scholarly journals Toxicity of azathioprine: why and when? analysis of the prevalence of polymorphism in Joinville, SC, Brazil

2012 ◽  
Vol 49 (2) ◽  
pp. 130-134 ◽  
Author(s):  
Gabriela Roncone Gastal ◽  
Simone Moreira ◽  
Caroline Furtado Noble ◽  
Leslie Ecker Ferreira ◽  
Paulo Henrique Condeixa de França ◽  
...  
Keyword(s):  
Blood Donors ◽  
Thiopurine Methyltransferase ◽  
Normal Allele ◽  
Wild Type ◽  
Drug Induced ◽  
Acute Leukemias ◽  
Allelic Variants ◽  
Risk Of Death ◽  
Inflammatory Bowel ◽  
Tpmt Gene

CONTEXT: The use of thiopurine drugs such as azathioprine and 6-mercaptopurine has become quite common in the treatment of inflammatory bowel disease, transplantation and acute leukemias. Despite their effectiveness, these drugs are capable of causing drug-induced toxicity with the risk of death by myelosuppression. It is now known that these complications occur because of genetic polymorphisms of the thiopurinemethyltransferase (TPMT) enzyme, responsible for its metabolism. OBJECTIVE: To assess the prevalence of thiopurine methyltransferase polymorphisms in the population of Joinville, SC, Brazil. METHODS: We analyzed the frequency of four main allelic variants of the TPMT gene in 199 blood donors from Joinville, from February to April 2010. RESULTS: The normal allele ("wild-type") was found in 93.9% of subjects studied. TPMT variants were detected in 12 subjects (6.03%). CONCLUSIONS: From this study, it was estimated at 6% the risk of toxicity by the administration of azathioprine and 6-mercaptopurine to patients in Joinville.

scholarly journals Thiopurine S-methyltransferase genetic polymorphisms in adult patients with inflammatory bowel diseases in the Latvian population

2020 ◽  
Vol 13 ◽  
pp. 175628482093742
Author(s):  
Polina Zalizko ◽  
Juris Stefanovics ◽  
Jelizaveta Sokolovska ◽  
Natalia Paramonova ◽  
Evija Klavina ◽  
...  
Keyword(s):  
Gene Polymorphisms ◽  
Fragment Length Polymorphism ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
Allelic Variants ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Tpmt Gene ◽  
European Populations

Background: Thiopurine methyltransferase (TPMT) plays a significant role in the metabolism of thiopurines, and, for patients with inflammatory bowel disease (IBD), it is useful to perform TPMT genotyping prior to azathioprine (AZA) treatment. In this study, we determined TPMT gene polymorphisms in a cohort of IBD patients in Latvia. Methods: DNA samples were obtained from 244 IBD patients, and qPCR was performed for detection of rs1800462, rs1800460, and rs1142345 single-nucleotide polymorphisms (SNPs). Three common, non-functional TPMT alleles ( TPMT*2, *3B, and *3C) were identified (women, 51%; men, 49%). TPMT*2, *3A, *3B, and *3C allelic variants detected using qPCR were consistent with restriction fragment length polymorphism (RFLP) data. Results: Among patients, 78% had ulcerative colitis and 22% had Crohn’s disease, with 93.9% of the former carrying a wild-type homozygous TPMT*1/*1 genotype and 6.1% carrying heterozygous genotypes. The most frequent polymorphisms were TPMT*1/*3A (5.3%: two variants: TPMT*3B and TPMT*3C), TPMT*1/*3C (0.4%), and TPMT*1/*2 (0.4%). None of the patients carried a TPMT*3B polymorphism and no patients were homozygous for any mutation. Conclusion: This is the first study to identify TPMT gene polymorphisms in adult IBD patients in Latvia. The results indicate that the frequency of common TPMT alleles is similar to that of other European populations.

scholarly journals Correlation between Thiopurine S-Methyltransferase Genotype and Adverse Events in Inflammatory Bowel Disease Patients

Medicina ◽  
2019 ◽  
Vol 55 (8) ◽  
pp. 441 ◽  
Author(s):  
Ribaldone ◽  
Adriani ◽  
Caviglia ◽  
Nicolò ◽  
Agnesod ◽  
...  
Keyword(s):  
Adverse Events ◽  
Therapeutic Option ◽  
Gene Mutations ◽  
Homozygous Mutation ◽  
Allelic Variants ◽  
Entire Cohort ◽  
Significant Difference ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Tpmt Gene

