Repurposing metformin as adjuvant therapy in patients with ulcerative colitis treated with mesalamine: A randomized controlled double-blinded study.

BACKGROUND: Ulcerative colitis (UC) is a type of inflammatory bowel disease associated with persistent inflammation. Animal studies proved the efficacy of metformin in UC. AIM: To investigate the potential role of metformin and its protective pathways in patients with UC. METHODS: This is a randomized, controlled, and double-blinded clinical trial that included 60 participants with mild to moderate UC and was divided randomly into two groups (n = 30). For 6 months, the mesalamine group received 1 g of mesalamine three times daily (t.i.d.). For six months, the metformin group received mesalamine 1 g t.i.d. and metformin 500 mg twice daily. A gastroenterologist evaluated patients at baseline and 6 months after starting the treatment in order to measure serum levels of zonulin, sphingosine 1 phosphate (S1P), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Biopsies from the colon were used to measure gene expression of zonula occuldin-1 (ZO-1), signal transducer and activator of factor-3 (STAT-3), and intracellular adhesion molecule-1 (ICAM-1). The numeric pain rating scale (NRS) and partial Mayo score were also assessed for each patient. RESULTS: When compared to the mesalamine group, the metformin group demonstrated a statistical decrease in serum IL-6, zonulin, TNF-α, SIP, gene expression of ICAM-1 and STAT-3, and a significant increase in colonic ZO-1 when compared to the mesalamine group. The metformin group also showed a significant decrease in NRS and partial Mayo score index in comparison with the mesalamine group. CONCLUSION: Metformin may be a promising additional therapy for UC patients. Trial registration identifier: NCT05553704.

Allopurinol Prevents Cirrhosis-Related Complications: A Quadruple Blind Placebo-Controlled Trial.

BACKGROUND: Complications associated with liver cirrhosis are various and potentially fatal. The treatment options to counteract hepatic decompensation are limited. Therefore, the study aimed to explore the use of allopurinol in preventing the recurrence of liver cirrhosis-related complications. METHODS: One hundred patients with hepatic decompensation were randomized into 1:1 ratio to receive either allopurinol 300 mg or placebo tablets once daily for 6 months. The primary endpoint was the incidence of cirrhosis-related complications (overt ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatorenal syndrome, and hepatic encephalopathy). RESULTS: Six months following treatment, allopurinol reduced the relative risk (RR) of any first complication experienced after enrollment by 56% (hazard ratio [HR] 0.44; 95% confidence interval [CI], 0.27-0.62); P ˂ .001). Allopurinol decreased the RR of overt ascites by 67% (HR 0.33; 95% CI, 0.0098-0.94); P = .039] and reduced the RR of spontaneous bacterial peritonitis by about 75% (HR 0.25; 95% CI, 0.05-0.76; P = .01). Likewise, allopurinol was linked to an 80% reduction in the RR of developing hepatorenal syndrome (HR 0.2; 95% CI, 0.04-0.87; P = .033). CONCLUSION: Allopurinol significantly decreased the recurrence of overall liver cirrhosis-related complications. Therefore, allopurinol may constitute a promising agent for patients with hepatic decompensation. These positive outcomes could be a result of its ability to reduce bacterial translocation and inflammation. GOV IDENTIFIER: NCT005545670.

Phytochemical investigation, antibacterial, and ameliorative potential effects of Tamarix nilotica on LPS-induced acute lung injury model in mice.

