Higher Daily Dose Research Articles

The Role of Palliative Radiotherapy in Bleeding from Locally Advanced Gastrointestinal Tumors

Patients with locally advanced gastrointestinal tumors present with typical symptoms including pain, obstructive problems with passage disorders and bleeding. The last of them negatively affects their quality of life and is potentially lethal. Palliative radiotherapy is used in hemostatic indication to control bleeding from locally advanced or recurrent inoperable gastrointestinal tumors for many years. This review summarizes information and available literature about mechanisms, efficiency and toxicity of palliative radiotherapy used in hemostatic indication, separately for each part of the digestive system. Although most of the published studies are retrospective, all of them show fast, effective and technically safe control of bleeding with minimal risk of toxicity and show an improvement of quality of life. Hypofractionated radiotherapy, with a smaller number of high doses, seems to be the appropriate palliative fractionation schedule. The higher daily dose is associated with faster initiation of hemostatic effect, while few radiotherapy treatment sessions are comfortable for patients; both of them meet the basic principles of state-of-the-art palliative care. In addition to external beam radiotherapy, high dose rate brachytherapy represents another possibility in this indication, especially for locally advanced inoperable anal and rectal cancer. Brachytherapy is simple, practical and most importantly a one-time procedure with high local effect without significant toxicity. Radiotherapy is an important treatment possibility for palliative care of bleeding from locally advanced inoperable gastrointestinal cancers. Future prospective studies employing modern radiotherapeutic techniques and procedures are needed to provide consistent and clear evidence in order to weigh risks against benefits of palliative hemostatic radiotherapy in current daily clinical practice.Key words: locally advanced gastrointestinal tumors - bleeding - palliative radiotherapy The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 8. 5. 2017Accepted: 23. 7. 2017.

Population pharmacokinetics of oral baclofen at steady-state in alcoholic-dependent adult patients.

Baclofen has been proposed for few years to help treating alcohol dependence at higher doses than those used in neurology. Baclofen pharmacokinetics has been previously well described at low oral or intravenous doses but remains poorly investigated with such high oral doses. We here describe dose regimens of baclofen in 143 alcohol-dependent patients treated with steady-state oral doses of baclofen. Plasma baclofen levels were measured in blood samples using liquid chromatography coupled with tandem mass spectrometry. One hundred and forty-nine baclofen concentrations were sampled 30 min to 15 h after the last dose, and baclofen pharmacokinetics was determined using population pharmacokinetics approach. Our population, whose average age and BMI were 51.5 years and 25.5 kg/m2 , respectively, was composed of two-thirds of men. Daily baclofen doses ranged from 15 to 250 mg and 26% were higher than 120 mg. A one-compartment model with first-order absorption and elimination allowed to determine mean values for clearance (CL/F), volume of distribution (V/F) and absorption rate constant at 8.0 L/h, 44.5 L and 2.23 h-1 , respectively. Inter-individual variability on CL/F and V/F was 27.4 and 86% for the parameters. None of the demographic and biological covariates significantly decreased inter-individual variability. A proportional relationship between oral dose and plasma baclofen exposure indicated a linear pharmacokinetics of baclofen even at doses over 120 mg/day. Our large population study evidenced a linear pharmacokinetics of oral baclofen even at high daily doses with an inter-individual variability of baclofen exposure that could not be explained by demographic and biological data.

A combination of nanosystems for the delivery of cancer chemoimmunotherapeutic combinations: 1-Methyltryptophan nanocrystals and paclitaxel nanoparticles

