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INTRODUCTION: The neurotrophin nerve growth factor has a demonstrated role in pain transduction and pathophysiology. OBJECTIVES: Two randomized, double-blind, placebo-controlled, phase 1 studies were conducted to evaluate safety, tolerability, and analgesic efficacy of single doses of tanezumab, a humanized anti-nerve growth factor monoclonal antibody, in chronic or acute pain. METHODS: In the first study (CL001), patients with moderate to severe pain from osteoarthritis (OA) of the knee received a single intravenous infusion of tanezumab (3-1000 µg/kg) or placebo in a dose-escalation (part 1; N = 42) or parallel-arm (part 2; N = 79) study design. The second study (CL002) was a placebo-controlled dose-escalation (tanezumab 10-1000 µg/kg; N = 50) study in patients undergoing bunionectomy surgery. RESULTS: Adverse event rates were generally similar across treatments. Most adverse events were generally mild to moderate in severity and no patients discontinued as a result of adverse events. Adverse events of abnormal peripheral sensation were more common with higher doses of tanezumab (≥100 µg/kg) than with placebo. These were generally mild to moderate in severity. Tanezumab provided up to 12 weeks of effective analgesia for OA knee pain, with statistically significant improvements at doses ≥100 µg/kg (P < 0.05). By contrast, no trend for analgesic activity was found when tanezumab was administered 8 to 16 hours before bunionectomy. CONCLUSIONS: The demonstration of a favorable safety profile and clinical efficacy in OA pain supports clinical development of tanezumab as a potential treatment for chronic pain conditions.
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Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of mixed dyslipidemia. The aim of the study was to evaluate the pharmacokinetic, pharmacodynamic, and safety characteristics of anacetrapib following single doses in healthy, young Japanese men. In a double-blind, randomized, placebo-controlled, 3-panel, single-rising-dose study, 6 healthy young Japanese male or white male subjects (aged 19 to 44 years) received single oral doses of 5 to 500 mg anacetrapib, and 2 received placebo. Plasma and urine drug concentrations were measured 0-168 hours postdose, and plasma CETP inhibition was measured 0-24 hours postdose. Urinary anacetrapib levels were all below quantitation limits. Plasma concentrations of anacetrapib increased approximately less than dose-proportionally. Consumption of a traditional Japanese breakfast prior to dosing increased the plasma pharmacokinetics of anacetrapib in Japanese subjects compared with fasted conditions, to a similar extent as in white subjects. CETP activity measured over 0-24 hours postdose resulted in significant inhibition. Anacetrapib was generally well tolerated, and there were no serious adverse experiences. No clinically meaningful differences in PK and CETP inhibition parameters were found between Japanese and white subjects.
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Anticolesterolemiantes/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Oxazolidinonas/farmacología , Adulto , Anticolesterolemiantes/sangre , Pueblo Asiatico , Proteínas de Transferencia de Ésteres de Colesterol/sangre , Citocromo P-450 CYP3A/metabolismo , Método Doble Ciego , Voluntarios Sanos , Humanos , Masculino , Oxazolidinonas/sangre , Población Blanca , Adulto JovenRESUMEN
This 21-week, open-label, phase 2a trial aimed to evaluate the pharmacodynamics and safety of multiple, escalating infusions of BPS804, a neutralizing, anti-sclerostin antibody, in adults with moderate osteogenesis imperfecta (OI). Patients received BPS804 (three escalating doses each separated by 2 weeks [5, 10, and 20 mg/kg]) or no treatment (reference group). The primary efficacy endpoints were mean changes from baseline to day 43 in: procollagen type 1 N-terminal propeptide (P1NP), procollagen type 1 C-terminal propeptide (P1CP), bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and type 1 collagen cross-linked C-telopeptide (CTX-1). Mean change from baseline to day 141 in lumbar spine areal bone mineral density (aBMD) was also assessed. BPS804 safety and tolerability were assessed every 2 weeks. Overall, 14 adults were enrolled (BPS804 group: n = 9, mean age 30.7 years, mean aBMD Z-score -2.6; reference group, n = 5, mean age 27.4 years, mean aBMD Z-score -2.2). In the BPS804 group, P1NP, P1CP, BSAP, and OC were increased by 84% (p < 0.001), 53% (p = 0.003), 59% (p < 0.001), and 44% (p = 0.012), respectively, versus baseline (reference: P1NP, +6% [p = 0.651]; P1CP, +5% [p = 0.600]; BSAP, -13% [p = 0.582]; OC, -19% [p = 0.436]). BPS804 treatment downregulated CTX-1 by 44% from baseline (reference: -7%; significance was not tested for this biomarker), and increased aBMD by 4% (p = 0.038; reference group: +1%; p = 0.138). BPS804 was generally well tolerated. There were 32 adverse events reported in nine patients; none was suspected to be treatment-related. There were no treatment-related fractures. BPS804 stimulates bone formation, reduces bone resorption, and increases lumbar spine aBMD in adults with moderate OI. This paves the way for a longer-term, phase 3 trial into the efficacy, safety, and tolerability of BPS804 in patients with OI. © 2017 American Society for Bone and Mineral Research.
