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1.
CNS Drugs ; 2021 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-34826114

RESUMO

BACKGROUND: Given the limited treatment options for younger children with attention-deficit/hyperactivity disorder (ADHD), a clinical study for SHP465 treatment was warranted. OBJECTIVES: We aimed to evaluate the pharmacokinetics, safety, and tolerability of SHP465 mixed amphetamine salts (MAS) 6.25 mg after multiple once-daily doses in children aged 4-5 years with ADHD. METHODS: In this open-label multicenter study, SHP465 MAS 6.25 mg once daily was administered for 28 days to children aged 4-5 years with ADHD; baseline ADHD Rating Scale-5 total score ≥ 28 (boys) or ≥ 24 (girls) and Clinical Global Impression-Severity scale score ≥ 4. Blood samples were collected in the pharmacokinetic-rich group predose on day 1 week 1 and day 7 week 4 (predose, postdose at 2, 5, 8, 12, 16, 24, and 48 hours); and in the pharmacokinetic-sparse group predose on day 1 weeks 1, 2, and 3 and 24 hours postdose on day 7 week 4 . Key pharmacokinetic parameters included maximum plasma drug concentration (Cmax), plasma trough drug concentration, time to Cmax during a dosing interval (tmax), area under the concentration-time curve from time 0 to time of last collected sample, area under the concentration-time curve over the dosing interval (24 h) at steady state (AUCtau,ss), first-order rate constant associated with the terminal phase of elimination, terminal half-life (t1/2), total clearance of drug from plasma after oral administration, and apparent volume of distribution at steady state. Safety endpoints included treatment-emergent adverse events and vital signs. RESULTS: Mean ± standard deviation age and body mass index of 24 participants (66.7% male) were 4.8 ± 0.41 years and 17.2 ± 3.18 kg/m2, respectively. The most common ADHD was the combined presentation (91.7%); ratings were 50% markedly ill and 45.8% moderately ill on the Clinical Global Impression-Severity scale. Plasma d-amphetamine and l-amphetamine steady state was attained by predose on treatment day 8, consistent with the half-life. Peak steady-state plasma concentration (median tmax) for both d-amphetamine and l-amphetamine occurred at 7.92 h postdose on day 7 week 4 and thereafter declined monoexponentially, with a geometric mean t1/2 of 10.4 and 12.3 h for d-amphetamine and l-amphetamine, respectively. For both d-amphetamine and l-amphetamine, Cmax and AUCtau,ss were comparable between children aged 4 years (n = 3) and children aged 5 years (n = 8) regardless of sex. In total, 14 treatment-emergent adverse events were reported by 45.8% (11/24) of participants. Five treatment-emergent adverse events, reported for four (16.7%) participants, were considered treatment related; affect lability occurred in two (8.3%) participants, and insomnia, accidental overdose, and increased blood pressure each occurred in one (4.2%) participant. CONCLUSIONS: In children aged 4-5 years with ADHD, following multiple once-daily administrations of SHP465 MAS 6.25 mg, the pharmacokinetic profile of plasma d-amphetamine and l-amphetamine was generally consistent among participants. Between-individual variability of plasma d-amphetamine and l-amphetamine steady-state exposure was low to moderate. SHP465 MAS was generally well tolerated in this study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03327402 (31 October, 2017).

