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AIMS: TMS-007, an SMTP family member, modulates plasminogen conformation and enhances plasminogen-fibrin binding, leading to promotion of endogenous fibrinolysis. Its anti-inflammatory action, mediated by soluble epoxide hydrolase inhibition, may contribute to its efficacy. Evidence suggests that TMS-007 can effectively treat experimental thrombotic and embolic strokes with a wide time window, while reducing haemorrhagic transformation. We aim to evaluate the safety, pharmacokinetics and pharmacodynamics of TMS-007 in healthy volunteers. METHODS: This was a randomized, placebo-controlled, double blind, dose-escalation study, administered as a single intravenous infusion of TMS-007 in cohorts of healthy male Japanese subjects. Six cohorts were planned, but only five were completed. In each cohort (n = 8), individuals were randomized to receive one of five doses of TMS-007 (3, 15, 60, 180 or 360 mg; n = 6) or placebo (n = 2). RESULTS: TMS-007 was generally well tolerated, and no serious adverse events were attributed to the drug. A linear dose-dependency was observed for plasma TMS-007 levels. No symptoms of bleeding were observed on brain MRI analysis, and no bleeding-related responses were found on laboratory testing. The plasma levels of the coagulation factor fibrinogen and the anti-fibrinolysis factor α2 -antiplasmin levels were unchanged after TMS-007 dosing. A slight increase in the plasma level of plasmin-α2 -antiplasmin complex, an index of plasmin formation, was observed in the TMS-007 group in cohort 2. CONCLUSIONS: TMS-007 is generally well tolerated and exhibits favourable pharmacokinetic profiles that warrant further clinical development.
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Antifibrinolíticos , Fibrinolisina , Humanos , Masculino , Fenol , Fenoles/farmacología , Plasminógeno , Hemorragia/tratamiento farmacológico , Antiinflamatorios/farmacología , Método Doble Ciego , Relación Dosis-Respuesta a DrogaRESUMEN
AIMS: To compare the effect of a dipeptidyl peptidase-4 inhibitor (DPP4-i) and a sulfonylurea (SU) on daily glucose fluctuation in drug-naïve Japanese patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A total of 53 drug-naïve Japanese patients with T2DM (HbA1c, 7.0%-9.0%; fasting plasma glucose, 6.1 mmol/L or higher) were randomly assigned to either sitagliptin 50 mg qd or glibenclamide 2.5 mg per day (given in divided doses) in a 1:1 ratio. A continuous glucose monitoring (CGM) device was used to obtain 24-hour glucose profiles for each patient at baseline and at Week 2. The primary study endpoint was change from baseline in mean amplitude of glucose excursion (MAGE) during a 24-hour period. A key secondary endpoint was change from baseline in the standard deviation (SD) of 24-hour glucose levels. RESULTS: After 2 weeks of treatment, a numerically greater reduction in MAGE from baseline was observed in the sitagliptin group compared with the glibenclamide group, but the between-treatment difference was not statistically significant (LS mean difference [95% CI]: -0.48 mmol/L [-1.31, 0.34]; P = .245). However, a significantly greater reduction in the change from baseline in SD was observed in the sitagliptin group compared with the glibenclamide group (LS mean difference [95% CI]: -0.33 mmol/L [-0.62, -0.03]; P = .029). CONCLUSIONS: This study suggests that the DPP4 inhibitor sitagliptin has a greater ability to reduce daily glucose fluctuation than the SU glibenclamide in drug-naïve Japanese patients with T2DM. ClinicalTrials.gov: NCT02318693.