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Anticuerpos Monoclonales/administración & dosificación , Densidad Ósea/efectos de los fármacos , Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Osteogénesis Imperfecta/tratamiento farmacológico , Proteínas Adaptadoras Transductoras de Señales , Adolescente , Adulto , Fosfatasa Alcalina/sangre , Femenino , Marcadores Genéticos , Humanos , Masculino , Osteocalcina/sangre , Osteogénesis Imperfecta/sangre , Fragmentos de Péptidos/sangre , Procolágeno/sangreRESUMEN
INTRODUCTION: Phase-0 studies, including microdosing, also called Exploratory Investigational New Drug (eIND) or exploratory clinical trials, are a regulatory framework for first-in-human (FIH) trials. Common to these approaches is the use and implied safety of limited exposures to test articles. Use of sub-pharmacological doses in phase-0/microdose studies requires sensitive analytic tools such as accelerator mass spectrometer (AMS), Positron Emission Tomography (PET), and Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) to determine drug disposition. Areas covered: Here we present a practical guide to the range of methodologies, design options, and conduct strategies that can be used to increase the efficiency of drug development. We provide detailed examples of relevant developmental scenarios. Expert opinion: Validation studies over the past decade demonstrated the reliability of extrapolation of sub-pharmacological to therapeutic-level exposures in more than 80% of cases, an improvement over traditional allometric approaches. Applications of phase-0/microdosing approaches include study of pharmacokinetic and pharmacodynamic properties, target tissue localization, drug-drug interactions, effects in vulnerable populations (e.g. pediatric), and intra-target microdosing (ITM). Study design should take into account the advantages and disadvantages of each analytic tool. Utilization of combinations of these analytic techniques increases the versatility of study designs and the power of data obtained.
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Tomografía de Emisión de Positrones/métodos , Espectrometría de Masas en Tándem/métodos , Interacciones Farmacológicas , Humanos , Reproducibilidad de los ResultadosRESUMEN
ST-246 is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. To this end, a phase 2, double-blind, randomized, placebo-controlled, multicenter trial was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of ST-246 when administered as a single daily oral dose (400 mg or 600 mg) for 14 days in fed adult volunteers. ST-246 was safe and well tolerated, with no deaths or serious adverse events reported during the study. There was a low incidence of treatment-emergent adverse events (TEAEs), the most common of which were mild nausea and headache. There were no clinically significant results from laboratory assessments, vital sign measurements, physical examinations, or electrocardiograms. The PK and dose proportionality of ST-246 were determined. The PK analysis showed that steady state was achieved by day 5 for the ST-246 400-mg treatment group and by day 6 for the 600-mg group. The dose proportionality analysis showed that the 400- and 600-mg ratio of dose-normalized peak drug concentration in plasma (C(max)) and relative exposure for each dosing interval (AUC(τ)) ranged from 80% to 85%. However, the 90% confidence intervals did not include 1.0, so dose proportionality could not be concluded. Overall, ST-246 was shown to be safe, and the PK was predictable. These results support further testing of ST-246 in a multicenter pivotal clinical safety study for licensure application.
