Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS: DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS: 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had ß-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION: In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING: EU Seventh Framework Programme.

[Influence of drugs on urological diseases]. / Einfluss von Medikamenten auf urologische Krankheiten.

A number of drugs prescribed for the treatment of various diseases can induce urological symptoms as side effects. Antihypertensive drugs (particularly alpha blockers) can result in stress incontinence, whereas selective serotonin reuptake inhibitors (SSRI) can cause urge incontinence and estrogen promotes both forms. A wide range of drugs with anticholinergic activity, among them neuroleptics, tricyclic antidepressants and certain drugs used in airway disorders are associated with urinary retention. Only very few drugs bear a relevant risk for urolithiasis, i. e. the diuretic triamterene and protease inhibitors, such as indinavir; however, the widely used combination of calcium and vitamin D supplementation for prevention of osteoporosis may be an underdiagnosed cause of renal calculi. Drug-induced sexual dysfunction is a frequent side effect of antihypertensive treatment, particularly with beta adrenoceptor blockers and diuretics. The SSRI and some neuroleptics can also impair sexual function.

El uso de hierbas medicinales puede producir graves problemas nefrológicos y urológicos / The use of medicinal herbs may cause serious nephrologic and urologic diseases

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Comparison of natural product use between primary care and nephrology patients.

BACKGROUND: The use of natural products is increasing, but healthcare professionals may underestimate the use of these agents by patients. It is unknown whether natural product use differs between primary care and specialty clinic patients, such as those in a nephrology clinic. OBJECTIVE: To compare patterns of natural product use between primary care and nephrology clinic patients. METHODS: One thousand adult patients from each clinic were randomly mailed an anonymous questionnaire to determine current and past use of natural products. RESULTS: A total of 491 surveys were returned, for an overall response rate of 26% (25% primary care; 28% nephrology clinic). Current use of natural products was similar between the primary care and nephrology groups (34% vs 29%, respectively; p = NS). Primary care patients were more likely to have taken a natural product in the past (57% vs 45%; p < 0.05); Echinacea was the most common product taken by those patients (26%). Green tea was the most common natural product taken by nephrology clinic patients (18%). More primary care patients took Echinacea compared with nephrology clinic patients (26% vs 12%; p < 0.01). Adverse reactions led to discontinuation of the natural product in 7% of respondents. CONCLUSIONS: Active use of natural products was similar between the survey respondents. Documentation and monitoring of natural product use by healthcare professionals working with primary care and nephrology clinic patients are recommended.

Health effects in community residents near a uranium plant at Fernald, Ohio, USA.

OBJECTIVES: Health outcomes in persons who lived in the area surrounding a U.S. Department of Energy (DOE) uranium processing plant near Fernald, Ohio were evaluated using data of Fernald Medical Monitoring Program (FMMP) participants. METHODS: Residential history information was used to identify participants who lived in close proximity to the plant (less than 2 miles), in the direction of groundwater runoff (south of the plant), or used a well or cistern as a drinking water source. Standardized prevalence ratios (SPRs) for certain disease endpoints were calculated using the U.S. National Health Interview Survey(NHIS) and the National Health and Nutrition Examination Survey (NHANES) data files for comparison rates. RESULTS: Findings suggest that prior living within the Fernald exposure domain is related to increased prevalence of urinary system disease. Statistically significant elevations of bladder disease (standardized prevalence ratio or SPR = 1.32) and kidney disease (SPR = 2.15), including sub-categories, kidney stones (SPR = 3.98) and chronic nephritis (SPR = 2.03) were noted, as well as increased rates for hematuria and urethral stricture. In regression analyses with adjustment forage and sex, serum creatinine levels were increased in those who had lived close to the plant. Increased white blood cell count and hemoglobin levels, and decreased mean corpuscular volume were also found in those living less than 2 miles from the plant. Those who used a well or cistern for drinking water were found to have increased urinary microalbumin, red blood cell count and hematocrit. CONCLUSIONS: These preliminary findings will provide the basis for future hypothesis testing incorporating important determinants of exposure not included in this study, such as duration and calendar year of exposure, location relevant to prevailing wind direction, and age at exposure.

[Incidence of urinary tract diseases among workers in the Masovian Refining and Petrochemical Plants in Plock 1978-1981]. / Czestosc wystepowania chorób narzadów ukladu moczowego u pracowników Mazowieckich Zakladów Rafineryjnych i Petrochemicznych w Plocku w latach 1978-1981.

The studies were aimed at estimation of the incidence rate of genito-urinary tract diseases among employees of the Mazovian Refining and Petrochemical Plants in Plock. In 1978-1981, 873 employees were examined, including 244 females and 629 males. Most of them, namely 572 (65%), were employed in those plants for more than 5 years. In 190 persons (21.8%) either history of urologic diseases (41 persons) or current diseases (149 persons) were found. The incidence rate of genito-urinary tract diseases was similar to that observed in general population. The studies are continued.