RESUMEN
PURPOSE: Preladenant is an orally administered adenosine2A (A2A) receptor antagonist in phase III development for Parkinson's disease treatment. This thorough QT/QTc study evaluated its potential effects on cardiac repolarization. METHODS: This was a randomized, double-blind, positive- and placebo-controlled, four-period crossover study performed under steady-state exposure of clinical and supratherapeutic doses of preladenant (10 mg BID and 100 mg BID, respectively, for 5 days), moxifloxacin (400 mg on day 5), or placebo in 60 healthy adult volunteers. The potential effect on QTcF was measured by the largest upper bound of 95 % one-sided CIs for the mean changes from time-matched baseline ECG recordings compared with placebo. Plasma preladenant concentrations were also determined on day 5. RESULTS: The QTcF difference for moxifloxacin compared with placebo exceeded 5 ms from 1 to 12 h postdose, establishing assay sensitivity. The QTcF interval was similar between the preladenant and placebo treatment groups: the upper bound of the 95 % one-sided CI for the mean difference in QTcF between preladenant and placebo was less than 10 ms at all time points for the supratherapeutic treatment group (1.3 to 5.7 ms, mean difference: -1.3 to 2.7 ms) and the therapeutic treatment group (0.4 to 4.3 ms, mean difference: -2.1 to 1.5 ms), substantially below the threshold of regulatory concern. The supratherapeutic dose (100 mg BID) provided a Cmax margin of 6.1-fold and AUC margin of 6.9-fold, respectively, compared with 10 mg BID. CONCLUSIONS: At clinical and supratherapeutic doses, preladenant is not associated with QTc prolongation.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/efectos adversos , Antiparkinsonianos/efectos adversos , Síndrome de QT Prolongado/inducido químicamente , Pirimidinas/efectos adversos , Triazoles/efectos adversos , Antagonistas del Receptor de Adenosina A2/administración & dosificación , Antagonistas del Receptor de Adenosina A2/farmacología , Adolescente , Adulto , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacología , Compuestos Aza/administración & dosificación , Compuestos Aza/efectos adversos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Electrocardiografía , Femenino , Fluoroquinolonas , Humanos , Masculino , Persona de Mediana Edad , Moxifloxacino , Pirimidinas/administración & dosificación , Pirimidinas/farmacología , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Triazoles/administración & dosificación , Triazoles/farmacología , Adulto JovenRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Preladenant (SCH420814, MK-3814) is a highly selective orally bioavailable non-methylxanthine adenosine 2A (A(2A) ) receptor antagonist under investigation for the treatment for Parkinson's disease. This study evaluated the safety, tolerability and pharmacokinetics of preladenant at single and multiple doses for the first time in humans. METHODS: These were two randomized, double-blind, placebo-controlled, ascending-dose studies, one evaluating single rising preladenant doses (5-200 mg) compared with placebo and the other evaluating multiple rising preladenant doses (10-200 mg once daily over 10 days) compared with placebo. Safety was the primary end point of both studies. Safety evaluations, physical examinations, electrocardiograms, vital signs determinations and routine laboratory tests were performed before and at intervals throughout the studies. Blood samples were collected immediately before study drug administration and at various time points after dosing. Pharmacokinetic assessments of plasma preladenant and metabolites SCH434748 and SCH446637 were performed. RESULTS AND DISCUSSION: One hundred and eight healthy adult men were randomly assigned in a 3 : 1 ratio to receive oral preladenant or matching placebo capsules under fasting conditions. Preladenant reached peak plasma concentrations in â¼1 h and then declined rapidly. Dose-related increases in exposure were observed up to 100 mg/day; accumulation was negligible at all doses. Transient mild increases in blood pressure occurred within a few hours after preladenant administration; blood pressure changes were neither cumulative nor dose-related nor associated with clinical sequelae. WHAT IS NEW AND CONCLUSION: Preladenant was generally well tolerated up to the maximum dose tested (200 mg/day).