IDO is an enzyme that tumors use to create a state of immunosupression. 1-d-methyltryptophan (1-MT) is an IDO pathway inhibitor. After being successfully evaluated in preclinical studies, current clinical trials are actually analyzing its efficacy as monotherapy or in combination with multiple chemotherapeutic agents such as paclitaxel. 1-MT very poor solubility in water and many other solvents precludes its ease parenteral administration. It is currently administered by oral route because high daily doses were well-tolerated and effectively inhibited the IDO activity although only 25% of dose was recovered in plasma.The present work describes the preparation and characterization of 1-MT nanocrystals in order to enhance its solubility, dissolution rate, biodisponibility as well as facilitate its administration by parenteral route. A bottom-down approach of nanoprecipitation with an antisolvent was used for the fabrication of the nanocrystals and the choice of stabilizers was critical for reducing the size. Thermal analysis and x-ray diffraction indicated modifications in the drug crystalline state by the process. Through the reduction size and crystalline state modifications the dissolution characteristics of raw material were significantly increased. In a Lewis Lung cancer mice model, the nanocrystals strategy facilitated the sc administration and its antitumoral activity was similar to that of i.v. paclitaxel. The best efficacy was achieved when sc 1-MT nanocrystals were administered in combination with oral paclitaxel loaded in poly(anhydride) nanoparticles. Take together, 1-MT nanocrystals delivery performs a nanotechnological strategy suitable to modify the current route and schedule for its administration.

Evaluation of haemodialysis as a protective technique for preventing high daily dose amikacin nephrotoxicity: an experimental study in an ovine model

Changes in pharmacokinetic parameters of critically ill patients make the treatment of infections challenging, particularly when multidrug-resistant bacteria are involved. The aim of this study was to evaluate the ability of haemodialysis to reduce the exposure to high dose amikacin and prevent nephrotoxicity. Amikacin 50 mg/kg was administered intravenously to six adult sheep once-daily for four days. The sheep were divided into two groups according to the implementation (group 1) or not (group 2) of haemodialysis. In group 1, haemodialysis was performed for 4 h, initiated 2 h after starting amikacin infusion. Amikacin area under the curve (AUC) and trough concentrations (Cmin) were used as markers of amikacin-induced nephrotoxicity. The median haemodialysis amikacin clearance was 2.14 L/h (35.6 mL/min), 14% of the mean total body clearance for 24 h. Haemodialysis reduced Cmin (group 1: 0.3 µg/mL [0.3–1.1]; group 2: 1.4 µg/mL [1.1–3.9]; P = 0.0003). A trend towards reduced AUC with haemodialysis was observed (group 1: 1450 µg/mL⋅h [1311–1716]; group 2: 3126 µg/mL⋅h [2581–3171]; P = 0.10). In conclusion, haemodialysis seems interesting in reducing AUC and Cmin after the injection of high-dose of amikacin, parameters known to be involved in its induced nephrotoxicity, in an experimental ovine model.

Beta-Blocker Drug Use and Survival among Patients with Pancreatic Adenocarcinoma.

Preclinical studies have suggested that β-adrenergic signaling is involved in pancreatic cancer progression. Prompted by such studies, we investigated an association between beta-blocker drug use with improved cancer-specific survival in a large, general population-based cohort of patients with pancreatic ductal adenocarcinoma (PDAC). All patients diagnosed with a first primary PDAC in Sweden between 2006 and 2009 were identified through the Swedish Cancer Register (n = 2,394). We obtained information about use of beta-blockers and other medications through linkage with the national Prescribed Drug Register. Cancer-specific mortality was assessed using the Swedish Cause of Death Register. We used multivariable Cox regression adjusted for sociodemographic factors, tumor characteristics, comorbidity score, and other medications to estimate HRs and 95% confidence intervals (CI) for cancer-specific mortality associated with beta-blocker use during the 90-day period before cancer diagnosis. A total of 2,054 (86%) died, with pancreatic cancer recorded as the underlying cause of death during a maximum of 5-year follow-up (median 5 months). Patients who used beta-blockers (n = 522) had a lower cancer-specific mortality rate than nonusers (adjusted HR, 0.79; 95% CI, 0.70-0.90; P < 0.001). This observed rate reduction was more pronounced among patients with localized disease at diagnosis (n = 517; adjusted HR, 0.60; 95% CI, 0.43-0.83; P = 0.002), especially for users with higher daily doses (HR, 0.54; 95% CI, 0.35-0.83; P = 0.005). No clear rate differences were observed by beta-blocker receptor selectivity. Our results support the concept that beta-blocker drugs may improve the survival of PDAC patients, particularly among those with localized disease. Cancer Res; 77(13); 3700-7. ©2017 AACR.

