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BACKGROUND & AIMS: Fatigue has high negative impact on many patients with primary biliary cholangitis (PBC) and treatment options are limited. Recently we showed favorable effects of four weeks of high-dose thiamine treatment on fatigue in patients with inflammatory bowel disease. We aimed to investigate the effect and safety of high-dose (600-1800 mg daily) oral thiamine treatment on chronic fatigue in patients with PBC. METHODS: Randomized, double-blinded, placebo-controlled crossover trial including patients with severe PBC-related fatigue. Participants were allocated 1:1 to either group 1) 4 weeks of high-dose thiamine, 4 weeks of washout, and 4 weeks of placebo; or group 2) 4 weeks of placebo, washout, and high-dose thiamine, respectively. Fatigue severity was quantified using the fatigue subscale of the PBC-40 questionnaire. The primary outcome was a fatigue reduction of ≥ 5 points after 4 weeks of high-dose thiamine treatment. RESULTS: We enrolled 36 patients; 34 completed the study. The overall mean reduction in fatigue was 5.0 points (95% CI: 2.5 to 7.5; p < 0.001) for the combined group 1 and group 2. Crossover analysis showed a mean increase in fatigue of 0.3 points (95% CI: -4.2 to 3.8) after high-dose thiamine treatment compared to a 1.4 points (95% CI: 6.2 to -3.4) mean reduction after placebo (p = 0.55). Only mild and transient adverse events were recorded. CONCLUSION: Four weeks of high-dose oral thiamine treatment in patients with PBC was well tolerated and safe. However, high-dose thiamine was not superior to placebo in reducing PBC-related fatigue. TRIAL REGISTRATION: The trial was registered in the ClinicalTrials.gov (NCT04893993) and EudraCT (2020-004935-26).
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Síndrome de Fatiga Crónica , Cirrosis Hepática Biliar , Tiamina , Humanos , Método Doble Ciego , Tiamina/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: We previously demonstrated that people with primary sclerosing cholangitis (PSC) had reduced gut microbial capacity to produce active vitamin B6 (pyridoxal 5'-phosphate [PLP]), which corresponded to lower circulating PLP levels and poor outcomes. Here, we define the extent and biochemical and clinical impact of vitamin B6 deficiency in people with PSC from several centers before and after liver transplantation (LT). METHODS: We used targeted liquid chromatography-tandem mass spectrometry to measure B6 vitamers and B6-related metabolic changes in blood from geographically distinct cross-sectional cohorts totaling 373 people with PSC and 100 healthy controls to expand on our earlier findings. Furthermore, we included a longitudinal PSC cohort (n = 158) sampled prior to and serially after LT, and cohorts of people with inflammatory bowel disease (IBD) without PSC (n = 51) or with primary biliary cholangitis (PBC) (n = 100), as disease controls. We used Cox regression to measure the added value of PLP to predict outcomes before and after LT. RESULTS: In different cohorts, 17-38% of people with PSC had PLP levels below the biochemical definition of a vitamin B6 deficiency. The deficiency was more pronounced in PSC than in IBD without PSC and PBC. Reduced PLP was associated with dysregulation of PLP-dependent pathways. The low B6 status largely persisted after LT. Low PLP independently predicted reduced LT-free survival in both non-transplanted people with PSC and in transplant recipients with recurrent disease. CONCLUSIONS: Low vitamin B6 status with associated metabolic dysregulation is a persistent feature of PSC. PLP was a strong prognostic biomarker for LT-free survival both in PSC and recurrent disease. Our findings suggest that vitamin B6 deficiency modifies the disease and provides a rationale for assessing B6 status and testing supplementation. IMPACT AND IMPLICATIONS: We previously found that people with PSC had reduced gut microbial potential to produce essential nutrients. Across several cohorts, we find that the majority of people with PSC are either vitamin B6 deficient or have a marginal deficiency, which remains prevalent even after liver transplantation. Low vitamin B6 levels strongly associate with reduced liver transplantation-free survival as well as deficits in biochemical pathways dependent on vitamin B6, suggesting that the deficiency has a clinical impact on the disease. The results provide a rationale for measuring vitamin B6 and to investigate whether vitamin B6 supplementation or modification of the gut microbial community can help improve outcomes for people with PSC.