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Antivirales/farmacocinética , Benzamidas/farmacocinética , Isoindoles/farmacocinética , Administración Oral , Adolescente , Adulto , Anciano , Antivirales/administración & dosificación , Antivirales/efectos adversos , Antivirales/sangre , Área Bajo la Curva , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Benzamidas/sangre , Disponibilidad Biológica , Método Doble Ciego , Esquema de Medicación , Femenino , Semivida , Humanos , Isoindoles/administración & dosificación , Isoindoles/efectos adversos , Isoindoles/sangre , Masculino , Persona de Mediana Edad , PlacebosRESUMEN
BACKGROUND: To our knowledge, there is no direct information on lycopene metabolism in humans. OBJECTIVE: The objective of this study was to quantify the long-term human bioavailability of lycopene in plasma and skin after a single dose of (14)C-lycopene and to profile the metabolites formed. DESIGN: We preselected 2 male subjects as lycopene absorbers and gave them an oral dose of 10 mg synthetic lycopene combined with ≈6 µg [6,6',7,7'-(14)C]lycopene (≈30,000 Bq; 92% trans lycopene). The appearance of (14)C in plasma, plasma triacylglycerol-rich lipoprotein (TRL) fraction, urine, expired breath carbon dioxide, and skin biopsies was measured over 42 d. The (14)C in lycopene-isomer fractions from plasma and TRL fraction was measured to assess the isomerization of lycopene in vivo. RESULTS: We quantified (14)C from (14)C-lycopene in plasma, the plasma TRL fraction, expired carbon dioxide, urine, and skin. The time to maximum concentration (t(max)) of total (14)C-lycopene in plasma was 6 h, and the elimination half-life (t(1/2)) was 5 d, which were different from the t(max) and t(1/2) of unlabeled lycopene (0.5 and 48 d, respectively). (14)C-Lycopene was extensively isomerized after dosing as a 92% all-trans isomer at dosing but changed to 50% trans, 38% 5 cis, 1% 9 cis, and 11% other cis isomers after 24 h. A similar pattern of isomerization was seen in plasma TRL fractions. CONCLUSIONS: Lycopene was extensively isomerized after dosing and rapidly metabolized into polar metabolites excreted into urine with the rapid peak of (14)CO(2) after dosing, which implies that ß-oxidation was involved in the lycopene metabolism. Lycopene or its metabolites were detected in skin for up to 42 d.
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Carotenoides/farmacocinética , Piel/metabolismo , Adulto , Disponibilidad Biológica , Biopsia , Pruebas Respiratorias , Dióxido de Carbono/metabolismo , Isótopos de Carbono/metabolismo , Carotenoides/sangre , Carotenoides/metabolismo , Humanos , Isomerismo , Lipoproteínas/sangre , Licopeno , Masculino , Espectrometría de Masas/métodos , Persona de Mediana Edad , Triglicéridos/sangre , UrinálisisRESUMEN
AIMS: Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 (DPP-4) used to treat type 2 diabetes. The present aim was to evaluate pharmacokinetic (PK), pharmacodynamic (PD) and safety characteristics of sitagliptin following single doses in healthy, young Japanese males. METHODS: In this alternating two-panel, randomized, controlled double-blind study, six healthy Japanese male subjects (aged 20-46 years) in each panel received single oral doses of 5-400mg sitagliptin and two received placebo. Plasma and urine drug concentrations were measured from 0-48h post dose and plasma DPP-4 inhibition from 0-24h post dose. The results were compared with historical data from young, healthy non-Japanese males. RESULTS: Plasma concentrations of sitagliptin increased approximately in proportion to dose; maximum concentrations occurred 2-6h post-dose. The mean apparent terminal half-life for plasma sitagliptin was 9-14h, with the half-life slightly decreasing as the dose increased. The mean dose fraction excreted unchanged in the urine was 0.73-1.00. Ingestion of a traditional Japanese breakfast prior to dosing had only a minor effect on PK parameters. After correction for dilution and competition effects during assay, doses of sitagliptin ≥50mg resulted in weighted average DPP-4 inhibition from 0-24h post-dose >94% (without correction, >78%). No clinically meaningful differences in PK and DPP-4 inhibition parameters were found between Japanese and non-Japanese subjects. Sitagliptin was generally well tolerated and there were no serious adverse experiences or episodes of hypoglycaemia. CONCLUSIONS: The PK and PD findings from this study are consistent with once daily dosing of sitagliptin in Japanese patients with type 2 diabetes.