Chemotherapy Induces Oral Mucositis in Mice Without Additional Noxious Stimuli

Oral mucositis (OM) is a serious side effect of cancer chemotherapy. The pathobiology of oral mucositis remains incompletely understood due to lack of appropriate models which recapitulate the human condition. Existing rodent models are intraperitoneal and require radiation, chemical or mechanical injury to the chemotherapy protocol to induce oral lesions. We aimed to develop an OM mouse model that is induced solely by chemotherapy and reproduces macroscopic, histopathologic and inflammatory characteristics of the human condition. Female C57BL/6 mice were given intravenous 5-Fluorouracil (5-FU) injections every 48 hours, for 2 weeks. A high daily dose of intraperitoneal administration was tested for comparison. Mice were monitored daily for weight loss. Epithelial histomorphometric analyses in tongue, esophageal and intestinal tissues were conducted coupled with assessment of apoptosis, cell proliferation, neutrophilic infiltration and the integrity of adherens junctions by immunohistochemistry. Neutropenia was assessed in peripheral blood and bone marrow. Tissues were analyzed for pro-inflammatory cytokines at the protein and mRNA levels. Daily intraperitoneal administration of 5-FU led to rapid weight loss and intestinal mucositis, but no oral inflammatory changes. Intravenous administration triggered atrophy of the oral and esophageal epithelium accompanied by reduction in cell proliferation and increased apoptosis. Coincidental with these changes were up-regulation of NF-κB, TNFα, IL-1β, GM-CSF, IL-6 and KC. Despite neutropenia, increased oral neutrophilic infiltration and reduced E-cadherin was observed in oroesophageal mucosae. We developed a novel experimental tool for future mechanistic studies on the pathogenesis of chemotherapy-induced OM.

Associations of Drug Lipophilicity and Extent of Metabolism with Drug-Induced Liver Injury.

Drug-induced liver injury (DILI), although rare, is a frequent cause of adverse drug reactions resulting in warnings and withdrawals of numerous medications. Despite the research community’s best efforts, current testing strategies aimed at identifying hepatotoxic drugs prior to human trials are not sufficiently powered to predict the complex mechanisms leading to DILI. In our previous studies, we demonstrated lipophilicity and dose to be associated with increased DILI risk and, and in our latest work, we factored reactive metabolites into the algorithm to predict DILI. Given the inconsistency in determining the potential for drugs to cause DILI, the present study comprehensively assesses the relationship between DILI risk and lipophilicity and the extent of metabolism using a large published dataset of 1036 Food and Drug Administration (FDA)-approved drugs by considering five independent DILI annotations. We found that lipophilicity and the extent of metabolism alone were associated with increased risk for DILI. Moreover, when analyzed in combination with high daily dose (≥100 mg), lipophilicity was statistically significantly associated with the risk of DILI across all datasets (p < 0.05). Similarly, the combination of extensive hepatic metabolism (≥50%) and high daily dose (≥100 mg) was also strongly associated with an increased risk of DILI among all datasets analyzed (p < 0.05). Our results suggest that both lipophilicity and the extent of hepatic metabolism can be considered important risk factors for DILI in humans, and that this relationship to DILI risk is much stronger when considered in combination with dose. The proposed paradigm allows the convergence of different published annotations to a more uniform assessment.

Comparative effectiveness of allopurinol versus febuxostat for preventing incident renal disease in older adults: an analysis of Medicare claims data

ObjectiveTo assess the comparative effectiveness of allopurinol versus febuxostat for preventing incident renal disease in elderly.MethodsIn a retrospective cohort study using 2006–2012 Medicare claims data, we included patients newly treated...