Acute lung injury (ALI) is a serious illness with a high mortality rate of 40-60%. It is characterised by systemic inflammatory processes and oxidative stress. Gram-negative bacterial infections are the major cause of ALI, and lipopolysaccharide (LPS) is the major stimulus for the release of inflammatory mediators. Hence, there is an urgent need to develop new therapies which ameliorate ALI and prevent its serious consequences. The Middle Eastern native plant Tamarix nilotica (Ehrenb) Bunge belongs to the family Tamaricaceae, which exhibits strong anti-inflammatory and antioxidant effects. Thus, the current work aimed to ensure the plausible beneficial effects of T. nilotica different fractions on LPS-induced acute lung injury after elucidating their phytochemical constituents using LC/MS analysis. Mice were randomly allocated into six groups: Control saline, LPS group, and four groups treated with total extract, DCM, EtOAc and n-butanol fractions, respectively, intraperitoneal at 100 mg/kg doses 30 min before LPS injection. The lung expression of iNOS, TGF-ß1, NOX-1, NOX-4 and GPX-1 levels were evaluated. Also, oxidative stress was assessed via measurements of MDA, SOD and Catalase activity, and histopathological and immunohistochemical investigation of TNF-α in lung tissues were performed. T. nilotica n-butanol fraction caused a significant downregulation in iNOS, TGF-ß1, TNF-α, NOX-1, NOX-4, and MDA levels (p ˂ 0.05), and significantly elevated GPX-1 expression levels, SOD, and catalase activity (p ˂ 0.05), and alleviated all histopathological abnormalities confirming its advantageous role in ALI. The antibacterial activities of T. nilotica and its different fractions were investigated by agar well diffusion method and broth microdilution method. Interestingly, the n-butanol fraction exhibited the best antibacterial activity against Klebsiella pneumoniae clinical isolates. It also significantly reduced exopolysaccharide quantity, cell surface hydrophobicity, and biofilm formation.

Clinical comparative study assessing the effect of ivabradine on neopterin and NT-Pro BNP against standard treatment in chronic heart failure patients.

PURPOSE: Heart rate reduction (HR) is a cornerstone in heart failure therapy as it improves patient outcomes. The aim of this study is to evaluate short-term effect of ivabradine on NT-Pro BNP and neopterin in heart failure patients and assess the association between HR and these biomarkers. METHODS: Sixty patients on standard heart failure therapy were randomly allocated into ivabradine group (n = 30) and non-ivabradine group (n = 30). Ivabradine 5 mg twice daily was given for 3 months. Lipid profile and kidney functions were performed and blood samples for NT-Pro BNP and neopterin were analysed at baseline and after 3 months of intervention in both groups. RESULTS: There was a significant improvement in NYHA class in ivabradine group (p < 0.001). Ejection fraction was improved in ivabradine and non-ivabradine groups after intervention (p < 0.001), with a greater improvement in ivabradine group (p = 0.026). Heart rate was reduced in ivabradine group (p < 0.001) and non-ivabradine group (p < 0.001) yet greater reduction was seen in ivabradine group (p < 0.001). Serum creatinine and blood urea nitrogen were reduced in ivabradine group (Scr: p = 0.001, BUN: p = 0.001). NT-Pro BNP and neopterin levels significantly decreased in ivabradine group (NT-Pro BNP: p < 0.001, neopterin p < 0.001). Significant positive correlation was found between HR and biomarker levels after intervention (NT-Pro BNP: r = 0.475, p < 0.001, neopterin: r = 0.384, p = 0.002). CONCLUSION: Ivabradine therapy reduced levels of both biomarkers which correlated well with HR. Biomarker levels might provide a tool for assessing ivabradine effectiveness in HF. Trial registration Date: June 26, 2020. Identifier: NCT04448899. Link: Ivabradine in Patients with Congestive Heart Failure-Full Text View-ClinicalTrials.gov.

