RESUMO
This study evaluated the short-term effects of tofacitinib treatment on peripheral blood leukocyte phenotype and function, and the reversibility of any such effects following treatment withdrawal in healthy volunteers. Cytomegalovirus (CMV)-seropositive subjects received oral tofacitinib 10â¯mg twice daily for 4â¯weeks and were followed for 4â¯weeks after drug withdrawal. There were slight increases in total lymphocyte and total T-cell counts during tofacitinib treatment, and B-cell counts increased by up to 26%. There were no significant changes in granulocyte or monocyte counts, or granulocyte function. Naïve and central memory T-cell counts increased during treatment, while all subsets of activated T cells were decreased by up to 69%. T-cell subsets other than effector memory cluster of differentiation (CD)4+, activated naïve CD4+ and effector CD8+ T-cell counts and B-cell counts, normalized 4â¯weeks after withdrawal. Following ex vivo activation, measures of CMV-specific T-cell responses, and antigen non-specific T-cell-mediated cytotoxicity and interferon (IFN)-γ production, decreased slightly. These T-cell functional changes were most pronounced at Day 15, partially normalized while still on tofacitinib and returned to baseline after drug withdrawal. Total natural killer (NK)-cell counts decreased by 33%, returning towards baseline after drug withdrawal. NK-cell function decreased during tofacitinib treatment, but without a consistent time course across measured parameters. However, markers of NK-cell-mediated cytotoxicity, antibody-dependent cellular cytotoxicity and IFN-γ production were decreased up to 42% 1â¯month after drug withdrawal. CMV DNA was not detectable in whole blood, and there were no cases of herpes zoster reactivation. No new safety concerns arose. In conclusion, the effect of short-term tofacitinib treatment on leukocyte composition and function in healthy CMV+ volunteers is modest and largely reversible 4â¯weeks after withdrawal.
Assuntos
Inibidores de Janus Quinases/farmacologia , Leucócitos/efeitos dos fármacos , Piperidinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Adulto , Idoso , Artrite Reumatoide/tratamento farmacológico , Feminino , Voluntários Saudáveis , Humanos , Leucócitos/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Fenótipo , Piperidinas/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
Hypoxemia can be life-threatening, both acutely and chronically. Because hypoxemia causes vascular dysregulation that further restricts oxygen availability to tissue, it can be pharmacologically addressed. We hypothesized that theophylline can be safely combined with the ß2-adrenergic vasodilator bambuterol to improve oxygen availability in hypoxemic patients. Ergogenicity and hemodynamic effects of bambuterol and theophylline were measured in rats under hypobaric and normobaric hypoxia (12% O2). Feasibility in humans was assessed using randomized, double-blind testing of the influence of combined slow-release theophylline (300 mg) and bambuterol (20 mg) on adverse events (AEs), plasma K+, pulse, blood pressure, and drug interaction. Both drugs and their combination significantly improved hypoxic endurance in rats. In humans, common AEs were low K+ (<3.5 mmol/L; bambuterol: 12, theophylline: 4, combination: 13 episodes) and tremors (10, 0, 14 episodes). No exacerbation or serious AE occurred when drugs were combined. A drop in plasma K+ coincided with peak bambuterol plasma concentrations. Bambuterol increased heart rate by approximately 13 bpm. Drug interaction was present but small. We report promise, feasibility, and relative safety of combined theophylline and bambuterol as a treatment of hypoxemia in humans. Cardiac safety and blood K+ will be important safety endpoints when testing these drugs in hypoxemic subjects.
Assuntos
Hipóxia/tratamento farmacológico , Terbutalina/análogos & derivados , Teofilina/farmacologia , Adulto , Animais , Disponibilidade Biológica , Interações Medicamentosas , Feminino , Meia-Vida , Hemodinâmica/efeitos dos fármacos , Humanos , Hipóxia/sangue , Hipóxia/fisiopatologia , Masculino , Condicionamento Físico Animal , Ratos , Segurança , Terbutalina/efeitos adversos , Terbutalina/farmacocinética , Terbutalina/farmacologia , Terbutalina/uso terapêutico , Teofilina/efeitos adversos , Teofilina/farmacocinética , Teofilina/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
AIMS: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of edoxaban, an oral direct factor Xa inhibitor, in healthy subjects switching from warfarin. METHODS: Seventy-two subjects were randomized to edoxaban 60 mg once daily (n = 48) or matching placebo (n = 24) for 5 days at 24 h after the last dose of warfarin treatment (INR 2.0 to 3.0). Safety/tolerability was the primary outcome measure. Pharmacokinetics, INR, aPTT, anti-FXa, thrombin generation and other coagulation assays were assessed. RESULTS: Seventy-two subjects were randomized and 64 subjects received at least one dose of edoxaban (n = 43) or placebo (n = 21) after achieving a target INR of 2.0 to 3.0 on warfarin treatment. Edoxaban 60 mg administered 24 h post-warfarin appeared to be safe and well tolerated. Adverse events were similar across treatments. For bleeding-related adverse events, eight subjects tested positive for faecal occult blood, five subjects during warfarin treatment and three subjects during edoxaban treatment. The mean (SD) baseline (post-dose of warfarin) INR was 2.31 (0.193) which increased to 3.84 (0.744) over 2 h during the edoxaban treatment (P < 0.0001 vs. placebo), returning to post-warfarin baseline within 12 h. A similar time course of effects for the other coagulation assays was observed in accordance with the drugs' mechanisms of action. CONCLUSION: In this study of healthy subjects, edoxaban administered 24 h after the last dose of warfarin was safe and well tolerated with transient increases across the various coagulation assays above post-warfarin baseline levels.