High doses of cholecalciferol alleviate the progression of hyperparathyroidism in patients with CKD Stages 3-4: results of a 12-week double-blind, randomized, controlled study.

BackgroundCalcidiol insufficiency may accelerate the development of secondary hyperparathyroidism (SHPT). We tested the effect of a substantial increase in calcidiol on mineral metabolism in patients with chronic kidney disease (CKD).MethodsNinety-five patients with CKD Stages 3–4, parathyroid hormone (PTH) above 6.8 pmol/L and calcidiol below 75 nmol/L were randomized to receive either cholecalciferol 8000 IU/day or placebo for 12 weeks. The primary endpoint was difference in the mean change in iPTH after 12 weeks. The proportion of participants having a 30% reduction in PTH and the effect on hand grip strength, fatigue and different biochemical variables were also investigated.ResultsBaseline calcidiol was 57.5 ± 22 and 56.8 ± 22 nmol/L in the cholecalciferol and placebo groups, respectively. The corresponding concentrations of PTH were 10.9 ± 5 and 13.1 ± 9 pmol/L. Calcidiol increased to 162 ± 49 nmol/L in patients receiving cholecalciferol, and PTH levels remained constant at 10.5 ± 5 pmol/L. In the placebo group, calcidiol remained stable and PTH increased to 15.2 ± 11 pmol/L. The mean change in PTH differed significantly between the two groups (P < 0.01). The proportion of subjects reaching a 30% decrease in PTH did not differ. No effect on grip strength, fatigue, phosphate or fibroblast growth factor 23 was observed. Cholecalciferol treatment resulted in stable calcium concentrations and a substantial increase in calcitriol.ConclusionTreatment with high daily doses of cholecalciferol in patients with CKD Stages 3–4 halts the progression of SHPT and does not cause hypercalcaemia or other side effects.

Micronutrient supplementation in adults with HIV infection.

Micronutrient supplementation in adults with HIV infection.

Impact of a daily exercise dose on knee joint cartilage – a systematic review and meta-analysis of randomised controlled trials in healthy animals

Purpose: To investigate the impact of a daily exercise dose on cartilage composition and thickness, by conducting a systematic review of randomized controlled trials (RCTs) involving healthy animals. Methods: A systematic literature search was performed within the databases MEDLINE, EMBASE, Web of Science and CINAHL for studies published prior to October 2015 with no restriction on publication year or language. We included randomized controlled trials of healthy animals assessing the impact of exercise on cartilage aggrecan content, collagen content and cartilage thickness. The following studies were excluded: non-RCTs, studies which did not investigate any of the outcomes of interest or knee joints, studies with genetically modified animals, comorbidities, non-English full text, and where treatment arms involved other interventions besides exercise. In dog studies, we used the British Kennel Club recommendations for exercise to categorize dogs into low, moderate or high dose of exercise. To classify the dose of exercise programs in rodents as low, moderate or high, we used the American Physiological Society guideline for the design of animal exercise protocols. To determine the dose of exercise in rabbits and sheep, we used the authors’ own classifications, since no existing exercise dosage classifications were found in the literature. A narrative synthesis of the effect of a daily exercise dose on knee cartilage aggrecan, collagen and thickness was performed. We classified the effect of exercise on knee cartilage aggrecan content, collagen content and thickness as: positive (‘+’) or negative (‘-’) when a significant difference (P<0.05) was reported in favor of the exercise (‘+’) or control (‘-’) group; and as similar (‘=’) when no significant difference between the intervention and control groups was reported. A subset of studies reporting sufficient data was combined in meta-analysis using a random-effects model. Meta-regression analyses were performed to investigate the impact of covariates. Results: The literature search resulted in 1,144 publications of which 112 individual studies were identified as potentially eligible and checked in full text. Ultimately, twenty-nine RCTs, involving 64 comparisons, were included. In the low dose exercise group, 21/25 comparisons reported decreased or no effect on cartilage aggrecan, collagen and thickness. In the moderate dose exercise group, all 12 comparisons reported either no or increased effect. In the high dose exercise group, 19/27 comparisons reported decreased effect. A meta-analysis of 14 studies investigating cartilage thickness showed no effect in the low dose exercise group (SMD -0.02; 95%CI -0.42 to 0.38; I2=0.0%), large but non-significant cartilage thickening in the moderate dose exercise group (SMD 0.95; 95%CI -0.33 to 2.23; I2=72.1%) and non-significant cartilage thinning in the high dose exercise group (SMD -0.19; 95%CI -0.49 to 0.12; I2=0.0%). Results were independent of analyzed covariates. Conclusions: Our results suggest that the relationship between daily exercise dose and cartilage composition and thickness is non-linear. While a low daily dose of exercise may have no effects and a high daily dose of exercise may have negative effects, a moderate daily dose of exercise may have positive effects on cartilage composition and thickness in healthy animals.

