RESUMEN
The µ1 opioid receptor (OPRM1) genetic variant A118G results in decreased µ-receptor binding potential in the brain and increases morphine requirement. We hypothesized that OPRM1 A118G polymorphism will affect morphine-induced respiratory depression (MIRD) risk in children receiving morphine. A prospective genotype-blinded study was conducted in 88 healthy adolescents (11-18 years; 67% female, 85% Caucasian) who underwent spine fusion for scoliosis. They were followed for 48 h postoperatively for MIRD, pain scores, morphine consumption and use of analgesic adjuvants. Patients were genotyped for OPRM1 A118G variant-76% were wild type (AA) and 24% heterozygous/homozygous for variant (AG/GG). Multivariable logistic regression showed that the risk of MIRD in patients with AA genotype was significantly higher (odds ratio 5.6, 95% CI: 1.4-37.2, P=0.030). Presence of G allele was associated with higher pain scores (effect size 0.73, P=0.045). This novel association is an important step toward predicting MIRD susceptibility and personalizing morphine use.
Asunto(s)
Morfina/efectos adversos , Polimorfismo de Nucleótido Simple/genética , Receptores Opioides mu/genética , Insuficiencia Respiratoria/inducido químicamente , Insuficiencia Respiratoria/genética , Columna Vertebral/cirugía , Adolescente , Alelos , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Niño , Femenino , Genotipo , Homocigoto , Humanos , Masculino , Morfina/administración & dosificación , Estudios Prospectivos , Receptores Opioides mu/metabolismo , Insuficiencia Respiratoria/metabolismo , Riesgo , Escoliosis/cirugíaRESUMEN
Opioid-related respiratory depression (RD) is a serious clinical problem as it causes multiple deaths and anoxic brain injuries. Morphine is subject to efflux via P-glycoprotein transporter encoded by ABCB1, also known as MDR1. ABCB1 polymorphisms may affect blood-brain barrier transport of morphine and therefore individual response to its central analgesic and adverse effects. This study aimed to determine specific associations between common ABCB1 genetic variants and clinically important outcomes including RD and RD resulting in prolonged stay in hospital with intravenous morphine in a homogenous pediatric surgical pain population of 263 children undergoing tonsillectomy. Children with GG and GA genotypes of ABCB1 polymorphism rs9282564 had higher risks of RD resulting in prolonged hospital stays; adding one copy of the minor allele (G) increased the odds of prolonged hospital stay due to postoperative RD by 4.7-fold (95% confidence interval: 2.1-10.8, P=0.0002).
Asunto(s)
Analgésicos Opioides/efectos adversos , Predisposición Genética a la Enfermedad/genética , Insuficiencia Respiratoria/inducido químicamente , Insuficiencia Respiratoria/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Alelos , Analgésicos Opioides/uso terapéutico , Niño , Femenino , Genotipo , Humanos , Tiempo de Internación , Masculino , Morfina/efectos adversos , Morfina/uso terapéutico , Dolor/tratamiento farmacológico , Farmacogenética/métodos , Estudios Prospectivos , RiesgoRESUMEN
BACKGROUND: Data are lacking on the use of topical therapies in combination with tumour necrosis factor blockers for the treatment of psoriasis. OBJECTIVES: To assess the efficacy and safety of adalimumab (ADA) with topical calcipotriol/betamethasone (C/B) in patients with psoriasis resembling those treated in routine clinical practice. METHODS: A 16-week, randomized, vehicle-controlled trial was conducted in patients with moderate to severe psoriasis and previous failure, intolerance or contraindications to two or more systemic treatments. All patients received ADA (80 mg, week 0; 40 mg every other week, weeks 1-15) in addition to either topical C/B or drug-free vehicle applied once daily for 4 weeks, and as needed thereafter. The primary endpoint was 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75) at week 16. RESULTS: A total of 730 patients received either ADA + C/B (n = 366) or ADA + vehicle (n = 364). PASI 75 response was initially higher with the combination therapy [14.8% for ADA + C/B vs. 5.8% for ADA + vehicle at week 2 (P < 0.001); and 40.7% vs. 32.4%, respectively, at week 4 (P = 0.021)]. After week 4, the trend was towards a higher response with ADA monotherapy, with no statistical difference in the PASI 75 response at week 16 (64.8% for ADA + C/B vs. 70.9% for ADA monotherapy, P = 0.086). Safety findings were consistent with previous ADA trials. CONCLUSIONS: ADA + C/B resulted in more rapid and higher efficacy within the first 4 weeks; thereafter, the trend was towards a higher response with ADA monotherapy. There was no statistical difference in the PASI 75 response at week 16. Both treatment regimens were well tolerated.