Assuntos
Anticoagulantes , Inibidores do Fator Xa , Piridinas , Tiazóis , Varfarina/administração & dosagem , Administração Oral , Adolescente , Adulto , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Testes de Coagulação Sanguínea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/farmacocinética , Piridinas/farmacologia , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Tiazóis/farmacocinética , Tiazóis/farmacologiaAssuntos
Arginina/análogos & derivados , Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa , Antagonistas de Heparina/farmacologia , Piperazinas/farmacologia , Piridinas/antagonistas & inibidores , Tiazóis/antagonistas & inibidores , Arginina/farmacocinética , Arginina/farmacologia , Antagonistas de Heparina/farmacocinética , Humanos , Piperazinas/farmacocinéticaRESUMO
The oral anticoagulant edoxaban, a factor Xa inhibitor, will likely be coadministered with digoxin in some patients with atrial fibrillation. Both drugs are substrates for P-glycoprotein. The objective of this phase 1, parallel study was to assess the effects of coadministration of both drugs on their respective pharmacokinetics (PK) and pharmacodynamics (PD). Forty-eight subjects, aged 18 to 45 years, received either edoxaban 60 mg once daily × 7 days (n = 24) or digoxin 0.25 mg twice daily × 2 days and once daily × 5 days (n = 24) and then concomitantly for 7 days. Serial blood and urine samples were collected for digoxin and edoxaban concentrations on days 7 and 14. Serial coagulation assays were measured for edoxaban on days 7 and 14. Edoxaban PK parameters demonstrated mild increases in area under the curve and peak concentrations of 9.5% and 15.6%, respectively, when coadministered with digoxin. Although digoxin PK parameters demonstrated increased area under the curve and peak concentrations of 8.3% and 28%, respectively, plasma concentrations were within the established therapeutic range. Edoxaban PD were consistent with PK. Both drugs were well tolerated alone or in combination. No clinically significant changes in PK, PD, or renal elimination were observed with concomitant administration of edoxaban and digoxin.
Assuntos
Digoxina/farmacocinética , Inibidores do Fator Xa , Piridinas/farmacocinética , Tiazóis/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Área Sob a Curva , Cardiotônicos/efeitos adversos , Cardiotônicos/farmacocinética , Cardiotônicos/farmacologia , Estudos Cross-Over , Digoxina/efeitos adversos , Digoxina/farmacologia , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piridinas/efeitos adversos , Piridinas/farmacologia , Tiazóis/efeitos adversos , Tiazóis/farmacologia , Fatores de Tempo , Adulto JovemRESUMO
MW01-6-189WH (MW189) is a novel central nervous system-penetrant small-molecule drug candidate that selectively attenuates stressor-induced proinflammatory cytokine overproduction and is efficacious in intracerebral hemorrhage and traumatic brain injury animal models. We report first-in-human, randomized, double-blind, placebo-controlled phase 1 studies to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous doses of MW189 in healthy adult volunteers. MW189 was safe and well tolerated in single and multiple doses up to 0.25 mg/kg, with no clinically significant concerns. The most common drug-related treatment-emergent adverse event was infusion-site reactions, likely related to drug solution acidity. No clinically concerning changes were seen in vital signs, electrocardiograms, physical or neurological examinations, or safety laboratory results. PK analysis showed dose-proportional increases in plasma concentrations of MW189 after single or multiple doses, with approximately linear kinetics and no significant drug accumulation. Steady state was achieved by dose 3 for all dosing cohorts. A pilot pharmacodynamic study administering low-dose endotoxin to induce a systemic inflammatory response was done to evaluate the effects of a single intravenous dose of MW189 on plasma cytokine levels. MW189 treatment resulted in lower levels of the proinflammatory cytokine TNF-α and higher levels of the anti-inflammatory cytokine IL-10 compared with placebo treatment. The outcomes are consistent with the pharmacological mechanism of MW189. Overall, the safety profile, PK properties, and pharmacodynamic effect support further development of MW189 for patients with acute brain injury.
