RESUMEN
Indomethacin, a nonspecific prostaglandin synthetase inhibitor, gained popularity several decades ago as a potent tocolytic agent. This popularity, however, was tempered by concerns over fetal and neonatal complications associated with its use. However, with better recognition of the safety limitations, there has been a renewed interest in using indomethacin for acute tocolysis. More recently, the tocolytic potential of cyclooxygenase-2 (COX-2) specific inhibitors has gained much interest as well as the theoretical minimization of side effects associated with these agents. This article reviews the pharmacology and efficacy of indomethacin and some of the newer cyclooxygenase-2 inhibitors, and discusses the potential adverse fetal and neonatal effects associated with their use. Guidelines will be presented that will assist theclinician in using indomethacin as an effective tocolytic while avoiding untoward effects.
Asunto(s)
Trabajo de Parto Prematuro/prevención & control , Antagonistas de Prostaglandina/uso terapéutico , Tocolíticos/uso terapéutico , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/efectos adversos , Inhibidores de la Ciclooxigenasa/uso terapéutico , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Indometacina/efectos adversos , Indometacina/uso terapéutico , Isoenzimas/antagonistas & inhibidores , Proteínas de la Membrana , Embarazo , Prostaglandina-Endoperóxido SintasasRESUMEN
OBJECTIVE: Indomethacin, an inhibitor of cyclooxygenase types 1 and 2, and nimesulide, a cyclooxygenase 2 selective inhibitor, are both well-known inhibitors of prostaglandin production. It has been assumed that the tocolytic mechanism of nimesulide and indomethacin is only through decreased prostaglandin production. The purpose of this study was to test the hypothesis that either nimesulide or indomethacin, or both, has a mechanism of action on human myocytes other than inhibition of prostaglandin production. STUDY DESIGN: Human uterine myometrium was obtained from consenting patients during cesarean deliveries. Myocytes were cultured, plated, and loaded with a calcium-dependent fluorescent dye, calcium green 1. The relative concentrations of intracellular free calcium were determined by measurement of time-dependent fluorescence changes by means of a video fluorimeter. In all experiments, cells were stimulated with prostaglandin F2alpha, 30 micromol/L. Experiments were performed without pretreatment (control) or with pretreatment consisting of indomethacin, 10 micromol/L, or nimesulide, 30 micromol/L. The percentages of cells demonstrating calcium increases were counted and compared by means of the Fisher exact test. A P value =.05 was considered significant. RESULTS: After prostaglandin F2alpha exposure, 33% of cells showed an increase in intracellular free calcium under control conditions. When pretreated with nimesulide, 39% of cells responded to prostaglandin F2alpha (P =.59). When pretreated with indomethacin, only 16% of cells responded to prostaglandin F2alpha (P =.019). CONCLUSIONS: Pretreatment with nimesulide failed to reduce the fraction of cells that responded to prostaglandin F2alpha. In contrast, pretreatment with indomethacin significantly reduced the fraction of responding cells. These data suggest that, in vitro, indomethacin exhibits a mechanism of tocolysis other than inhibition of prostaglandin synthesis.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Calcio/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Indometacina/farmacología , Músculo Liso/embriología , Sulfonamidas/farmacología , Tocolíticos/farmacología , Útero/metabolismo , Células Cultivadas , Dinoprost/farmacología , Femenino , Humanos , Membranas Intracelulares/efectos de los fármacos , Membranas Intracelulares/metabolismo , Músculo Liso/citología , Músculo Liso/efectos de los fármacos , Valores de Referencia , Útero/citología , Útero/efectos de los fármacosRESUMEN
Current therapy for hemophilia B requires large intravenous doses of factor IX (F.IX) given in the clinic or at home. Although home therapy is possible for many patients, it is often complicated by factors such as the lack of good venous access. Very little is known about extravascular routes for administering proteins like F.IX (57 kD) or other vitamin K-dependent procoagulant factors into the circulation. Questions about the absorption rate from extravascular administration as well as plasma recovery and bioavailability have arisen recently with the growing availability of highly purified procoagulant proteins and increased interest in gene therapy of hemophilia B. Therefore, a group of studies were undertaken to determine the absorption rate, plasma recovery, and bioavailability of high purity, human plasma-derived F.IX concentrates administered via extravascular routes in hemophilia B dogs and in one human hemophilia B subject. Five hemophilia B dogs were given human F.IX via either a subcutaneous (s.c.), intramuscular (i.m.), intraperitoneal (i.p.) or intravenous (i.v.) route. In a subsequent study, a single SC administration of human F.IX was compared to an identical i.v. dose of F.IX in the human hemophilia B subject. All extravascular routes of F.IX administration in both the canine and human gave lower levels of circulating plasma F.IX than the i.v. route, however all routes resulted in measurable F.IX activity. Of the extravascular routes, the i.m. injection in the canine resulted in a bioavailability of 82.8%, while the s.c. injection resulted in a bioavailability of 63.5%. F.IX reached the plasma compartment by all extravascular routes used, confirming that F.IX can be absorbed extravascularly. The duration of measurable F.IX activity following extravascular administration is prolonged beyond that typically seen with i.v. administration. These data show that significant levels of F.IX may be obtained via s.c. injection in canine and human hemophilia B subjects and further highlight the potential of extravascular routes of administration for future experimental and clinical uses of F.IX and other procoagulant proteins.