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Hipoglucemiantes/administración & dosificación , Pirazinas/administración & dosificación , Triazoles/administración & dosificación , Administración Oral , Adulto , Pueblo Asiatico , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Hipoglucemiantes/efectos adversos , Masculino , Persona de Mediana Edad , Pirazinas/efectos adversos , Proyectos de Investigación , Fosfato de Sitagliptina , Estadística como Asunto , Triazoles/efectos adversos , Adulto JovenRESUMEN
CONTEXT: Pain associated with superficial procedures, including intravenous (IV) access procedures, should be prevented when possible, especially in children. OBJECTIVES: To evaluate a topical local anesthetic patch containing lidocaine 70 mg/tetracaine 70 mg with a heating element designed to warm the skin and facilitate rapid delivery of local anesthetics into the skin. The pilot study was designed to provide data to inform the design of the definitive study to evaluate the impact of controlled heat on the efficacy of the lidocaine/tetracaine patch (patch) when applied before IV cannulation. METHODS: Subjects in the pilot study were randomized to eight groups that varied by heated vs. unheated patch, 20 vs. 30 minute application, and 16 vs. 18 G catheter. Subjects in the definitive study were randomized in a double-blind manner to receive either the heated or unheated patch, 20 minutes before vascular access, using a 16 G catheter in the antecubital space of the arm. In both studies, the primary efficacy measure was subject-reported pain intensity using a visual analog scale. RESULTS: Pilot study: Subjects who received the heated patch (n=43) vs. the unheated patch (n=37) had lower mean pain intensity scores (14.7 vs. 23.5mm, P=0.04). Pain intensity scores did not differ significantly by application time, but the difference between the 16 and 18 G catheter groups approached statistical significance (22.8 vs. 14.9 mm, P=0.05). Definitive study: Mean pain intensity scores for the heated patch group (n=124) vs. the unheated patch group (n=126) were 14.2 and 20.5mm, respectively (P=0.006). CONCLUSION: Heated patches provided significantly better pain relief compared with unheated patches. All the subjects tolerated the patches well, with few adverse effects.
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Analgesia/métodos , Calor/uso terapéutico , Dolor/prevención & control , Flebotomía/efectos adversos , Administración Cutánea , Adolescente , Adulto , Anciano , Anestésicos Locales/administración & dosificación , Anestésicos Locales/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Lidocaína/administración & dosificación , Lidocaína/uso terapéutico , Masculino , Persona de Mediana Edad , Dolor/etiología , Dimensión del Dolor , Proyectos Piloto , Resultado del TratamientoRESUMEN
Laropiprant (LRPT), a prostaglandin D(2) receptor-1 antagonist shown to reduce niacin-induced flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This open-label, randomized, 2-period crossover study assessed the pharmacokinetics of single-dose rosiglitazone in the presence and absence of multiple-dose LRPT. Twelve healthy male and female subjects, 34-64 years of age, received two, once-daily oral treatments in random sequence separated by >/=3-day washout: (1) multiple-dose LRPT 40 mg/day for 7 days (Days 1 to 7) coadministered with single-dose rosiglitazone 4 mg on Day 6; (2) single-dose rosiglitazone 4 mg on Day 1. Comparability was declared because the 90% confidence interval (CI) for the AUC(0-infinity) geometric mean ratio (GMR; rosiglitazone + LRPT/rosiglitazone alone) [0.92 (0.86, 0.99)], was contained within prespecified bounds (0.70, 1.43). The C(max) GMR (90% CI) for rosiglitazone was 0.98 (0.95, 1.02). There was no evidence of clinically meaningful alterations in the pharmacokinetics of rosiglitazone, a probe CYP2C8 substrate, following coadministration of multiple-dose LRPT in healthy subjects. Therefore, findings suggest that LRPT does not inhibit CYP2C8-mediated metabolism.