Assuntos
Anti-Inflamatórios/administração & dosagem , Inflamação/tratamento farmacológico , Piperazinas/administração & dosagem , Piridazinas/administração & dosagem , Piridinas/administração & dosagem , Adulto , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/farmacocinética , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Piridazinas/efeitos adversos , Piridazinas/farmacocinética , Piridinas/efeitos adversos , Piridinas/farmacocinética , Adulto JovemRESUMO
Plasma gelsolin (pGSN) is the secreted isoform of an intracellular actin remodeling protein found in high concentrations in human plasma. Clinical studies demonstrate reduced pGSN concentrations in several disease states, including severe trauma, burns, and sepsis. Markedly decreased pGSN concentrations in these conditions precede and predict adverse clinical outcomes. In this study, we measured pGSN in patients with chronic granulomatous disease (CGD), a primary immunodeficiency characterized by recurrent infections and dysregulated inflammation. pGSN was quantified using a sandwich ELISA in plasma from healthy volunteers, clinically stable CGD patients, and X-linked CGD carriers and in sera from 12 CGD patients undergoing bone marrow transplantation. pGSN was also quantified in healthy volunteers challenged with intravenous endotoxin. pGSN concentrations were lower in CGD patients without active infection or systemic inflammation compared with healthy control subjects. In CGD patients undergoing bone marrow transplantation, pGSN concentrations increased significantly following successful transplant. X-linked carriers of CGD had normal pGSN. Despite reduction of pGSN in CGD patients, we did not detect significant changes in pGSN over 24 h following challenge of healthy volunteers with intravenous endotoxin (4 ng/kg) that elicited a febrile response. We describe, for the first time, significantly lower pGSN in clinically stable patients with CGD compared with age- and sex-matched healthy volunteers. Low pGSN levels in CGD patients significantly increased following bone marrow transplantation. X-linked carriers of CGD had normal pGSN. In healthy volunteers challenged with intravenous endotoxin, pGSN is not an acute phase reactant.
Assuntos
Gelsolina/sangue , Doença Granulomatosa Crônica/sangue , Doença Granulomatosa Crônica/diagnóstico , Adolescente , Adulto , Biomarcadores/sangue , Transplante de Medula Óssea/métodos , Estudos de Coortes , Endotoxinas/toxicidade , Feminino , Febre/sangue , Febre/induzido quimicamente , Febre/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
PURPOSE: The purpose of the present study was to assess the safety and efficacy of oral diclofenac potassium liquid-filled soft gelatin capsule (DPSGC) that uses ProSorb dispersion technology (Xanodyne Pharmaceuticals, Inc, licensed from AAIPharma, Wilmington, NC), to treat adult patients with acute pain after third molar extraction. PATIENTS AND METHODS: In the present multicenter, randomized, double-blind, placebo-controlled trial, patients experiencing a baseline level of pain (≥ 50 mm on a 100-mm visual analog scale within 4 hours after surgery) were randomized to receive a single dose of DPSGC at 25, 50, or 100 mg or placebo. Pain intensity and relief were assessed for 6 hours after dosing. The efficacy endpoints included the summed pain intensity difference, total pain relief, and the median time to the onset of perceptible and meaningful pain relief (using the 2-stopwatch method). RESULTS: A total of 249 randomized patients had a significant increase in the summed pain intensity difference and total pain relief values at 3 and 6 hours across all DPSGC-treated groups compared with the placebo group (P < .0001). The onset of perceptible and meaningful pain relief was significantly faster in all DPSGC groups than in the placebo group, including the DPSGC 25-mg group (25 minutes [P = .0002] and 52 minutes [P < .0001] for perceptible and meaningful pain relief, respectively). Significantly fewer patients in the DPSGC groups required rescue medication compared with those in the placebo group (P < .0001). The global evaluation scores were significantly greater for the patients who received DPSGC than for those who received placebo (P < .0001), and more than 65% of DPSGC-treated patients rated the medication as good, very good, or excellent compared with 18% of the placebo-treated patients. DPSGC was generally well tolerated, and no serious adverse events were reported. CONCLUSIONS: The results from the present single-dose study of postoperative dental pain suggest that DPSGC offers significant pain relief compared with placebo and that the study medication provided was well tolerated by patients who required pain relief after third molar extraction.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Diclofenaco/administração & dosagem , Dente Serotino/cirurgia , Dor Pós-Operatória/tratamento farmacológico , Extração Dentária , Absorção , Administração Oral , Adolescente , Adulto , Analgésicos/uso terapêutico , Anti-Inflamatórios não Esteroides/farmacocinética , Cápsulas , Diclofenaco/farmacocinética , Método Duplo-Cego , Feminino , Seguimentos , Gelatina , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/etiologia , Medição da Dor , Satisfação do Paciente , Placebos , Segurança , Fatores de Tempo , Extração Dentária/efeitos adversos , Resultado do Tratamento , Vômito/etiologia , Adulto JovemRESUMO
Nitroxyl (HNO) is a reactive nitrogen molecule that has potential therapeutic benefits for patients with acute heart failure. The results of the first-in-human study for BMS-986231, a novel HNO donor, are reported. The aim of this sequential cohort study was to evaluate the safety, tolerability, and pharmacokinetic profile of BMS-986231 after 24- and 48-hour intravenous infusions in healthy volunteers. Eighty subjects were randomized and dosed. Seven cohorts (stratum A) received BMS-986231 0.1, 0.33, 1, 3, 5, 10, and 15 µg/kg/min or placebo, infused over 24 hours. An additional cohort (stratum B) received 10 µg/kg/min or placebo, infused over 48 hours. Adverse events (AEs) were reported for 30 days after completion of infusion. Blood/urine samples were collected at regular intervals; other parameters (blood pressure, heart rate/rhythm, cardiac index) were also assessed. Headaches were the most commonly reported drug-related AE (48%) in those who received BMS-986231, although their severity was reduced by hydration. No other significant drug-related AEs were noted. BMS-986231 was associated with dose-dependent and well-tolerated reductions in systolic and diastolic blood pressure versus baseline; cardiac index, as measured noninvasively, was increased. BMS-986231 had no clinically significant effect on heart rate/rhythm or laboratory parameters. Its mean elimination half-life was 0.7-2.5 hours. BMS-986231 was safe and well-tolerated for up to 24 hours (15 µg/kg/min) or 48 hours (10 µg/kg/min), with a favorable hemodynamic profile observed. Ongoing studies continue to evaluate the potential benefit of BMS-986231 in patients with acute heart failure.