A Potential Role of Ethosuximide and Pentoxifylline in Relieving Abdominal Pain in Irritable Bowel Syndrome Patients Treated with Mebeverine: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND AND PURPOSE: Irritable bowel syndrome (IBS) is defined as an association of chronic abdominal pain with bowel habit abnormalities, without clear organic dysfunction. T-type calcium channels and low-grade mucosal inflammation are linked to abdominal pain; however, medical treatments for IBS abdominal pain are largely ineffective. In this study, we investigated if pentoxifylline (PTX) and ethosuximide could potentially alleviate abdominal pain in patients with IBS treated with mebeverine. METHODS: We recruited 150 patients from Tanta University Hospital to this randomized, prospective, and double blinded study. Patients were randomly allocated to three groups (n = 50). Group 1 (mebeverine) received 135 mg mebeverine three times/day (t.i.d). Group 2 (ethosuximide group) received 135 mg mebeverine t.i.d plus 250 mg ethosuximide twice daily (b.i.d) and group 3 (PTX group) received 135 mg mebeverine t.i.d plus 400 mg PTX b.i.d. Patients were assessed by a gastroenterologist at baseline and 6 months after therapy. Serum interleukin-8 (IL-8), IL-6, tumor necrosis-α (TNF-α), fecal myeloperoxidase, and fecal neutrophil gelatinase associated lipocalin (NGAL) levels were measured before and after therapy. The numeric pain rating scale (NRS) was also assessed before and after therapy. PRIMARY OUTCOMES: Reduced NRS scores and abdominal pain relief. SECONDARY OUTCOMES: Decreased inflammatory biomarkers. RESULTS: After 6 months, groups 2 and 3 showed a significantly greater reduction in serum IL-8, IL-6, TNF-α, fecal myeloperoxidase, and fecal NGAL levels when compared to group 1 after therapy. Both groups 2 and 3 showed significant reductions in NRS scores when compared to the group 1. CONCLUSION: Ethosuximide and PTX may be promising, novel adjunct drugs to antispasmodics for relieving abdominal pain in patients with IBS. TRIAL REGISTRATION: Identifier: NCT04217733.

Pentoxifylline, a nonselective phosphodiesterase inhibitor, in adjunctive therapy in patients with irritable bowel syndrome treated with mebeverine.

BACKGROUND: Irritable bowel syndrome (IBS) is a functional gastrointestinal condition marked by chronic bowel pain or discomfort, as well as changes in abdominal motility. Despite its worldwide prevalence and clinical impact, the cause of IBS is unknown. Inflammation could play a fundamental role in the development of IBS. The aim of this study was to examine whether pentoxifylline, a competitive nonselective phosphodiesterase inhibitor, is useful in alleviating abdominal pain in IBS patients treated with mebeverine. METHODS: A randomized, controlled, and prospective clinical study that included 50 outpatients who met the inclusion criteria for IBS. Patients are allocated randomly into two groups (n = 25). Group 1 (mebeverine group) received mebeverine 135 mg three times daily (t.i.d) for three months. Group 2 (pentoxifylline group) received mebeverine 135 mg t.i.d and pentoxifylline 400 mg two times daily for three months. Patients were assessed by a gastroenterologist at baseline and three months after the medication had been started. The serum levels of interleukin-6, interleukin-8 and tumor necrosis factor-alpha, fecal Neutrophil Gelatinase Associated Lipocalin (NGAL), and fecal myeloperoxidase were measured at the start and after three months of therapy. The Numeric Pain Rating scale (NRS) was assessed at baseline and after therapy. RESULTS: the pentoxifylline group showed a significant decrease in the level of measured biomarkers and a significant decrease in NRS. CONCLUSION: Pentoxifylline could be a promising adjuvant anti-inflammatory drug in the treatment of abdominal pain in IBS patients treated with mebeverine.

Open-label pilot study of ethosuximide as adjunctive therapy for relieving abdominal pain related to Irritable Bowel Syndrome.