Infant Respiratory Tract Infections or Wheeze and Maternal Vitamin D in Pregnancy: A Systematic Review.

Respiratory tract infections (RTIs) are a common cause of morbidity and mortality in young children and can be associated with wheeze. Vitamin D can have a protective role against RTI. A systematic search of PubMed, Embase and the Cochrane library was performed. Titles and abstracts were evaluated, and selected articles were reviewed by 2 authors. We included randomized controlled trials (RCTs) investigating the effect of vitamin D supplementation during pregnancy on RTIs or wheeze in children of 5 years of age or younger. Observational studies on the association between serum 25-hydroxyvitamin D during pregnancy, or at birth, and RTIs and/or wheeze were included. The protocol was registered on PROSPERO (Registration number: CRD42015019183). Of 4 RCTs, 1 showed a protective effect of a high daily dose (2000 IU) of vitamin D during pregnancy on offspring RTI doctor visits (P = 0.004; the RCT also included 800 IU/d supplement to the infants until 6 months). Meta-analysis of 3 RCTs showed a reduced relative risk for offspring wheeze when mothers were supplemented with vitamin D during pregnancy [relative risk: 0.81 (95% confidence interval: 0.68-0.97), P = 0.025]. In 3 of 4 strong-quality, and 5 of 10 moderate-quality observational studies, an inverse association between pregnancy and cord 25-hydroxyvitamin D and subsequent wheeze and/or RTI was seen. Growing evidence supports a preventive role of vitamin D during pregnancy on offspring wheeze and/or RTI. Recommendations in future intervention studies may need to exceed current recommendations of vitamin D supplementation during pregnancy to show benefit against childhood wheeze or infections.

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) as a first presentation of systemic lupus erythematosus

Peripheral nervous system involvement frequently occurs in systemic lupus erythematosus (SLE) patients. However, chronic inflammatory demyelinating polyneuropathy (CIDP) is an unusual presentation that can develop before, after, or simultaneously with the onset of SLE. This paper reports the case of a 20-year-old man with diabetes mellitus (DM) and CIDP accompanied by SLE. The patient complained of progressive weakness in the bilateral upper and lower extremities that had begun 2 months prior to this visit. He was diagnosed with CIDP and treated with intravenous immunoglobulin (IVIG), but had little improvement. A plasma exchange was then scheduled, but it was not helpful either. The patient developed polyarthritis, oral ulcer, and a worsening of his muscle weakness two weeks later. A neurologic examination revealed 3/5 muscle strength in the upper and lower extremities, absent deep tendon reflex (DTR), and impaired position sense. The patient was diagnosed with SLE because of pancytopenia, lymphopenia, pleuropericardial effusion, proteinuria, high titer anti-nuclear antibody (ANA), and anti-dsDNA. A kidney biopsy revealed stage IV lupus nephritis. The patient received 3 pulses of methyl prednisolone, 6 months of cyclophosphamide, and a high daily dose of prednisolone. His proteinuria improved, and he regained the ability to ambulate with a normal gait after about 2.5 months. To the best of the authors’ knowledge, the concurrency of CIDP with SLE and DM has not been previously reported.