2.
Epilepsy Res ; 174: 106651, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34020149

RESUMO

BACKGROUND: In Japan, intravenous (IV) administration of antiepileptic drugs in a healthcare setting is the preferred treatment option that is both licensed and recommended for initial treatment of status epilepticus (SE). However, prompt conveyance to a healthcare institution and IV access may be difficult in patients experiencing a seizure and so delay treatment. Thus, there is an unmet need for an alternative effective antiepileptic drug with an easier and more rapid mode of administration. In this study we evaluated a midazolam hydrochloride oromucosal solution (MHOS) that can be simply and rapidly administered to patients in SE. METHODS: A Phase 3, interventional, multicenter, nonrandomized study was conducted in 28 clinical centers in Japan. Pediatric subjects in convulsive SE received treatment with buccal MHOS with dosage based on their age. The primary efficacy outcome was the percentage of subjects with seizure termination within 10 min and a 30-min absence of visible seizure activity from time of administration. Safety evaluations included respiratory depression and the frequency of treatment-emergent adverse events (TEAEs). Pharmacokinetic (PK) profile was also assessed. RESULTS: The study population comprised 25 subjects with a median age of 2.8 years and median bodyweight of 13.4 kg. The primary efficacy outcome was achieved in 80 % of subjects; 84 % of subjects had seizure resolution within 10 min. Nine subjects experienced a total of 13 TEAEs, and protocol-defined respiratory depression occurred in one subject. Mean maximum plasma midazolam concentration was 78.0 ng/mL, and mean time to peak concentration was 20.5 min, demonstrating that achieving maximum plasma midazolam concentration is not required for seizure cessation. CONCLUSIONS: The efficacy, safety and pharmacokinetic profile of MHOS in pediatric Japanese subjects was consistent with that observed in non-Japanese populations. Compared to IV treatments, MHOS offers easier administration which may reduce the time to treatment and thereby minimize the sequelae of prolonged seizures.

3.
J Clin Pharmacol ; 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31853995

RESUMO

Lanabecestat, a novel ß-site amyloid precursor protein-cleaving enzyme 1 inhibitor evaluated for Alzheimer treatment, inhibits P-glycoprotein (P-gp) activity in vitro. After oral 50-mg lanabecestat administration, gastric fluid lanabecestat concentrations exceed half-maximal inhibitory concentration (IC50 ), suggesting P-gp inhibition at the intestinal wall. Plasma drug concentrations following 50 mg lanabecestat administered once daily are <10% of IC50 , suggesting minimal systemic P-gp interaction. Dabigatran etexilate (DE) is the prodrug of dabigatran, a thrombin inhibitor and P-gp substrate, making dabigatran exposure an intestinal P-gp activity indicator. This study (NCT02568397) was conducted in 60 healthy subjects receiving a single dose of 150 mg DE alone or during a lanabecestat treatment regimen. On day 16, lanabecestat and DE were coadministered; on day 20, DE was dosed 4 hours after lanabecestat. Safety was assessed using clinical labs, electrocardiogram, vital signs, Columbia Suicide Severity Rating Scale scores, adverse events, and eye and skin examinations. Pharmacokinetic/pharmacodynamic samples were collected up to 36 hours postdose. Geometric mean plasma dabigatran area under the curve from time 0 to infinity (AUC0-∞ ) and the maximum plasma drug concentration (Cmax ) increased by 15% and 17%, respectively, when coadministered with lanabecestat. When DE was dosed 4 hours after lanabecestat, there was no effect on plasma dabigatran AUC0-∞ , Cmax , or thrombin time. DE had no effect on lanabecestat's AUC0-∞ and Cmax at steady state (day 16) versus lanabecestat alone (day 15). No clinically relevant safety concerns were observed. Lanabecestat has no clinically meaningful effect on dabigatran exposure or on P-gp activity at the intestinal wall.