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Colangitis Esclerosante , Enfermedades Inflamatorias del Intestino , Deficiencia de Vitamina B 6 , Humanos , Deficiencia de Vitamina B 6/complicaciones , Colangitis Esclerosante/complicaciones , Colangitis Esclerosante/cirugía , Estudios Transversales , Vitamina B 6 , Enfermedades Inflamatorias del Intestino/complicaciones , HígadoRESUMEN
Peptide receptor radionuclide therapy (PRRT) is a treatment for neuroendocrine tumours (NET). Renal impairment is a known side effect due to kidney fibrosis. We investigated the association between novel specific fibrosis markers and kidney function following PRRT. We included 38 patients who had all finished PRRT. In serum and urine, we analysed levels of three different fibrosis markers, PRO-C6 (type VI collagen formation), PRO-C3 (type III collagen formation) and C3M (type III collagen degradation). We determined kidney function by the 51Cr-EDTA plasma clearance. We used Wilcoxon rank sum test and Spearman's rank correlation to evaluate the association between the fibrosis markers and kidney function. We included 38 NET patients, 25 small-intestinal NET, 6 pancreatic NET, 2 pulmonary NET and 5 other types of NET. Median age was 69 years (IQR: 61-73). Median time from last PRRT to inclusion was 8 months (IQR: 3-20). We found significantly increased levels of serum PRO-C6 (p = .007) and urinary PRO-C6 (p = .033) and significantly decreased levels of urinary C3M (p = .035) in patients with impaired kidney function. Further, we observed a negative association between serum PRO-C6 and kidney function (rho = -0.33, p = .04) and a positive association between urinary C3M and kidney function (rho = 0.37, p = .02). We showed an association between the three fibrosis markers, serum PRO-C6, urinary PRO-C6 and urinary C3M and kidney function. These markers may help to improve the understanding of potential pathological tissue turnover and potentially improve monitoring of kidney function after PRRT in NET patients.
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Tumores Neuroendocrinos , Anciano , Biomarcadores , Colágeno Tipo III , Colágeno Tipo VI , Complemento C3 , Ácido Edético , Fibrosis , Humanos , Riñón/metabolismo , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/radioterapia , Radioisótopos , Receptores de Péptidos/metabolismoRESUMEN
Background: Biologically based complementary medicines (BB-CMs) are popular in patients with cancer. However, there are only limited data for BB-CMs in patients with neuroendocrine tumors (NET). We aimed to identify the prevalence and type of BB-CM use and the association to the nutritional risk score (NRS-2002) in NET patients. Methods: We performed a cross-sectional questionnaire study in NET outpatients at the Department of Hepatology and Gastroenterology at Aarhus University Hospital. The nutritional risk was determined by the NRS-2002. Results: We included 186 patients (51% women, median age 66 years). Sixty-six percent were regular BB-CM users. Forty-two percent used at least two supplements. The most popular BB-CMs were vitamin and mineral supplements (47%), calcium and vitamin D (34%). One-third used non-vitamin non-mineral supplements such as fish oil, herbs, Ginger, Q-10, garlic and probiotics. The use of BB-CMs was associated with female gender (48% vs. 37%, p < .05). Intake was significantly more frequent among patients with an NRS score ≥ 3, (60% vs. 76%) and in patients with change in performance status (58% vs. 76%), (p < .05, all). Patients reporting dietary changes used BB-CMs more frequently than patients without dietary changes (61% vs. 77%) (p < .05). Conclusions: In our study, 66% percent of NET patients use BB-CM and 42% used two or more supplements. Vitamins with and without herbal ingredients, minerals, calcium, vitamin D, and fish oil were the most popular supplements. The use of BB-CMs was associated with an NRS score ≥ 3, change in dietary intake, female gender, and change in ECOG performance status.
