RESUMEN
BACKGROUND: Previous studies concluded that the decline in strength in patients with amyotrophic lateral sclerosis (ALS) is a linear function. If so, a patient's natural history might serve as the control, instead of placebo, in a clinical trial. METHODS: A placebo-controlled ALS clinical trial included a natural history phase, followed by a 6-month treatment phase. Each patient's forced vital capacity (FVC) score and maximal voluntary isometric contraction (MVIC) raw scores were measured monthly, standardized, and averaged into megascores. For 138 patients, the arm, leg, FVC, arm+leg combination, and arm+leg+FVC combination megascore slopes during the natural history phase and during the placebo phase were compared. RESULTS: The mean slope of megascores during the natural history phase and the mean slope during the placebo phase were not different for the arm, leg, and arm+leg megascores, but were different for the FVC and arm+leg+FVC combination megascores. CONCLUSIONS: Natural history controls may be useful in ALS exploratory trials that use arm megascore slope as the primary outcome measure. However, there are distinct limitations to the use of natural history controls, so that Phase 3 ALS clinical trials require placebo controls.
Asunto(s)
Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Factores de Crecimiento Nervioso/uso terapéutico , Placebos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Esclerosis Amiotrófica Lateral/fisiopatología , Brazo/fisiopatología , Método Doble Ciego , Estudios de Seguimiento , Humanos , Pierna/fisiopatología , Contracción Muscular , Músculo Esquelético/fisiopatología , Examen Físico/métodos , Control de Calidad , Ensayos Clínicos Controlados Aleatorios como Asunto/tendencias , Proyectos de Investigación , Músculos Respiratorios/fisiopatología , Estadística como Asunto , Resultado del Tratamiento , Capacidad VitalRESUMEN
Preclinical investigations indicated that recombinant human ciliary neurotrophic factor (rhCNTF) may have potential as therapy for amyotrophic lateral sclerosis (ALS). We evaluated the safety and efficacy of rhCNTF in a prospective, double-blind, placebo-controlled trial in 570 patients with ALS. Patients were randomized to receive 0.5, 2, or 5 micrograms/kg/day rhCNTF, or placebo, for 6 months. The primary efficacy end point was the change from baseline to the last on-treatment value of a combination megascore for limb strength (maximum voluntary isometric contraction) and pulmonary function. Secondary end points included individual arm and leg megascores, pulmonary function tests, an activities-of-daily-living outcome measure, and survival. The four treatment groups were similar at baseline with respect to age, sex, disease duration, and muscle strength values. At all doses tested, rhCNTF had no beneficial effect on the primary or secondary end points. Certain adverse events, as follows, appeared to be dose related: injection site reactions, cough, asthenia, nausea, anorexia, weight loss, and increased salivation. There was an increased number of deaths at the highest dose level. rhCNTF had no beneficial effect on any measure of ALS progression. There were increased adverse events in the 5 micrograms/kg group and increased deaths.
Asunto(s)
Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Proteínas del Tejido Nervioso/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Factor Neurotrófico Ciliar , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Persona de Mediana Edad , Factores de Crecimiento Nervioso/uso terapéutico , Proteínas del Tejido Nervioso/efectos adversos , Estudios Prospectivos , Proteínas Recombinantes , Análisis de SupervivenciaRESUMEN
Clinical trials of anticytokines in sepsis have not been as straightforward as had been anticipated from results in animal models of sepsis and the role of cytokines in sepsis is now in question. Retrospective analysis of the results of a phase III trial of interleukin-1 (IL-1) receptor antagonist suggests that sepsis-induced adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), renal dysfunction, and shock are valuable markers of patients in whom IL-1 is a pathogenic mediator and in whom IL-1ra can reduce mortality. A re-examination of the effects of IL-1ra in animal models of sepsis supports the validity of this analysis. A new phase III clinical trial will confirm or disprove the hypothesis that IL-1 is a mediator of pathology, and IL-1ra is a valuable therapy for sepsis complicated by ARDS, DIC, renal dysfunction, or shock.