4.
Clin Pharmacol Drug Dev ; 7(3): 233-243, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29319935

RESUMO

The relative bioavailability of lanabecestat administered as 2 tablet formulations versus an oral solution was investigated. This phase 1 single-center, open-label, randomized, 3-period crossover study involved healthy male and nonfertile female subjects aged 18-55 years (NCT02039180). Subjects received a single 50-mg lanabecestat dose as solution, tablet A, or tablet B on day 1 of each crossover period; 14 of 16 subjects completed the study. Relative bioavailability based on plasma lanabecestat AUC0-∞ (area under the plasma drug concentration-time curve from zero to infinity) geometric mean ratio versus oral solution (primary variable) was: tablet A, 1.052 (90% confidence interval [CI], 1.001-1.106); tablet B, 1.040 (0.989-1.093). These 90%CIs for geometric mean ratios are within accepted standard bioequivalence boundaries for all other pharmacokinetic (PK) parameters for both lanabecestat and metabolite (AZ13569724). All 3 formulations had similar plasma lanabecestat concentration-time profiles. Six adverse events were reported by 6 subjects (37.5%, all mild). GastroPlus modeling predicted a negligible impact of gastric pH changes on systemic PK (up to pH 7.4). Both tablet formulations fall within standard accepted bioequivalence criteria versus the oral solution. A single 50-mg lanabecestat dose was well tolerated as a solution or tablet formulation in this population.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Imidazóis/farmacocinética , Compostos de Espiro/farmacocinética , Administração Oral , Adulto , Disponibilidade Biológica , Estudos Cross-Over , Composição de Medicamentos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Imidazóis/administração & dosagem , Imidazóis/química , Masculino , Pessoa de Meia-Idade , Soluções Farmacêuticas/administração & dosagem , Soluções Farmacêuticas/química , Soluções Farmacêuticas/farmacocinética , Compostos de Espiro/administração & dosagem , Compostos de Espiro/química , Comprimidos , Adulto Jovem
5.
J Clin Pharmacol ; 57(11): 1460-1471, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28618005

RESUMO

Lanabecestat (AZD3293; LY3314814) is an orally active potent inhibitor of human ß-secretase 1 in clinical development for the treatment of Alzheimer disease. In this first Japanese clinical study for an Alzheimer disease intervention to include cerebrospinal fluid (CSF) sampling in Japanese elderly healthy subjects, we report the pharmacokinetics and effects on plasma and CSF amyloid-ß (Aß) peptides of lanabecestat in a phase 1 study involving 40 healthy Japanese subjects (NCT02005211). No safety and tolerability concerns were identified in healthy Japanese subjects exposed to lanabecestat up to the highest doses given, which is consistent with observations in a US phase 1 study of lanabecestat. Exposure to lanabecestat was similar for young and elderly subjects and increased in a dose-dependent manner. For elderly subjects, plasma lanabecestat half-life after multiple dosing was 12 to 17 hours (on days 10 and 14). Robust plasma and CSF Aß peptide reductions were also seen at all doses, with CSF Aß42 concentrations reduced by 63% and 79% in the 15- and 50-mg lanabecestat groups, respectively. CSF soluble amyloid-ß precursor protein ß also decreased following lanabecestat treatment. Suppression of CSF Aß peptides was similar in elderly healthy Japanese subjects and US patients with mild to moderate Alzheimer disease. Lanabecestat is a promising potentially disease-modifying treatment in phase 3 development for patients with early Alzheimer disease.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Líquido Cefalorraquidiano/metabolismo , Imidazóis/uso terapêutico , Plasma/metabolismo , Compostos de Espiro/uso terapêutico , Adulto , Idoso , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Grupo com Ancestrais do Continente Asiático , Encéfalo/metabolismo , Método Duplo-Cego , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/metabolismo , Adulto Jovem
6.
Bioanalysis ; 9(10): 813-826, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28434245

RESUMO

AIM: AZD3293 is a novel BACE1 inhibitor in Phase III development for Alzheimer's disease. Sensitive and robust bioanalytical methods were required to quantitate AZD3293 and its metabolite AZ13569724 in human biological matrices. METHODOLOGY/RESULTS: Human plasma was prepared by protein precipitation. Linearity for both analytes was in the range of 0.5-500 ng/ml with up to 100-fold dilution. Plasma ultrafiltrate samples were prepared using Centrifree® ultrafiltration device. Urine and CSF samples were analyzed directly after dilution. A 27% decrease in AZD3293 concentrations in the CSF collection apparati was found due to nonspecific binding. Incurred sample reanalysis was acceptable. CONCLUSION: Methods for simultaneous quantitation of AZD3293 and its metabolite AZ13569724 in human biological matrices have been validated and successfully applied to clinical studies.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Análise Química do Sangue/métodos , Cromatografia Líquida/métodos , Imidazóis/sangue , Imidazóis/metabolismo , Compostos de Espiro/sangue , Compostos de Espiro/metabolismo , Espectrometria de Massas em Tandem/métodos , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Imidazóis/farmacologia , Limite de Detecção , Compostos de Espiro/farmacologia , Fatores de Tempo
7.
J Alzheimers Dis ; 55(3): 1039-1053, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27767991