Alcohol and Drug Use and Aberrant Drug-Related Behavior Among Patients on Chronic Opioid Therapy

ABSTRACTObjective: To better identify individuals on chronic opioid therapy (COT) at high risk for aberrant-drug related behavior (ADRB). We examine whether patients with low level alcohol and drug use have similar characteristics to those with alcohol and drug disorders. We then examined the relationship of alcohol and drug use to ADRBs among COT patients. Methods: The sample was 972 randomly selected COT patients (age 21–80 years old) from a large health system in Northern California, USA, and interviewed in 2009. Logistic regression models were used to model the dependent variables of: alcohol use, illicit drug use, alcohol disorders, illicit drug disorders, and ADRBs. Results: The odds of daily/weekly alcohol use were lower for those with a high daily opioid dose (120+ mg/day vs. <20 mg/day) (OR = 0.32, p < 0.010). Illicit drug disorders were associated with depression (OR = 2.31, p < .001) and being on a high daily opioid dose (OR = 5.51, p < .01). Participants with illicit drug use had higher odds of giving (OR = 2.57, p < 0.01) and receiving opioids from friends or family (OR = 3.25, p < 0.001), but disorder diagnoses were not associated with ADRBs. Conclusions: Findings reinforce that illicit drug use should be of high concern to clinicians prescribing opioids, and suggest it should be considered separately from alcohol use and alcohol disorders in the evaluation of ADRBs. Frequent alcohol use is low, but not uncommon, and suggests a need to discuss specific issues regarding safe use of opioids among persons who use alcohol that may differ from their risk of drug use.

Impact of a daily exercise dose on knee joint cartilage - a systematic review and meta-analysis of randomized controlled trials in healthy animals.

To investigate the impact of a daily exercise dose on cartilage composition and thickness, by conducting a systematic review of randomized controlled trials (RCTs) involving healthy animals. A narrative synthesis of the effect of a daily exercise dose on knee cartilage aggrecan, collagen and thickness was performed. A subset of studies reporting sufficient data was combined in meta-analysis using a random-effects model. Meta-regression analyses were performed to investigate the impact of covariates. Twenty-nine RCTs, involving 64 comparisons, were included. In the low dose exercise group, 21/25 comparisons reported decreased or no effect on cartilage aggrecan, collagen and thickness. In the moderate dose exercise group, all 12 comparisons reported either no or increased effect. In the high dose exercise group, 19/27 comparisons reported decreased effect. A meta-analysis of 14 studies investigating cartilage thickness showed no effect in the low dose exercise group (SMD-0.02; 95% CI-0.42 to 0.38; I2=0.0%), large but non-significant cartilage thickening in the moderate dose exercise group (SMD 0.95; 95% CI-0.33 to 2.23; I2=72.1%) and non-significant cartilage thinning in the high dose exercise group (SMD-0.19; 95% CI-0.49 to 0.12; I2=0.0%). Results were independent of analyzed covariates. The overall quality of the studies was poor because of inadequate reporting of data and high risk of bias. Our results suggest that the relationship between daily exercise dose and cartilage composition, but not necessarily cartilage thickness, may be non-linear. While we found inconclusive evidence for a low daily dose of exercise, a high daily dose of exercise may have negative effects and a moderate daily dose of exercise may have positive effects on cartilage matrix composition in healthy animals.