Asunto(s)
Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Betametasona/uso terapéutico , Calcitriol/análogos & derivados , Fármacos Dermatológicos/uso terapéutico , Psoriasis/tratamiento farmacológico , Adalimumab , Administración Tópica , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Calcitriol/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada/métodos , Europa (Continente) , Femenino , Humanos , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
AIMS: The objective of our study was to define the interaction between either unfractionated heparin (UFH) or a low molecular weight heparin, reviparin (REV), and the pharmacodynamic profile of the GPIIb/IIIa-antagonists abciximab (ABC) or tirofiban (T). METHODS: Two studies each containing 18 healthy subjects were performed, and all were pretreated with aspirin (ASA) for 3 days. Volunteers then received UFH (5000 IU bolus/infusion 7 IU kg(-1) h(-1) for 7 h, n = 6), REV (4200-anti-Xa-IU s.c., n = 6) or placebo (n = 6). One hour later, ABC (study I) or T (study II) were given by i.v. infusion for 6 h. The pharmacodynamic effects measured were bleeding time (BT), fibrinogen-binding at the GPIIb/IIIa-receptor (FIB), expression of the platelet secretion marker CD62, and ADP (20 microM)- and collagen (5 microg ml(-1))-induced platelet aggregation. RESULTS: After treatment with both GPIIb/IIIa-antagonists, prolongation of BT occurred to a similar magnitude (approximately 25-30 min) and was not affected by UFH or REV-comedication. ABC or T with ASA alone resulted in nearly the same magnitude of reduction in FIB and platelet aggregation. After coadministration with UFH, FIB was significantly higher (thus less inhibited) than after after T + ASA alone (19 +/- 16% vs 55 +/- 36%) or ABC + ASA alone (8 +/- 9% vs 32 +/- 11%). This attenuation of FIB was not seen with REV. Inhibition of ADP-and collagen-induced aggregation tended to be attenuated by treatment with UFH (e.g. ADP-induced aggregation at 0.25 h after ABC + ASA alone =13 +/- 4%; after coadministration with UFH = 40 +/- 26%). No such changes were noted with REV. Minor reductions in CD62-expression were seen in subjects given ABC or T alone, but expression was not affected by UFH or REV. CONCLUSIONS: Co-medication with UFH attenuated platelet inhibition during treatment with GPIIb/IIIa-antagonists, but these effects were not seen with the low molecular weight heparin reviparin. The results show that administration of reviparin together with abciximab or tirofiban did not adversely affect the pharmacodynamic profile of these GPIIb/IIIa-antagonists.
Asunto(s)
Anticoagulantes/farmacología , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Abciximab , Adolescente , Adulto , Anticuerpos Monoclonales/farmacología , Unión Competitiva/efectos de los fármacos , Tiempo de Sangría , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Interacciones Farmacológicas , Inhibidores del Factor Xa , Fibrinógeno/metabolismo , Citometría de Flujo , Heparina/farmacología , Heparina de Bajo-Peso-Molecular/farmacología , Humanos , Fragmentos Fab de Inmunoglobulinas/farmacología , Masculino , Tiempo de Tromboplastina Parcial , Agregación Plaquetaria/efectos de los fármacos , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Selectinas/efectos de los fármacos , Selectinas/metabolismo , Tirofibán , Resultado del Tratamiento , Tirosina/análogos & derivados , Tirosina/farmacologíaRESUMEN
BACKGROUND: Hirudin selectively inhibits thrombin without cofactors and is eliminated via the kidneys. Recombinant hirudin (r-hi) has a terminal elimination half-life (t1/2) of about 50 to 100 minutes. Coupling of polyethylene glycol (PEG) to r-hi, giving PEG-hirudin (PEG-Hi), prolongs its t1/2 while enhancing efficacy. We looked at the pharmacodynamic and pharmacokinetic behavior of PEG-Hi in patients with impaired renal function. METHODS: Anticoagulant activity and the pharmacokinetic parameters of a single intravenous bolus injection of 0.05 mg/kg body weight PEG-Hi were studied in 38 subjects. They were assigned to five groups: group IA, creatinine clearance (CCr) >/= 80 mL/min, 8 healthy volunteers; group IB, CCr >/= 80 mL/min, 8 patients with normal renal function); group II, CCr 79 to 50 mL/min, 7 patients with mild chronic renal failure (CRF); group III, CCr 49 to 20 mL/min, 10 patients with moderate CRF; and group IV, CCr
Asunto(s)