RESUMO

AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (ß-secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer's disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1-750 mg with a food-effect component (n = 72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n = 31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer's disease (Part 2, n = 16). AZD3293 was generally well tolerated up to the highest doses given. No notable food effects were observed. PK following multiple doses (Part 2) were tmax of 1 to 3 h and mean t1/2 of 16 to 21 h across the 15 to 150 mg dose range. For single doses of ≥5 mg, a ≥70% reduction was observed in mean plasma Aß40 and Aß42 concentrations, with prolonged suppression for up to 3 weeks at the highest dose level studied. Following multiple doses, robust reductions in plasma (≥64% at 15 mg and ≥78% at ≥50 mg) and cerebrospinal fluid (≥51% at 15 mg and ≥76% at ≥50 mg) Aß peptides were seen, including prolonged suppression even with a QW dosing regimen. AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma Aß with a QW dosing schedule has been reported. Two Phase III studies of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antipsicóticos/farmacocinética , Antipsicóticos/uso terapêutico , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Compostos de Espiro/farmacocinética , Compostos de Espiro/uso terapêutico , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Alimentos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fatores de Tempo , Adulto Jovem
8.
J Alzheimers Dis ; 50(4): 1109-23, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26890753

RESUMO

A growing body of pathological, biomarker, genetic, and mechanistic data suggests that amyloid accumulation, as a result of changes in production, processing, and/or clearance of brain amyloid-ß peptide (Aß) concentrations, plays a key role in the pathogenesis of Alzheimer's disease (AD). Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid-ß protein precursor (AßPP) to Aß peptides, with the soluble N terminal fragment of AßPP (sAßPPß) as a direct product, and BACE1 inhibition is an attractive target for therapeutic intervention to reduce the production of Aß. Here, we report the in vitro and in vivo pharmacological profile of AZD3293, a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. The in vitro potency of AZD3293 was demonstrated in several cellular models, including primary cortical neurons. In vivo in mice, guinea pigs, and dogs, AZD3293 displayed significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aß40, Aß42, and sAßPPß. The in vitro potency of AZD3293 in mouse and guinea pig primary cortical neuronal cells was correlated to the in vivo potency expressed as free AZD3293 concentrations in mouse and guinea pig brains. In mice and dogs, the slow off-rate from BACE1 may have translated into a prolongation of the observed effect beyond the turnover rate of Aß. The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Compostos de Espiro/administração & dosagem , Compostos de Espiro/farmacocinética , Administração Oral , Peptídeos beta-Amiloides/metabolismo , Animais , Análise Química do Sangue , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/enzimologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Cobaias , Humanos , Cinética , Masculino , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/metabolismo
9.
Neurotox Res ; 28(3): 185-94, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26194617