High doses of antipsychotic polypharmacy are related to an increase in serum levels of pentosidine in patients with schizophrenia

BackgroundCarbonyl stress in patients with schizophrenia has been reported to be reflected by an increase in peripheral pentosidine levels. This cohort study tested whether the accumulation of pentosidine was related to the disease severity or the treatment (routine administration of high antipsychotic doses). MethodsWe followed up our original investigation using a new group of 137 patients with acute schizophrenia and 45 healthy subjects, and then pooled the two cohorts to conduct the following analysis on a total of 274 patients. The associations of serum pentosidine and pyridoxal levels with duration of education, estimated duration of medication, the severity of symptoms, and daily doses of antipsychotics, antiparkinsonian drugs, and anxiolytics were evaluated by multiple linear regression analysis. ResultsThe combined cohort of 274 patients exhibited abnormally high serum levels of pentosidine, were associated with a higher daily dose of antipsychotic drugs and a longer estimated duration of medication without statistical significance of diagnosis. This was also observed in the patients treated with antipsychotic polypharmacy, but the serum pentosidine levels of patients treated with first- or second-generation antipsychotic monotherapy showed no relationship with these two variables. ConclusionHigh levels of serum pentosidine were associated with high daily doses of antipsychotic drugs and a longer estimated duration of medication in patients treated with antipsychotic polypharmacy.

Prognostic role of β-blocker selectivity and dosage regimens in heart failure patients. Insights from the MECKI score database.

The use of β-blockers represents a milestone in the treatment of heart failure with reduced ejection fraction (HFrEF). Few studies have compared β-blockers in HFrEF, and there is little data on the effects of different doses. The present study aimed to investigate in a large database of HFrEF patients (MECKI score database) the association of β-blocker treatment with a composite outcome of cardiovascular death, urgent heart transplantation or left ventricular assist device implantation, addressing the role of β-selectivity and dosage regimens. In 5242 HFrEF patients, we investigated the role of: (i) β-blocker treatment vs. non-β-blocker treatment, (ii) β1-/β2-receptor-blockers vs. β1-selective blockers, and (iii) daily β-blocker dose. Patients were followed for 3.58 years, and 1101 events (18.3%) were observed; 4435 patients (86.8%) were on β-blockers, while 807 (13.2%) were not. At 5 years, β-blocker-patients showed a better outcome than non-β-blocker-subjects [hazard ratio (HR) 0.48, P < 0.0001], while also considering potential confounders. A comparable prognosis was observed at 5 years in the β1-/β2-receptor-blocker (n = 2219) vs. β1-selective group (n = 2216) (HR 0.95, P = ns). A better prognosis was observed in high-dose (>2 5 mg carvedilol equivalent daily dose, n = 1005) patients than in both medium dose (12.5-25 mg, n = 1431) and low dose (<12.5 mg, n = 1960) (HR 1.97, P < 0.001; HR 1.95, P = 0.001, respectively), with no differences between the last two groups (HR 0.84, P = ns). In a large population of chronic HFrEF patients, β-blockers were associated with a more favourable prognosis without any difference between β1- and β2-receptor-blockers vs. β1-selective blockers. A better outcome was observed in subjects receiving a high daily dose.

Effects of Crystal Derived from Stevia rebaudiana Leaves on Alloxan Induced Type-1 Diabetic Mice

The study was undertaken to investigate the antidiabetic effects of crystals derived from Stevia rebaudiana leaves in normal rats and alloxan induced diabetic mice. Normal rats were used to evaluate whether the stevia crystal have any adverse effects on body weight and blood glucose of healthy rats. The rats were divided into two groups (n=5); healthy control rats and stevia treated healthy rats (1 g/kg/day orally). To evaluate the antidiabetic effects of stevia crystal, mice were divided into five equal (n=5) groups; healthy control, diabetic control, stevia crystal @ 250 and 500 mg/kg bwt, and Amaryl® @ 800 µg/kg daily to compare the efficacy. Alloxan monohydrate was injected in mice at a dose rate of 120 mg/kg intraperitoneally for diabetic induction. Result of the present study showed that stevia crystal at a high daily dose did not have any significant effect on body weight but it reduced blood glucose level non-significantly in healthy animal. The antidiabetic effects of stevia crystal was evaluated based on glucose lowering capacity, improvement of body weight loss, changes in lipid profile, and renal and pancreas protective capacity. Treatment with stevia crystal @500 mg/kg improved body weight loss and reduced blood glucose level significantly (P<0.01) in diabetic animal. Stevia @500 mg/kg decreased cholesterol level non-significantly whereas it reduce the triglyceride level significantly (P<0.01). In histopathology study, stevia crystal showed renal and pancreas protective effect with slightly restoration of structural damage in both organs. Based on present studies data it may conclude that crystalline compounds derived from Stevia rebaudiana leaves may have antidiabetic properties that need further characterization

The Risk Factors for the Wearing-off Phenomenon in Parkinson's Disease in Japan: A Cross-sectional, Multicenter Study.