Antitrombinas/farmacocinética , Excipientes/farmacocinética , Hirudinas/farmacocinética , Fallo Renal Crónico/tratamiento farmacológico , Polietilenglicoles/farmacocinética , Adulto , Anciano , Creatinina/sangre , Creatinina/orina , Endopeptidasas , Femenino , Fibrinógeno/metabolismo , Fibrinolíticos , Humanos , Masculino , Persona de Mediana Edad , Tiempo de Tromboplastina ParcialRESUMEN
AIMS: To investigate potential interactions between reviparin and acetylsalicylic acid (ASA 300 mg o.d. from day 1-5). METHODS: In an open, randomized, three-way-cross over study nine healthy volunteers received reviparin (s.c. injection of 6300 anti-Xa units) or placebo from days 3 to 5 and acetylsalicylic acid (ASA 300 mg) or placebo from days 1 to 5. Assessments included bleeding time (BT), collagen (1 microg ml-1) induced platelet aggregation (CAG), heptest, plasma antifactor Xa-activity and activated partial thromboplastin time (aPTT). RESULTS: Median bleeding time at day 5 was 5.5 min after reverparin alone and after ASA alone and was 9.6 min after the combination of reviparin and ASA. ASA treatment reduced CAG from 84% to 40 to 50% of Amax; values after combined treatment of reviparin with ASA were not different from those after ASA alone. aPTT was prolonged to 32 s after reviparin; this effect was not modified if subjects received ASA. Combined treatment with ASA and reviparin had no effect on plasma anti-Xa-activity and heptest compared with reviparin alone. CONCLUSIONS: We could not entirely exclude a small interaction between reviparin and ASA on bleeding time, but the effect is probably without clinical significance.
Asunto(s)
Anticoagulantes/farmacología , Aspirina/farmacología , Heparina de Bajo-Peso-Molecular/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Adulto , Anticoagulantes/efectos adversos , Aspirina/efectos adversos , Tiempo de Sangría , Estudios Cruzados , Método Doble Ciego , Interacciones Farmacológicas , Factor Xa/metabolismo , Femenino , Hemostasis/efectos de los fármacos , Heparina de Bajo-Peso-Molecular/efectos adversos , Humanos , Masculino , Tiempo de Tromboplastina Parcial , Inhibidores de Agregación Plaquetaria/efectos adversos , Pruebas de Función PlaquetariaRESUMEN
PEG-Hirudin, a chemically defined conjugate of recombinant hirudin and two molecules of polyethylene glycol (PEG)-5000 is a highly selective direct thrombin inhibitor with a significantly longer duration of action than non-conjugated recombinant hirudin permitting once daily subcutaneous administration. A series of placebo-controlled, randomized, Phase I clinical trials were conducted in 75 healthy volunteers to investigate the anticoagulant effects, safety and pharmacodynamics of PEG-Hirudin when administered intravenously as a bolus injection, infusion, and subcutaneously. After single i.v. injections of various doses of PEG-Hirudin (0.03-0.3 mg/kg) dose-dependent increases in anti-IIa activity and APTT were observed. Four hours after injection of 0.3 mg/kg, mean plasma concentration expressed in terms of anti-IIa activity was still 0.89 micrograms/ml, corresponding to a 1.8-fold prolongation of APTT. Continuous intravenous infusions of 0.01 and 0.02 mg/kg/h PEG-Hirudin resulted in maximum anti-IIa activities of 0.42 micrograms/ml and 0.77 micrograms/ml, respectively, at the end of a six-hour infusion period without having reached steady state at this time. After termination of the infusion, anticoagulant activity displayed an immediate exponential decrease. The anticoagulant activities of single subcutaneous doses of 0.05 to 0.6 mg/kg were studied in a further series of investigations and slow increases and prolonged durations of anti-IIa activity and APTT prolongation were found. Repeated, once daily subcutaneous administrations of 0.2 to 0.4 mg/kg for five days resulted in dose-dependent prolongations of APTT and increases in anti-IIa activity without completely reaching steady state conditions. In a further study, 0.3 mg/kg of PEG-Hirudin was given as an i.v. bolus injection followed by three repeated single daily s.c. injections. In this trial, the APTT was shorter than expected from previous studies; therefore, a direct comparison of various APTT reagents was made in the intravenous infusion trial. Of the APTT reagents tested, BioMérieux Silimat and IL-ellagic acid proved to be the most sensitive to PEG-Hirudin. The hirudin derivative PEG-Hirudin was tolerated very well without immuno-allergic side effects. In view of the significantly prolonged anticoagulant efficacy in comparison to non-conjugated r-hirudin, PEG-Hirudin is a promising compound especially for repeated once daily subcutaneous administration.