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Terapias Complementarias , Suplementos Dietéticos , Tumores Neuroendocrinos/tratamiento farmacológico , Evaluación Nutricional , Anciano , Estudios Transversales , Dinamarca , Femenino , Aceites de Pescado/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Minerales/uso terapéutico , Estado Nutricional , Fitoterapia , Encuestas y Cuestionarios , Vitamina D/uso terapéuticoRESUMEN
BACKGROUND AND AIMS: In 2009, the Danish Government instituted "Fast Track Clinical Pathways" (FTCP) to accelerate diagnosis and treatment of cancers including hepatocellular carcinoma (HCC). We examined how the implementation of FTCP affected the time from referral to diagnosis and treatment as well as the patient survival. METHODS: 309 consecutive patients with suspected HCC were included, 79 referred during the period 2007-2008 (before FTCP) and 230 during 2009-2011. Of those, 271 (88%) were diagnosed with HCC and 161 (60%) had cirrhosis, in most cases caused by alcohol. RESULTS: The time from referral to the first visit was reduced from a mean 16.4 (11.5) to 5.4 (6) days (p<0.001) and the time from the first visit to the Multidisciplinary Tumour Conference (MDT) treatment decision from 34.9 (27.9) to 16.1 (14.4) days (p<0.001). The total time from referral to treatment was reduced from 53.2 (37.9) to 35.9 (23.1) days (p<0.001). There was a weak trend of improved survival after FTCP: 231 (147-368) vs. 293 (227-396) days (p=0.11). CONCLUSIONS: The implementation of FTCP reduced the total time from referral to treatment by three weeks; however, without significant effects on overall mortality. While shortened waiting time is a comfort for the patient, it remains to be elucidated whether it will change the prognosis.
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Carcinoma Hepatocelular/terapia , Vías Clínicas/organización & administración , Prestación Integrada de Atención de Salud/organización & administración , Detección Precoz del Cáncer/métodos , Neoplasias Hepáticas/terapia , Derivación y Consulta/organización & administración , Tiempo de Tratamiento/organización & administración , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidad , Toma de Decisiones Clínicas , Dinamarca , Eficiencia Organizacional , Femenino , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Evaluación de Programas y Proyectos de Salud , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Listas de Espera , Adulto JovenRESUMEN
Non-alcoholic fatty liver disease and especially non-alcoholic steatohepatitis (NASH) and fibrosis are associated with severe liver disease and increased cardiovascular risk. It is therefore important to identify patients with NASH fibrosis. Therapeutical options include life style intervention and pharmacological treatment with vitamin E and pioglitazone; however, evidence of effect is scarce for all options. New treatments are under investigation and include glucagon-like peptide-1, farnesoid receptor as well as peroxisome proliferator-activated receptor-α/δ agonists. Bariatric surgery may be an option in selected patients.
