Novel Budesonide Suppository and Standard Budesonide Rectal Foam Induce High Rates of Clinical Remission and Mucosal Healing in Active Ulcerative Proctitis: a Randomised, Controlled, Non-inferiority Trial.

BACKGROUND AND AIMS: Proctitis is the least extensive type of ulcerative colitis, for which rectal therapy is rarely studied and is underused. This study evaluated the efficacy, safety, and patient's preference of a novel formulation of budesonide suppository 4 mg, compared with a commercially available budesonide rectal foam 2 mg, for the treatment of mild to moderate ulcerative proctitis. METHODS: This was a randomised, double-blind, double-dummy, active-controlled trial. Patients were randomly assigned in a 1:1 ratio to receive either budesonide 4 mg suppository or budesonide 2 mg foam once daily for 8 weeks. The co-primary endpoints were changes from baseline to Week 8 in clinical symptoms, for which clinical remission was defined as having a modified Ulcerative Colitis-Disease Activity Index [UC-DAI] subscore for stool frequency of 0 or 1 and a subscore for rectal bleeding of 0, and mucosal healing, defined as having a modified UC-DAI subscore for mucosal appearance of 0 or 1. Using a more stringent criterion, we additionally analysed deepened mucosal healing, which was defined as a mucosal appearance subscore of 0. Patient's preference, physician's global assessment, and quality of life were also assessed and analysed. RESULTS: Overall, 286 and 291 patients were included in the 4 mg suppository and 2 mg foam groups, respectively. Budesonide 4 mg suppository met the prespecified criterion for non-inferiority to the 2 mg foam in both co-primary endpoints of clinical remission and mucosal healing. Secondary endpoints consistently supported the non-inferiority of the suppository. Trends in favour of the suppository were observed in the subgroup of mesalazine non-responders. More patients reported a preference for the suppository over rectal foam. CONCLUSIONS: In patients with ulcerative proctitis, budesonide 4 mg suppository was non-inferior to budesonide 2 mg foam in efficacy, and both were safe and well tolerated.

Relation between redox homeostasis blood parameters in cirrhotic patients and endothelial dysfunction development.

BACKGROUND: Liver is one of the first organs to be exposed to reactive oxygen species (ROS). But the data about the levels of redox homeostasis parameters in the patients with liver cirrhosis (LC) are contradictory. We hypothesized that the levels of malondialdehyde and catalase should change in accordance with the LC severity causing the endothelial dysfunction. METHODS: In a randomized way with the preliminary stratification by the presence of LC 81 patients and 20 healthy volunteers were examined. To determine the contents of catalase, malondialdehyde, cyclic guanosine monophosphate, endothelin-1, renin, aldosterone, natriuretic peptide, the routine standardized methods were used. RESULTS: Patients with LC revealed the statistically significant increase of malondialdehyde and decrease of catalase levels in parallel with the increase of cyclic guanosine monophosphate, endothelin-1, renin, aldosterone, natriuretic peptide contents and disease course worsening according to the Child-Pugh criteria. It testifies the huge oxidative stress impact on the organism. Initially, at the stage of LC compensation, it slightly stimulates the activation of antioxidant system, followed by its gradual suppression at the stages of sub- and decompensation. Disorders of redox homeostasis lead to the endothelial dysfunction that becomes the background of extrahepatic comorbid disorders. CONCLUSIONS: Cirrhotic patients have significant abnormalities in the redox homeostasis, which become the background of the endothelial dysfunction - common trigger mechanism for the syntrophic comorbid diseases and early pathophysiologic symptom of the unfavorable prognosis for such patients.

A Helicobacter pylori-associated insulin resistance in asymptomatic sedentary young men does not correlate with inflammatory markers and urine levels of 8-iso-PGF2-α or 1,4-dihydroxynonane mercapturic acid.