Asunto(s)
Interleucina-1/fisiología , Receptores de Interleucina-1/antagonistas & inhibidores , Sepsis/tratamiento farmacológico , Sialoglicoproteínas/farmacología , Coagulación Intravascular Diseminada/etiología , Método Doble Ciego , Humanos , Proteína Antagonista del Receptor de Interleucina 1 , Enfermedades Renales/complicaciones , Enfermedades Renales/etiología , Placebos , Síndrome de Dificultad Respiratoria/etiología , Sepsis/complicaciones , Sepsis/mortalidad , Choque/etiología , Tasa de SupervivenciaRESUMEN
OBJECTIVES: To determine the efficacy of misoprostol for the prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced duodenal and gastric ulcers in arthritis patients receiving NSAID therapy. DESIGN: A randomized, double-blind, multicenter, placebo-controlled trial. SETTING: Six hundred thirty-eight private, Veterans Affairs, health maintenance, and academic practices. PATIENTS: Six hundred thirty-eight patients with chronic inflammatory or noninflammatory arthritis who were taking an NSAID but who did not have a gastric or duodenal ulcer on screening endoscopy received treatment with ibuprofen, piroxicam, naproxen, sulindac, tolmetin, indomethacin, or diclofenac daily for 3 months. Four hundred fifty-five (71%) patients completed the trial. INTERVENTIONS: Patients meeting the entry criteria were randomized to receive either misoprostol, 200 micrograms, or placebo, four times a day for 12 weeks. MAIN OUTCOME MEASURES: The endoscopy was repeated at 4, 8, and 12 weeks. The development of a duodenal or gastric ulcer (defined as a circumscribed mucosal defect > or = 0.5 cm in diameter and with perceptible depth) was regarded as prophylactic failure. RESULTS: By 12 weeks, a duodenal ulcer developed in 2 of 320 (0.6%; 95% CI, 0.2% to 3.9%) patients randomized to receive misoprostol, compared with 15 of 323 (4.6%; CI, 2.8% to 8%) patients receiving placebo (P = 0.002). A gastric ulcer developed in 6 of 320 (1.9%; (CI, 0.8% to 4.4%) patients, compared with in 25 of 323 (7.7%; CI, 5.1% to 11.4%), respectively. CONCLUSION: Misoprostol significantly lowers the frequency of both duodenal and gastric ulcer development in patients who require long-term therapy with NSAIDS.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Artritis/tratamiento farmacológico , Úlcera Duodenal/prevención & control , Misoprostol/uso terapéutico , Úlcera Gástrica/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Úlcera Duodenal/inducido químicamente , Úlcera Duodenal/epidemiología , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/epidemiologíaRESUMEN
Cystic fibrosis (CF) is a genetic disorder that leads to a defect in chloride ion transport and results in pancreatic and pulmonary insufficiency. The pulmonary disease is characterized by bacterial colonization and inflammation with excessive levels of neutrophils and neutrophil elastase within the lung. Neutrophil elastase is considered to be one of the major mediators of the pulmonary damage. Secretory leukocyte protease inhibitor (SLPI) is a natural anti-protease found in the upper airways and has been successfully produced by recombinant technology. SLPI is effective in reducing elastase-induced damage in vitro and in vivo and has recently been administered safely as an aeroeol to CF patients with evidence of biochemical efficacy.
