Effect of addition of silymarin to renin-angiotensin system inhibitors on proteinuria in type 2 diabetic patients with overt nephropathy: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: A large proportion of patients with type 2 diabetes mellitus have diabetic nephropathy. Despite current therapies including renin-angiotensin system inhibitors, diabetic nephropathy progresses to end-stage renal disease in most of these patients. Therefore, there is an urgent need to find new treatments for such patients. The aim of this study was to evaluate the efficacy of silymarin, an herbal drug with antioxidant and anti-inflammatory properties, in preventing the progression of diabetic nephropathy. STUDY DESIGN: Randomized, double-blind, placebo-controlled, 2-arm parallel trial. SETTING & PARTICIPANTS: 60 patients with type 2 diabetes with macroalbuminuria (urinary albumin excretion >300 mg/24 h) despite treatment with the maximum dose of a renin-angiotensin system inhibitor for more than 6 months and estimated glomerular filtration rate >30 mL/min/1.73 m(2). INTERVENTION: Patients were randomly assigned to 2 equal groups to receive three 140-mg tablets of silymarin or 3 tablets of placebo daily for 3 months. OUTCOMES: The primary outcome was absolute change in urinary albumin-creatinine ratio (UACR) from baseline to the end of the treatment phase. MEASUREMENTS: UACR and urinary and serum levels of TNF-α (tumor necrosis factor α; an inflammatory marker), malondialdehyde (MDA; an oxidative stress marker), and TGFß (transforming growth factor ß; a marker of fibrosis) at baseline and the end of the treatment phase. RESULTS: Although UACR decreased in both groups, this decrement was significantly higher in the silymarin compared with the placebo group; mean difference in change in UACR between the 2 groups was -347 (95% CI, -690 to -4) mg/g. Urinary levels of TNF-α and urinary and serum levels of MDA also decreased significantly in the silymarin compared with the placebo group. LIMITATIONS: Small sample size and short duration of the treatment phase. CONCLUSIONS: Silymarin reduces urinary excretion of albumin, TNF-α, and MDA in patients with diabetic nephropathy and may be considered as a novel addition to the anti-diabetic nephropathy armamentarium.

Comparative effects of silymarin and vitamin E supplementation on oxidative stress markers, and hemoglobin levels among patients on hemodialysis.

BACKGROUND: The incidence of accelerated atherosclerosis among patients on hemodialysis is very high and oxidative stress (OS) is a potentially major contributor to their morbidity and mortality. OBJECTIVE: To evaluate the effects of Silymarin and/or vitamin E on OS markers and hemoglobin levels in patients on hemodialysis. METHODS: Eighty patients on hemodialysis were randomized into four groups: Group 1 received silymarin 140 mg 3 times daily; Group 2 received vitamin E 400 IU/day; Group 3 received silymarin 140 mg 3 times daily and vitamin E 400 IU/day; and Group 4 was the control. Samples were obtained at baseline and on day 21 for measurement of malondialdehyde (MDA), red blood cell (RBC) glutathione peroxidase (GPX), and hemoglobin. RESULTS: Combination of silymarin and vitamin E led to a reduction in the MDA levels (7.84 ± 1.84 vs. 9.20 ± 2.74 nmol/mL; p = 0.008). There was a significant increase in RBC GPX levels in all treatment groups compared with controls after 3 weeks. This was more pronounced in the group receiving combination compared with the group receiving vitamin E or the control group (5.78 ± 3.51, 4.22 ± 1.63, and 3.16 ± 1.89 IU/grHb, respectively; p < 0.001). There was also a significant increase in mean hemoglobin of all treatment groups compared with the control. CONCLUSIONS: Oral supplementation with silymarin and vitamin E leads to reduction in MDA, increase in RBC GPX, and increase in hemoglobin levels in patients with end-stage renal disease. Studies with larger sample sizes and longer follow-up are required to investigate the effect of silymarin on cardiovascular outcomes and erythropoietin requirement.

