RESUMO
UNLABELLED: Congenital factor XIII (FXIII) deficiency is an extremely rare, potentially life-threatening bleeding disorder. Routine prophylactic management is recommended for individuals with clinically relevant FXIII deficiency. This prospective, multicentre, open-label study evaluated the long-term efficacy and safety of prophylactic infusions of FXIII concentrate (human) 40 IU kg(-1) in patients with congenital FXIII deficiency. FXIII concentrate (human) was administered every 4 weeks for 12 months. Dosing was adjusted to maintain trough FXIII activity levels of 5-20%. Logistical and ethical constraints precluded use of a placebo control group. Annualized incidence of spontaneous bleeding was compared with historical rates; safety was assessed as a secondary objective. Forty-one patients were enrolled and completed the study. The annualized rate for spontaneous bleeding episodes requiring FXIII treatment was 0.000 episodes per patient-year (95% CI: 0.000; 0.097). The study met its primary endpoint: the upper limit of the 95% CI was substantially below the historical rate of 2.5 bleeding episodes per patient-year. Five spontaneous bleeding episodes (involving three patients; none requiring FXIII treatment) and eight trauma-related bleeding episodes (two requiring FXIII treatment) occurred. Five patients had surgery during the study, only one of whom required FXIII treatment for post-surgical bleeding. Most patients (≥ 85%) had trough FXIII activity levels ≥ 10%. No patient discontinued treatment due to an adverse event. No adverse events related to thromboembolism or viral transmission were reported. Prophylactic treatment with FXIII concentrate (human) was well tolerated and prevented spontaneous bleeding episodes that were serious enough to require treatment with FXIII-containing product. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov/ct2/show/NCT00885742.
Assuntos
Deficiência do Fator XIII/congênito , Fator XIII/uso terapêutico , Hemorragia/tratamento farmacológico , Adolescente , Adulto , Biomarcadores Farmacológicos , Criança , Pré-Escolar , Fator XIII/farmacocinética , Deficiência do Fator XIII/tratamento farmacológico , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos , Adulto JovemRESUMO
OBJECTIVES: To evaluate the effect of selective blockade of type B cholecystokinin receptors on gall bladder contraction in normal humans and to compare methods for quantitative analysis of gall bladder contraction. METHODS: L-365,260, a novel, nonpeptide cholecystokinin antagonist shown to be selective for type B cholecystokinin receptors, was administered every 6 h over a 5-7 day period. Plasma levels of L-365,260 were determined by high pressure liquid chromatography. Gallbladder contraction after a standardized fatty meal was measured by ultrasonography, and results were calculated by ellipsoid or sum of cylinders methods. RESULTS: L-365,260 levels were comparable to levels in earlier studies demonstrating inhibition of pentagastrin-stimulated acid secretion in normal subjects and blockade of anxiogenic effects of cholecystokinin injections in patients with panic disorder. Regardless of the method used for estimating gallbladder size, none of the L-365,260 doses studied inhibited gallbladder contraction. Gallbladder size was most consistently estimated by the ellipsoid method using measurements normalized to individual values for minimum and maximum gallbladder dimensions. CONCLUSIONS: Multiple oral doses of L-365,260 do not alter ultrasonographically assessed gallbladder contraction at doses shown to be clinically effective in earlier studies. Despite being more difficult to implement, the sum of cylinders method for estimating gall bladder size offers no advantage over the ellipsoid method.
Assuntos
Benzodiazepinonas/farmacologia , Esvaziamento da Vesícula Biliar/efeitos dos fármacos , Compostos de Fenilureia , Receptores da Colecistocinina/antagonistas & inibidores , Adulto , Idoso , Análise de Variância , Benzodiazepinonas/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Vesícula Biliar/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Receptores da Colecistocinina/efeitos dos fármacos , Valores de Referência , Fatores de Tempo , UltrassonografiaRESUMO
This open-label, multicenter study was designed to assess the electrophysiological properties of intravenous recainam, an investigational Class I antiarrhythmic agent. In 25 patients undergoing electrophysiological studies for the evaluation of arrhythmias, recainam was administered intravenously in a loading infusion (0.1 mg/kg/min) for 40 minutes, followed by a maintenance infusion (0.02 mg/kg/min) until the completion of the study. Electrophysiological measurements were obtained at baseline, 30 minutes after initiation of the loading infusion, and 30 minutes after termination of the infusion during washout. Conduction intervals, refractory periods, and sinus node recovery times were measured during sinus rhythm and during atrial or ventricular pacing. Vital signs were obtained and recorded before, during, and after recainam infusion. The results showed no change in mean arterial pressure, but heart rate increased slightly by 4 beats/min following recainam infusion. Recainam produced a generalized slowing of intracardiac conduction. The mean intraatrial conduction time, measured at an atrial paced cycle length of 600 msec, increased during recainam loading infusion by 44%, from 38.8% +/- 2.8 to 53.0 +/- 5.4 msec; intranodal conduction time increased by 10%, from 102.0 +/- 5.5 to 112.1 +/- 5.2 msec; and infranodal conduction time increased by 31% from 53.1 +/- 3.0 to 70.7 +/- 3.8 msec. Slowed conduction persisted during washout. The mean right atrial effective refractory period was significantly prolonged (+7% at 600 msec cycle length and +8% at 450 msec cycle length, P less than 0.05 and P less than 0.01, respectively) during recainam loading and remained so during washout.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Adulto , Idoso , Antiarrítmicos/administração & dosagem , Antiarrítmicos/efeitos adversos , Arritmias Cardíacas/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Estimulação Cardíaca Artificial , Eletrocardiografia , Eletrofisiologia , Feminino , Sistema de Condução Cardíaco/efeitos dos fármacos , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversosRESUMO
We studied the frequency-dependent effects of quinidine on the right ventricular action potential and QRS duration in 10 patients (nine men and one woman; mean age, 57 +/- 14 years) undergoing electrophysiologic studies for clinical indications. The right ventricular monophasic action potential, electrocardiographic, and conventional intracardiac electrical signals from various sites were recorded at different pacing cycle lengths from 30 seconds to 1 minute before and after a 10-mg/kg i.v. quinidine infusion. We used the extrastimulus technique to determine the effects of quinidine on ventricular refractory periods at different pacing cycle lengths and on the abrupt changes of the action potential duration. The action potential duration progressively decreased as the ventricular pacing rate increased at baseline and after quinidine infusion. Quinidine significantly increased the action potential duration from that of control by 25 msec (p less than 0.02) at the relatively slow pacing cycle lengths of 600, 500, and 400 msec. Quinidine's effect on the action potential duration was attenuated at the pacing cycle length of 350 msec and became negligible at 300 msec. In contrast, quinidine progressively lengthened the QRS duration as the pacing rate increased (20, 18, 37, 46, and 34 msec at pacing cycle lengths of 600, 500, 400, 350, and 300 msec, respectively; p less than 0.05). There were no rate-dependent changes in the QRS duration during the control period. The relation between the ventricular refractory periods and the action potential duration at different pacing cycle lengths was also determined before and after quinidine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Estimulação Cardíaca Artificial , Eletrocardiografia , Sistema de Condução Cardíaco/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Quinidina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação QuímicaRESUMO
CGS 10078B (CGS; 1-[2,3-dihydro-1,4-(2S)-benzodioxin-2-yl]-5-[2,3-dihydro-1,4-(2R)- benzodioxin-2-yl]-3-(1R,5S)-aza-1,5-pentanediol methane sulfonate) is an agent with alpha- and beta-receptor and calcium channel blocking actions. To study its antiarrhythmic activity, cats were anesthetized with alpha-chloralose, ventilated, and given atropine and gallamine. CGS (10 or 20 mg/kg, i.v.) was infused 15 min prior to ouabain. Bolus injections of ouabain (25 micrograms/kg, i.v.) were given every 15 min until death (D). Some cats were pretreated with reserpine (R; 5 mg/kg, i.p.) 24 h prior to the experiment. In other cats 6-hydroxydopamine (6-OHDA; 20 mg/kg, i.v.) was administered 3 days prior to CGS 20 mg/kg and ouabain. Data were compared with those of Lathers [Eur. J. Pharmacol. 64: 95, 1980], i.e., with 12 cats who received only ouabain and with 11 pretreated with timolol (T; 5 mg/kg, i.v.) prior to ouabain. After CGS (10 or 20 mg/kg, i.v.), but just prior to the first dose of ouabain, the blood pressure (BP) was decreased (p less than 0.05) from control (165 +/- 6 vs. 96 +/- 7, and 136 +/- 5 vs. 90 +/- 10 mm Hg, respectively). Comparable heart rate (HR) values were also decreased (p less than 0.05) from 225 +/- 17 to 166 +/- 14 and from 193 +/- 8 to 152 +/- 6 beats/min. 11 min after T, BP and HR had decreased (p less than 0.05) from 133 +/- 6 to 103 +/- 7 mm Hg and from 134 +/- 4 to 104 +/- 6 beats/min, respectively. Ouabain did not influence these decreases in BP and HR. CGS (10 or 20 mg/kg, i.v.) increased (p less than 0.05) the time to ouabain-induced arrhythmia (AR) and D. The magnitude of the protection appeared to be similar to that afforded by T. R given prior to CGS (20 mg/kg, i.v.) also increased the time to ouabain-induced AR and D while 6-OHDA increased the time to AR. The CGS protection against ouabain-induced AR was still present in animals pretreated with R or 6-OHDA. This indicates that the antiarrhythmic affect is not dependent upon adrenergic neuronal blockade.
Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Antiarrítmicos/farmacologia , Dioxinas/farmacologia , Ouabaína/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Gatos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hidroxidopaminas/farmacologia , Labetalol/farmacologia , Masculino , Oxidopamina , Timolol/farmacologiaRESUMO
The present study was designed to investigate whether or not interaction with the adrenergic neurons is important for the antifibrillatory effect of bretylium. The direct action of bretylium on cardiac electrophysiological properties, as indicated by effective refractory period prolongation, was also assessed. In pentobarbital-anesthetized, open-chest dogs, bretylium, 5 mg/kg i.v., increased ventricular fibrillation threshold rapidly and markedly. The effect peaked in 1 h and was sustained for at least 3 h. Complete adrenergic neuronal blockade also occurred within 30 min. Effective refractory period lengthening was minimal and variable. When bretylium's access to the adrenergic neurons was prevented either by antagonism of the presynaptic amine transport pump with desipramine or by chemical sympathectomy with 6-hydroxydopamine, the antifibrillatory effect was absent. Furthermore, when blockade of adrenergic neurotransmission by bretylium was reversed by the administration of d-amphetamine, ventricular fibrillation threshold also decreased. Data from all groups of experiments revealed that changes in effective refractory period did not correlate, in either magnitude or direction, with changes in ventricular fibrillation threshold. Thus, it can be concluded that interaction with adrenergic neurons is important for bretylium's antifibrillatory action and that absence of sympathetic neurotransmission contributes to the elevation of ventricular fibrillation threshold.