarding potential logistic and methodologic challenges. We conclude that the patient perspective is a critical component in defining treatment benefit and in interpreting the meaningfulness of a change (or lack thereof). Engaging with patients is needed at multiple steps along the long road of drug discovery.

12.
Br J Pharmacol ; 148(1): 102-13, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16501580

RESUMO

1 The reversible fatty acid amide hydrolase (FAAH) inhibitor OL135 reverses mechanical allodynia in the spinal nerve ligation (SNL) and mild thermal injury (MTI) models in the rat. The purpose of this study was to investigate the role of the cannabinoid and opioid systems in mediating this analgesic effect. 2 Elevated brain concentrations of anandamide (350 pmol g(-1) of tissue vs 60 pmol g(-1) in vehicle-treated controls) were found in brains of rats given OL135 (20 mg kg(-1)) i.p. 15 min prior to 20 mg kg(-1) i.p. anandamide. 3 Predosing rats with OL135 (2-60 mg kg(-1) i.p.) 30 min before administration of an irreversible FAAH inhibitor (URB597: 0.3 mg kg(-1) intracardiac) was found to protect brain FAAH from irreversible inactivation. The level of enzyme protection was correlated with the OL135 concentrations in the same brains. 4 OL135 (100 mg kg(-1) i.p.) reduced by 50% of the maximum possible efficacy (MPE) mechanical allodynia induced by MTI in FAAH(+/+)mice (von Frey filament measurement) 30 min after dosing, but was without effect in FAAH(-/-) mice. 5 OL135 given i.p. resulted in a dose-responsive reversal of mechanical allodynia in both MTI and SNL models in the rat with an ED(50) between 6 and 9 mg kg(-1). The plasma concentration at the ED(50) in both models was 0.7 microM (240 ng ml(-1)). 6 In the rat SNL model, coadministration of the selective CB(2) receptor antagonist SR144528 (5 mg kg(-1) i.p.), with 20 mg kg(-1) OL135 blocked the OL135-induced reversal of mechanical allodynia, but the selective CB(1) antagonist SR141716A (5 mg kg(-1) i.p.) was without effect. 7 In the rat MTI model neither SR141716A or SR144528 (both at 5 mg kg(-1) i.p.), or a combination of both antagonists coadministered with OL135 (20 mg kg(-1)) blocked reversal of mechanical allodynia assessed 30 min after dosing. 8 In both the MTI model and SNL models in rats, naloxone (1 mg kg(-1), i.p. 30 min after OL135) reversed the analgesia (to 15% of control levels in the MTI model, to zero in the SNL) produced by OL135.


Assuntos
Amidoidrolases/antagonistas & inibidores , Analgésicos/farmacologia , Dor/prevenção & controle , Piridinas/farmacologia , Amidoidrolases/genética , Amidoidrolases/metabolismo , Animais , Ácidos Araquidônicos/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Relação Dose-Resposta a Droga , Endocanabinoides , Inibidores Enzimáticos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor/enzimologia , Medição da Dor , Alcamidas Poli-Insaturadas/metabolismo , Ratos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Medula Espinal/enzimologia
13.
Nucl Med Biol ; 33(6): 801-10, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16934699