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Enfermedad del Hígado Graso no Alcohólico , Cirugía Bariátrica , Chalconas/uso terapéutico , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapéutico , Vías Clínicas , Humanos , Hipoglucemiantes/uso terapéutico , Estilo de Vida , Liraglutida/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/cirugía , Pioglitazona/uso terapéutico , Propionatos/uso terapéutico , Medición de Riesgo/métodos , Vitamina E/uso terapéuticoRESUMEN
BACKGROUND: Goblet cell carcinoma (GCC) of the appendix is a rare disease. Treatment options vary according to disease staging. Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) may improve survival in patients with peritoneal spreading. OBJECTIVE: The aim of this study was to examine the prognosis of patients with appendiceal GCC treated per protocol, and to evaluate the results of CRS+HIPEC in cases of peritoneal spreading. METHODS: From 2009 to 2016, a total of 48 GCC patients were referred to the European Neuroendocrine Tumour Center of Excellence, Aarhus University Hospital. All patients received treatment per protocol according to disease staging. In patients with localized disease, the treatment was a right hemicolectomy. Patients with peritoneal spread who met the inclusion criteria for CRS + HIPEC, as well as patients with high-risk features of developing peritoneal spread, received CRS + HIPEC. If too-extensive disease was found, palliative chemotherapy was offered. RESULTS: Overall survival for patients with localized disease (n = 6) or deemed at risk of peritoneal spread (n = 8) was 100% after a median follow-up of 3.5 years. In patients with peritoneal spread and eligible for CRS+HIPEC(n = 27), the median survival was 3.2 years [95% confidence interval (CI) 2.3-4.1] and the 5-year survival rate was 57%. In contrast, the median survival for patients with too-extensive intraperitoneal disease (n = 7) was 1.3 years (95% CI 0.6-2.0), with a 3-year survival rate of 20%. CONCLUSIONS: Long-term survival can be achieved in patients with peritoneal spread treated with CRS + HIPEC. CRS+HIPEC was associated with a favorable outcome in GCC patients at high-risk of developing peritoneal spread.
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Adenocarcinoma/terapia , Neoplasias del Apéndice/terapia , Procedimientos Quirúrgicos de Citorreducción/mortalidad , Células Caliciformes/patología , Hipertermia Inducida/mortalidad , Recurrencia Local de Neoplasia/terapia , Neoplasias Peritoneales/terapia , Adenocarcinoma/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Apéndice/patología , Quimioterapia Adyuvante , Quimioterapia del Cáncer por Perfusión Regional , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Neoplasias Peritoneales/patología , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Advanced HCC is a clinical challenge with limited treatment options. The multikinase inhibitor sorafenib is the first and only agent showing a survival benefit in these patients. In this study we evaluate the efficacy and tolerability of sorafenib in an unselected patient population. Furthermore we explore the role of alpha-fetoprotein (αFP) as a potential biomarker for treatment efficacy and correlation to survival. METHODS: Seventy-six patients with advanced HCC, not eligible for locoregional therapy, treated with sorafenib between 2007 and 2009 were included. Followup was until 2011. RESULTS: Patients in PS 0-1 had a median overall survival (mOS) of 6.2 months, compared to 1.8 months in patients with poorer PS (P = 0.005). Child-Pugh A patients had a mOS of 6.6 months versus 3.6 months among patients in Child-Pugh B or C (P = 0.0001). Serum αFP ≥ 200 at baseline was prognostic for a shorter survival. All patients with radiologically verified tumor response and baseline αFP ≥ 200 experienced a significant decline in αFP within the first four weeks of treatment. CONCLUSION: The survival of patients with advanced HCC treated with sorafenib is dependent on performance status and liver function. Treatment of patients with compromised liver function and poor performance status cannot be recommended. The correlation between αFP and objective tumor response warrants further investigation.
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Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Anciano , Antineoplásicos/efectos adversos , Biomarcadores/sangre , Carcinoma Hepatocelular/mortalidad , Femenino , Humanos , Hipertensión/inducido químicamente , Hígado/efectos de los fármacos , Hígado/fisiopatología , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Pronóstico , Estudios Retrospectivos , Sorafenib , Resultado del Tratamiento , alfa-Fetoproteínas/análisisRESUMEN
National guidelines for treatment of ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, and hyponatremia have been approved by the Danish Society of Gastroenterology and Hepatology. Ascites develops in approximately 60% of patients with cirrhosis during a 10 year period and is frequently associated with complications that determine the course of the disease and the prognosis. These evidence-based guidelines are divided in two parts and consider definitions, pathophysiology, diagnostic aspects, treatment, and prophylaxis.