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Hipoglucemiantes/farmacocinética , Indoles/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Tiazolidinedionas/farmacocinética , Adulto , Estudios Cruzados , Interacciones Farmacológicas , Femenino , Humanos , Persona de Mediana Edad , RosiglitazonaRESUMEN
The effects of ACE-011 on safety, pharmacokinetics, and bone biomarkers were evaluated in healthy, postmenopausal women. Our data indicate that ACE-011 results in a sustained increase in biomarkers of bone formation and reduction in markers of bone resorption. The activin type IIA receptor (ActRIIA) is the high-affinity receptor for activin. ACE-011 is a dimeric fusion protein consisting of the extracellular domain of the human ActRIIA linked to the Fc portion of human IgG1. ACE-011 binds to activin, preventing activin from binding endogenous receptors. A randomized, double-blind, placebo-controlled study was conducted to evaluate the safety and tolerability of ACE-011. Forty-eight healthy, postmenopausal women were randomized to receive either a single dose of ACE-011 or placebo and were followed for 4 mo. Dose levels ranged from 0.01 to 3.0 mg/kg intravenously and from 0.03 to 0.1 mg/kg subcutaneously. Safety and pharmacokinetic (PK) analyses and the biological activity of ACE-011, as assessed by markers of bone turnover, and follicle stimulating hormone (FSH) levels were measured. No serious adverse events (AEs) were reported. AEs were generally mild and transient. The PK of ACE-011 was linear over the dose range studied, with a mean half-life of 24-32 days. The absorption after subcutaneous dosing was essentially complete. ACE-011 caused a rapid and sustained dose-dependent increase in serum levels of bone-specific alkaline phosphatase (BSALP) and a dose-dependent decrease in C-terminal type 1 collagen telopeptide (CTX) and TRACP-5b levels. There was also a dose-dependent decrease in serum FSH levels consistent with inhibition of activin. ACE-011 is a novel agent with biological evidence of both an increase in bone formation and a decrease in bone resorption. ACE-011 may be an effective therapy in a variety of diseases involving bone loss.
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Posmenopausia/efectos de los fármacos , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/farmacología , Anciano , Biomarcadores/metabolismo , Resorción Ósea/metabolismo , Demografía , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Hormona Folículo Estimulante/sangre , Humanos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Persona de Mediana Edad , Osteogénesis/efectos de los fármacos , Placebos , Posmenopausia/sangre , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacocinéticaRESUMEN
BACKGROUND: A 7-valent pneumococcal conjugate vaccine (7vPnC) has markedly reduced invasive pneumococcal disease (IPD) in routine use in the USA and is in clinical development in Japan. But a 13-valent pneumococcal conjugate vaccine (13vPnC) would cover even more serotypes. Because vaccines are administered to children by s.c. injection in Japan but by i.m. injection in the USA, a phase I study of s.c. injected 13vPnC in healthy Japanese adults was appropriate before commencing trials in Japanese children and older adults. METHODS: This was a randomized comparison in healthy Japanese adults of s.c. administered 13-valent pneumococcal conjugate vaccine and s.c. administered 23-valent plain polysaccharide pneumococcal vaccine (23vPn). Local and systemic reactions were recorded in a daily diary for 14 days after injection. IgG antibodies to serotype-specific capsular polysaccharide were measured on enzyme-linked immunosorbent assay on samples taken before and approximately 1 month after immunization. RESULTS: A total of 15 subjects were evaluable for safety review in each treatment group. There was a trend towards more local reactions in the 13vPnC group, which may be associated with s.c. administration of aluminum-containing vaccines as used routinely in Japan; but the local reactogenicity was mostly mild or moderate. Both 13vPnC and 23vPn were immunogenic for all types, with the exception of 6A, which is not included in 23vPn and for which only 13vPnC was immunogenic. CONCLUSIONS: Overall, immunogenicity and tolerance was adequate to lead to studies of 13vPnC in both infants and older adults in Japan, using the s.c. route if appropriate.