Asunto(s)
Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Triazoles/administración & dosificación , Triazoles/efectos adversos , Adolescente , Adulto , Área Bajo la Curva , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Ayuno , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico , Pirimidinas/farmacocinética , Triazoles/farmacocinética , Adulto JovenRESUMEN
AIM: Rheumatic mitral patients reach their fifth decade of life more often now than in the past. The purpose of this study is to provide insight into improving morbidity and mortality in these patients. METHODS: This retrospective study included 105 patients aged 50 years or more. Seventy-five underwent mechanical valve replacement and 30 received a bioprosthetic valve. Data were collected from medical records and outpatient department (OPD) registers. Follow-up included transthoracic 2D echocardiography, supported by clinical parameters, and X-ray findings. RESULTS: Mean age was 58.52+/-2.4 years. Follow-up period ranged from one to eleven years (mean 6.8+/-0.9 years). Immediate perioperative mortality included five patients (4.76%) and long term mortality included three patients (3%). 35 patients previously underwent closed and open commissurotomy and balloon valvotomy. Multivariate analysis showed age, repeat surgery, atrial fibrillation, tricuspid valve disease, and preoperative functional status to be incremental risk factors. Freedom from repeat operation at 3 and 6 years was 90% and 85% in group I (<60 years), respectively. Actuarial survival at 4 and 6 years of follow up was 94.24% and 88.52%, respectively. CONCLUSION: With improving life expectancy and early interventions, the number of < or = 50-year old rheumatic valvular disease patients is increasing. The present study showed a marked improvement for this subset of patients, although age still remains the main risk factor along with atrial fibrillation, repeat surgery, stroke and tricuspid valve disease.
Asunto(s)
Enfermedades de las Válvulas Cardíacas/cirugía , Implantación de Prótesis de Válvulas Cardíacas , Válvula Mitral/cirugía , Cardiopatía Reumática/complicaciones , Factores de Edad , Anciano , Fibrilación Atrial/etiología , Fibrilación Atrial/mortalidad , Bioprótesis , Gasto Cardíaco Bajo/etiología , Gasto Cardíaco Bajo/mortalidad , Femenino , Estudios de Seguimiento , Enfermedades de las Válvulas Cardíacas/etiología , Enfermedades de las Válvulas Cardíacas/mortalidad , Enfermedades de las Válvulas Cardíacas/patología , Prótesis Valvulares Cardíacas , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Implantación de Prótesis de Válvulas Cardíacas/instrumentación , Mortalidad Hospitalaria , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Válvula Mitral/patología , Modelos de Riesgos Proporcionales , Reoperación , Estudios Retrospectivos , Cardiopatía Reumática/mortalidad , Cardiopatía Reumática/patología , Cardiopatía Reumática/cirugía , Medición de Riesgo , Factores de Riesgo , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/mortalidad , Factores de Tiempo , Resultado del Tratamiento , Válvula Tricúspide/patologíaAsunto(s)
Procedimientos Quirúrgicos Cardíacos , Conducto Arterioso Permeable/terapia , Embolización Terapéutica/efectos adversos , Cuerpos Extraños/cirugía , Válvula Tricúspide , Niño , Ecocardiografía Doppler , Femenino , Cuerpos Extraños/diagnóstico por imagen , Cuerpos Extraños/etiología , Humanos , Radiografía Torácica , Válvula Tricúspide/diagnóstico por imagenAsunto(s)
Cardiotónicos/sangre , Digoxina/sangre , Adulto , Cardiotónicos/farmacocinética , Digoxina/farmacocinética , Etnicidad , Femenino , Humanos , IndiaRESUMEN
We present a rare case of a patient with interrupted aortic arch with Ebstein's anomaly of the tricuspid valve and rheumatic mitral stenosis. This patient presented in early adulthood, which makes his case even more unusual. We successfully treated the mitral stenosis and the interrupted aortic arch through a left lateral thoracotomy, but we decided against correcting the Ebstein's anomaly, which was mild. The hemodynamic effects of each lesion, independently and in the presence of each other, are discussed.