Effect of oral cromolyn sodium on CKD-associated pruritus and serum tryptase level: a double-blind placebo-controlled study.

BACKGROUND: Generalized pruritus is a significant complication in end-stage renal disease patients. The mechanism is unknown and most treatments are ineffective. This study is the first clinical trial designed to evaluate the effect of cromolyn sodium (CS) on renal itch. METHODS: Sixty-two haemodialysis (HD) patients with pruritus were enrolled into the study and were randomly assigned to receive CS or placebo (135 mg three times daily) for 8 weeks. Patients were asked to record the severity of their pruritus on each dialysis session on a visual analogue scale (VAS) during the 8 weeks of treatment and 4 weeks following discontinuation of treatment. Serum tryptase levels were determined at baseline, after 8 weeks of treatment and 4 weeks after discontinuation of treatment. RESULTS: Data were analysed in 21 patients in the CS group and 19 patients in the placebo group that completed the study. A significant difference was seen in the severity of pruritus between the two groups during the period of study. Level of pruritus decreased from 8.48 +/- 2.2 to 0.9 +/- 1.8 after 8 weeks of treatment with CS. Geometric mean of serum tryptase at baseline and 8 weeks after treatment were 21.3 and 19.5 ng/ml for the CS group and 18.03 and 18.2 ng/ml for the placebo group, respectively. Although the geometric mean of tryptase had decreased in the CS group, this decrease was not statistically significant (P = 0.214). CONCLUSION: CS can significantly reduce the severity of pruritus in HD patients, but this effect is not due to a decrease in serum tryptase level.

Detection of prescription errors by a unit-based clinical pharmacist in a nephrology ward.

OBJECTIVE: To determine the impact of a clinical pharmacist on detection and prevention of prescription errors at the nephrology ward of a referral hospital. SETTING: Nephrology ward of a major referral hospital in Southern Iran. METHOD: During a 4-month period, a clinical pharmacist was assigned to review medication order sheets and drug orders three times a week at the nephrology ward. Besides chart review, the clinical pharmacist participated in medical rounds once a week. The occurrence of prescribing errors, and related harm was determined on hospitalized patients in this ward during the 4 month period. When an error was detected, intervention was made after agreement of the attending physician. MAIN OUTCOME MEASURES: Number and types of prescribing errors, level of harm, and number of interventions were determined. RESULTS: Seventy six patient charts were reviewed during the 4-month period. A total of 818 medications were ordered in these patients. Eighty six prescribing errors were detected in 46 hospital admissions. The mean age of the patients was 47.7 +/- 17.2. Fifty five percent were male while 45% were female. Different types of prescribing errors and their frequencies were as follows: wrong frequency (37.2%), wrong drug selection (19.8%), overdose (12.8%), failure to discontinue (10.5%), failure to order (7 %), under- dose (3.5%), wrong time (3.5%), monitoring (3.5%), wrong route (1.2%), and drug interaction (1.2 %). The attending physician agreed to 96.5% of the prescription errors detected, and interventions were made. Although 89.5% of the detected errors caused no harm, 4(4.7%) of the errors increased the need for monitoring, 2 (2.3%) increased length of stay, and 2 (2.3%) led to permanent patient harm. CONCLUSION: presence of a clinical pharmacist at the nephrology ward helps in early detection of prescription errors, and therefore potential prevention of negative consequences due to drug administration.

Silymarin and milk thistle extract may prevent the progression of diabetic nephropathy in streptozotocin-induced diabetic rats.