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Antibacterianos/uso terapéutico , Ascitis , Diuréticos/uso terapéutico , Cirrosis Hepática/complicaciones , Paracentesis/métodos , Peritonitis , Ascitis/diagnóstico , Ascitis/etiología , Ascitis/metabolismo , Ascitis/fisiopatología , Ascitis/terapia , Líquido Ascítico/metabolismo , Líquido Ascítico/microbiología , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/microbiología , Infecciones Bacterianas/fisiopatología , Infecciones Bacterianas/terapia , Protocolos Clínicos/normas , Terapia Combinada , Medicina Basada en la Evidencia/normas , Humanos , Cirrosis Hepática/fisiopatología , Pruebas de Sensibilidad Microbiana , Peritonitis/diagnóstico , Peritonitis/microbiología , Peritonitis/fisiopatología , Peritonitis/terapia , Supuración/complicaciones , Supuración/fisiopatologíaRESUMEN
INTRODUCTION: Knowledge of the importance of diet on gastrointestinal function and symptoms is generally poorly. In recent years, The New Nordic Food Culture is suggested to have favourable effects. Unfortunally there are huge waiting lists at the most popular restaurants, so we investigated the more traditional "Nordic kitchen". There are no previous studies concerning intake of fried bacon and parsley sauce (FBPS) in healthy middle-aged footballers. MATERIAL AND METHODS: Non-blinded, non-randomized, crossover study with a questionnaire survey of 18 healthy old boys footballers before and after FBPS intake. Ten players responded to the questionnaire, including one who was not exposed to FBPS. RESULTS: The median intake was 15 pieces of fried bacon (range 12-23), 1.5 dl parsley sauce (range 1-5 dl), and eight potatoes (range 6-30), but no dessert. We found a significantly increased stool frequency and a trend towards change in consistency compared to baseline. We found increased abdominal pain and a decrease in general well-being, but could not demonstrate any impact on complaints from the family. CONCLUSION: In otherwise healthy old boys footballers the FBPS diet has great impact on a range of gastrointestinal symptoms. FBPS affected stool frequency and abdominal pain, but caused no effect on family complaints. We cannot exclude a dose-response effect or a gender/age phenomenon; and we suggest supplemental dose-response studies and studies including women of all ages. Further, we recommend a detailed dietary assessment before referring patients with gastrointestinal symptoms for invasive procedures like colonoscopy or CT-scanning. TRIAL REGISTRATION: none FUNDING: none.
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Dolor Abdominal/etiología , Dieta/efectos adversos , Heces , Enfermedades Gastrointestinales/etiología , Adulto , Estudios Cruzados , Familia , Humanos , Masculino , Productos de la Carne/efectos adversos , Persona de Mediana Edad , Petroselinum/efectos adversos , Índice de Severidad de la Enfermedad , Fútbol , Solanum tuberosum/efectos adversos , Encuestas y CuestionariosRESUMEN
BACKGROUND: Patients with Crohn's disease (CD) often develop malnutrition due to disease activity. We aimed to assess the effect of two different enteral supplements of Impact(R) Powder (IP; Novartis, Switzerland) on leptin levels and nutritional status in active CD patients during prednisolone treatment and tapering. METHODS: Thirty-one CD patients were randomized to IP Extra (group 1) or IP Standard (group 2). Leptin levels, nutritional, clinical and biochemical markers were studied at inclusion, after 5 and after 9 weeks of the study. RESULTS: Leptin levels, body mass index (BMI) and total cholesterol increased significantly within both groups at week 5 compared to inclusion. Leptin levels correlated with BMI in both groups at inclusion and in group 2 at week 9. In group 1, triglyceride levels remained unchanged, while levels in group 2 increased significantly at week 5 compared to inclusion. Clinical and biochemical markers improved during the study compared to inclusion. CONCLUSIONS: Increased leptin levels during the study progress were transient, decreasing due to prednisolone withdrawal at the end of the study. Both formulas used as adjuvant therapy to prednisolone treatment were able to improve nutritional status in CD patients.