Asunto(s)
Síndromes del Arco Aórtico/complicaciones , Anomalía de Ebstein/complicaciones , Estenosis de la Válvula Mitral/complicaciones , Cardiopatía Reumática/complicaciones , Adulto , Síndromes del Arco Aórtico/diagnóstico , Síndromes del Arco Aórtico/cirugía , Anomalía de Ebstein/diagnóstico , Anomalía de Ebstein/cirugía , Humanos , Masculino , Estenosis de la Válvula Mitral/diagnóstico , Estenosis de la Válvula Mitral/cirugía , Cardiopatía Reumática/diagnóstico , Cardiopatía Reumática/cirugíaRESUMEN
OBJECTIVE: To evaluate and discuss etiopathology, clinical manifestations and surgical outcome of a rare subset of unruptured aneurysm of the sinus of Valsalva which erodes into the interventricular septum. METHODS: Between 1989 and 1995, seven cases of unruptured aneurysm of the sinus of Valsalva eroding into the interventricular septum underwent surgical correction at the King Edward VII Memorial Hospital, Bombay. The origin of all these aneurysms was from the right coronary sinus. The mean age of presentation was 31 years. All patients were male. Calcification of the aneurysm was seen in three. Three patients presented without aortic regurgitation; all had complete heart block. Four patients presented with aortic regurgitation and in addition, two had complete heart block. Preoperative left ventricular function was poor in patients with aortic regurgitation (Ejection fraction range; 30-42%), when compared to those without aortic regurgitation (Ejection fraction range; 48-52%). Of those without aortic regurgitation at initial presentation, one patient developed progressive aortic regurgitation after 3 years requiring surgery. While two other patients were operated at earliest for closure of aneurysm, even in the absence of aortic regurgitation. All those with aortic regurgitation required surgery for aortic valve replacement and closure of aneurysm. Aneurysm was closed by direct suturing of the ostium in two patients and by patch closure in five patients. Permanent pacemaker was implanted in five patients. RESULT: There was no operative death. Patients who underwent aortic valve replacement required postoperative ionotropic support. Two patients, who underwent surgery in absence of aortic regurgitation, remain free of aortic regurgitation at the end of 36 and 42 months of follow-up. One of the patients with calcific aneurysmal sac underwent successful re-replacement of the aortic valve for paravalvar leak after a 2 year interval. CONCLUSION: Unruptured aneurysm of the sinus of Valsalva eroding into the interventricular septum should be operated at the earliest, which makes surgery simple and prevents development of complications such as aortic regurgitation and heart block.
Asunto(s)
Aneurisma de la Aorta/patología , Aneurisma de la Aorta/cirugía , Seno Aórtico , Adulto , Aneurisma de la Aorta/complicaciones , Aneurisma de la Aorta/etiología , Insuficiencia de la Válvula Aórtica/etiología , Calcinosis/patología , Bloqueo Cardíaco/etiología , Tabiques Cardíacos/patología , Implantación de Prótesis de Válvulas Cardíacas , Ventrículos Cardíacos , Humanos , Masculino , Reoperación , Volumen Sistólico , Resultado del TratamientoAsunto(s)
Aneurisma Falso/etiología , Cateterismo Cardíaco/efectos adversos , Arteria Femoral , Nervio Femoral/lesiones , Paresia/etiología , Aneurisma Falso/cirugía , Angiografía Coronaria/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso Periférico/etiologíaRESUMEN
Coronary sinus thrombosis was found at autopsy of a boy who had undergone intracardiac repair of tetrology of Fallot. During the operation persistent left superior vena cava was cannulated through the right atrium via the coronary sinus. There was also evidence of myocardial infarction in the region of the interventricular septum.
