RESUMEN
BACKGROUND: Natalizumab is a recombinant monoclonal antibody approved for the treatment of patients with multiple sclerosis and patients with Crohn's disease. Because of its immunosuppressive effects, natalizumab has been associated with a number of atypical and opportunistic infections. AIM: To describe and summarize six spontaneously reported post-marketing cases of clinically significant drug induced-liver injury associated with natalizumab use. METHODS: The FDA maintains a database of adverse event reports (AERS). We searched the AERS database for reports of serious liver injury associated with natalizumab use from November 2004, when the drug was approved, through 30 June 2008. RESULTS: The search resulted in six spontaneously reported post-marketing cases of severe drug-induced liver injury. Four of six patients developed liver injury with elevations of serum transaminases and hyperbilirubinemia after only a single infusion of natalizumab. One of these patients experienced repeated increases of aminotransferases and bilirubin when natalizumab was re-administered. CONCLUSIONS: Serious hepatic injury may occur in association with natalizumab use. Health professionals should be alerted to possible serious liver injury in patients receiving natalizumab.
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas , Esclerosis Múltiple/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Femenino , Humanos , Masculino , Persona de Mediana Edad , NatalizumabRESUMEN
BACKGROUND: Topiramate was approved for the treatment of epilepsy in 1999 and has since been approved for the prevention of migraine headache. It is structurally different from the majority of antiepileptic medications and is pharmacodynamically unique in its ability to inhibit the enzyme carbonic anhydrase. Postmarketing reports of topiramate-associated hypothermia have occurred but this adverse event has not been well characterized. Data mining of an adverse event database was used to assist in the identification of hypothermia. OBJECTIVE: We sought to explore a possible association between the concomitant use of topiramate and valproic acid and the induction of hypothermia. METHODS: This was a pharmacovigilance case series survey of spontaneous hypothermia, a reported adverse event in patients treated with topiramate and valproic acid, alone and in combination. The U.S. Food and Drug Administration's Adverse Events Reporting System (AERS) database was searched for reports of hypothermia in association with the use of topiramate. A data mining algorithm was used on the AERS to identify scores for hypothermia associated with antiepileptic drugs. RESULTS: We identified 22 unduplicated reports of hypothermia in patients exposed to topiramate. Three of the 22 were confounded by patient overdoses with multiple drugs and not considered. Use of more than one antiepileptic drug was reported in most of the remaining 19 reports. Of these 19 reports, valproic acid was mentioned in 7. Two of the 19 reports mentioned topiramate only. Eleven of the 19 patients were men. The median age of the 19 patients was 40 years (range, 3(1/2)-82 years). Body temperatures ranged from 29.5 degrees C (moderate hypothermia) to 35 degrees C (mild hypothermia) with a median of 34 degrees C. Eleven of 18 reports of hypothermia occurred during the cooler months (one report did not indicate the time of year in which hypothermia occurred). Comorbid conditions included hypothyroidism in six reports, five in patients who received valproic acid concomitantly with topiramate and five reports of hyperammonemia in similarly treated patients. Data mining scores (empirical Bayes geometric mean) for antiepileptic drugs ranged from a high of 5.845 for phenobarbital to 2.956 for gabapentin. Hypothermia was reported 4.7 times more frequently when topiramate was used than was statistically expected. CONCLUSION: We have found hypothermia, defined as an unintentional drop in body core temperature to <35 degrees C, to be associated with concomitant administration of topiramate (a carbonic anhydrase inhibitor) and valproic acid in patients who have tolerated either drug alone. Data mining analysis for topiramate showed a signal of hypothermia. Topiramate was reported 4.72 times more frequently in the database than would be statistically expected when considering all other drugs. Topiramate may act pharmacodynamically to potentiate the effects of valproic acid as a result of its ability to decrease blood HCO(3) (-) and increase blood ammonia levels.