Asunto(s)
Antitrombinas/efectos adversos , Antitrombinas/farmacocinética , Hirudinas/análogos & derivados , Tiempo de Tromboplastina Parcial , Adulto , Antitrombinas/administración & dosificación , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Estudios de Seguimiento , Hirudinas/administración & dosificación , Hirudinas/efectos adversos , Hirudinas/farmacocinética , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Infusiones Intravenosas , Inyecciones Intravenosas , Inyecciones Subcutáneas , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Placebos , Proteínas Recombinantes/efectos adversos , Valores de Referencia , Factores de TiempoRESUMEN
Complete occlusion of the left renal artery for 60 min in the rat produced anuric acute renal failure after 1 day. Using fluorescence microscopy, a television system combined with double slit densitometry, and micropuncture techniques, tubular pressure and tubular flow rates were determined in different segments of superficial nephrons. Intratubular pressures in proximal convolutions of the postischemic kidney were largely heterogeneous due to abnormally increased flow resistance in proximal tubules which were filled with loose obstructive material. Proximal tubular pressure in the control kidney was independent of the site of its measurement and had a mean value of 14.1 mm Hg. In the postischemic kidney pressure decreased gradually along the proximal tubule, its value in the early and late segments being 16.3 and 9.7 mm Hg, respectively. Low pressure in late proximal convolutions excludes a significant flow impediment due to obstruction in more distal segments. The mean nephron filtration rate (SNGFR) obtained by extrapolation of tubular flow data was 62% of the control value, whereas tubular reabsorption was estimated to be 50% above normal. Reduced SNGFR and increased outflux caused a total reabsorption of tubular fluid within 60% of proximal convoluted tubule length. The partial reduction of SNGFR can be explained by increased pressure in early proximal convolutions and reduced glomerular plasma flow known for these kidneys, without postulating a change in glomerular permeability. Tubular obstruction and increased passive outflux in proximal tubules due to cellular damage appear to be crucial mechanisms responsible for the loss of renal function in this model of acute renal failure.
Asunto(s)
Lesión Renal Aguda/fisiopatología , Anuria/complicaciones , Isquemia/complicaciones , Absorción , Lesión Renal Aguda/complicaciones , Animales , Tasa de Filtración Glomerular , Hemodinámica , Presión Hidrostática , Riñón/irrigación sanguínea , Túbulos Renales Proximales/fisiopatología , Nefronas/fisiopatología , Ratas , Ratas EndogámicasRESUMEN
With the use of a new fluorescent microscopic technique, we were able to measure the mean intracapillary velocities and pressures of single capillary loops of renal glomeruli of living rats. The technique involved photographing and recording the flow of fluorescent latex particles through the glomerular loops with a television monitor. In 25 rats the single glomerular loop flow velocity was 781 +/- (SD) 271 micrometers . sec-1. The mean diameter of the capillary loops measured 8.4 +/- 1.4 micrometers; their lengths were 72.3 +/- 37.5 micrometers. From the decrease in velocity of flow along the capillary loop, we were able to evaluate the filtration equivalent for the capillary surface. It was possible to measure intracapillary pressures of single glomerular loops continuously under microscopic control. High intracapillary pressures correlated with high intracapillary velocities. From the data we obtained, we were unable to calculate a filtration equilibrium at the ends of the observed capillary loops. For further correlations, we injected the glomeruli we had studied in the living state and examined them with the scanning electron microscope.