RESUMO

The potent histamine H(3) receptor antagonist JNJ-10181457 (1) was successfully labeled with (11)C in a novel one-pot reaction sequence, with high chemical yield (decay-corrected yield, 28+/-8%) and high specific radioactivity (56+/-26 GBq/mumol). The binding of [(11)C]1 to H(3) receptors was studied in vitro in rat brain and in vivo in rats and mice. The in vitro binding of [(11)C]1 in rat coronal brain slices showed high binding in the striatum, and this binding was blocked by histamine and by two known H(3) antagonists, JNJ-5207852 (2) and unlabeled Compound (1), in a concentration-dependent manner. The biodistribution of [(11)C]1 in rats was measured at 5, 10, 30 and 60 min. The uptake of [(11)C]1 in regions rich in H(3) receptors was highest at 30 min, giving 0.98%, 1.41%, 1.28% and 1.72% dose/g for the olfactory bulb, hippocampus, striatum and cerebral cortex, respectively. However, the binding of [(11)C]1 in the rat brain could not be blocked by pretreatment with either Compound (2) (30 min or 24 h pretreatment) or cold Compound (1) (30-min pretreatment). The biodistribution of [(11)C]1 in a second species (Balb/c mice) showed a higher overall uptake of the radioligand with an average brain uptake of 8.9% dose/g. In C57BL/6-H(3)(-/-) knockout mice, a higher brain uptake was also observed. Analyses of metabolites and plasma protein binding were also undertaken. It appeared that [(11)C]1 could not specifically label H(3) receptors in rodent brain in vivo. Possible causes are discussed.


Assuntos
Radioisótopos de Carbono , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacocinética , Morfolinas/síntese química , Morfolinas/farmacocinética , Piperidinas/síntese química , Piperidinas/farmacocinética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , Receptores Histamínicos H3/metabolismo , Animais , Autorradiografia , Encéfalo/metabolismo , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Distribuição Tecidual
14.
Bioanalysis ; 8(4): 285-95, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26847798

RESUMO

AIMS: Heparan sulfate (HS) accumulates in the central nervous system in mucopolysaccharidosis III type A (MPS IIIA). A validated LC-MS/MS assay was developed to measure HS in human cerebrospinal fluid (CSF). METHODS & RESULTS: HS was extracted and digested and the resultant disaccharides were derivatized with a novel label, 4-butylaniline, enabling isoform separation and isotope-tagged analog introduction as an internal standard for LC-MS/MS. The assay has a LLOQ for disaccharides of 0.1 µM, ±20% accuracy and ≤20% precision. CSF samples from patients with MPS IIIA showed elevated HS levels (mean 4.9 µM) compared with negative controls (0.37 µM). CONCLUSION: This assay detected elevated HS levels in the CSF of patients with MPS IIIA and provides a method to assess experimental therapies.


Assuntos
Cromatografia Líquida/métodos , Heparitina Sulfato/líquido cefalorraquidiano , Mucopolissacaridose III/líquido cefalorraquidiano , Espectrometria de Massas em Tandem/métodos , Adolescente , Criança , Pré-Escolar , Cromatografia Líquida/normas , Heparitina Sulfato/isolamento & purificação , Humanos , Lactente , Limite de Detecção , Valores de Referência
15.
J Med Chem ; 48(6): 2229-38, 2005 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-15771465

RESUMO

Two new series of 4-(1-alkyl-piperidin-4-yloxy)-benzonitriles and 4-(1-isopropyl-piperidin-4-yloxy)-benzylamines have been prepared. In vitro activity was determined at the recombinant human H(3) receptor and several members of these new series were found to be potent H(3) antagonists. The present compounds contain a 4-phenoxypiperidine core, which behaves as a conformationally restricted version of the 3-amino-1-propanol moiety common to the many previously described non-imidazole histamine H(3) ligands. One selected member of the new series, 4-[4-(1-isopropyl-piperidin-4-yloxy)-benzyl]-morpholine (13g), was found to be a potent, highly selective H(3) receptor antagonist with in vivo efficacy in a rat EEG model of wakefulness at doses as low as 1 mg/kg sc.


Assuntos
Antagonistas dos Receptores Histamínicos/síntese química , Piperidinas/síntese química , Receptores Histamínicos H3/efeitos dos fármacos , Animais , Autorradiografia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Eletroencefalografia , Eletromiografia , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Masculino , Conformação Molecular , Piperidinas/química , Piperidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Sono/efeitos dos fármacos , Relação Estrutura-Atividade , Vigília/efeitos dos fármacos
16.
Orphanet J Rare Dis ; 10: 50, 2015 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-25902842