WHAT IS KNOWN AND OBJECTIVES: There is clear evidence for an association between irritable bowel syndrome (IBS) and visceral hypersensitivity. This clinical study aimed to assess the adjunct role of ethosuximide, an antiepileptic drug with T-type calcium channel blocking activity, in the relieving of IBS-related abdominal pain. METHODS: This is a prospective, 3-month, randomized and controlled study of parallel groups. Fifty outpatients who met the inclusion criteria participated in the trial. Patients were allocated randomly: 25 received mebeverine 135 mg three times daily (t.i.d), whereas the other 25 received mebeverine 135 mg t.i.d and ethosuximide 500 mg t.i.d. At baseline and 12 weeks after starting the drug, patients were evaluated by a gastroenterologist. Serum tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-8 (IL-8), faecal myeloperoxidase and faecal neutrophile gelatinase-associated lipocalin (NGAL) levels were tested before and after treatment. The Numeric Pain Rating Scale (NRS) was assessed before and after three months of therapy. RESULTS AND DISCUSSION: After 12 weeks, the ethosuximide group showed a statistically and significantly greater reduction in the serum levels of TNF-α, IL-6, IL-8, faecal myeloperoxidase and faecal NGAL in comparison with the control group after the treatment. Moreover, the ethosuximide group showed a statistically significant decrease in NRS compared with the mebeverine group. WHAT IS NEW AND CONCLUSION: Ethosuximide could be a promising adjunct to antispasmodics in the treatment of IBS patients. Trial registration identifier: NCT04217733.

Comparative randomized trial evaluating the effect of proton pump inhibitor versus histamine 2 receptor antagonist as an adjuvant therapy in diffuse large B-cell lymphoma.

The development of drug resistance remains the major obstacle to clinical efficacy of cancer chemotherapy. Consequently, finding new therapeutic options for cancerous patients is an urgent need. Sixty newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients were recruited from Clinical Oncology Department, Faculty of Medicine, Menoufia University, Egypt prospectively randomized to three groups (n = 20 for each group). Group one (control group) received R-CHOP standard chemotherapy {Rituximab, Cyclophosphamide, Hydroxyldaunorubicin (Doxorubicin)®, Vincristine (oncovin)®, prednisolone in the first five days of cycle}, group two received lansoprazole (LAN) 60 mg p.o. bid for only one week before starting each of cycle + R-CHOP and group three received famotidine (FAM) 40 mg p.o. once daily one week before cycle and continues daily through the cycle + R-CHOP for six cycles. Blood samples were obtained for biochemical analysis of transforming growth factor-ß (TGF-ß), Basic fibroblast growth factor (bFGF), interleukin-9 (IL-9), nuclear factor-kappa B (NF-κB) and Caspase 3 before and after six cycles of therapy. The obtained data showed that LAN and FAM resulted in significant decrease in (LDH, TGF-ß, bFGF and IL-9, respectively) and significant increase in (Caspase-3). In addition, LAN produced a significant elevation in the response rate compared to the control group or the FAM group. Both LAN and FAM as adjuvant therapy represents a promising anticancer strategy in DLBCL by modulation of malignancy homeostasis mechanisms and boosting chemotherapy antitumor effects without further toxicity. In addition, LAN has a synergetic effect in improving the response rate.Trial registration Clinical Trial.gov Identifier: NCT0364707.

Comparative study to evaluate the effect of l-carnitine plus glimepiride versus glimepiride alone on insulin resistance in type 2 diabetic patients.