Objective Parkinson's disease (PD) is a common, progressive, neurodegenerative disorder. With progression of PD, the wearing-off phenomenon occurs more frequently as a motor complication, decreasing the patient's quality of life. The aim of this study was to investigate the risk factors for the wearing-off phenomenon in Japanese PD patients. Methods All of the study participants were clinically diagnosed as having PD. Each patient was assessed for the wearing-off phenomenon based on the findings of clinical assessments and interviews that were conducted during a single visit. The risk factors for wearing-off were analyzed by univariate and multivariate logistic regression analyses. Results Wearing-off was observed in 101 of the 180 (56.1%) patients who were enrolled in this study. The multivariate logistic regression analysis revealed that the onset of PD at ≥69 years of age (odds ratio [OR], 0.22; 95% confidence interval [CI], 0.05-0.88; p=0.032), female sex (OR, 6.49; 95% CI, 2.34-17.99; p<0.001), catechol-O-methyltransferase (COMT) inhibitor treatment (OR, 19.59; 95% CI, 3.55-108.11; p<0.001) and a high daily levodopa dosage (≥600 mg/day) (OR, 7.69; 95% CI, 1.41-41.84; p=0.018) were independent predictive factors for wearing-off in Japanese PD patients. Conclusion Age at the symptomatic disease onset, female sex, COMT inhibitor treatment, and a high daily levodopa dose were associated with the occurrence of wearing-off in Japanese PD patients. Physicians need to consider the risk factors and carefully choose medications for PD patients to postpone the occurrence of this phenomenon for as long as possible.

Mineral and Bone Status in Tunisian Maintenance Hemodialysis Patients: The National Bone and Mineral Metabolism Observatory

In Tunisia, data assessing the status of mineral and bone disorders (MBD) among dialysis patients is scarce. In order to address this gap in the literature, we sought to conduct this observational study including 4868 patients from 108 hemodialysis facilities nationwide, aiming to: (i) report parameters of MBD during the first quarter 2006, (ii) determine the levels of compliance with the recommendations of the Kidney Disease Outcome Quality Initiative (K/ DOQI), and (iii) compare these levels of compliance with those of Dialysis Outcomes and Practice Patterns Study (DOPPS). Mean serum phosphorus, calcium, calcium- phosphorus product and intact parathyroid hormone (iPTH) concentrations were respectively 1.74 mmol/L, 2.28 mmol/L, 3.95 mmol²/l² and 254 pg/ml. MBD’s measures were met the K/DOQI’s guidelines in 44.1% of cases for serum phosphorus, 42.5% of cases for serum calcium, 68.6% of the cases for calcium phosphorus product, 20.2% of cases for iPTH and 3.3% of cases for these four parameters taken together. These results were comparable to those observed in the DOPPS study. The most phosphate binder prescribed was calcium carbonate (91.2% of cases) with high average daily dose (superior to 1500 mg in 45.8% of cases). Sevelamer and aluminum salt were prescribed respectively in 0.5% and 0.10% of patients. The only active vitamin D available in Tunisia was alfacalcidol; it was prescribed in 49.7% of patients with a mean weekly dose of 4.04 μg. A calcium dialysate bath of 1.75; 1.50 and 1.25 mmol/L were prescribed respectively in 80.2%, 14.7% and 5.1% of cases. This is the first exhaustive study reporting MBD abnormalities in Tunisia and, to our knowledge, in Africa. A second study was stated in January