Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria.

BACKGROUND AND OBJECTIVES: This report summarizes the first phase 1 trial treating patients with microalbuminuric diabetic kidney disease (DKD) using FG-3019, a human monoclonal antibody to connective tissue growth factor (CTGF). CTGF is critically involved in processes of progressive fibrosis, including DKD. This phase 1, open-label, dose-escalation trial evaluated safety, pharmacokinetics, and possible therapeutic effects of FG-3019 on albuminuria, proteinuria, and tubular proteins. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Microalbuminuric subjects (n = 24) with type 2 (79%) or type 1 (21%) diabetes received 3 or 10 mg/kg FG-3019 dosed intravenously every 14 days for four doses. Albuminuria and safety follow-up were to days 62 and 365, respectively. RESULTS: No infusion was interrupted for symptoms, although 5 of 24 subjects had mild infusion-day adverse events thought to be possibly drug-related. No subject developed anti-FG-3019 antibodies. FG-3019 clearance was lower at 10 mg/kg than at 3 mg/kg, suggesting a saturable elimination pathway. Although this study was not designed for efficacy testing, it was notable that urinary albumin/creatinine ratio (ACR) decreased significantly from mean pretreatment ACR of 48 mg/g to mean post-treatment (day 56) ACR of 20 mg/g (P = 0.027) without evidence for a dose-response relationship. CONCLUSIONS: Treatment of microalbuminuric DKD subjects using FG-3019 was well tolerated and associated with a decrease in albuminuria. The data demonstrate a saturable pathway for drug elimination, minimal infusion adverse events, and no significant drug-attributable adverse effects over the year of follow-up. Changes in albuminuria were promising but require validation in a prospective, randomized, blinded study.

Safety profile and metabolic effects of 14 days of treatment with DIO-902: results of a phase IIa multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in patients with type 2 diabetes mellitus.

BACKGROUND: Elevated levels of cortisol have been implicated in the development of type 2 diabetes mellitus and the metabolic syndrome. Modulation of cortisol levels and activity may be useful in the treatment of type 2 diabetes and its comorbidities. OBJECTIVE: The purpose of this study was to evaluate the safety profile and pharmacodynamic effects of DIO-902 (2S,4R-ketoconazole), an inhibitor of cortisol synthesis. METHODS: Subjects with type 2 diabetes who were between the ages of 18 and 70 years and were drug naive or receiving metformin at a stable dose were randomized to receive one of the following once daily at bedtime for 14 days: ketoconazole 400 mg; DIO-902 200, 400, or 600 mg; or placebo. Tolerability was assessed based on adverse events reported by subjects and the results of physical examinations and standard hematology, chemistry, and urinalysis tests performed on days 8 and 15. Glycosylated hemoglobin (HbA1c) and levels of fructosamine, fasting glucose, lipoproteins, and C-reactive protein were measured at baseline and the end of treatment. The Jonckheere-Terpstra test was used to test for an ordinal dose-response trend between the DIO-902 doses and placebo. Morning (7:30 am) salivary cortisol levels were measured and overnight plasma cortisol levels were analyzed as a 12-hour AUC at baseline and the end of treatment. Adrenocorticotropic hormone (ACTH) levels were measured and an ACTH stimulation test was used to assess adrenal reserve at baseline and the end of treatment. RESULTS: The study enrolled 21 women (58.3%) and 15 (41.7%) men. Their mean (SD) age was 55.4 (8.5) years; mean HbA1c, 8.1% (1.3%); and mean duration of diabetes, 4.8 (3.7) years. White subjects were in the majority (86.1%), with black subjects constituting 11.1% of the population and those of other racial backgrounds constituting 2.8%; 47.2% of subjects were of Hispanic ethnicity. The proportions of subjects experiencing any adverse event were 62.5% in the ketoconazole group; 60.0%, 83.3%, and 100% in the DIO-902 200-, 400-, and 600-mg groups, respectively; and 50.0% in the placebo group. Gastrointestinal disorders were the most common adverse event, reported in 12.5% of the ketoconazole group, 35.0% of the combined DIO-902 treatment group, and 16.7% of the placebo group. Headache, the second most commonly reported adverse event, was reported in 12.5% of the ketoconazole group, 30.0% of the overall DIO-902 group, and none of the placebo group. DIO-902 treatment was not associated with any significant differences in measures of glycemic control relative to placebo or any significant decreases in mean morning salivary cortisol levels or mean overnight cortisol exposure. Dose-dependent reductions from baseline were seen in mean levels of low-density lipoprotein cholesterol (mean percent reductions: -11.39, -23.38, and -42.10 with DIO-902 200, 400, and 600 mg, respectively; P<0.001), as well as in total cholesterol (P<0.001) and high-density lipoprotein cholesterol (P=0.034). Mean levels of C-reactive protein were significantly reduced relative to placebo at all doses of DIO-902 (P=0.027); no reductions in either of these parameters were seen in the placebo group. CONCLUSION: In this small, short-term study in subjects with type 2 diabetes, DIO-902 was generally well tolerated, although it was associated with an increased incidence of gastrointestinal disorders and headache. Levels of low-density lipoprotein cholesterol were significantly decreased in subjects treated with DIO-902.

Frecuencia de las malformaciones congénitas en las autopsias del Hospital Nacional de Niños (1974-1981) / Congenital malformations frequency evaluated by autopsy at the National Children's Hospital (1974-1981)

Se revisaron 1272 protocolos de autopsia del Hospital Nacional de Niños de San José de Costa Rica, entre los años de 1974 a 1981 inclusive, encontrándose 464 casos de malformaciones congénitas. Las cardiopatías congénitas forman el grupo más frecuente de malformaciones; el segundo grupo moderadamente frecuente fue el constituido por malformaciones múltiples y del aparato digestivo. Las del sistema nervioso, aparatos genito-urinario y respiratorio fueron poco frecuentes y la del aparato locomotor y endocrino fueron escasas. Se enuncian las 11 cardiopatías más frecuentes y las malformaciones con las cuales se asocian. Se clasifican las malformaciones múltiples por síndromes y por aparatos y sistemas. Enfatizamos sobre las anomalías agregadas al síndrome de Down. Se clasifican las malformaciones del aparato digestivo, detallando las atresias y sus asociaciones. Se hace lo mismo con las anomalías más frecuentes de los otros sistemas. Se resumem las diez lesiones letales más frecuentes y se dividen en aisladas, asociadas a otras malformaciones o formando parte de un cuadro de malformaciones múltiples. Es de importancia en este trabajo el haber determinado la mayor o menor frecuencia de cada una de las malformaciones y el porcentaje de asociación a otras lesiones congénitas y otros. Los datos pueden servir de base para orientar el estudio clínico de pacientes con este grupo de enfermedades. Se hace una comparación de tres trabajos de autores nacionales, uno de ellos sobre morbi-mortalidadd perinatal y los otros dos sobre mortalidad. Las coincidencias con notables...