AIM: Insulin resistance (IR) is predominant in type 2 diabetic patients. This study aimed to investigate benefits from adding l-carnitine to ongoing glimepiride compared to glimepiride monotherapy on IR in diabetic patients who failed to achieve their glycemic goals on glimepiride monotherapy. METHODS: 58 patients were recruited from Internal Medicine Department, Tanta University Hospital, Egypt then prospectively randomized to receive their glimepiride dose 2 mg twice daily (group 1) or glimepiride 2 mg twice daily + l-carnitine 1 g m twice daily (group 2) for 6 months. Fasting blood samples were collected at baseline, 3 and 6 months after treatment for analysis of fasting and postprandial blood glucose [FBG &PPBG], glycated hemoglobin [HbA1c %], fasting insulin, extracellular part of insulin regulated aminopeptidase [IRAPe] as a novel marker, tumor necrosis factor-alpha [TNF-α], visfatin and lipid panel. Body mass index [BMI] and homeostasis model assessment of insulin resistance [HOMA-IR] were calculated. Data were statistically analyzed by SPSS using unpaired Student's t-test and one way analysis of variance; p ≤ 0.05 was considered statistically significant. RESULTS: The obtained data suggested that adding l-carnitine to glimepiride has a significantly beneficial effect on FBG, PPBG, HbA1c, fasting insulin, HOMA-IR index, IRAPe, TNF-α, visfatin and lipid panel parameters but doesn't have effect on BMI and blood pressure. CONCLUSION: The co-administration of l-carnitine with glimepiride represents a new therapeutic strategy for better controlling diabetic patients as it resulted in more beneficial effects on direct and indirect biomarkers of insulin resistance than glimepiride alone.

Effect of ketotifen in obese patients with type 2 diabetes mellitus.

AIM: Mast cells are found to be an important contributor in obesity induced insulin resistance. We evaluate the effect of ketotifen in obese patient with type 2 diabetes (T2DM) treated with glimepiride. METHOD: In a randomized controlled study we recruited forty-eight obese patients with T2DM from Internal Medicine Department at Tanta University Hospital, Egypt. They were classified into three groups: group 1, those who received glimepiride (GL) 3mg/d alone; group 2, those who received GL 3mg/d+ketotifen 1mg once daily; and group 3, those who received GL 3mg/d+ketotifen 1mg twice daily. Fasting blood samples were obtained before and 12weeks after treatment for biochemical analysis of glycemic and inflammatory biomarkers. Data were statistically analyzed by paired Student's t-test and one way analysis of variance; p<0.05 was considered statistically significant. RESULTS: The obtained data suggested that the addition of ketotifen in twice daily dose has a beneficial effect on all measured parameters except adiponectin. However, glimepiride plus ketotifen once daily only affected the level of inflammatory biomarkers without any significant effect on other parameters. CONCLUSIONS: The co-administration of ketotifen twice daily plus glimepiride improves glycemic and inflammatory process in obese patients with T2DM.

Cardiovascular risk in Egyptian healthy consumers of different types of combined oral contraceptives pills: A comparative study.

This study aimed to evaluate the associated cardiovascular risk in Egyptian healthy consumers of different types of combined oral contraceptives pills (COCPs) via determination of lipids profiles, Castelli index I, leptin, adiponectin, and resistin concentrations as cardiovascular risk factors. In this cross-sectional study, the study groups consisted of control group that represented by 30 healthy married women who were not on any contraceptive mean or any hormonal therapy and had normal menstrual cycles, group two consisted of 30 women who were users of Levonorgesterl 0.15 mg plus Ethinylestradiol 0.03 mg as 21 days cycle, group three consisted of 30 women who were users of Gestodene 0.075 mg plus Ethinylestradiol 0.03 mg as 21 days cycle, and group four consisted of 30 women who were users of Drospirenone 3 mg plus Ethinylestradiol 0.03 mg as 21 days cycle. One-way analysis of variance followed by LSD post hoc test was used for comparison of variables. P value <0.05 was considered to be significant. The comparison of the studied groups revealed that COCPs containing levonorgestrel plus ethinylestradiol resulted in significantly lower adiponectin level, and significantly higher leptin and resistin levels with more atherogenic lipid profile presented by significantly higher LDL-C, significantly lower HDL-C concentrations, and significantly higher atherogenic index. Formulation containing ethinylestradiol combined with gestodene neither altered adipose tissue function nor showed deleterious effect on lipid panel. Formulation containing ethinylestradiol combined with drospirenone resulted in significantly higher HDL-C and adiponectin concentrations. In conclusion, the uptake of COCPs containing levonorgestrel plus ethinylestradiol is associated with high cardiovascular risk since this formulation showed significantly lower adiponectin concentration, significantly higher leptin, resistin, and atherogenic index as compared to other studied groups. By contrast, the formulations containing ethinylestradiol combined with third generation progestin gestodene or fourth generation progestin drospirenone are associated with low cardiovascular risk since they neither altered adipose tissue function nor impaired lipoprotein metabolism as experienced by their favorable effect on leptin, adiponectin, and resistin, with non-changed atherogenic index, higher HDL-C levels and lower LDL-C levels as compared to levonorgestrel plus ethinylestradiol formulation.