RESUMO

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease. Post-mortem hallmarks of MSA neuropathology include oligodendroglial α-synuclein (αSYN) inclusions, striatonigral degeneration, olivopontocerebellar atrophy, and increased microglial activation that accompanies the wide spread neurodegeneration. Recently, we demonstrated upregulation of myeloperoxidase (MPO) in activated microglia and provided evidence for the role of microglial MPO in the mediation of MSA-like neurodegeneration (Stefanova et al. Neurotox Res 21:393-404, 2015). The aim of the current study was to assess the therapeutic potency of MPO inhibition (MPOi) in a model of advanced MSA. We replicated the advanced pathology of MSA by intoxicating transgenic PLP-α-synuclein transgenic mice with 3-nitropropionic acid (3NP). After onset of the full-blown pathology, MSA mice received either MPOi or vehicle over 3 weeks. Motor phenotype and neuropathology were analyzed to assess the therapeutic efficacy of MPOi compared to vehicle treatment in MSA mice. MPOi therapy initiated after the onset of severe MSA-like neuropathology in mice failed to attenuate motor impairments and neuronal loss within the striatum, substantia nigra pars compacta, inferior olives, pontine nuclei, and cerebellar cortex. However, we observed a significant reduction of microglial activation in degenerating brain areas. Further, nitrated αSYN accumulation was reduced in the striatonigral region. In summary, delayed-start MPOi treatment reduced microglial activation and levels of nitrated αSYN in a mouse model of advanced MSA. These effects failed to impact on motor impairments and neuronal loss in contrast to previously reported disease modifying efficacy of early-start therapy with MPOi in MSA.


Assuntos
Encéfalo/efeitos dos fármacos , Microglia/efeitos dos fármacos , Atrofia de Múltiplos Sistemas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Peroxidase/antagonistas & inibidores , Pirimidinonas/farmacologia , Pirróis/farmacologia , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Camundongos Transgênicos , Microglia/patologia , Microglia/fisiologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Atrofia de Múltiplos Sistemas/patologia , Atrofia de Múltiplos Sistemas/fisiopatologia , Proteína Proteolipídica de Mielina/genética , Proteína Proteolipídica de Mielina/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Nitrocompostos , Peroxidase/metabolismo , Propionatos , Índice de Gravidade de Doença , Resultado do Tratamento , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
10.
Brain ; 138(Pt 9): 2687-700, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26137956

RESUMO

Impaired mitochondrial function, oxidative stress and formation of excessive levels of reactive oxygen species play a key role in neurodegeneration in Parkinson's disease. Myeloperoxidase is a reactive oxygen generating enzyme and is expressed by microglia. The novel compound AZD3241 is a selective and irreversible inhibitor of myeloperoxidase. The hypothesized mechanism of action of AZD3241 involves reduction of oxidative stress leading to reduction of sustained neuroinflammation. The purpose of this phase 2a randomized placebo controlled multicentre positron emission tomography study was to examine the effect of 8 weeks treatment with AZD3241 on microglia in patients with Parkinson's disease. Parkinson patients received either AZD3241 600 mg orally twice a day or placebo (in 3:1 ratio) for 8 weeks. The binding of (11)C-PBR28 to the microglia marker 18 kDa translocator protein, was examined using positron emission tomography at baseline, 4 weeks and 8 weeks. The outcome measure was the total distribution volume, estimated with the invasive Logan graphical analysis. The primary statistical analysis examined changes in total distribution volume after treatment with AZD3241 compared to baseline. Assessments of safety and tolerability of AZD3241 included records of adverse events, vital signs, electrocardiogram, and laboratory tests. The patients had a mean age of 62 (standard deviation = 6) years; 21 were male, three female and mean Unified Parkinson's Disease Rating Scale III score (motor examination) ranged between 6 and 29. In the AD3241 treatment group (n = 18) the total distribution volume of (11)C-PBR28 binding to translocator protein was significantly reduced compared to baseline both at 4 and 8 weeks (P < 0.05). The distribution volume reduction across nigrostriatal regions at 8 weeks ranged from 13-16%, with an effect size equal to 0.5-0.6. There was no overall change in total distribution volume in the placebo group (n = 6). AZD3241 was safe and well tolerated. The reduction of (11)C-PBR28 binding to translocator protein in the brain of patients with Parkinson's disease after treatment with AZD3241 supports the hypothesis that inhibition of myeloperoxidase has an effect on microglia. The results of the present study provide support for proof of mechanism of AZD3241 and warrant extended studies on the efficacy of AZD3241 in neurodegenerative disorders.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Microglia/efeitos dos fármacos , Doença de Parkinson , Tomografia por Emissão de Pósitrons , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Radioisótopos de Flúor , Seguimentos , Humanos , Masculino , Microglia/diagnóstico por imagem , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Polimorfismo de Nucleotídeo Único/genética , Ligação Proteica/efeitos dos fármacos , Pirimidinas/sangue , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Receptores de GABA/genética , Índice de Gravidade de Doença
11.
Clin Pharmacol Drug Dev ; 4(6): 434-41, 2015 11.
Artigo em Inglês | MEDLINE | ID: mdl-27137715