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Glucemia/análisis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Gliburida/administración & dosificación , Hipoglucemiantes/administración & dosificación , Fosfato de Sitagliptina/administración & dosificación , Anciano , Automonitorización de la Glucosa Sanguínea , Diabetes Mellitus Tipo 2/sangre , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Esquema de Medicación , Ayuno/sangre , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Compuestos de Sulfonilurea/administración & dosificación , Resultado del TratamientoRESUMEN
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by the degeneration of motor neurons and typically results in death within 3-5 years from onset. Familial ALS (FALS) comprises 5%-10% of ALS cases, and the identification of genes associated with FALS is indispensable to elucidating the molecular pathogenesis. We identified a Japanese family affected by late-onset, autosomal-dominant ALS in which mutations in genes known to be associated with FALS were excluded. A whole- genome sequencing and parametric linkage analysis under the assumption of an autosomal-dominant mode of inheritance with incomplete penetrance revealed the mutation c.2780G>A (p. Arg927Gln) in ERBB4. An extensive mutational analysis revealed the same mutation in a Canadian individual with familial ALS and a de novo mutation, c.3823C>T (p. Arg1275Trp), in a Japanese simplex case. These amino acid substitutions involve amino acids highly conserved among species, are predicted as probably damaging, and are located within a tyrosine kinase domain (p. Arg927Gln) or a C-terminal domain (p. Arg1275Trp), both of which mediate essential functions of ErbB4 as a receptor tyrosine kinase. Functional analysis revealed that these mutations led to a reduced autophosphorylation of ErbB4 upon neuregulin-1 (NRG-1) stimulation. Clinical presentations of the individuals with mutations were characterized by the involvement of both upper and lower motor neurons, a lack of obvious cognitive dysfunction, and relatively slow progression. This study indicates that disruption of the neuregulin-ErbB4 pathway is involved in the pathogenesis of ALS and potentially paves the way for the development of innovative therapeutic strategies such using NRGs or their agonists to upregulate ErbB4 functions.
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Esclerosis Amiotrófica Lateral/genética , Receptores ErbB/genética , Mutación , Neurregulinas/genética , Anciano , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Esclerosis Amiotrófica Lateral/patología , Pueblo Asiatico/genética , Canadá , Análisis Mutacional de ADN , Receptores ErbB/metabolismo , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Neurregulinas/metabolismo , Linaje , Fosforilación , Receptor ErbB-4 , Análisis de Secuencia de ADN , Transducción de SeñalRESUMEN
BACKGROUND AND OBJECTIVE: Teriparatide acetate was developed in the form of a synthetic analogue of the Nterminal peptide (1-34) of human parathyroid hormone for the treatment of osteoporosis; it is administered subcutaneously once weekly. However, it is not known whether the pharmacokinetics (PK) of this drug is affected by renal impairment, and this study was conducted to look into this question. METHODS: A multi-center study was conducted at six hospitals in Japan. Subjects were enrolled and grouped on the basis of renal function stratified as: normal function to mild renal impairment (estimated GFR(e-GFR): ≥ 60.0 mL/min/1.73 m2) (8 subjects), moderate impairment (eGFR: 30.0 - 59.9 mL/min/1.73 m2) (5 subjects), and severe impairment (eGFR: 15.0 - 29.9 mL/min/1.73 m2) (5 subjects). The PK parameters, blood and urine electrolytes concentrations, and safety profiles were assessed following a single subcutaneous injection of teriparatide acetate (56.5 µg as teriparatide). RESULTS: The elimination half-life (t1/2) and the mean residence time extrapolated to infinity were significantly prolonged in the group with severe renal impairment (t1/2: 5.0 hours) compared with normal to mild and moderate impairment groups (t1/2: 1.5 hours and 1.2 hours, respectively). However, virtually all of the teriparatide was eliminated from the blood after 24 hours. Given that the drug is administered once weekly, it appeared highly unlikely that accumulation of the drug in the body would become a problem even with repeated administration. There were no particular problems with safety or tolerability. CONCLUSIONS: In treatment with teriparatide acetate once-per week formulation, prescription at the usual dosage appears to be appropriate even in renally impaired patients.