Assuntos
Doadores de Óxido Nítrico/farmacocinética , Óxidos de Nitrogênio/farmacocinética , Adulto , Pressão Sanguínea/efeitos dos fármacos , Estudos de Coortes , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Insuficiência Cardíaca/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica , Humanos , Infusões Intravenosas , Masculino , Doadores de Óxido Nítrico/efeitos adversos , Doadores de Óxido Nítrico/sangue , Doadores de Óxido Nítrico/farmacologia , Óxidos de Nitrogênio/efeitos adversos , Óxidos de Nitrogênio/sangue , Óxidos de Nitrogênio/farmacologia , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: The calcimimetic cinacalcet lowers blood para-thyroid hormone (PTH), calcium and phosphorus levels and calcium-phosphorus product in patients with chronic kidney disease receiving dialysis. Cinacalcet is metabolized primarily through oxidative and conjugative pathways. Hepatic disease has the potential to alter cinacalcet metabolism. Thus, it is important to establish the potential for altered cinacalcet metabolism according to the level of hepatic function. This study aimed to evaluate the pharmacokinetics and pharmacodynamics of cinacalcet in subjects with different degrees of hepatic function. METHODS: This was a phase I, open-label, single-dose, parallel-group, single-centre study that included 24 subjects (six with normal hepatic function and six each with mild, moderate and severe hepatic impairment according to Child-Pugh criteria). Subjects were given a single 50 mg oral dose of cinacalcet. Blood samples were taken for pharmacokinetic (pre-dose and up to 120 hours post-dose) and pharmacodynamic (pre-dose and up to 72 hours post-dose) evaluations. Plasma concentrations of cinacalcet were determined using a validated normal phase turbo ion spray liquid chromatography-mass spectrometry/mass spectrometry assay. Serum ionized calcium levels were determined by standard biochemical measures, and PTH levels were determined using an immunometric intact PTH (iPTH) assay. The primary endpoints of the study were area under the concentration-time curve from 0 to time t (AUC(t)), AUC from 0 to infinity (AUC(infinity)) and maximum plasma concentration (C(max)). Other pharmacokinetic parameters (time to C(max) [t(max)], terminal half-life [t((1/2))(beta)], total body clearance [CL/F] and protein binding) and the effect of cinacalcet on plasma PTH and serum calcium were secondary endpoints. RESULTS: Total cinacalcet exposure (AUC(infinity)) was comparable in subjects with normal hepatic function and mild hepatic impairment. In subjects with moderate and severe hepatic impairment, mean AUC(infinity) was 2.4- and 4.2-fold higher, respectively, than in healthy subjects. Cinacalcet t((1/2))(beta) was 1.3- and 1.7-fold longer in subjects with moderate and severe hepatic impairment, respectively, compared with subjects with normal hepatic function. Mean C(max) and t(max), as well as protein binding, were similar in all groups. Consistent with the increase in cinacalcet exposure, decreases in iPTH tended to be greater and prolonged in subjects with moderate and severe hepatic impairment. In this study, cinacalcet was well tolerated. CONCLUSION: These data demonstrate that cinacalcet can be used without dose adjustment in patients with mild hepatic impairment. However, increased drug exposure observed in subjects with moderate to severe hepatic impairment indicates that iPTH and serum calcium levels should be monitored closely and physicians should be more cautious about dose titration in patients with moderate or severe hepatic impairment.