Effect of ketoprofen and indomethacin on methotrexate pharmacokinetics in mice plasma and tumor tissues.

Methotrexate (MTX) has been used in combination with nonsteroidal anti-inflammatory drugs in the treatment of inflammatory diseases as well as malignancies. Severe adverse effects with this combination may occur, usually resulting from inhibition of renal transporters. Solid Ehrlich carcinoma was experimentally induced by implantation of Ehrlich ascites Carcinoma cells subcutaneously into the thigh of mice, and after 30 days, mice were divided into three groups: Group I that served as control group received MTX (50 mg/kg, i.p.); Group II received ketoprofen (100 mg/kg, i.p.) and then after half an hour received MTX (50 mg/kg, i.p.); Group III received indomethacin (10 mg/kg, i.p.) and then after half an hour received MTX (50 mg/kg, i.p.). Plasma and tissue samples were collected at different time points and then MTX concentrations were determined by HPLC. The injection of ketoprofen or indomethacin before MTX injection resulted in significant increase in the AUC and CPmax of MTX (p < 0.05) and significant decrease in CL/F and Vd/F of MTX (p < 0.05) in mice plasma. The effects were more significant after injection of indomethacin than in case of ketoprofen. The study showed that administration of ketoprofen or indomethacin prior to MTX caused significant decrease in MTX elimination and significant increase in MTX extent of absorption which may lead to severe adverse effects if coadministered in human.

Study of the pharmacokinetic and pharmacogenetic contribution to the toxicity of high-dose methotrexate in children with acute lymphoblastic leukemia.

Methotrexate inhibits the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate by methylenetetrahydrofolate reductase (MTHFR). MTHFR has a common functional polymorphism C677T. The present study aimed to investigate the prevalence of MTHFR polymorphisms in Egyptian children with ALL and the relation to MTX-related toxicity, relapse, and MTX pharmacokinetic parameters. Forty patients with ALL were included in the study. They were treated according to ALL-NCI total XIII protocol. MTX-related toxicity and MTX pharmacokinetic parameters were assessed during therapy. MTHFR genotyping was done with a PCR-based restriction fragment length polymorphism assay, and MTX pharmacokinetic parameters were assessed by HPLC. The MTHFR C677T polymeric allele frequencies were 55, 35, and 10% for CC, CT, and TT genotypes, respectively, among the studied patients with ALL. MTX therapy was significantly associated with toxicity signs in TT genotype: elevated transaminases (P < 0.0001), elevated serum alpha 1-microglobulin protein (P < 0.0001), anemia (P < 0.0001), neutropenia (P < 0.0001), thrombocytopenia (P < 0.0001), and elevated CSF-ß-glucuronidase activity (P < 0.0001). Patients with TT genotype showed significant increase in MTX t(½) and AUC (P < 0.0001), while MTX elimination rate and total body clearance were significantly decreased (P < 0.0001 and P < 0.05, respectively) compared with CC genotype. The TT genotype was significantly associated with relapse in 2 years in 50% compared with 28.57% in CT and 13.64% in CC alleles. The overall 2-year survival was significantly lower in TT genotype (50%) compared with CC genotype (90.91%; P = 0.01). MTHFR TT genotype is significantly associated with increased toxicity during methotrexate therapy as well as increased relapse rate in pediatric patients with ALL. In future, MTX dose adjustment in ALL treatment protocols should be considered based on patient's genotype.