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Conservadores de la Densidad Ósea/farmacocinética , Insuficiencia Renal/metabolismo , Teriparatido/farmacocinética , Anciano , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Proyectos Piloto , Teriparatido/administración & dosificación , Teriparatido/efectos adversosRESUMEN
INTRODUCTION: A new algorithm for causality assessment of drugs and fatal cerebral haemorrhage (ACAD-FCH) was published in 2021. However, its use in clinical practice has not been verified. OBJECTIVES: This study aimed to explore the practical value of the ACAD-FCH when applying information available in clinical practice. METHODS: The medical records of patients who died at the University of Tokyo Hospital in 2020 were reviewed, and cases with intracranial haemorrhage were selected. Two evaluators independently assessed these cases using three methods (the ACAD-FCH, Naranjo algorithm, and WHO-UMC scale). The number of 'Yes', 'No', and 'No information/Do not know' responses to each question by both evaluators were summed and compared. Inter-rater reliability was evaluated for each method using agreement rates and kappa coefficients with 95% confidence intervals (CI). RESULTS: Among 316 deaths, 24 cases with intracranial haemorrhage were evaluated. The proportion of ?No information/Do not know' responses for each question was 35.6% (95% CI 31.4-40.6%) for the ACAD-FCH and 66.9% (95% CI 62.5-71.1%) for the Naranjo algorithm. The respective agreement rates and kappa coefficients were 0.917 (0.798-1.00) and 0.867 (0.675-1.00) for the ACAD-FCH, 0.708 (0.512-0.904) and 0.139 (-0.236 to 0.513) for the Naranjo algorithm, and 0.50 (0.284-0.716) and 0.326 (0.110-0.541) for the WHO-UMC scale, respectively. CONCLUSION: Our findings suggest the utility of the ACAD-FCH when assessing death cases with intracranial haemorrhage. However, larger studies including intra-rater assessments are warranted for further validation of this algorithm.
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OBJECTIVE: HTLV-1 infection causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), resulting in loss of motor function. In this Phase 2 trial, we assessed the efficacy and safety of l-arginine in patients with HAM/TSP. METHODS: This open-label, single-arm, Phase 2 study enrolled patients diagnosed with HAM/TSP. Patients received l-arginine at a dose of 20 g orally for 1 week and were followed-up for 3 weeks. The primary endpoint was change in walking speed in the 10-m walk test (10MWT). The main secondary endpoints were change in Timed Up and Go Test (TUGT) time, improvement in inflammatory markers in cerebrospinal fluid (CSF), safety, and tolerability. RESULTS: The study enrolled 20 patients (13 [65%] female) with a mean age of 67.8 years (95% CI 62.3 to 73.3). Although the primary endpoint, the changes in 10MWT time between baseline (Day 0) and Day 7, did not reach statistical significance (mean percent change in time -3.5%, 95% CI -10.8% to 3.7%; P = 0.32), a significant improvement was detected between baseline and Day 14 (-9.4%, 95% CI -16.6% to -2.2%; P = 0.01). Significant improvements were also observed in selected secondary endpoints, including in TUGT time (-9.1%, 95% CI -15.5% to -2.7%; P < 0.01), and in neopterin concentration in CSF (-2.1 pmol/mL, 95% CI -3.8 to -0.5; P = 0.01). Adverse events were infrequent, mild, and resolved rapidly. INTERPRETATION: l-arginine therapy improved motor function and decreased CSF inflammatory markers. l-arginine thus represents a promising therapeutic option for patients with HAM/TSP. TRIAL REGISTRATION NUMBER: UMIN000023854.