A potential contribution of H. pylori contamination to low-grade inflammation, oxidative stress (OS) and insulin resistance as well as correlations between these parameters in asymptomatic sedentary males was analysed. We enrolled 30 apparently healthy asymptomatic young subjects (18 H. pylori negative and 12 positive) and measured whole blood glucose, glycated haemoglobin, insulin, C-peptide, cortisol, aldosterone, testosterone, thyroid stimulating hormone, C-reactive protein, interleukins 6 and 10, TNF-alpha and comet assay. As markers of OS, we used urine levels of iso-PGF2-α and 1,4-dihydroxynonane mercapturic acid (DHN-MA). Twofold elevation of fasting insulin level and HOMA index in H. pylori-positive subjects (p < .05) was shown. Inflammatory parameters and monocyte DNA damage, urine levels of DHN-MA and iso-PGF2-α did not show significant differences between the groups. The early stage of H. pylori-triggered metabolic derangements in sedentary subjects include development of insulin resistance in H. pylori-positive subjects; however, there is no evidence of systemic inflammatory and OS-related changes.

Amaranth oil reduces accumulation of 4-hydroxynonenal-histidine adducts in gastric mucosa and improves heart rate variability in duodenal peptic ulcer patients undergoing Helicobacter pylori eradication.

Helicobacter pylori-induced oxidative stress in gastric mucosa (GM) is a milieu for the development of chronic gastritis, duodenal peptic ulcer (DPU), gastric cancer, and a number of extragastric diseases. Because our previous study revealed the accumulation of the protein adducts of lipid peroxidation product 4-hydroxynonenal (HNE) in GM, which persists after eradication of H. pylori, the aim of the study was to test whether Amaranth oil supplementation in addition to standard anti-Helicobacter treatment could prevent such accumulation of HNE in GM in H. pylori-positive DPU patients. Seventy-five patients were randomly split into two groups: group 1 - standard treatment (n = 39) and group 2 - standard treatment with additional supplementation of 1 ml of concentrated oil from amaranth seeds (Amaranthus cruenthus L., n = 36). Clinical analysis, including endoscopy with biopsies from antrum and corpus of the stomach were performed before and after the treatment, as was heart rate variability (HRV) recorded, as parameter of systemic, extragastric pathophysiological alterations in DPU patients. Improvement of clinical, endoscopic and histologic manifestations, and successful ulcer healing were observed in both the groups. Moreover, supplementation of amaranth oil in addition to standard anti-H. pylori treatment significantly reduced accumulation of HNE-histidine adducts in GM and increased HRV in DPU patients (p < .05). Therefore, standard treatments of DPU require additional therapeutic approaches, in accordance with integrative medicine principles, aiming to reduce persistence of oxidative stress, as was successfully done in our study by the use of amaranth oil.

Highly purified calf hemodialysate (Actovegin®) may improve endothelial function by activation of proteasomes: A hypothesis explaining the possible mechanisms of action.

Highly purified calf hemodialysate (HPCH) known as Actovegin® or Solcoseryl® is one of the most controversial drugs currently marketed worldwide. It is not registered as drug in some countries and therefore its medical use there is illegal, while in others it is often among the top 10 of the best-selling medications. It could be also found in the list of the "most useless drugs" and was banned for short time by World Anti-Doping Agency as performance enhancer. However, the degree of its usefulness or uselessness remains unclear and there is not enough convincing data to make reliable conclusions. HPCH is claimed to have wound/muscular injuries healing, neuroprotective and antioxidant properties, to enhance glucose uptake and oxygen consumption, and possibly to improve performance of athletes. Since HPCH consists of over 200 naturally occurring substances which potentially may exert some pharmacological effects, it is extremely difficult to perform pharmacokinetic and pharmacodynamical studies. In this paper we have analyzed the available literature concerning clinical evidence, in vitro, ex vivo and in vivo effects of HPCH. Based on these data we suggest that the main target of the drug may be endothelium and improvement of endothelial function may be responsible for numerous largely nonspecific effects. We also propose the improvement of protein quality control by the means of activation of ubiquitin-proteasomal system as the most important biochemical mechanism responsible for its effects. The role of sphingolipids as potential proteasome-activators is extensively discussed. The effects of HPCH may also include direct or indirect ones on NF-kB-, Nrf2- and FOXO-mediated regulation of metabolic processes in the cells, which result in improved protein quality control, enhanced energy metabolism and increased resistance to oxidative stress.