RESUMO

BACKGROUND: Twenty-eight treatment-naïve mucopolysaccharidosis II patients (16 months-7.5 years) received 0.5 mg/kg idursulfase weekly for one year in NCT00607386. Serum anti-idursulfase immunoglobulin G antibodies (Abs) were seen in 68% of patients. METHODS: This post hoc analysis examined the relationship between Ab status, genotype, adverse events (AEs), and efficacy. Event rate analyses, time-varying proportional hazards (Cox) modeling, and landmark analyses were performed to evaluate the relationship between Ab status and safety. We calculated the cumulative probability of AEs by genotype to evaluate the relationship between genotype and safety. Urinary glycosaminoglycan (uGAG) concentration, index of liver size, and spleen volume were compared by Ab status and genotype. SAFETY RESULTS: The overall infusion-related AE (IRAE) rate was higher in Ab+ patients than in Ab- ones. However, the rate was highest before Abs developed, then decreased over time, suggesting that Abs did not confer the risk. A landmark analysis of patients who were IRAE-naïve at the landmark point found that Ab+ patients were no more likely to experience post-landmark IRAEs than were Ab- patients. In the genotype analysis, all patients in the complete deletion/large rearrangement (CD/LR) and frame shift/splice site mutation (FS/SSM) groups seroconverted, compared with only one-third of patients in the missense mutation (MS) group (p < 0.001). The cumulative probability of having ≥1 IRAE was 87.5% in the CD/LR group and 46.2% in the MS group, with a shorter time to first IRAE in the CD/LR group (p = 0.004). EFFICACY RESULTS: Ab+ patients had a reduced response to idursulfase for liver size and uGAG concentration, but not for spleen size. However, when percent change from baseline in liver size and in uGAG level at Week 53 were adjusted for genotype, the difference was significant only for neutralizing Ab+ groups. In the genotype analysis, the CD/LR and FS/SSM groups had a reduced response in liver size and uGAG concentration compared with the MS group. CONCLUSIONS: Safety outcomes and spleen size response on idursulfase treatment appeared to be associated with genotype, not Ab status. Liver size and uGAG response on idursulfase treatment at Week 53 appeared to be associated with both neutralizing Ab status and genotype.


Assuntos
Terapia de Reposição de Enzimas , Iduronato Sulfatase/efeitos adversos , Iduronato Sulfatase/uso terapêutico , Mucopolissacaridose II/tratamento farmacológico , Criança , Pré-Escolar , Genótipo , Humanos , Iduronato Sulfatase/administração & dosagem , Iduronato Sulfatase/imunologia , Imunoglobulina G/sangue , Lactente , Fígado/patologia , Masculino , Mucopolissacaridose II/sangue , Tamanho do Órgão , Fatores de Risco , Baço/patologia , Resultado do Tratamento
17.
Clin Ther ; 37(2): 311-24, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25438724

RESUMO

PURPOSE: Encenicline (EVP-6124) is a selective α7 nicotinic acetylcholine receptor partial agonist being developed for cognitive impairment in Alzheimer's disease and schizophrenia. We report on 2 single-dose studies to assess the relative bioavailability, pharmacokinetic profile, tolerability, and cognitive effects of encenicline in healthy volunteers. METHODS: A single ascending-dose study assessed the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of encenicline in healthy male volunteers. Subjects received a single 1-, 3.5-, 7-, 20-, 60-, or 180-mg oral solution dose of encenicline or placebo. A second single-dose, randomized, open-label, 3-period, crossover study in healthy male and female subjects compared the relative bioavailability of a 1-mg oral capsule versus a 1-mg oral solution dose of encenicline and evaluated the effects of food and sex on encenicline pharmacokinetic profile. FINDINGS: In the first study, encenicline was well tolerated and dose-proportional increases in C(max) (mean range 0.59-100 ng/mL) and AUC0-∞ (mean range 45.6-8890 ng·h/mL) were observed over a 1- to 180-mg dose range. Procognitive effects on the Digit Symbol Substitution Test were maximal at the 20-mg dose. In the second study, encenicline 1-mg oral capsules and oral solution were bioequivalent and there was no observed food effect on encenicline pharmacokinetic profile with the 90% confidence intervals of the treatment ratios for both comparisons (ie, capsule to solution and fed to fasted) for Cmax and AUC being within 80% to 125%. A 30% to 40% higher encenicline exposure in female subjects than respective values in male subjects was consistent with a 33% higher weight of the male subjects. No clinically relevant safety profile or tolerability effects of encenicline were observed. IMPLICATIONS: Encenicline was well tolerated at single doses up to 180 mg, and doses as low as 1 mg had dose- and time-dependent pharmacodynamic effects on the central nervous system. Oral capsule and solution were bioequivalent and were not affected by food. Although a sex effect on pharmacokinetic profile was observed, it was attributable to weight differences. Clinical Trial Registration at EudraCT: 2006-005623-42 and EudracT: 2008-000029-20.