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Infecciones por HTLV-I , Virus Linfotrópico T Tipo 1 Humano , Paraparesia Espástica Tropical , Humanos , Femenino , Anciano , Masculino , Equilibrio Postural , Estudios de Tiempo y Movimiento , Paraparesia Espástica Tropical/tratamiento farmacológicoRESUMEN
OBJECTIVES: This study aimed to evaluate the antiviral effects and safety of nafamostat in early-onset patients with coronavirus disease 2019 (COVID-19). METHODS: In this exploratory multicentre randomized controlled trial, patients were assigned to three groups within 5 days of symptom onset, with 10 participants in each group: nafamostat at either 0.2 mg/kg/h or 0.1 mg/kg/h or a standard-of-care group. The primary endpoint was area under the curve for decrease in SARS-CoV-2 viral load in nasopharyngeal samples from baseline to day 6. RESULTS: Of the 30 randomized patients, 19 received nafamostat. Overall, 10 patients received low-dose nafamostat, 9 patients received high-dose nafamostat, and 10 received standard-of-care. The detected viruses were Omicron strains. The regression coefficient for area under the curve for decrease in viral load as the response variable and nafamostat dose per body weight as the explanatory variable showed a significant relationship of -40.1 (95% confidence interval, -74.1 to -6.2; P = 0.022). Serious adverse events were not observed in either group. Phlebitis occurred in ca. 50% of patients treated with nafamostat. CONCLUSIONS: Nafamostat exerts virus load-reducing effects in patients with early-onset COVID-19.
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COVID-19 , Humanos , SARS-CoV-2 , Antivirales/efectos adversos , Guanidinas/efectos adversos , Resultado del TratamientoRESUMEN
OBJECTIVES: To evaluate the efficacy and safety of nafamostat combined with favipiravir for the treatment of COVID-19. METHODS: We conducted a multicenter, randomized, single-blind, placebo-controlled, parallel assignment study in hospitalized patients with mild-to-moderate COVID-19 pneumonia. Patients were randomly assigned to receive favipiravir alone (n = 24) or nafamostat with favipiravir (n = 21). The outcomes included changes in the World Health Organization clinical progression scale score, time to improvement in body temperature, and improvement in oxygen saturation (SpO2). RESULTS: There was no significant difference in the changes in the clinical progression scale between nafamostat with favipiravir and favipiravir alone groups (median, -0.444 vs -0.150, respectively; least-squares mean difference, -0.294; P = 0.364). The time to improvement in body temperature was significantly shorter in the combination group (5.0 days; 95% confidence interval, 4.0-7.0) than in the favipiravir group (9.0 days; 95% confidence interval, 7.0-18.0; P =0.009). The changes in SpO2 were greater in the combination group than in the favipiravir group (0.526% vs -1.304%, respectively; least-squares mean difference, 1.831; P = 0.022). No serious adverse events or deaths were reported, but phlebitis occurred in 57.1% of the patients in the combination group. CONCLUSION: Although our study showed no differences in clinical progression, earlier defervescence, and recovery of SpO2 were observed in the combination group.
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COVID-19 , Humanos , SARS-CoV-2 , Antivirales/uso terapéutico , Método Simple Ciego , Progresión de la Enfermedad , Resultado del TratamientoRESUMEN
Background: Functionally impaired variants of COQ2, encoding an enzyme in biosynthesis of coenzyme Q10 (CoQ10), were found in familial multiple system atrophy (MSA) and V393A in COQ2 is associated with sporadic MSA. Furthermore, reduced levels of CoQ10 have been demonstrated in MSA patients. Methods: This study was a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. Patients with MSA were randomly assigned (1:1) to either ubiquinol (1500 mg/day) or placebo. The primary efficacy outcome was the change in the unified multiple system atrophy rating scale (UMSARS) part 2 at 48 weeks. Efficacy was assessed in all patients who completed at least one efficacy assessment (full analysis set). Safety analyses included patients who completed at least one dose of investigational drug. This trial is registered with UMIN-CTR (UMIN000031771), where the drug name of MSA-01 was used to designate ubiquinol. Findings: Between June 26, 2018, and May 27, 2019, 139 patients were enrolled and randomly assigned to the ubiquinol group (n = 69) or the placebo group (n = 70). A total of 131 patients were included in the full analysis set (63 in the ubiquinol group; 68 in the placebo group). This study met the primary efficacy outcome (least square mean difference in UMSARS part 2 score (-1.7 [95% CI, -3.2 to -0.2]; P = 0.023)). The ubiquinol group also showed better secondary efficacy outcomes (Barthel index, Scale for the Assessment and Rating of Ataxia, and time required to walk 10 m). Rates of adverse events potentially related to the investigational drug were comparable between ubiquinol (n = 15 [23.8%]) and placebo (n = 21 [30.9%]). Interpretation: High-dose ubiquinol was well-tolerated and led to a significantly smaller decline of UMSARS part 2 score compared with placebo. Funding: Japan Agency for Medical Research and Development.