Background and Objectives: In patients with inflammatory bowel diseases (IBD), the use of azathioprine results in adverse events at a rate of 5% to 20%. The aim of the study was to assess a possible correlation between genetic variability of the enzyme thiopurine S-methyltransferase (TPMT) and the development of toxicity to azathioprine. Materials and Methods: A retrospective, single center, blind, case-control study was conducted on 200 IBD patients, of whom 60 cases suspended azathioprine due to toxicity (leukopenia, pancreatitis, hepatitis, and nausea or vomiting), and 140 controls continued treatment with the drug without adverse events. Results: In the entire cohort, only 8 cases of heterozygous mutations of TPMT were observed, corresponding to 4% mutated haplotype rate, much lower than that reported in literature (close to 10%). No homozygous mutation was found. Regarding the TPMT allelic variants, we did not find any statistically significant difference between patients who tolerated azathioprine and those who suffered from adverse events. (OR = 0.77, 95% CI = 0.08–7.72; p = 0.82). Conclusions: According to our study, in IBD patients, the search for TPMT gene mutations before starting treatment with azathioprine is not helpful in predicting the occurrence of adverse events. Importantly, patients with allelic variants should not be denied the therapeutic option of azathioprine, as they may tolerate this drug.

The Effect of Mianserin on Lifespan of Caenorhabditis elegans is Abolished by Glucose

2021 ◽  
Vol 13 ◽  
Author(s):  
Abdullah Almotayri ◽  
Jency Thomas ◽  
Mihiri Munasinghe ◽  
Markandeya Jois
Keyword(s):  
Caenorhabditis Elegans ◽  
Scaffolding Protein ◽  
Lifespan Extension ◽  
Wild Type ◽  
E Coli ◽  
C Elegans ◽  
Risk Of Death ◽  
Increased Risk ◽  
Antidepressant Use ◽  
Extension Effect

Background: The antidepressant mianserin has been shown to extend the lifespan of Caenorhabditis elegans (C. elegans), a well-established model organism used in aging research. The extension of lifespan in C. elegans was shown to be dependent on increased expression of the scaffolding protein (ANK3/unc-44). In contrast, antidepressant use in humans is associated with an increased risk of death. The C. elegans in the laboratory are fed Escherichia coli (E. coli), a diet high in protein and low in carbohydrate, whereas a typical human diet is high in carbohydrates. We hypothesized that dietary carbohydrates might mitigate the lifespan-extension effect of mianserin. Objective: To investigate the effect of glucose added to the diet of C. elegans on the lifespan-extension effect of mianserin. Methods: Wild-type Bristol N2 and ANK3/unc-44 inactivating mutants were cultured on agar plates containing nematode growth medium and fed E. coli. Treatment groups included (C) control, (M50) 50 μM mianserin, (G) 73 mM glucose, and (M50G) 50 μM mianserin and 73 mM glucose. Lifespan was determined by monitoring the worms until they died. Statistical analysis was performed using the Kaplan-Meier version of the log-rank test. Results: Mianserin treatment resulted in a 12% increase in lifespan (P<0.05) of wild-type Bristol N2 worms but reduced lifespan by 6% in ANK3/unc-44 mutants, consistent with previous research. The addition of glucose to the diet reduced the lifespan of both strains of worms and abolished the lifespan-extension by mianserin. Conclusion: The addition of glucose to the diet of C. elegans abolishes the lifespan-extension effects of mianserin.

scholarly journals Ulcerative Colitis and Sweet’s Syndrome: A Case Report and Review of the Literature

2008 ◽  
Vol 22 (3) ◽  
pp. 296-298 ◽  
Author(s):  
Massud Ali ◽  
Donald R Duerksen
Keyword(s):  
Ulcerative Colitis ◽  
Immunosuppressive Therapy ◽  
Neutrophilic Dermatosis ◽  
Sweet’S Syndrome ◽  
Review Of The Literature ◽  
Neutrophilic Infiltration ◽  
Drug Induced ◽  
Sweet's Syndrome ◽  
History Of ◽  
Inflammatory Bowel

A 47-year-old man with a history of ulcerative colitis on prednisone and azathioprine was admitted to the hospital with a four-day history of fever, skin rash, arthralgias and leukocytosis. A skin biopsy demonstrated neutrophilic infiltration of the dermis that was consistent with Sweet’s syndrome. He improved after several days with an increase in his prednisone and azathioprine. Sweet’s syndrome is a rare cutaneous manifestation of inflammatory bowel disease, with approximately 40 cases reported in the literature. In a previously reported case of a patient with ulcerative colitis-associated Sweet’s syndrome who was on azathioprine at the time of the skin eruption, the azathioprine was stopped, raising the possibility of drug-induced Sweet’s syndrome. In the present case, the azathioprine was actually increased with complete resolution of the skin manifestations. This would support the theory that immunosuppressive therapy is the mainstay of therapy for this condition. In conclusion, Sweet’s syndrome is a neutrophilic dermatosis that is rarely associated with ulcerative colitis. It may occur while on immunosuppressive therapy and responds to an intensification of immunosuppression.