Asunto(s)
Fibrosis Quística/tratamiento farmacológico , Proteínas , Inhibidores de Serina Proteinasa/uso terapéutico , Humanos , Elastasa de Leucocito , Elastasa Pancreática/antagonistas & inhibidores , Proteínas Inhibidoras de Proteinasas Secretoras , Proteínas Recombinantes/uso terapéutico , Inhibidor Secretorio de Peptidasas LeucocitariasRESUMEN
One hundred sixty-two patients chronically ingesting ibuprofen, piroxicam, or naproxen for osteoarthritis, who had abdominal pain and an endoscopically proven gastric ulcer were evaluated for eight weeks in a randomized, double-blind trial comparing misoprostol (200 micrograms four times daily with meals and at bedtime) (N = 77) with placebo (N = 85). Patients discontinued their usual daily dose of antiarthritic medication throughout the study period, and an endoscopy was performed at four weeks and eight weeks (if necessary) to assess ulcer healing. Gastric ulcers were defined as circumscribed breaks in the gastric mucosa of 0.3 cm in diameter or greater. Misoprostol therapy significantly accelerated the rate of gastric ulcer healing compared to placebo (P = 0.033). The cumulative percent healed after four and eight weeks of therapy for misoprostol versus placebo were: 83% vs 61% at four weeks and 96% vs 90% at eight weeks (P = 0.0028 and P = 0.0977, respectively by lifetable analysis). Relief of abdominal pain did not differ significantly between the treatment groups. Misoprostol significantly accelerates the healing of ibuprofen-, piroxicam-, or naproxen-induced gastric ulcers.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Misoprostol/uso terapéutico , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Misoprostol/efectos adversos , Úlcera Gástrica/patologíaRESUMEN
A prospective, randomized, open-label, triple crossover comparison of the effects of indomethacin, misoprostol, or the combination, on renal function was performed to assess the ability of an oral prostaglandin E analogue, misoprostol, to minimize indomethacin-induced decline in renal function in middle-aged women. Twelve healthy women (mean age: 60.5 +/- 1.6 yr) with normal renal function (serum creatinine: 81 +/- 9 umol/L) were studied; six women were normotensive, and six women were hypertensive with their blood pressure controlled with 50-mg hydrochlorothiazide daily. All patients were placed on a 2-g sodium daily diet for 2 weeks before initiation of the study. The subjects were prospectively randomized to receive each of three 4-day treatments of indomethacin (25 mg q 6hr), misoprostol (200 mcg q 6hr), or the combination of drugs with a 4-day washout between each treatment period. Measurements of GFR (urine accumulation of 99mTc-DTPA) and RPF (serum disappearance 131I-Hippuran), and urine collections for electrolytes were obtained before the first treatment period and on the fourth day of each treatment period. Three of the six hypertensive patients and three of the six normotensive patients had a decrease (greater than 10%) in GFR associated with indomethacin therapy. When misoprostol was given with the indomethacin, four of these six patients did not experience a decline in GFR (baseline GFR for six patients: 75.4 +/- 6.6 mL/min/1.73m2, GFR after indomethacin: 57.8 +/- 9.5 mL/min/1.73m2, GFR with combination of indomethacin and misoprostol: 69.7 +/- 3.5 mL/min/1.73m2. RPF was not consistently altered by subacute/chronic dosing of indomethacin, misoprostol, or the combination of the drugs. The authors conclude that misoprostol ameliorates indomethacin-induced renal dysfunction in salt-restricted and diuretic-treated middle-aged women with normal serum creatinine.
Asunto(s)
Alprostadil/análogos & derivados , Tasa de Filtración Glomerular/efectos de los fármacos , Indometacina/antagonistas & inhibidores , Circulación Renal/efectos de los fármacos , Alprostadil/farmacología , Femenino , Humanos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Persona de Mediana Edad , Misoprostol , Potasio/sangre , Potasio/orina , Estudios Prospectivos , Sodio/sangre , Sodio/orinaRESUMEN
OBJECTIVES: To compare the efficacy and frequency of adverse experiences of misoprostol and sucralfate in the prevention of gastric ulcers in patients receiving nonsteroidal anti-inflammatory drug (NSAID) therapy. DESIGN: A prospective, randomized, single-blind, multicenter trial. PATIENTS: Patients with osteoarthritis receiving treatment with ibuprofen, piroxicam, or naproxen and experiencing abdominal pain were eligible. INTERVENTIONS: Patients who were expected to receive at least 3 months of NSAID therapy and who did not have a gastric ulcer at the time of the initial screening endoscopy were randomized to receive misoprostol, 200 micrograms four times a day, or sucralfate, 1 g four times a day. A gastric ulcer was defined as a lesion of the gastric mucosa 0.3 cm or greater in diameter. Patients were followed clinically, and repeat endoscopies were performed after 4, 8, and 12 weeks. MAIN MEASUREMENT: The development of a gastric ulcer, which was regarded as a prophylaxis failure. RESULTS: Two hundred fifty-three patients were evaluable for efficacy analysis. A gastric ulcer developed in 2 of the 122 (1.6%, 95% CI, 0.3% to 6.4%) patients on misoprostol, compared with 21 of 131 patients on sucralfate (16%, CI, 10.4% to 23.7%). The difference in ulcer rates was 14.4% (CI, 10.4% to 19.5%; P less than 0.001). CONCLUSION: In patients receiving chronic NSAID therapy for osteoarthritis, treatment with misoprostol for 3 months was associated with a significantly lower frequency of gastric ulcer formation, compared with treatment with sucralfate (P less than 0.001).