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The effect of renal impairment on the pharmacokinetics of a single oral dose of memantine (10 mg) was determined in Japanese subjects. Subjects were assigned to four groups based on baseline creatinine clearance (CL(CR)): normal renal function (> 80 mL/min, n = 6), and mild (50 to ≤ 80 mL/min, n = 6), moderate (30 to < 50 mL/min, n = 6), and severe renal impairment (5 to < 30 mL/min, n = 7). Mean memantine maximum plasma concentration (C(max)) was similar in the groups (12.66, 17.25, 15.75, and 15.83 ng/mL, respectively), as was mean time to C(max) (6.2, 5.2, 4.3, and 5.4 h, respectively). However, exposure to memantine determined from mean area under the plasma concentration-time curve was 1.62-, 1.97-, and 2.33-times higher in subjects with mild, moderate, and severe renal impairment, respectively, as compared to controls with normal renal function. Mean memantine plasma elimination half-life increased according to increasing renal impairment (61.15, 83.00, 100.13, and 124.31 h, respectively), while mean cumulative urinary recovery of unchanged memantine in 72 h after dosing decreased according to increasing renal impairment (33.68%, 33.47%, 23.60%, and 16.17%, respectively). These results are the same as those in the previous study on caucasian individuals, when compared per body weight. It is suggested that the dose of memantine should be halved in patients with renal impairment.
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Antagonistas de Aminoácidos Excitadores/farmacocinética , Memantina/farmacocinética , Insuficiencia Renal/metabolismo , Anciano , Área Bajo la Curva , Pueblo Asiatico , Antagonistas de Aminoácidos Excitadores/efectos adversos , Antagonistas de Aminoácidos Excitadores/sangre , Femenino , Humanos , Masculino , Memantina/efectos adversos , Memantina/sangre , Persona de Mediana Edad , Población BlancaRESUMEN
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces parkinsonism in humans and animals. The effects of zonisamide on dopamine neurons were studied in MPTP-treated common marmosets (Callithrix jacchus). Groups of animals (n = 3) were treated with MPTP (2.5 mg/kg, every 24 h x 3); MPTP plus zonisamide (40 mg/kg administered 1 h before each MPTP dose); MPTP plus selegiline (a known MAO-B inhibitor) (2 mg/kg administered 1 h before each MPTP dose); and saline controls. An immunohistochemical study of the substantia nigra was performed 14 days after MPTP treatment in each group. MPTP reduced the mean number of tyrosine hydroxylase (TH)-positive neurons to 10% of the normal control group and mean cell size was significantly (P < 0.001) reduced from 424 to 159 µm². In the group pre-treated with zonisamide, the mean number of TH-positive neurons was reduced to 26% of that in the normal control group and the mean neuron size was significantly (P < 0.05) increased from 159 to 273 µm² compared with the group treated with MPTP alone. Moreover, in the group pre-treated with selegiline, the mean number of TH-positive neurons was 47% of that in the normal control group and the mean neuron size was increased significantly (P < 0.01) from 159 to 319 µm² compared to the group treated with MPTP alone. This observation suggests that zonisamide reduces MPTP toxicity.
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Antiparkinsonianos/farmacología , Isoxazoles/farmacología , Intoxicación por MPTP/tratamiento farmacológico , Trastornos Parkinsonianos/tratamiento farmacológico , Tirosina 3-Monooxigenasa/metabolismo , Animales , Callithrix , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/farmacología , Femenino , Humanos , Intoxicación por MPTP/metabolismo , Masculino , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Neurotoxinas/toxicidad , Trastornos Parkinsonianos/metabolismo , Selegilina/farmacología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , ZonisamidaRESUMEN
Parkinson's disease is a neurodegenerative, slowly progressive, age-related disorder. Numerous medications have been developed for its treatment and the prognosis of the disorder has improved greatly over recent years. However, the effects of medicines are variable among patients, and there are also daily fluctuations in the effects of medications in the same person. The factors that cause individual variations in the effects of medicines, the causes, and strategies to cope with these fluctuations are reviewed.