RESUMO

This randomized, double-blind, placebo-controlled, ascending-dose, crossover study evaluated single oral doses of naloxegol (NKTR-118; 8, 15, 30, 60, 125, 250, 500, and 1000 mg), a PEGylated derivative of naloxone, for safety and tolerability, antagonism of peripheral and central nervous system (CNS) effects of intravenous morphine, and pharmacokinetics. Healthy men were randomized 1:1 to naloxegol or naloxegol-matching placebo administered with morphine and lactulose in a 2-period crossover design. Periods were separated by a 5- to 7-day washout. Assessments included safety, tolerability, orocecal transit time (OCTT), pupillary miosis, and pharmacokinetics. The study was completed by 46 subjects. The most common adverse events were somnolence, dizziness, headache, and nausea. Greater reversal of morphine-induced delay in OCTT occurred with increasing naloxegol dose, demonstrating dose-ordered antagonism of morphine's peripheral gastrointestinal effects. Forty-four subjects showed no reversal of pupillary miosis; 2 showed potential partial reversal at 250 and 1000 mg, indicating negligible antagonism of morphine's CNS effects at doses ≤ 125 mg. Rapid absorption, linear pharmacokinetics up to 1000 mg, and low to moderate between-subject pharmacokinetic variability was observed. The pharmacokinetics of morphine or its glucuronide metabolites were unaltered by concurrent naloxegol administration. Naloxegol was generally safe and well tolerated at single doses up to 1000 mg.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Morfinanos/farmacocinética , Morfina/antagonistas & inibidores , Antagonistas de Entorpecentes/farmacocinética , Sistema Nervoso Periférico/efeitos dos fármacos , Polietilenoglicóis/farmacocinética , Receptores Opioides mu/antagonistas & inibidores , Administração Oral , Adolescente , Adulto , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Trânsito Gastrointestinal/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Miose/induzido quimicamente , Miose/metabolismo , Miose/fisiopatologia , Modelos Biológicos , Morfinanos/administração & dosagem , Morfinanos/efeitos adversos , Morfina/efeitos adversos , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/efeitos adversos , Países Baixos , Sistema Nervoso Periférico/metabolismo , Sistema Nervoso Periférico/fisiopatologia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Receptores Opioides mu/metabolismo , Adulto Jovem
12.
Clin Pharmacol Drug Dev ; 4(6): 442-8, 2015 11.
Artigo em Inglês | MEDLINE | ID: mdl-27137716

RESUMO

Opioid-induced constipation (OIC) is the most common and often a treatment-limiting adverse event (AE) of opioid therapy for chronic pain. Naloxegol (previously NKTR-118), a PEGylated derivative of naloxone that has minimal penetration of the central nervous system, has received regulatory approval as an oral therapy for OIC. This randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation study was performed to assess safety, tolerability, and pharmacokinetics of multiple doses of naloxegol in healthy volunteers. Four cohorts, each with 4 male and 4 female volunteers, were randomized 3:1 to a twice-daily naloxegol solution (25, 60, 125, and 250 mg) or matching placebo solution. Doses were given every 12 hours for 7 days, with a single final dose on the morning of day 8. All 32 subjects completed the study. The incidence of most AEs was similar in the naloxegol and placebo groups; no AE led to study discontinuation. Naloxegol was rapidly absorbed. Plasma naloxegol pharmacokinetics showed dose proportionality, negligible accumulation at steady state, and no sex differences. Naloxegol in doses up to 250 mg every 12 hours was generally safe and well tolerated in this healthy volunteer population.