Assuntos
Hepatopatias/metabolismo , Fígado/metabolismo , Naftalenos/farmacocinética , Administração Oral , Idoso , Área Sob a Curva , Cálcio/sangue , Cromatografia Líquida de Alta Pressão/métodos , Cinacalcete , Feminino , Meia-Vida , Cefaleia/induzido quimicamente , Humanos , Imunoensaio/métodos , Hepatopatias/sangue , Hepatopatias/fisiopatologia , Masculino , Espectrometria de Massas/métodos , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Naftalenos/administração & dosagem , Naftalenos/efeitos adversos , Náusea/induzido quimicamenteRESUMO
We hypothesized that concomitant pharmacological inhibition of the endothelin and adenosine pathway is safe and improves exercise performance in hypoxic humans, via a mechanism that does not involve augmentation of blood oxygenation. To test this hypothesis, we established safety and drug interactions for aminophylline (500 mg) plus ambrisentan (5 mg) in normoxic volunteers. Subsequently, a placebo-controlled study was employed to test the combination in healthy resting and exercising volunteers at simulated altitude (4,267 m). No serious adverse events occurred. Drug interaction was minimal or absent. Aminophylline alleviated hypoxia-induced headaches. Aminophylline, ambrisentan, and their combination all significantly (P < 0.05 vs. placebo) improved submaximal hypoxic exercise performance (19.5, 20.6, and 19.1% >placebo). Single-dose ambrisentan increased blood oxygenation in resting, hypoxic subjects. We conclude that combined aminophylline and ambrisentan offer promise to safely increase exercise capacity in hypoxemic humans without relying on increasing blood oxygen availability.
Assuntos
Aminofilina/efeitos adversos , Aminofilina/uso terapêutico , Endotelinas/efeitos dos fármacos , Exercício Físico/fisiologia , Hipóxia/tratamento farmacológico , Fenilpropionatos/efeitos adversos , Fenilpropionatos/uso terapêutico , Piridazinas/efeitos adversos , Piridazinas/uso terapêutico , Adenosina/metabolismo , Adolescente , Adulto , Altitude , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Endotelinas/metabolismo , Feminino , Humanos , Hipóxia/metabolismo , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Adulto JovemRESUMO
OBJECTIVE: To assess the differences in the pharmacokinetics and cardiac safety of ebastine and its active metabolite, carebastine, in patients with normal and impaired renal function. METHODS: Twenty-four patients with varying degrees of renal impairment (mild, moderate or severe: n = 8 per group) and 12 healthy subjects participated in an open-label, parallel-group, multicentre study. Ebastine 20mg was administered orally once daily for 5 days. Plasma concentrations of ebastine and carebastine were determined for 24 hours on day 1 and for 72 hours on day 5 by using a validated sensitive liquid chromatography-tandem mass spectrometry assay with a minimum quantifiable limit of 0.05 ng/mL for ebastine and 1.00 ng/mL for carebastine. Renal function was assessed by measuring 24-hour creatinine clearance (CL(CR)) at baseline. Cardiac and general safety parameters were also monitored. RESULTS: The pharmacokinetics of ebastine were not modified by renal impairment. No correlation between ebastine pharmacokinetics and renal function, as expressed by CL(CR) assessed 2 days prior to dosing, was observed. Comparison of the plasma exposure and the elimination half-life of ebastine and carebastine between groups showed no significant differences. Therefore, no apparent accumulation of ebastine and carebastine occurred, and steady-state concentrations of ebastine and carebastine were predictable from single-dose pharmacokinetics for both healthy subjects and patients with renal impairment, even though the variability between the groups was large. In addition, no differences were observed in the safety of ebastine between patients with renal impairment and healthy subjects when assessing adverse events, vital signs, laboratory parameters or ECGs. CONCLUSION: Ebastine was generally well tolerated in subjects with impaired renal function. No clinically important pharmacokinetic or safety differences were observed between patients with renal impairment and healthy subjects with normal renal function.
Assuntos
Butirofenonas/farmacocinética , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Piperidinas/farmacocinética , Insuficiência Renal/metabolismo , Administração Oral , Adulto , Idoso , Área Sob a Curva , Butirofenonas/administração & dosagem , Butirofenonas/efeitos adversos , Esquema de Medicação , Monitoramento de Medicamentos , Eletrocardiografia/efeitos dos fármacos , Feminino , Meia-Vida , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Insuficiência Renal/tratamento farmacológicoRESUMO
Of the new direct oral anticoagulants, direct factor Xa inhibitors are limited by the absence of a proven reversal agent. We assessed the safety, tolerability and impact on anticoagulation reversal of ciraparantag (PER977) alone and following a 60 mg dose of the FXa inhibitor edoxaban. Escalating, single IV doses of ciraparantag were administered alone and following a 60 mg oral dose of edoxaban in a double-blind, placebo-controlled fashion to healthy subjects. Serial assessments of the pharmacokinetics and pharmacodynamic effects of ciraparantag were performed. Eighty male subjects completed the study. Following edoxaban (60 mg), a single IV dose of ciraparantag (100 to 300 mg) demonstrated full reversal of anticoagulation within 10 minutes and sustained for 24 hours. Fibrin diameter within clots was restored to normal 30 minutes after a single dose of 100 to 300 mg ciraparantag as determined by scanning electron microscopy and change in fibrin diameter quantified by automated image analysis. Potentially related adverse events were periorbital and facial flushing and cool sensation following IV injection of ciraparantag. Renal excretion of ciraparantag metabolite was the main elimination route. There was no evidence of procoagulant activity following ciraparantag as assessed by D-dimer, prothrombin fragments 1.2, and tissue factor pathway inhibitor levels. In conclusion, ciraparantag in healthy subjects is safe and well tolerated with minor, non-dose limiting adverse events. Baseline haemostasis was restored from the anticoagulated state with doses of 100 to 300 mg ciraparantag within 10-30 minutes of administration and sustained for at least 24 hours.