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Antiparkinsonianos/farmacocinética , Antiparkinsonianos/uso terapéutico , Individualidad , Levodopa/farmacocinética , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Humanos , Levodopa/sangre , Enfermedad de Parkinson/sangreRESUMEN
The pathogenesis of acquired immunodeficiency syndrome dementia complex (ADC) is still poorly understood. Many studies suggest that proinflammatory cytokines such as IL-1beta and TNF-alpha released by microglia/macrophages or astrocytes play a role in CNS injury. A microscopic finding of a microglial nodule with multinucleated giant cells (MNGCs) is a histopathologic hallmark of ADC and named HIV encephalitis. However, in vivo expression of these cytokines in this microenvironment of HIV encephalitis is not yet clarified. One of the main reasons is complexities of brain pathology in patients who have died from terminal AIDS. In this study, we infected two macaques with macrophage-tropic Simian immunodeficiency virus SIV239env/MERT and examined expression of TNF-alpha and IL-1beta in inflammatory lesions with MNGCs and its relation to virus-infected cells using immunohistochemistry. One macaque showed typical inflammatory lesions with MNGCs in the frontal white matter. Small microglial nodules were also detected in the basal ganglia and the spinal cord. SIVenv positive cells were detected mainly in inflammatory lesions, and seemed to be microglia/macrophages and MNGCs based on their morphology. Expression of IL-1beta and TNF-alpha were detected in the inflammatory lesions with MNGCs, and these positive cells were found to be negative for SIVenv by double-labeling immunohistochemistry or immunohistochemistry of serial sections. There were a few TNF-alpha positive cells and almost no IL-1beta positive cells in the area other than inflammatory lesions. Another macaque showed scattered CD3+ cells and CD68+ cells in the perivascular regions of the white matter. SIVenv and TNF-alpha was demonstrated in a few perivascular macrophages. These findings indicate that virus-infected microglia/macrophages do not always express IL-1beta and TNF-alpha, which suggests an indirect role of HIV-1-infected cells in cytokine-mediated pathogenesis of ADC. Our macaque model for human ADC may be useful for better understanding of its pathogenesis.
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Encéfalo/patología , Encefalitis Viral/patología , Células Gigantes/patología , Interleucina-1beta/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Virus de la Inmunodeficiencia de los Simios , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Antígenos CD/metabolismo , Ganglios Basales/metabolismo , Ganglios Basales/patología , Encéfalo/metabolismo , Encéfalo/virología , Complejo CD3/metabolismo , Encefalitis Viral/metabolismo , Encefalitis Viral/virología , Inmunohistoquímica , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Macaca mulatta , Macrófagos/metabolismo , Macrófagos/patología , Macrófagos/virología , Microglía/metabolismo , Microglía/patología , Microglía/virología , ARN Viral/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Médula Espinal/metabolismo , Médula Espinal/patología , Proteínas del Envoltorio Viral/metabolismoRESUMEN
Clinical observations of patients with chronic diseases are often restricted in terms of duration. Therefore, obtaining a quantitative and comprehensive understanding of the chronology of chronic diseases is challenging, because of the inability to precisely estimate the patient's disease stage at the time point of observation. We developed a novel method to reconstitute long-term disease progression from temporally fragmented data by extending the nonlinear mixed-effects model to incorporate the estimation of "disease time" of each subject. Application of this method to sporadic Alzheimer's disease successfully depicted disease progression over 20 years. The covariate analysis revealed earlier onset of amyloid-ß accumulation in male and female apolipoprotein E ε4 homozygotes, whereas disease progression was remarkably slower in female ε3 homozygotes compared with female ε4 carriers and males. Simulation of a clinical trial suggests patient recruitment using the information of precise disease time of each patient will decrease the sample size required for clinical trials.