Assuntos
Morfinanos/farmacocinética , Antagonistas de Entorpecentes/farmacocinética , Polietilenoglicóis/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Área Sob a Curva , Método Duplo-Cego , Esquema de Medicação , Feminino , Absorção Gastrointestinal , Meia-Vida , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Morfinanos/administração & dosagem , Morfinanos/efeitos adversos , Morfinanos/sangue , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/efeitos adversos , Antagonistas de Entorpecentes/sangue , Países Baixos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Adulto Jovem
13.
J Antimicrob Chemother ; 67(4): 970-6, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22240402

RESUMO

OBJECTIVES: Amphotericin B inhalation powder (ABIP) is a novel dry-powder amphotericin B formulation that is directly delivered to the lung, resulting in elevated lung tissue drug concentrations of this polyene. We evaluated the prophylactic efficacy of single dose administration of ABIP in a guinea pig model of invasive pulmonary aspergillosis. METHODS: Guinea pigs were immunosuppressed with cyclophosphamide and cortisone acetate and challenged with Aspergillus fumigatus conidia in an aerosol chamber. Guinea pigs received prophylaxis with a single inhaled dose of ABIP at 0.05, 0.5, 4 or 10 mg/kg administered 24 h prior to infection. Treatment with oral voriconazole at doses of 5 or 10 mg/kg twice daily beginning 24 h post-challenge served as the positive control. RESULTS: Improvements in survival were observed with ABIP prophylaxis. A single inhaled dose of 4 mg/kg ABIP and treatment with 5 mg/kg voriconazole both improved median and percentage survival compared with untreated controls. In addition, pulmonary fungal burden, as assessed by cfu, quantitative PCR and galactomannan, was also reduced in a dose-dependent fashion with ABIP prophylaxis as well as with both doses of voriconazole treatment. CONCLUSIONS: Single-dose prophylaxis with inhaled ABIP as prophylaxis demonstrated a significant survival advantage and reductions in pulmonary fungal burden in this model of invasive pulmonary aspergillosis. Optimization of the dose and dosing frequency of ABIP dose may help to further enhance the anti-Aspergillus activity of this novel amphotericin B formulation.


Assuntos
Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Aspergillus fumigatus/patogenicidade , Quimioprevenção/métodos , Aspergilose Pulmonar Invasiva/prevenção & controle , Administração por Inalação , Animais , Aspergillus fumigatus/efeitos dos fármacos , Contagem de Colônia Microbiana , Cortisona/administração & dosagem , Cortisona/análogos & derivados , Ciclofosfamida/administração & dosagem , Modelos Animais de Doenças , Cobaias , Imunossupressores/administração & dosagem , Pulmão/microbiologia , Masculino , Pirimidinas/administração & dosagem , Análise de Sobrevida , Triazóis/administração & dosagem , Voriconazol
14.
Epilepsia ; 45(1): 20-7, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14692903