Asunto(s)
Anticonvulsivantes/efectos adversos , Fructosa/análogos & derivados , Hipotermia/inducido químicamente , Ácido Valproico/efectos adversos , Adolescente , Adulto , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Algoritmos , Amoníaco/sangre , Bicarbonatos/sangre , Niño , Preescolar , Bases de Datos Factuales , Interacciones Farmacológicas , Femenino , Fructosa/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Topiramato , Estados Unidos , United States Food and Drug Administration , Adulto JovenRESUMEN
The hydrolysis of lipoprotein triglycerides is catalyzed by lipoprotein lipase (LPL), an enzyme found in many tissues. We have examined tissue LPL activity (LPLA) in rats with experimentally-induced hyperthyroidism. In younger, lighter rats, hyperthyroidism was accompanied by a decrease in LPL in adipose tissue whereas heart and diaphragm muscle LPL activities were increased. These changes are consistent with the hypothesis that the hypercatabolism and increased beta-adrenergic activity of hyperthyroidism result in characteristic changes in tissue LPLA. In older, heavier hyperthyroid animals, however, adipose tissue LPLA was increased and heart and diaphragmatic LPLA were similar to control activities. Propranolol feeding abolished the thyroxine-induced increase in adipose tissue LPLA. In euthyroid animals of similar size the response of muscle LPLA to short-term starvation was also attenuated. These changes in tissue LPLA may provide a mechanism for shunting triglyceride fatty acids away from adipose tissue for utilization by muscle in the hyperthyroid state. During growth and aging, these adaptations are modified.
Asunto(s)
Tejido Adiposo/enzimología , Hipertiroidismo/enzimología , Lipoproteína Lipasa/metabolismo , Músculo Liso/enzimología , Tejido Adiposo/crecimiento & desarrollo , Envejecimiento , Animales , Peso Corporal , Diafragma/enzimología , Diafragma/crecimiento & desarrollo , Ayuno , Femenino , Corazón/crecimiento & desarrollo , Masculino , Desarrollo de Músculos , Músculo Liso/crecimiento & desarrollo , Miocardio/enzimología , Especificidad de Órganos , Propranolol/farmacología , Ratas , Factores Sexuales , Tiroxina/sangre , Triyodotironina/sangreRESUMEN
Lipoprotein lipase (LPL) activity was measured in adipose tissue, heart and diaphragm in Sprague--Dawley rats after estrogen therapy or orchiectomy. Enzyme activity was measured by incubation of tissue fragments with a triolein emulsion in the presence of serum and heparin. In confirmation of other work, depression of adipose tissue LPL followed estradiol treatment in pharmacologic or near-physiologic doses. Cardiac and diaphragmatic muscle LPL were increased. Estrogen-treated male animals showed growth retardation. However, they gained weight steadily and did not show significant differences in serum insulin, glucose of D-beta-hydroxybutyrate. The effects of estradiol in male animals were reversed by sequential fasting and re-feeding. At times during growth and aging in normal female rats, adipose tissue activity was decreased while cardiac and skeletal muscle activities were increased relative to males of the same age or body weight. Castration of male rats failed to reproduce the effect of estrogens on tissue lipoprotein lipase. These in vitro data suggest that exogenous estrogens may shift the flux of triglyceride fatty acids from storage in the adipose organ toward incorporation by muscle. These, and other data, raise the possibility that physiological estrogen secretion exerts a tonic influence over the synthesis and ultimate destination of triglyceride fatty acids.
Asunto(s)
Tejido Adiposo/enzimología , Diafragma/enzimología , Estradiol/farmacología , Lipoproteína Lipasa/metabolismo , Miocardio/enzimología , Testosterona/análogos & derivados , Tejido Adiposo/efectos de los fármacos , Animales , Castración , Diafragma/efectos de los fármacos , Estradiol/análogos & derivados , Corazón/efectos de los fármacos , Cinética , Masculino , Especificidad de Órganos , Ratas , Testosterona/farmacologíaRESUMEN
The degradation and excretion of 2-14C-uric acid were examined in three adult woolly monkeys (Lagothrix lagothrichia) to determine the basis for the relatively high serum and urinary uric acid concentrations previously reported in this species. Like man and the great apes which lack uricase, but in distinction to most other mammals, these animals converted very little urate to allantoin. Uric acid turnover, as has been reported for other New World monkeys, was several times that of normal man. Renal urate excretion as well as disposition by extrarenal mechanisms may protect Lagothrix vrom hyperuricemia. The capacity to convert urate to allantoin appears to have been lost late in the evolution of New World monkeys. The woolly monkey deserves further study as a primate model for investigations of enzyme replacement strategies.