Assuntos
Arginina/análogos & derivados , Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/administração & dosagem , Piperazinas/administração & dosagem , Piridinas/administração & dosagem , Tiazóis/administração & dosagem , Administração Oral , Adulto , Arginina/administração & dosagem , Arginina/efeitos adversos , Arginina/farmacocinética , Método Duplo-Cego , Monitoramento de Medicamentos/métodos , Inibidores do Fator Xa/efeitos adversos , Humanos , Injeções Intravenosas , Masculino , North Carolina , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Piridinas/efeitos adversos , Tiazóis/efeitos adversos , Tempo de Coagulação do Sangue TotalRESUMO
UNLABELLED: Intraarterial microdosing (IAM) is a novel drug development approach combining intraarterial drug delivery and microdosing. We aimed to demonstrate that IAM leads to target exposure similar to that of systemic full-dose administration but with minimal systemic exposure. IAM could enable the safe, inexpensive, and early study of novel drugs at the first-in-human stage and the study of established drugs in vulnerable populations. METHODS: Insulin was administered intraarterially (ipsilateral femoral artery) or systemically to 8 CD IGS rats just before blood sampling or 60-min (18)F-FDG uptake PET imaging of ipsilateral and contralateral leg muscles (lateral gastrocnemius) and systemic muscles (spinotrapezius). The (18)F-FDG uptake slope analysis was used to compare the interventions. Plasma levels of insulin and glucose were compared using area under the curve calculated by the linear trapezoidal method. A physiologically based computational pharmacokinetics/pharmacodynamics model was constructed to simulate the relationship between the administered dose and response over time. RESULTS: (18)F-FDG slope analysis found no difference between IAM and systemic full-dose slopes (0.0066 and 0.0061, respectively; 95% confidence interval [CI], -0.024 to 0.029; P = 0.7895), but IAM slope was statistically significantly greater than systemic microdose (0.0018; 95% CI, -0.045 to -0.007; P = 0.0147) and sham intervention (-0.0015; 95% CI, 0.023-0.058; P = 0.0052). The pharmacokinetics/pharmacodynamics data were used to identify model parameters that describe membrane insulin binding and glucose-insulin dynamics. CONCLUSION: Target exposure after IAM was similar to systemic full dose administration but with minimal systemic effects. The computational pharmacokinetics/pharmacodynamics model can be generalized to predict whole-body response. Findings should be validated in larger, controlled studies in animals and humans using a range of targets and classes of drugs.
Assuntos
Fluordesoxiglucose F18/administração & dosagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Algoritmos , Animais , Glicemia/metabolismo , Simulação por Computador , Sistemas de Liberação de Medicamentos , Fluordesoxiglucose F18/efeitos adversos , Fluordesoxiglucose F18/farmacocinética , Hipoglicemiantes/farmacologia , Interpretação de Imagem Assistida por Computador , Injeções Intra-Arteriais , Insulina/sangue , Insulina/farmacologia , Masculino , Modelos Estatísticos , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/farmacocinética , RatosRESUMO
OBJECTIVE: To assess the differences between patients with hepatic insufficiency and healthy subjects with regard to the pharmacokinetics, cardiac safety and overall safety of ebastine and its active metabolite carebastine. DESIGN: Open-label parallel-group study. PARTICIPANTS: 24 patients with varying degrees of hepatic insufficiency, as categorised by the Child-Pugh classification, and 12 healthy volunteers. METHODS: Healthy subjects and patients with Child-Pugh class A (n = 8) or B (n = 8) received ebastine 20 mg once daily for 7 days. Patients with Child-Pugh class C (n = 8) [single or repeated dose] received ebastine 10 mg. Plasma concentrations of ebastine and carebastine were determined for 23.5 hours following the initial dose on day 1 and for 96 hours following the dose on day 7 by using a sensitive liquid chromatography-tandem mass spectrometry assay with a minimum quantifiable limit of 0.05 microg/L for ebastine and 1.00 microg/L for carebastine. Hepatic function was assessed by blood clearance of indocyanine green 0.5 mg/kg administered intravenously on day 2. Cardiac and overall safety parameters were monitored. RESULTS: Overall, the pharmacokinetics of ebastine were not modified by hepatic impairment. No correlation between ebastine pharmacokinetics and hepatic function, as expressed by indocyanine green clearance, was observed. Comparison of the effective half-life of ebastine and carebastine between groups did not show relevant differences. Therefore, no apparent accumulation of ebastine occurred, and steady-state concentrations of ebastine and carebastine were predictable from single-dose pharmacokinetics both in healthy subjects and in hepatically impaired patients. Finally, no apparent difference was noted in the safety of ebastine between patients with hepatic insufficiency and healthy subjects as assessed by evaluation of adverse events, vital signs and laboratory parameters. CONCLUSION: Ebastine can be safely administered to patients with impaired hepatic function, as no clinically important differences can be anticipated from the pharmacokinetics and safety profile of ebastine/carebastine as compared with healthy subjects. Nevertheless, the dosage used in severely impaired patients (10mg daily) was half that used in patients with mild to moderate impairment, and any comedication did not include drugs affecting liver function; in clinical practice, both these factors should be taken into account.