Asunto(s)
Enfermedades de los Perros , Factor IX/uso terapéutico , Hemofilia B/terapia , Hemofilia B/veterinaria , Animales , Disponibilidad Biológica , Perros , Factor IX/administración & dosificación , Factor IX/farmacocinética , Semivida , Humanos , Inyecciones Intramusculares , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Tasa de Depuración Metabólica , Factores de TiempoRESUMEN
Hemophilia B is caused by a deficiency of blood clotting factor IX (FIX). Previous studies have shown that the delivery of a recombinant adenoviral vector expressing canine FIX (cFIX) resulted in a complete correction of hemophilia B in FIX-deficient dogs, but that cFIX expression decreased to only about 1-2% of normal levels 3 weeks after treatment. In the present study, therapeutic levels of cFIX expression capable of producing a partial correction of hemophilia B were maintained for at least 6 months after the coadministration of the cFIX-expressing adenovirus and the immunosuppressive agent cyclosporin A (CsA). These findings support a recent report (Yang et al., 1994) that host T-cell-mediated immunity against virally transduced cells is a major contributing factor to the transient nature of adenovirus-mediated gene expression in immunocompetent animals. Although a second administration of the cFIX-expressing adenovirus 6 months after the first infusion had only a minimal effect on plasma FIX levels in a dog that had been continuously treated with CsA, the prolonged expression of the transgene indicates that immunosuppression may be applicable in attaining long-term treatment of clinically relevant disorders.
Asunto(s)
Adenoviridae/genética , Factor IX/genética , Terapia Genética/métodos , Hemofilia B/terapia , Terapia de Inmunosupresión , Adenoviridae/inmunología , Animales , Anticuerpos Antivirales/sangre , Coagulación Sanguínea , Ciclosporina/farmacología , Perros , Factor IX/biosíntesis , Vectores Genéticos/genética , Hemofilia B/sangre , Inmunosupresores/farmacología , Pruebas de NeutralizaciónRESUMEN
Hemophilia B is a bleeding disorder caused by mutations in the factor IX gene. The disorder is X-linked recessive with a prevalence of about 1 in 30,000 Caucasian males. Factor IX is naturally synthesized in the liver and secreted into blood. Here we report the construction of recombinant adenoviral vectors containing the canine factor IX cDNA that are capable of transducing hepatocytes in mice at high efficiencies in vivo without partial hepatectomy. The recombinant viral vector was used to treat hemophilia B dogs by direct vector infusion into the portal vasculature of deficient animals. Plasma factor IX concentrations in the treated hemophilia B dogs increased from 0 to 300% of the level present in normal dogs, resulting in complete amelioration of the disease as demonstrated by normal blood coagulation and hemostatic measurements. Although plasma factor IX concentration started to decline after a few days, therapeutic levels of factor IX persisted for 1-2 months in the treated animals. The results validate the principle of in vivo hepatic gene delivery to reconstitute the genetic deficiency in a large animal model and suggest that gene therapy is achievable when long-acting vectors are developed.
Asunto(s)
Factor IX/genética , Terapia Genética , Hemofilia B/terapia , Hígado/metabolismo , Adenoviridae/genética , Animales , Secuencia de Bases , Clonación Molecular , ADN Viral , Perros , Femenino , Vectores Genéticos , Hemofilia B/genética , Hepatectomía , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Transducción Genética , Cromosoma XRESUMEN
The liver represents a model organ for gene therapy. A method has been developed for hepatic gene transfer in vivo by the direct infusion of recombinant retroviral vectors into the portal vasculature, which results in the persistent expression of exogenous genes. To determine if these technologies are applicable for the treatment of hemophilia B patients, preclinical efficacy studies were done in a hemophilia B dog model. When the canine factor IX complementary DNA was transduced directly into the hepatocytes of affected dogs in vivo, the animals constitutively expressed low levels of canine factor IX for more than 5 months. Persistent expression of the clotting factor resulted in reductions of whole blood clotting and partial thromboplastin times of the treated animals. Thus, long-term treatment of hemophilia B patients may be feasible by direct hepatic gene therapy in vivo.