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Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas/administración & dosificación , Adulto , Anticuerpos Antiidiotipos/inmunología , Anticuerpos Antibacterianos/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Humanos , Inmunoglobulina G/inmunología , Incidencia , Inyecciones Subcutáneas , Japón/epidemiología , Masculino , Persona de Mediana Edad , Infecciones Neumocócicas/epidemiología , Infecciones Neumocócicas/microbiología , Streptococcus pneumoniae/inmunología , Factores de Tiempo , Resultado del TratamientoRESUMEN
The remarkable sensitivity of accelerator mass spectrometry (AMS) is finding many new applications in pharmacology. In this study AMS was used to measure [(14)C]-Zidovudine (ZDV) concentrations at the drug's site of action (peripheral blood mononuclear cells, PBMCs) following a dose of 520 ng (less than one-millionth of the standard daily dose) to a healthy volunteer. In addition, the pharmacokinetics of this microdose were determined and compared to previously published parameters for therapeutic doses. Microdose ZDV pharmacokinetic parameters fell within reported 95% confidence intervals or standard deviations of most previously published values for therapeutic doses. Blood, urine, stool, saliva, and isolated PBMCs were collected periodically through 96 h postdose and analyzed for ZDV and metabolite concentrations. The results showed that ZDV is rapidly absorbed and eliminated, has one major metabolite, and is sequestered in PBMCs. (14)C mass balance assessments indicated a significant portion of ZDV remained after 96 h with a much prolonged elimination half-life. Results of this study demonstrate the usefulness of microdosing and AMS as a tool for studying the pharmacokinetic characteristics, including PBMC concentrations, of ZDV and underscore the value of AMS as a tool with which to perform pharmacokinetic and mass balance studies using trace amounts of radiolabeled compound.
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Leucocitos Mononucleares , Inhibidores de la Transcriptasa Inversa/farmacocinética , Zidovudina/farmacocinética , Adulto , Relación Dosis-Respuesta a Droga , Heces/química , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , Espectrometría de Masas/métodos , Inhibidores de la Transcriptasa Inversa/sangre , Inhibidores de la Transcriptasa Inversa/orina , Saliva/química , Distribución Tisular , Zidovudina/sangre , Zidovudina/orinaRESUMEN
OBJECTIVE: To evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of the acetyl-selective anticholinesterase, phenserine tartrate, in healthy elderly subjects. METHODS: 32 healthy elderly volunteers received single oral doses of phenserine tartrate (5-20 mg). Physical and vital signs were monitored over the ensuing 24 hours. Analyses were performed on plasma samples to determine PK, and PD were assessed using an erythrocyte acetylcholinesterase (AChE) inhibition assay. RESULTS: No serious adverse events (AEs) occurred; the most common were headache and vomiting. The MTD of phenserine tartrate was 10 mg. The Cmax and AUC(0-24) of phenserine increased with dose, but neither were dose-proportional. Subjects receiving 10 mg of phenserine tartrate had a Cmax of 1.95 ng/mL at 1.5 hours, and the mean peak inhibition (Imax) of AChE was 26% (range: 18-34%) at 1.75 hours (tImax) following dosing. The half-life of AChE inhibition (tI1/2) was 11 hours. Evaluation of PK/PD relationships suggested a linear correlation between plasma phenserine concentration and AChE inhibition in the blood. CONCLUSIONS: Phenserine tartrate was safe and well tolerated when administered as a single oral dose of either 5 mg or 10 mg. An increase in the severity and frequency of AEs occurred at the 20 mg dose level.