Assuntos
Butirofenonas/farmacocinética , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Hepatopatias/tratamento farmacológico , Piperidinas/farmacocinética , Adulto , Área Sob a Curva , Butirofenonas/efeitos adversos , Butirofenonas/metabolismo , Butirofenonas/uso terapêutico , Estudos de Casos e Controles , Feminino , Meia-Vida , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Absorção Intestinal , Hepatopatias/classificação , Hepatopatias/metabolismo , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Piperidinas/metabolismo , Piperidinas/uso terapêuticoRESUMO
BACKGROUND: Cinacalcet hydrochloride (HCl) can be used to manage the secondary hyperparathyroidism of patients with chronic kidney disease. This study investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of cinacalcet HCl over a dose range of 25 to 300 mg/d in patients receiving dialysis. METHODS: Hemodialysis patients were randomly assigned 4:1 to receive cinacalcet HCl or placebo in this double-blind study. Cinacalcet HCl doses were escalated weekly in 25-mg increments from 25 to 300 mg/d. Noncompartmental methods were used to analyze the pharmacokinetic parameters of cinacalcet (the free-base). The effects of cinacalcet concentration on plasma parathyroid hormone (PTH) and serum calcium levels were evaluated. RESULTS: Of 23 patients enrolled (17 patients, cinacalcet HCl; 6 patients, placebo), 10 patients (8 patients, cinacalcet HCl; 2 patients, placebo) completed the study. Plasma concentration, median area under the plasma concentration-time curve from time 0 to 24 hours after dosing, and maximal plasma concentration (Cmax ) of cinacalcet increased with doses up to 200 mg once daily. Median oral clearance ranged from 222 to 599 L/h, and median time after dosing when C max occurred ranged from 2 to 3 hours across all doses. The pharmacokinetics were linear over the 25- to 200-mg once-daily dose range, with no substantial increase in exposure at greater than 200 mg. Changes in plasma PTH concentrations correlated inversely with cinacalcet concentration. The concentration-effect relationship was well described by an inhibitory maximal effect model. Cinacalcet HCl was reasonably tolerated, and the incidence of adverse events was similar between groups (76%, cinacalcet; 80%, placebo). Gastrointestinal events were noted at greater doses and may be dose related. CONCLUSION: Cinacalcet HCl shows a dose-proportional increase in exposure over the range of 25 to 200 mg once daily in patients on hemodialysis therapy, and kinetics were linear up to 200 mg once daily. The incidence of adverse events was similar between groups.
Assuntos
Naftalenos/farmacologia , Naftalenos/farmacocinética , Diálise Renal/métodos , Adolescente , Adulto , Idoso , Cinacalcete , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naftalenos/administração & dosagemRESUMO
BACKGROUND: This study evaluates the efficacy of the new dihydropyridine calcium antagonist nisoldipine extended-release (ER) compared to amlodipine on ambulatory and clinic blood pressures (BP) and heart rates in African American patients with hypertension. METHODS: This prospective, double-blind trial randomized 192 patients with office diastolic BP of 95 to 114 mm Hg to receive either nisoldipine (20 to 60 mg once daily) or amlodipine (5 to 10 mg once daily) for 12 weeks in a titration-to-effect design. Using ambulatory monitoring, efficacy was assessed by measuring change from baseline in systolic and diastolic BP and heart rate during three time intervals: 24-h mean period, awake, and sleep. In addition, a subanalysis was performed to evaluate patients whose nocturnal decline in BP was elevated (nondippers) versus those whose BP declined by 10% or more (dippers). RESULTS: Substantial and significant mean changes from baseline in 24-h BP were observed for patients treated with nisoldipine ER (-23/-16 +/- 3/2 mm Hg) and amlodipine (-20/15 +/- 3/2 mm Hg) (between-group comparisons, P =.07 for systolic BP; P =.50 for diastolic BP). Significant and similar reductions also were observed for clinic, awake, and sleep BP. Reductions in BP in the nondippers was substantially greater than in patients with a dipper profile. Neither agent had a significant effect on ambulatory heart rate. Adverse events were mild and infrequent (headache, edema, and dizziness at rates of 4% to 15%), and similar for both agents. CONCLUSIONS: Nisoldipine ER was as effective as amlodipine in reducing 24-h BP in African-American patients with hypertension, with a similar adverse effect profile. Thus, this new therapy for delivery of a dihydropyridine calcium channel blocker is a useful antihypertensive strategy for African-American patients with hypertension.