Asunto(s)
Puente Cardiopulmonar/efectos adversos , Trombosis Coronaria/etiología , Tetralogía de Fallot/cirugía , Adolescente , Puente Cardiopulmonar/instrumentación , Trombosis Coronaria/patología , Resultado Fatal , Humanos , Masculino , Infarto del Miocardio/etiologíaRESUMEN
Cardiopulmonary bypass (CPB) can induce several haemodynamic alterations and therefore influence pharmacokinetics of various drugs. In order to assess the effect of CPB on plasma digoxin levels, these were monitored in patients undergoing open heart surgery involving CPB (n = 11), over a 24 hour period, starting just prior to commencement of surgery. For comparison, plasma digoxin was also monitored in a group of patients (n = 10) who underwent cardiac surgery not involving CPB. In 7 of the 11 patients in the CPB group, plasma digoxin levels (ng/ml) were significantly (p < 0.01) lower at the end of 24 hours (0.654 +/- 0.094) than basal levels (1.3114 +/- 0.2498). In contrast, in the non CPB group, 7 of 10 patients showed significantly higher (p < 0.001) plasma levels (ng/ml) at the end of 24 hours (0.477 +/- 0.125) as compared to basal levels (0.26 +/- 0.098). Thus, rather than the type of surgery, it appears that the pre-operative levels of plasma digoxin influence its pharmacokinetics.
Asunto(s)
Puente Cardiopulmonar , Cardiotónicos/sangre , Digoxina/sangre , Prótesis Valvulares Cardíacas , Válvula Mitral/cirugía , Cardiopatía Reumática/cirugía , Adulto , Cardiotónicos/uso terapéutico , Estudios de Casos y Controles , Digoxina/uso terapéutico , Femenino , Humanos , Masculino , Insuficiencia de la Válvula Mitral/cirugía , Estenosis de la Válvula Mitral/cirugía , Factores de TiempoRESUMEN
A male child presented with suspicion of tricuspid stenosis. Echocardiography revealed the presence of a mass arising from the free wall of the right ventricle and causing right-ventricular inflow obstruction but not involving the tricuspid valve. The tumour was excised via right ventriculotomy using cardiopulmonary bypass, resulting in survival and a satisfactory clinical course. Histological examination showed the tumour to be a fibroma. Tricuspid stenosis is an unusual presentation of right ventricular fibroma. Careful examination is essential to early diagnosis of cardiac fibromas, particularly in children with unexplained cardiac problems. Echocardiography is still a good method for confirmation of the diagnosis and for follow-up. In view of the unknown natural history of cardiac fibroma, surgical excision should be undertaken. Early detection and prompt excision results in immediate and complete relief of symptoms and prolongs the life span.
Asunto(s)
Ecocardiografía , Fibroma/diagnóstico por imagen , Neoplasias Cardíacas/diagnóstico por imagen , Ventrículos Cardíacos/diagnóstico por imagen , Estenosis de la Válvula Tricúspide/diagnóstico por imagen , Preescolar , Diagnóstico Diferencial , Fibroma/patología , Fibroma/cirugía , Neoplasias Cardíacas/patología , Neoplasias Cardíacas/cirugía , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/cirugía , Humanos , Masculino , Estenosis de la Válvula Tricúspide/patología , Estenosis de la Válvula Tricúspide/cirugía , Función Ventricular Derecha/fisiologíaRESUMEN
Repair of the mitral valve should be the primary goal in the surgical management of acute mitral regurgitation following valvotomy. The earlier the repair is done, the better it is because the preoperative haemodynamics affect the overall outcome. The disadvantages and anticoagulation of prosthetic valves are avoided. Besides, it is economical to avoid the high cost of the prosthetic valves in a poor socio-economic group of patients. With good patient selection and additional effort by the surgeon to acquire the necessary expertise to reproduce the techniques of mitral valve repair, a superior quality of life can be offered to these patients. The present study is a retrospective analysis of 14 patients who required emergency open heart surgery following balloon or closed mitral valvotomy. The valve was successfully repaired in 8 patients. The medium term follow-up indicates that repair is reproducible, safe, reliable, and a stable procedure free of complications.