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Progresión de la Enfermedad , Anciano , Anciano de 80 o más Años , Algoritmos , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/genética , Apolipoproteínas E/genética , Simulación por Computador , Interpretación Estadística de Datos , Femenino , Humanos , Masculino , Dinámicas no Lineales , Proyectos de Investigación , Tamaño de la Muestra , Factores SexualesRESUMEN
According to the World Health Organization Expert Consultation, current body mass index (BMI) cut-offs should be retained as an international classification. However, there are ethnic differences in BMI-associated health risks that may be caused by differences in body fat or skeletal muscle mass and these may affect the interpretation of phase angle and bioelectrical impedance vector analysis (BIVA). Therefore, the aim of this study was to compare body composition measured by bioelectrical impedance analysis among 1048 German, 1026 Mexican, and 995 Japanese adults encompassing a wide range of ages and BMIs (18-78 years; BMI, 13.9-44.3 kg/m2). Regression analyses between body composition parameters and BMI were used to predict ethnic-specific reference values at the standard BMI cut-offs of 18.5, 25, and 30 kg/m2. German men and women had a higher fat-free mass per fat mass compared with Mexicans. Normal-weight Japanese were similar to Mexicans but approached the German phenotype with increasing BMI. The skeletal muscle index (SMI, kg/m2) was highest in Germans, whereas in BIVA, the Mexican group had the longest vector, and the Japanese group had the lowest phase angle and the highest extracellular/total body water ratio. Ethnic differences in regional partitioning of fat and muscle mass at the trunk and the extremities contribute to differences in BIVA and phase angle. In conclusion, not only the relationship between BMI and adiposity is ethnic specific; in addition, fat distribution, SMI, and muscle mass distribution vary at the same BMI. These results emphasize the need for ethnic-specific normal values in the diagnosis of obesity and sarcopenia.
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Composición Corporal , Índice de Masa Corporal , Impedancia Eléctrica , Etnicidad , Tejido Adiposo/fisiología , Adolescente , Adulto , Anciano , Antropometría , Estudios Transversales , Femenino , Alemania/etnología , Humanos , Japón/etnología , Masculino , México/etnología , Persona de Mediana Edad , Músculo Esquelético/fisiología , Valores de Referencia , Análisis de Regresión , Adulto JovenRESUMEN
In this study, impact of a polymorphism of CYP2C19 on drug-drug interaction (DDI) was examined for etizolam. The effect of itraconazole (a strong CYP3A inhibitor) on the pharmacokinetics of etizolam (a substrate of CYP2C19 and CYP3A) was assessed in both extensive metabolizers (EMs) and poor metabolizers (PMs) of CYP2C19. Sixteen participants (8 EMs and 8 PMs) received a single oral dose of etizolam (0.25 mg) on day 1. The participants ingested itraconazole (200 mg twice a day) on days 2-5. On day 5, participants received an oral dose of etizolam (0.25 mg) again. Before coadministration of itraconazole (day 1), the area under the time-plasma concentration curve from time zero to infinity (AUC∞ ) of etizolam was higher in PMs than in EMs (2.65-fold, Pâ <â .01). Coadministration of itraconazole increased the AUC∞ of etizolam 1.66-fold and 2.34-fold in EMs and PMs, respectively (day 5). Consequently, AUC∞ was 6.18-fold higher in PMs with itraconazole than that in EMs without itraconazole. The increase by itraconazole was larger in PMs (Pâ <â .01). In heterozygous EMs (hEMs), AUC∞ was simulated to be 2.56-fold higher with itraconazole than that in EMs without itraconazole. We found that in vitro measurements of fraction metabolized (fm ) using the liver microsome prepared from PM donors would be helpful to predict polymorphism-dependent DDIs. These results suggest that the PMs and hEMs of a polymorphic CYP would be at higher risk of DDIs relative to EMs for drugs metabolized by both polymorphic and nonpolymorphic CYPs such as etizolam.