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Arginina/administración & dosificación , Enfermedad de Crohn/terapia , Suplementos Dietéticos , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-6/administración & dosificación , Glucocorticoides/uso terapéutico , Leptina/sangre , Estado Nutricional , Prednisolona/uso terapéutico , ARN/administración & dosificación , Adolescente , Adulto , Anciano , Índice de Masa Corporal , Enfermedad de Crohn/sangre , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: Catabolism and growth impairment are well-known complications of inflammatory bowel disease (IBD). This may be caused by the disease activity itself and/or the medical treatment, and both may lead to changes in the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis. The aim of the present study was to examine the effects of enteral nutrition, Impact Powder, as adjuvant therapy to corticosteroid treatment on changes in the GH/IGF-I axis in patients with Crohn's disease (CD). MATERIAL AND METHODS: The patients were randomized to 3-IP (omega-3-fatty acid (FA), 3 g/day) or 6-IP (omega-6-FA, 9 g/day). Changes in total IGF-I (tIGF-I) and total IGF-II (tIGF-II), free IGF-I (fIGF-I), IGF binding proteins (IGFBP-1 and IGFBP-3), IGFBP-3 protease activity and insulin levels were examined in 31 patients with active CD (CDAI: 186-603) during treatment with prednisolone (40 mg for 1 week) and tapering the dose by 5 mg/week. Clinical and biochemical markers of inflammation were studied at day 0, and after 5 and 9 weeks. RESULTS: There were no differences at baseline between the two groups. During the treatment period, tIGF-I, fIGF-I and IGFBP-3 increased significantly in both groups compared to baseline (p<0.05) without differences between the groups. Insulin and IGFBP-1 showed no significant changes throughout the treatment period. CONCLUSIONS: There was no difference between 3-IP and 6-IP as adjuvant enteral nutrition on the GH/IGF-I axis. The changes observed in the GH/IGF-I axis are in line with previously published studies and may be explained by corticosteroid treatment; however, we cannot exclude an additional effect of omega3-/omega6 FA as adjuvant enteral nutrition.
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Corticoesteroides/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Ácidos Grasos Omega-3/uso terapéutico , Ácidos Grasos Omega-6/uso terapéutico , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/efectos de los fármacos , Somatomedinas/efectos de los fármacos , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Índice de Masa Corporal , Proteína C-Reactiva/metabolismo , Enfermedad de Crohn/sangre , Endopeptidasas/sangre , Endopeptidasas/efectos de los fármacos , Femenino , Humanos , Inmunoensayo , Insulina/sangre , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/clasificación , Masculino , Persona de Mediana Edad , Prednisolona/uso terapéutico , Somatomedinas/clasificación , Somatomedinas/metabolismo , Resultado del TratamientoRESUMEN
The objective of this study was to compare the effect of an angiotensin-converting enzyme (ACE) inhibitor and a calcium channel blocker on the development of renal changes in diabetic rats. Diabetes was induced by an intravenous injection of streptozotocin in normotensive Wistar rats. Treatment was commenced immediately in 1 set of rats with 4 treatment arms: nitrendipine (250 mg/kg fodder), enalapril (35 mg/L drinking water), both treatments in combination, or placebo. Treatment was continued for 9 weeks. Another set of rats was left with untreated diabetes for 3 months followed by 7 weeks treatment as above. When starting treatment right after induction of diabetes, nitrendipine significantly reduced urinary albumin excretion (UAE) to the nondiabetic level (P < .05) without reducing blood pressure (BP), whereas enalapril failed to significantly reduce UAE despite a reduction in BP. Combining the two treatments showed no further reduction in UAE compared to monotherapy with nitrendipine, despite a lower BP. When leaving diabetic rats untreated for 3 months, only the coadministration of nitrendipine and enalapril showed a significant reduction in UAE compared to monotherapy and placebo treatment, but showed no significant effect on BP.