RESUMO

PURPOSE: To evaluate pregabalin (PGB), 150 mg/day, and PGB, 600 mg/day, as an add-on treatment for patients with refractory partial seizures concurrently treated with one to three anticonvulsants (AEDs). METHODS: An international (13 countries), multicenter (45 centers), 12-week, double-blind, randomized study in which patients with partial seizures received placebo (n = 96); PGB, 150 mg/day (n = 99); or PGB, 600 mg/day (n = 92); given 3 times a day (t.i.d.). The primary efficacy criterion was reduction in seizure frequency during treatment as compared with baseline, as measured by RRatio, the symmetrical percentage change in seizure rates determined from daily seizure diaries. The RRatio between the 8-week baseline (pretreatment phase) and the 12-week treatment period were compared between each of the PGB groups and the placebo group by using an analysis of variance analysis of the intent-to-treat population. RESULTS: PGB, 150 mg/day and 600 mg/day, were both significantly more effective than placebo in reducing the RRatio [-11.5 (p = 0.0007) and -31.4 (p < or = 0.0001), respectively, vs. 0.9]. These RRatio values correspond to seizure-frequency reductions from baseline of -1.8, 20.6, and 47.8% for placebo, 150 mg/day, and 600 mg/day, respectively. PGB efficacy was significantly dose related (p < or = 0.0001). Secondary efficacy variables corroborated the findings of the primary analysis. Significantly more patients were responders (> or =50% reduction in seizure frequency) in the PGB, 600 mg/day (43.5%), group than in the placebo group (6.2%) (p < or = 0.001). PGB was well tolerated. Dose-related, treatment-emergent adverse events (> or =10%), mostly mild or moderate in intensity, were somnolence, dizziness, ataxia, diplopia, and weight gain. The withdrawal rate due to adverse events was 10% of patients at 150 mg/day and 18.5% of patients at 600 mg/day, compared with 6.2% of patients receiving placebo. CONCLUSIONS: PGB, 150 mg/day and 600 mg/day, is highly effective and well-tolerated add-on therapy in patients with partial seizures.


Assuntos
Epilepsias Parciais/tratamento farmacológico , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/administração & dosagem , Adolescente , Adulto , Idoso , Análise de Variância , Intervalos de Confiança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Epilepsias Parciais/sangue , Epilepsias Parciais/fisiopatologia , Feminino , Humanos , Internacionalidade , Masculino , Pessoa de Meia-Idade , Pregabalina , Ácido gama-Aminobutírico/sangue
15.
Antimicrob Agents Chemother ; 47(2): 689-96, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12543679

RESUMO

Cefdinir (Omnicef; Abbott Laboratories) is a cephalosporin antibiotic primarily eliminated by the kidney. Nonlinear renal elimination of cefdinir has been previously reported. Cefdinir renal transport mechanisms were studied in the erythrocyte-free isolated perfused rat kidney. Studies were performed with drug-free perfusate and perfusate containing cefdinir alone to establish the baseline physiology and investigate cefdinir renal elimination characteristics. To investigate cefdinir renal transport mechanisms, inhibition studies were conducted by coperfusing cefdinir with inhibitors of the renal organic anion (probenecid), organic cation (tetraethylammonium), or dipeptide (glycylsarcosine) transport system. Cefdinir concentrations in biological samples were determined using reversed-phase high-performance liquid chromatography. Differences between treatments and controls were evaluated using analysis of variance and Dunnett's test. The excretion ratio (ER; the renal clearance corrected for the fraction unbound and glomerular filtration rate) for cefdinir was 5.94, a value indicating net renal tubular secretion. Anionic, cationic, and dipeptide transport inhibitors all significantly affected the cefdinir ER. With probenecid, the ER was reduced to 0.59, clearly demonstrating a significant reabsorptive component to cefdinir renal disposition. This finding was confirmed by glycylsarcosine studies, in which the ER was elevated to 7.95, indicating that reabsorption was mediated, at least in part, by the dipeptide transporter system. The effects of the organic cation tetraethylammonium, in which the ER was elevated to 7.53, were likely secondary in nature. The anionic secretory pathway was found to be the predominant mechanism for cefdinir renal excretion.


Assuntos
Cefalosporinas/farmacocinética , Dipeptídeos/farmacologia , Rim/efeitos dos fármacos , Probenecid/farmacologia , Tetraetilamônio/farmacologia , Animais , Transporte Biológico , Cefdinir , Cefalosporinas/metabolismo , Cromatografia Líquida de Alta Pressão , Rim/metabolismo , Masculino , Taxa de Depuração Metabólica , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
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