Assuntos
Agonistas Nicotínicos/farmacocinética , Quinuclidinas/farmacocinética , Tiofenos/farmacocinética , Administração Oral , Adulto , Disponibilidade Biológica , Cápsulas , Cognição/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Jejum , Feminino , Interações Alimento-Droga , Voluntários Saudáveis , Humanos , Masculino , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/efeitos adversos , Quinuclidinas/administração & dosagem , Quinuclidinas/efeitos adversos , Receptores Nicotínicos , Fatores Sexuais , Equivalência Terapêutica , Tiofenos/administração & dosagem , Tiofenos/efeitos adversos
18.
Mol Genet Metab Rep ; 5: 103-106, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28649553

RESUMO

In mucopolysaccharidoses (MPS), glycosaminoglycans (GAG) accumulate in tissues. In MPS II, approximately two-thirds of patients are cognitively impaired. We investigated levels of GAG in cerebrospinal fluid (CSF) in different populations from four clinical studies (including NCT00920647 and NCT01449240). Data indicate that MPS II patients with cognitive impairment have elevated levels of CSF GAG, whereas those with the attenuated phenotype typically have levels falling between those of the cognitively affected patients and healthy controls.

19.
ACS Med Chem Lett ; 6(4): 450-4, 2015 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-25893048

RESUMO

The preclinical characterization of novel phenyl(piperazin-1-yl)methanones that are histamine H3 receptor antagonists is described. The compounds described are high affinity histamine H3 antagonists. Optimization of the physical properties of these histamine H3 antagonists led to the discovery of several promising lead compounds, and extensive preclinical profiling aided in the identification of compounds with optimal duration of action for wake promoting activity. This led to the discovery of two development candidates for Phase I and Phase II clinical trials.

20.
J Med Chem ; 46(18): 3938-44, 2003 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-12930154

RESUMO

4-(Aminoalkoxy)benzylamines were prepared and screened for in vitro activity at the human histamine H(3) receptor. Some members of this series exhibited subnanomolar binding affinities. Analogues in which one nitrogen atom was replaced with a methine group showed greatly reduced binding affinities. Six members of this series were found to be antagonists in a cell-based model of human histamine H(3) receptor activation. One member of this series, 1-[4-(3-piperidin-1-ylpropoxy)benzyl]piperidine (7b), was found to be a selective and potent human H(3) receptor antagonist.


Assuntos
Benzilaminas/síntese química , Antagonistas dos Receptores Histamínicos/síntese química , Piperidinas/síntese química , Receptores Histamínicos H3/efeitos dos fármacos , Animais , Benzilaminas/metabolismo , Benzilaminas/farmacologia , Células CACO-2 , Linhagem Celular , Córtex Cerebral/metabolismo , AMP Cíclico/biossíntese , Antagonistas dos Receptores Histamínicos/metabolismo , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Técnicas In Vitro , Permeabilidade , Piperidinas/metabolismo , Piperidinas/farmacologia , Ratos , Receptores Histamínicos H3/metabolismo , Relação Estrutura-Atividade
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