Asunto(s)
Cateterismo/efectos adversos , Insuficiencia de la Válvula Mitral/etiología , Insuficiencia de la Válvula Mitral/cirugía , Estenosis de la Válvula Mitral/terapia , Enfermedad Aguda , Adulto , Urgencias Médicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia de la Válvula Mitral/fisiopatología , Selección de Paciente , Calidad de Vida , Reproducibilidad de los Resultados , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Using a 3 x 3 Latin Square design, a possible interaction between diprafenone HCl a class IC antiarrhythmic drug with nonspecific beta-antagonist activity and propranolol HCl was investigated in nine young, healthy, caucasian, male volunteers. The volunteers randomly received 3 single-dose treatments: (A) 200 mg DHCl, (B) 80 mg PHCl, and (C) 200 mg DHCl and 80 mg PHCl. Scheduled blood samples were taken and plasma concentrations of both diprafenone and propranolol were measured by sensitive and specific assay methods. Lead II electrocardiogram intervals at rest, heart rate during erect bicycle ergometry, and echocardiographic variables at rest and shortly after exercise were recorded. The data analysis used compartment model independent methods. There was no evidence for a pharmacokinetic interaction between the two drugs. With DHCl, two of the nine subjects showed greatly increased areas under the plasma concentration-time curves and apparent disposition half-lives in the presence and absence of PHCl, indicating that metabolism of diprafenone may be subject to pharmacogenetic polymorphism. There was evidence for a pharmacodynamic interaction between DHCl and PHCl regarding the negative chronotropic effect at rest and during exercise. There was no difference in the pharmacodynamics and tolerability of the three treatments in suspected "poor" and "extensive metabolizers" of DHCl.
Asunto(s)
Antiarrítmicos/farmacología , Propafenona/análogos & derivados , Propranolol/farmacología , Adolescente , Adulto , Antiarrítmicos/administración & dosificación , Antiarrítmicos/sangre , Esquema de Medicación , Combinación de Medicamentos , Interacciones Farmacológicas , Electrocardiografía/efectos de los fármacos , Prueba de Esfuerzo/efectos de los fármacos , Semivida , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Propafenona/administración & dosificación , Propafenona/sangre , Propafenona/farmacología , Propranolol/administración & dosificación , Propranolol/sangre , Descanso , Sensibilidad y EspecificidadRESUMEN
Anomalous pulmonary venous connection of the entire left lung into the left innominate vein is very rare. 5 patients with this anomaly were managed in the authors' institution over the last 12 years. Clinically they were diagnosed as cases of pretricuspid left-to-right shunt at atrial level. Cardiac catheterisation and angiography demonstrated the anomalous drainage of the entire left lung into the left innominate vein. Anastomosis between the vertical vein and the left atrium was established using conventional cardiopulmonary bypass, hypothermia, and cold cardioplegic diastolic arrest of the heart. Postoperative course was uneventful. 4 of the 5 patients presented for follow-up during 1-12 years (mean 6.5 years). All are asymptomatic and have been studied with echocardiography, angiography, and magnetic resonance imaging techniques. The anastomatic site was found to be non obstructive in all the patients.
Asunto(s)
Venas Pulmonares/anomalías , Venas Pulmonares/cirugía , Adolescente , Adulto , Venas Braquiocefálicas/anomalías , Puente Cardiopulmonar , Preescolar , Ecocardiografía , Femenino , Paro Cardíaco Inducido , Atrios Cardíacos/cirugía , Humanos , Hipotermia Inducida , Imagen por Resonancia Magnética , MasculinoRESUMEN
Afovirsen sodium is a 20-mer phosphorothioate oligonucleotide designed to be complementary to the messenger ribonucleic acid sequence for the translation initiation codon of the E2 protein vital to replication of human papillomaviruses types 6 and 11. 14C-Labeled afovirsen was given as a single-dose intradermal injection in each of four warts of five patients to determine the time-dependent changes in concentration of intact afovirsen in genital warts and to determine the systemic absorption and elimination of radiolabeled compound. Intact afovirsen in genital warts was determined by high pressure liquid chromatography analysis of protease K digested extracts. Intact afovirsen was present in wart tissue for at least 72 hours at concentrations several times in excess of the estimated minimal inhibitory concentration of 1 mumol/L. Absorption of radiolabeled afovirsen from the injection site was rapid, with a peak plasma concentration achieved within 1 hour. Clearance of afovirsen was primarily attributable to slow metabolism, with about 30% of the radiolabel eliminated as 14C-CO2 in expired air over a 6-day period after dosing. Radioactivity eliminated in urine represented metabolites of afovirsen. From the clinical pharmacokinetic data presented here and from previously published pharmacokinetic data in rats, the disposition of afovirsen in humans appears to be relatively similar to that in rats. These data suggest that once or twice weekly dosing regimen in the clinic may be appropriate.