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Inhibidores de la Colinesterasa/efectos adversos , Inhibidores de la Colinesterasa/farmacocinética , Fisostigmina/análogos & derivados , Acetilcolinesterasa/efectos de los fármacos , Anciano , Área Bajo la Curva , Eritrocitos/efectos de los fármacos , Eritrocitos/enzimología , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Fisostigmina/efectos adversos , Fisostigmina/farmacocinéticaRESUMEN
OBJECTIVE: To determine the pharmacokinetics of fluvoxamine in children and adolescents and to compare pharmacokinetic data from adolescents to adults from a previous study. METHOD: Fluvoxamine was titrated to a target dose of 100 mg b.i.d. in children (6-11 years) and 150 mg b.i.d. in adolescents (12-17 years) with obsessive-compulsive disorder or other disorder requiring fluvoxamine treatment. Serum samples were collected over 12 hours after 12 or more consecutive doses of 25, 50, 100, and 150 mg. RESULTS: Sixteen children (seven females, nine males) and 18 adolescents (nine females, nine males) were included in the pharmacokinetic analyses. Children demonstrated higher mean peak plasma concentration, higher mean area under the plasma concentration-time curve, and lower apparent oral clearance compared with adolescents. Compared with male children, female children had higher mean area under the plasma concentration-time curve, higher mean peak plasma concentration, and more reports of adverse events. However, the area under the plasma concentration-time curve was not directly correlated with frequency or severity of adverse events. Pharmacokinetics were nonlinear over the dose range studied. No pharmacokinetic differences were apparent between adolescents and adults on 150 mg b.i.d. CONCLUSIONS: These pharmacokinetic results suggest that children (especially females) have a higher exposure to fluvoxamine than adolescents, whereas adolescents and adults appear to have similar exposure to fluvoxamine.
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Ansiolíticos/administración & dosificación , Ansiolíticos/farmacocinética , Trastornos de Ansiedad/sangre , Trastornos de Ansiedad/tratamiento farmacológico , Fluvoxamina/administración & dosificación , Fluvoxamina/farmacocinética , Trastorno Obsesivo Compulsivo/sangre , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Adolescente , Ansiolíticos/uso terapéutico , Niño , Citocromo P-450 CYP2D6/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Fluvoxamina/uso terapéutico , Humanos , MasculinoRESUMEN
BACKGROUND: (+)-Calanolide A is a naturally occurring nonnucleoside reverse transciptase inhibitor (NNRTI) that exhibits enhanced activity against HIV-1 isolates with the Y181C mutation and retains activity against HIV-1 isolates with dual Y181C and K103N mutations. Previous studies have demonstrated that (+)-calanolide A has a favorable safety profile in both animal and human subjects. METHOD: In this study, the safety and pharmacokinetics of multiple escalating doses of (+)-calanolide A were evaluated in a total of 47 healthy, HIV-seronegative individuals. RESULTS: All adverse events seen in the study were mild to moderate in intensity and were transient. The most common adverse events seen were headache, dizziness, nausea, and taste perversion (oily aftertaste). Laboratory abnormalities were determined to be clinically insignificant or unrelated to (+)-calanolide A administration. No dose-related pattern in adverse event or laboratory abnormality incidence was apparent. In all cohorts examined, administration of (+)-calanolide A produced highly variable plasma levels and absorption profiles. No accumulation of parent compound was seen over the 5-day treatment course, with the day 5 area under the curve (AUC) being approximately one half of that seen on the first day of dosing. Steady-state trough plasma levels were determined in the two highest dose cohorts (600 mg and 800 mg bid for 5 days). Mean elimination half-life in the two highest dosing cohorts combined was 15.5 hours in men and 35.2 hours in women. CONCLUSION: These pharmacokinetic properties, together with the benign safety profile, and unique in vitro resistance pattern warrant the continued development of this potential new antiviral agent.