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Citocromo P-450 CYP2C19/metabolismo , Diazepam/análogos & derivados , Interacciones Farmacológicas/fisiología , Itraconazol/uso terapéutico , Adulto , Área Bajo la Curva , Citocromo P-450 CYP2C19/genética , Diazepam/uso terapéutico , Interacciones Farmacológicas/genética , Genotipo , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Polimorfismo Genético/genéticaRESUMEN
In the treatment of Parkinson's disease, levodopa, DCI, MAO-B inhibitor, COMT inhibitors, dopamine receptor agonists, amantadine, anticholinergics have been applied and new drugs are being developed. Levodopa is still the golden standard in the treatment of Parkinson's disease. The study on levodopa bioavailability showed 3-4 times differences in individual patients. Drug-food interactions are prominent in levodopa. Low protein food increased levodopa bioavailability and improved no ON or delayed ON in the treatment of Parkinson's disease. Vitamine C or magnesium did not alter the bioavailability of levodopa. The bioavailability of levodopa between the levodopa/carbidioa (100/12.5) group and the levodopa/benserazide (100/25) group was studied in patients with Parkinson's disease by population PK study. C(max) of levodopa in levodeopa/benserazide group was twice as high as in levodopa/carbidopa group. Domperidone, a dopamine receptor antagonist applied as an antiemetic inceases vowel movement. The effect of domperidone on levodopa bioavailability was studied, and the combination of domperidone with levodopa increased AUC of levodopa. Clarythromycin or grape fruit juice inhibits both of CYP3A4 and P-glycoprotein which work on metabolism and absorption of drugs. Coadministration of clarythromycin with ergot alkaloids such as cabergoline or bromocriptine increased the AUC up to 2-3 times. Amantadine is excreted through kidney without being metabolized and renal function is the most important factor in the blood concentration of amantadine. In elder women with the body weight of 50 kg or less, creatinine clearance is less than 50 ml/min even though the serum creatinine is within the normal range. Selegiline is metabolized through CYP2D6 and 3A4. Coadministration of qunidine, cimetidine, maclorides, antifungals, grape fruit juice increase the bioavailability of selegiline and may augment the antiparkinsonian effect.
Asunto(s)
Antiparkinsonianos/farmacocinética , Levodopa/farmacocinética , Enfermedad de Parkinson/tratamiento farmacológico , Área Bajo la Curva , Domperidona/farmacocinética , Antagonistas de Dopamina/farmacocinética , Interacciones Farmacológicas , Humanos , Individualidad , Enfermedad de Parkinson/metabolismoRESUMEN
PURPOSE: The Ministry of Health, Labour and Welfare (MHLW) of Japan launched a regulatory science research project in which the aim is to promote the establishment of guidelines for the development of innovative drugs thorough interactions between academia and Japan's regulatory agency, the Pharmaceuticals and Medical Devices Agency (PMDA). In this project, a research system with the aim of developing a guideline for the clinical evaluation of drugs intended for the treatment of Alzheimer's disease (AD) was established. METHODS: Two research groups were set up: (1) the Biomarker and Clinical Evaluation Group to establish biomarker-based criteria for the clinical evaluation of drugs for AD, and (2) the Modeling and Simulation (M&S) Group to create a disease model of AD using M&S techniques based on data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Furthermore, a human resource exchange between the University of Tokyo Hospital and the PMDA is conducted to establish a guideline that is suitable for regulatory use. FINDINGS: As an interim report of this project, issues that require consideration for the clinical evaluation and development were summarized, including topics such as the use of biomarkers in the inclusion criteria, the efficacy endpoint, and the clinical data package required for application in Japan. IMPLICATIONS: As the result of collaboration between the University of Tokyo Hospital and PMDA, this document is the first to summarize perspectives on the development of drugs for AD in Japan.