Asunto(s)
Antivirales/farmacocinética , Condiloma Acuminado/metabolismo , Tionucleótidos/farmacocinética , Adulto , Antivirales/uso terapéutico , Secuencia de Bases , Radioisótopos de Carbono , Cromatografía Líquida de Alta Presión , Condiloma Acuminado/tratamiento farmacológico , Humanos , Masculino , Datos de Secuencia Molecular , Tionucleótidos/uso terapéuticoRESUMEN
Differences in extent of amoxicillin absorption from various regions of the gastrointestinal tract were determined and compared with the same dose administered orally. Nine healthy men were intubated at a proximal (duodenum or jejunum) or distal (ileum or colon) site with use of a 15-foot double lumen nasointestinal tube. Amoxicillin solutions (375 mg in 120 ml water) were delivered on 2 successive days as a bolus or a 4-hour infusion. Subjects were reintubated at another site and amoxicillin administration was repeated. Subjects with colonic intubation received only infusions. Finally, all subjects received an oral dose of amoxicillin solution. Plasma samples were obtained at 16 time points over a 10-hour period and assayed for amoxicillin by use of an HPLC method. Area under the concentration-time curve and the maximum plasma concentration were computed to evaluate amoxicillin absorption. Amoxicillin absorption was rate and site dependent in the gastrointestinal tract. The drug was well absorbed in the duodenum and jejunum, with no significant differences in absorption when administered as a bolus or 4-hour infusion, but absorption was decreased and rate dependent in the ileum, where more drug was absorbed as an infusion compared with a bolus. Amoxicillin was unabsorbed when infused in all colonic regions.
Asunto(s)
Amoxicilina/farmacocinética , Absorción Intestinal/fisiología , Intestino Grueso/metabolismo , Intestino Delgado/metabolismo , Adulto , Amoxicilina/administración & dosificación , Análisis de Varianza , Disponibilidad Biológica , Humanos , Masculino , Valores de Referencia , Factores de TiempoRESUMEN
Myxoma of the right ventricle is of very rare occurrence. An adult male patient presented with Class III dyspnoea and occasional haemoptysis and clinically was suspected to have pulmonary stenosis. Magnetic resonance imaging study revealed presence of myxoma arising from the right-ventricular free wall and prolapsing into the pulmonary artery but not involving the pulmonary valve. The myxoma was excised via right ventriculotomy using cardiopulmonary bypass. The patient had an uneventful recovery. The relevant literature is reviewed.
Asunto(s)
Neoplasias Cardíacas/complicaciones , Mixoma/complicaciones , Obstrucción del Flujo Ventricular Externo/etiología , Adulto , Neoplasias Cardíacas/cirugía , Ventrículos Cardíacos , Humanos , Masculino , Mixoma/cirugía , Arteria Pulmonar/patologíaRESUMEN
Stem cell adhesion to bone-marrow derived stroma, plays a crucial role in haemopoiesis. However, there is very little information as to the nature of the adhesion molecule. In this paper we have shown that human bone-marrow derived stroma can be established in tissue culture. This stroma is able to adhere human bone-marrow mononuclear cells including the multipotent stem cell, viz. CFU-GEMM. Their adherence increases when the stroma is treated with lymphokines in the form of PHA-treated leucocyte conditioned medium (PHA-LCM). Triton X-100 extracts of the untreated and PHA-LCM treated stroma were analysed on single dimension PAGE. It was observed that PHA-LCM treated stromal extracts showed two extra bands and an increase in the density of a band of approximately 14 kDa. Whether these changes have anything to do with the increased adhesion of stem cell is not yet known.