Assuntos
Anlodipino/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Negro ou Afro-Americano , Bloqueadores dos Canais de Cálcio/uso terapêutico , Hipertensão/tratamento farmacológico , Nisoldipino/uso terapêutico , Vasodilatadores/uso terapêutico , Adulto , Idoso , Anlodipino/administração & dosagem , Anlodipino/efeitos adversos , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Monitorização Ambulatorial da Pressão Arterial , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/efeitos adversos , Ritmo Circadiano/efeitos dos fármacos , Diástole/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Avaliação de Medicamentos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Incidência , Masculino , Pessoa de Meia-Idade , Nisoldipino/administração & dosagem , Nisoldipino/efeitos adversos , Estudos Prospectivos , Sístole/efeitos dos fármacos , Resultado do Tratamento , Estados Unidos/epidemiologia , Vasodilatadores/administração & dosagem , Vasodilatadores/efeitos adversosRESUMO
The objective of this study was to evaluate the potential for hemostatic interaction between a full analgesic dose of parecoxib sodium (parecoxib), a prodrug of the COX-2 specific inhibitor valdecoxib, and unfractionated heparin (UFH) in healthy male subjects. This open-label, single-center study comprised two treatment periods. In treatment period I, fasted, eligible subjects (n = 18) received a UFH bolus (4000 U) followed by a 36-hour UFH infusion (start dose 10-14 U/kg). Activated partial thromboplastin time (aPTT), prothrombin time (PT), and platelet counts were measured at regular intervals up to 24 hours after the end of the UFH infusion. After a 2-day washout, patients randomized to treatment period II received a full analgesic dosage of parecoxib 40 mg bid intravenously (IV) for 6 days (n = 18), with concomitant UFH (same regimen as treatment period I) on day 5 (n = 18). APTT, PT, and platelet counts were evaluated at regular intervals up to 24 hours after UFH infusion. Coadministration of parecoxib 40 mg bid IV with UFH (treatment period II) had no significant effect on aPTT, PT, or platelet counts, which were similar to those of participants receiving UFH alone (treatment period I) at all time points. These results show that a full analgesic dose of parecoxib, a COX-2-specific inhibitor available for parenteral administration, can be coadministered with UFH without affecting blood coagulation parameters. Therefore, parecoxib may be administered to patients who are receiving UFH for thromboprophylaxis.
Assuntos
Heparina/farmacocinética , Isoenzimas/antagonistas & inibidores , Isoxazóis/farmacocinética , Adulto , Fatores de Coagulação Sanguínea , Ciclo-Oxigenase 2 , Esquema de Medicação , Quimioterapia Combinada , Heparina/administração & dosagem , Humanos , Infusões Intravenosas , Isoenzimas/farmacologia , Isoxazóis/administração & dosagem , Isoxazóis/efeitos adversos , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Contagem de Plaquetas/métodos , Prostaglandina-Endoperóxido Sintases/farmacologia , Tempo de Protrombina/métodosRESUMO
OBJECTIVE: MAP0004 is an investigational product which delivers dihydroergotamine (DHE) through the lung via a breath-synchronized metered dose inhaler. The objective of this study was to compare the acute effects of orally inhaled and intravenous (IV) DHE to placebo on maximum change and area under the curve for pulmonary arterial systolic pressure (PASP). RESEARCH DESIGN AND METHODS: A randomized, double-blind, placebo-controlled, 3-period, crossover study of 24 health adults. Trial registration NCT01089062. Study assessments included pharmacokinetics, electrocardiograms (ECG), and validated echocardiographic (Doppler)-derived measures of PASP by echocardiogram. The primary endpoint was the absolute change in calculated PASP using area under the curve, 0 to 2 hours (AUC(0-2h)). RESULTS: The change in PASP with IV DHE was significantly different than MAP0004 and placebo (AUC(0-2h)2857, 2624, and 2453 mmHg*min, respectively). After a second dose of MAP0004, AUC(0-4h) remained lower with MAP0004 than with a single dose of IV DHE. Adverse events were more common with IV DHE than with MAP0004 or placebo. None of the treatments produced clinically significant changes in PASP or other cardiac parameters. Changes in PASP were significantly smaller with MAP0004 compared with IV DHE. CONCLUSION: These results indicate the effects 1 mg of orally inhaled DHE on the cardiovascular system are less than with 1 mg of IV DHE, and that serial echocardiography can be a useful noninvasive means of assessing acute systemic effects.