Helicobacter pylori in sedentary men is linked to higher heart rate, sympathetic activity, and insulin resistance but not inflammation or oxidative stress.

AIM: To compare anthropometric parameters, body composition, hormonal and inflammatory profiles, oxidative stress indices, and heart rate variability (HRV) in Heliobacter pylori (H.pylori) positive and negative healthy sedentary participants. METHODS: Among 30 recruited apparently healthy male participants (age between 20 and 40) enrolled in this cross-sectional study, 18 were H.pylori negative and 12 were positive (stool antigen test). Participants underwent routine physical examination and body composition determination. The following biochemical parameters were determined in blood: fasting whole blood glucose, glycated hemoglobin, insulin, C-peptide, cortisol, aldosterone, testosterone, thyroid stimulating hormone, C-reactive protein, interleukins 6 and 10, tumor necrosis factor-α, and the urinary level of 1,4-dihydroxynonane mercapturic acid. For HRV evaluation, electrocardiogram in supine position and in orthostatic test was performed. RESULTS: H.pylori contamination was not significantly associated with any changes in anthropometric parameters, body composition, blood pressure, fasting glucose, or glycated hemoglobin levels. No significant difference was found for inflammatory markers as well as 1,4-dihydroxynonane mercapturic acid. H.pylori-positive participants, however, had significantly higher heart rate (P=0.009), sympathetic/parasympathetic balance in orthostatic test (P=0.029), fasting insulin level (P=0.037), and HOMA-index (P=0.047). CONCLUSIONS: H.pylori contamination is linked to a significantly higher heart rate, sympathetic activation, and increased insulin resistance, while inflammatory and oxidative stress markers remain unaffected in healthy sedentary male subjects.

The correlations of glycated hemoglobin and carbohydrate metabolism parameters with heart rate variability in apparently healthy sedentary young male subjects.

INTRODUCTION: Sedentary lifestyle is a major risk factor for diabetes, cardiovascular and many other age-related diseases. Heart rate variability (HRV) reflects the function of regulatory systems of internal organs and may sensitively indicate early metabolic disturbances. We hypothesize that quantitative and qualitative changes of HRV in young subjects may reflect early metabolic derangements responsible for further development of clinically significant disease. AIM: The aim of our study was to determine whether the parameters of carbohydrate metabolism (fasting blood glucose, HBA1c and surrogate insulin sensitivity/resistance indices) correlate with anthropometric data and HRV. METHODS: The study group consisted of 30 healthy sedentary male subjects aged 20-40, nonsmokers, mainly office and research employees, medical staff and students. Athletes, actively training more than one hour per week, severely obese and men of physical work were excluded from the study. HRV parameters were derived from short term ECG records (five minutes intervals) in supine position and during orthostatic test. Anthropometric data included height, weight, body mass index (BMI), age and body composition (estimation by bioelectric impedance method). The fasting blood glucose, insulin and C-peptide, homeostatic model assessment (HOMA-IR) index and glycated hemoglobin (HbA1c) were evaluated. Linear correlation coefficient (r) was calculated using Statistica 10.0 software. RESULTS AND DISCUSSION: HOMA-IR index correlated positively with body weight, visceral fat and BMI (p=0.047, 0.027 and 0.017 respectively). In supine position pNN50 positively correlated with glucose/insulin ratio (p=0.011) and heart rate with HOMA-IR (p=0.006). In orthostatic test negative correlations of HBA1c with standard deviation, total and low frequency power were determined (p=0.034, 0.400 and 0.403 respectively), which indicates a gradual worsening of functional capacity of cardiovascular system with low-grade increase (under the conventional threshold) of HBA1c. CONCLUSIONS: In apparently healthy sedentary subjects HRV reduction correlates with the age advancement, subclinical deteriorations of carbohydrate metabolism and excessive fat accumulation.