Asunto(s)
Haplorrinos/metabolismo , Ácido Úrico/metabolismo , Animales , Inulina/metabolismo , Masculino , Tasa de Depuración Metabólica , Pirazinamida/farmacología , Urato Oxidasa/deficienciaRESUMEN
Short-term oral contraceptive therapy has been reported to decrease postheparin lipolytic activity (PHLA). Resistance to heparin has been held responsible for this effect. To test several alternative explanations, we studied both PHLA and heparin concentrations in nine control women and nine women receiving long-term estrogen-progestin therapy after they were given heparin intravenously (10 units/kg). There were no significant differences in the concentration of heparin, its rate of disappearance, or calculated space of distribution between control and treated groups. PHLA was depressed (p less than 0.05) by approximately 50% during long-term estrongen-progestin therapy. PHLA disappearance was similar in both groups. Thus, reduced PHLA in women receiving long-term oral contraceptive therapy cannot be related to altered heparin metabolism or to accelerated enzyme disappearance from plasma. Long-term estrogen-progestin administration may decrease the heparin-facilitated release of individual triglyceride hydrolase activities or enhance the affinity of enzyme binding to tissues.
Asunto(s)
Anticonceptivos Orales/farmacología , Congéneres del Estradiol/farmacología , Heparina/metabolismo , Lipasa/metabolismo , Congéneres de la Progesterona/farmacología , Depresión Química , Etinilestradiol/farmacología , Femenino , Humanos , Mestranol/farmacología , Noretindrona/farmacología , Noretinodrel/farmacología , Norgestrel/farmacología , Factores de Tiempo , Triglicéridos/metabolismoRESUMEN
Published data have suggested that hypertriglyceridemia in obesity may result from the combination of hepatic overproduction and diminished removal of triglyceride-rich lipoproteins. Diminished catabolism might be expected if tissue lipoprotein lipase activity were decreased, a finding which has been reported in biopsies of adipose tissue from obese subjects. Abnormalities in heparin-released triglyceride lipase activity (PHLA) in obesity have not been reported, however. We have examined the possibility that methods for the measurement of PHLA might have failed to reveal such a defect because of the disproportionality between plasma volume and increasing body mass in obesity. Since it is usual to administer heparin on the basis of body weight, higher plasma heparin levels would be achieved in obese individuals. We performed standard PHLA assays in lean and obese volunteers. In the obese, heparin levels were consistently higher than in lean individuals although PHLA values were similar in both. Thus, PHLA in obesity appeared to be inappropriate for the heparin levels attained in plasma. Pharmacokinetic studies suggest that a decrease in PHLA available for release by heparin rather than heparin insensitivity underlies this phenomenon.
Asunto(s)
Heparina/efectos adversos , Lipidosis/inducido químicamente , Obesidad/complicaciones , Adulto , Esquema de Medicación , Ácidos Grasos no Esterificados/metabolismo , Femenino , Heparina/administración & dosificación , Humanos , Hiperlipidemias/enzimología , Lipidosis/enzimología , Lipoproteína Lipasa/metabolismo , Masculino , Obesidad/enzimología , Triglicéridos/metabolismoRESUMEN
We have developed a simplified method for the quantitative assay of lipoprotein lipase in cow's milk based on the hydrolysis of a glyceride emulsion in semisolid agarose gel. The area of clearing produced thereby is a function of enzyme concentration. Absolute molar rates for unknown samples may be calculated if standards of known activity are used concurrently. The precision of the simplified assay compared favorably with a method based on titrimetric determination of the rate of free fatty acid release. A modified assay has been used to assess the potency of lipoproteins in lipoprotein lipase activation.