OBJECTIVES: To investigate the effect of silymarin and milk thistle extract on the progression of diabetic nephropathy (DN) in rats. METHODS: Diabetes was induced with a single intraperitoneal (IP) injection of streptozotocin (STZ) (60 mg/kg). Silymarin (100 mg/kg/d) or the extract (1.2 g/kg/d) was gavaged for 4 weeks. Blood glucose (BS), serum urea (S(u)), serum creatinine (S(cr)), and 24-h urine protein (Up) were measured and glomerular filtration rate (GFR) was calculated. Concentration of thiobarbituric acid reactive species (TBARS) and activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) were evaluated in the renal tissue. RESULTS: Data were expressed as mean +/- SEM. Silymarin or the extract had no significant effect on BS, S(cr), and GFR. Both milk thistle extract and silymarin, respectively, decreased S(u) (mg/dL) (87.1 +/- 7.78, p < 0.001; 84.5 +/- 7.15, p < 0.001), Up (mg) (5.22 +/- 1.56, p = 0.014; 5.67 +/- 0.86, p = 0.034), and tissue TBARS (nmol/mg protein) (0.67 +/- 0.04, p < 0.001; 0.63 +/- 0.07, p < 0.001) in diabetic rats, compared to diabetic control (DC) (S(u): 131.0 +/- 4.55, Up: 8.3 +/- 0.84, TBARS: 0.94 +/- 0.06). Both the extract and silymarin could increase the activity of CAT (IU/mg protein) (25.5 +/- 4.0, p = 0.005; 20 +/- 1.8, p = 0.16) and GPx (IU/mg protein) (0.86 +/- 0.05, p = 0.005; 0.74 +/- 0.04, p = 0.10), respectively, in diabetic rats compared to DC (CAT = 14.4 +/- 2.0, GPx = 0.57 +/- 0.02). CONCLUSION: Milk thistle extract, to a lesser extent silymarin, can attenuate DN in rats possibly by increasing kidney CAT and GPx activity and decreasing lipid peroxidation in renal tissue.

Knowledge, attitudes, and perceptions of pharmacists to adverse drug reaction reporting in Iran.

OBJECTIVE: Adverse Drug Reactions (ADRs) are a major cause of patient morbidity and mortality. Spontaneous reporting of ADRs remains the cornerstone of pharmacovigilance and is important in maintaining patient safety. In order to determine whether our pharmacovigilance system could be improved, and identify reasons for under-reporting, a study to investigate the role of pharmacists in ADR reporting was performed in Shiraz. SETTING: The pharmacies in Shiraz, capital of Fars province in Iran. METHODS: A questionnaire was prepared to investigate knowledge and attitude of pharmacists regarding ADR reporting. The questionnaire was given to 200 pharmacists who participated in a pharmacist association meeting. MAIN OUTCOMES MEASURED: The knowledge of pharmacovigilance practice, reasons for not reporting ADR, and perceptions of the Iranian pharmacists on pharmacovigilance practice were evaluated. RESULTS: The response rate was 55% (n = 110). 29% of the respondents were not aware of the Iranian Pharmacovigilance Center. More than half of those responding felt that ADR reporting should be voluntary, while 26% felt it was a professional obligation. As for the purposes of ADR reporting scheme, 60% of the pharmacists falsely believed that monitoring ADR spontaneous reports aims at measuring the incidence of ADR. 42% of the pharmacists indicated that they have suspected an ADR without reporting it. Doubt about causality was the major reason for not reporting an ADR. Although our ADR center states that all suspected reactions to any drug on the market must be reported, only 17% of the respondents seemed to be aware of this responsibility. CONCLUSION: Our pharmacists have little knowledge regarding the operation, purposes, and usefulness of ADR spontaneous reporting system. However, education and training will be important in maintaining and increasing ADR reports from pharmacists.

Cigarette smoking and incident chronic kidney disease: a systematic review.

BACKGROUND: Several studies have examined the role of cigarette smoking in the development of renal disease in human populations. However, there have been no systematic reviews on the evidence linking smoking with incident renal disease. METHODS: We performed an evidence-based evaluation of peer-reviewed research published during 1966-2005, from a search of five databases, including Ovid MEDLINE and EMBASE. RESULTS: Of the 28 studies that were reviewed, 11 were excluded from the final analysis due to poor methodological quality (n = 6), no reported risk estimate for the association between smoking and kidney disease (n = 3), inability to find a Japanese translator (n = 1), and duplicate cohort (n = 1). Seventeen studies were included in the final analysis; seven studies found an overall significant association between smoking and incident chronic kidney disease, and three studies found a significantly increased risk of chronic kidney disease in current smokers that was gender and/or dose related. An increased risk of developing chronic kidney disease among smokers was significantly associated with male gender (relative risk 2.4, 95% confidence interval 1.2-4.5), >20 cigarettes smoked/day (odds ratio 1.51, 95% confidence interval 1.06-2.15, and relative risk 2.3, 95% confidence interval 1.2-4.3), and smoking >40 years (odds ratio 1.45, 95% confidence interval 1.00-2.09). A pooled estimate of the relative risk (meta-analysis) was deemed inappropriate due to the heterogeneity in methodologies utilized by the different studies. CONCLUSIONS: This comprehensive review reveals overall evidence for current cigarette smoking as a risk factor for incident chronic kidney disease. Further investigation is needed to more carefully examine the strength of the association between cigarette smoking and incident kidney disease.

Low dose zymosan ameliorates both chronic and relapsing experimental autoimmune encephalomyelitis.

Zymosan has previously been reported to have both pro-inflammatory and anti-inflammatory effects. Here we demonstrate that low dose zymosan prevented or reversed chronic and relapsing paralysis in EAE. In suppressing CNS autoimmune inflammation, zymosan not only regulated APC costimulator and MHC class II expression, but also promoted differentiation of regulatory T cells. Following adoptive transfer of zymosan-primed CD4(+) T cells, recipient mice were protected from EAE. In contrast, a MAPK inhibitor and a blocker of ß-glucan, reversed the effects of zymosan. These results demonstrate that zymosan may be a promising beneficial agent for Multiple Sclerosis (MS).

The impact of genetic polymorphisms and patient characteristics on warfarin dose requirements: a cross-sectional study in Iran.

BACKGROUND: Warfarin is the most commonly prescribed oral anticoagulant drug for prophylaxis and treatment of venous and arterial thromboembolic disorders. Its anticoagulant effect is widely variable between patients because of pharmacodynamic, pharmacokinetic, and pharmacogenetic factors. OBJECTIVE: This study was conducted to identify the associations between demographic characteristics, warfarin maintenance dose, and genetic polymorphisms of cytochrome P450 (CYP) 2C19, CYP2C9, and vitamin K epoxide reductase complex subunit 1 (VKORC1). METHODS: This study was conducted from April 2005 to April 2008 at 3 warfarin clinics affiliated with Shiraz University of Medical Sciences. Blood samples were collected from patients with stable warfarin maintenance dose and a stable target international normalized ratio of 2 to 3. Patients who had a condition (including use of an interacting medication) affecting the metabolism of warfarin were excluded. CYP2C9, CYP2C19, and VKORC1 genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. The associations between demographic characteristics (eg, age, sex, body surface area, weight, height), genetic factors, and maintenance warfarin dose were examined by multiple linear regression. The probability of F as a criterion for removal of a variable from the multiple linear regression was set at 0.1. RESULTS: One hundred patients were enrolled in the study; complete data were available for 55, who were included in the regression analysis. Among this smaller group, the mean (SD) age was 53 (11) years (range, 25-80 years) and mean weight was 72 (15) kg (range, 42-125 kg); the mean warfarin dose was 27.2 (13.4) mg/week. The allelic frequencies of CYP2C9*2 and CYP2C9*3 were 27% and 9%, respectively. The allelic frequencies of CYP2C19*2 and CYP2C19*3 were 11% and 1%, respectively. Fifteen percent of our patients carried a VKORC1 genotype GG, whereas the AA and GA genotypes were seen in 18% and 58% of patients, respectively. Multiple linear regression analysis found that sex (P = 0.045), height (P = 0.024), age (P = 0.081), and VKORC1 (P = 0.004) and CYP2C9 (P = 0.011) polymorphism had significant influence on the maintenance dose of warfarin. They were associated with 41.3% of the variability in warfarin maintenance dose requirement. VKORC1 polymorphism (partial R(2) = 20.3%) and height (partial R(2) = 20.3%) had the greatest effects on warfarin maintenance dose requirement. CONCLUSION: Among the demographic and genetic factors evaluated in these Iranian patients, sex, height, age, CYP2C9, and VKORC1 had significant effects on warfarin maintenance dose requirements.

Early steroid withdrawal in solitary pancreas transplantation results in equivalent graft and patient survival compared with maintenance steroid therapy.

Although steroid withdrawal in simultaneous kidney pancreas transplantation has been shown to be feasible, the results of early steroid withdrawal in immunologically solitary pancreas transplantation are not well known. This study evaluated an early steroid withdrawal protocol in this group. The results of steroid withdrawal at 21 d post-transplant in solitary pancreas transplant recipients was compared with a control group consisting of solitary pancreas transplant recipients maintained on steroids (MG). Additional immunosuppression consisted of rabbit anti-thymocyte globulin induction followed by tacrolimus and mycophenolate mofetil in both groups. The withdrawal group (WG, n = 22) consisted of 11 pancreas transplant alone (PTA), six pancreas after kidney (PAK), and five simultaneous cadaveric pancreas living kidney (SPLK) recipients. The steroid maintenance group (MG, n = 32) consisted of 8 PTA, 11 PAK, and 13 SPLK recipients. Recipient and donor demographic characteristics were similar. Seventy eight percent of MG patients had infection-related complications in the first year compared with 50% of the WG patients (p = 0.04). The one-yr rejection, pancreas graft, and patient survival rates were 27.3% 95.5%, and 100% in the WG, and 37.5%, 81.3%, and 93.8% in the MG respectively and not significantly different. We conclude that early corticosteroid withdrawal in isolated pancreas transplantation results in fewer infections and can be achieved without an increased risk of rejection or graft loss over the first year.

Urinary cotinine as an objective measure of cigarette smoking in chronic kidney disease.

BACKGROUND: Smoking is a modifiable behaviour that may hasten the progression of chronic kidney disease (CKD). Cotinine, a nicotine metabolite, is measurable in body fluids, including urine, and can be utilized as an objective measure of smoking exposure. Its use has not been examined in the CKD population. METHODS: In this cross-sectional study, we evaluated use of 24-h urinary cotinine excretion (Ucot) as a quantitative index of smoking exposure in a CKD population. Methods of comparison included self-report and expired air carbon monoxide (eCO) as standard measures of smoking exposure. Assessments of kidney function included estimated glomerular filtration rate (eGFR) and 24-h urinary protein (Uprot) excretion. RESULTS: Sixty-one patients were enrolled, of whom 12 were excluded for incomplete urine collections. Of the remaining, 77% were active current smokers (mean cigarettes smoked: 12+/-7 per day). The mean eGFR was 47+/-25 ml/min/1.73 m2 with no significant differences among non-smokers. The mean eCO and Ucot were significantly higher in smokers vs non-smokers (12.5+/-6.9 ppm and 1.3+/-1.1 ppm and 1685.87+/-922.77 microg/d and 134.18+/-445.03 microg/d, respectively, P<0.001 for both). Ucot was weakly correlated with eGFR (R=0.40, P=0.005), but not with Uprot (R=0.09, P=0.54). In multivariate analyses, daily cigarette consumption and eCO were the only significant predictors of Ucot (P<0.05 for both). CONCLUSION: In this CKD cohort, Ucot is correlated with commonly used measures of smoking exposure and is minimally influenced by underlying renal function, demonstrating its potential utility in clinical trials examining change in smoking behaviour and effects on renal injury.