scholarly journals P586 Drug-induced lipid changes in patients with Inflammatory Bowel Disease: a single center, prospective study

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S538-S538
Author(s):  
J Sleutjes ◽  
A C de Vries ◽  
J E Roeters van Lennep ◽  
C J van der Woude
Keyword(s):  
Inflammatory Bowel Disease ◽  
Prospective Study ◽  
Induction Therapy ◽  
Bowel Disease ◽  
Pearson Correlation ◽  
Lipid Lowering ◽  
Single Center ◽  
Lipid Levels ◽  
Drug Induced ◽  
Inflammatory Bowel

Abstract Background Drug use in the treatment of inflammatory bowel disease (IBD) might negatively impact lipid levels. In this study, we assessed drug-induced changes in the lipid profile after IBD induction therapy. Methods In this single center, prospective study IBD patients aged ≥17 years who started systemic drug therapy (corticosteroids, thiopurines, methotrexate, infliximab, adalimumab, vedolizumab, ustekinumab and tofacitinib) for IBD were included. Exclusion criteria were pregnancy, history of liver transplantation and use of lipid lowering drugs. Data on cardiovascular risk profile, disease activity (HBI, SCCAI, CRP, FCP) and concomitant medication use were collected. To calculate mean lipid changes after induction therapy, nonfasting lipid levels (total cholesterol (TC), HDL-c, LDL-c, triglycerides (TG)) were measured before and 8–10 weeks after start of therapy. Pearson correlation test was performed to assess the association between lipid changes and CRP. Results A total of 183 patients (87 males (48%), median age 36 years (IQR 28–48), 128 Crohn’s disease (70%), 46 CU (3%), 9 IBD-U (7%)) were included. (Table 1) Fourty-nine patients were on concomitant steroids at baseline (31%). Relative increases in TC, HDL-c and LDL-c were significant after treatment with corticosteroids and tofacitinib (+9%, +17%, +8% and +19%, +29%, +24%, respectively) and decrease in TG after treatment with corticosteroids, thiopurines, infliximab, adalimumab, ustekinumab and tofacitinib (-9%, -14%, -10%, -8%, -11%, -8%, respectively). (Table 2, Figure 1) A significant inverse relationship was found between CRP and TC (R -.171), HDL-c (R -.202), LDL-c (R -.153) but not with TG. Conclusion Serum lipid levels increased most after start of corticosteroids and tofacitinib as compared to other drug therapies. Whether these changes are explained by the control of inflammation or by the mechanism of action of these agents remains undetermined.

scholarly journals Effects of Clinicopathological Characteristics on the Survival of Patients Treated with PD-1/PD-L1 Inhibitor Monotherapy or Combination Therapy for Advanced Cancer: A Systemic Review and Meta-Analysis

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Yuhan Wei ◽  
Yongfu Li ◽  
Qi Du ◽  
Xinyi Peng ◽  
Jiangtao Jin ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Combination Therapy ◽  
Survival Benefit ◽  
Malignant Tumors ◽  
Smoking Status ◽  
Systemic Review ◽  
Wild Type ◽  
Risk Of Death ◽  
Significant Difference ◽  
Ecog Ps

Background. PD-1/PD-L1 inhibitors have made unprecedented progress in the treatment of cancer. Methods. A systemic search was conducted for randomized controlled trials that compared PD-1/PD-L1 inhibitor monotherapy or combination therapy with nonimmunotherapy. Hazard ratios (HRs) of overall survival (OS) according to the sex, age, ECOG PS, smoking status, liver metastasis, PD-L1 expression, EGFR, and KRAS status of patients were analyzed. Results. Totally, 13 studies with monotherapy and 5 with combination regimens were included, and the pooled HRs of OS were 0.74 ( P < 0.001 ) and 0.64 ( P < 0.001 ), respectively. EGFR wild-type patients could benefit from immunotherapy monotherapy (HR, 0.77; P < 0.001 ) while those of the mutant type had no survival benefit (HR, 1.11; P = 0.54 ), and the difference was statistically significant (interaction, P = 0.005 ). KRAS wild-type patients had no survival benefit from monotherapy (HR, 0.89; P = 0.49 ). For combination therapy, both male and female derived benefits but female had a significantly reduced risk of death (HR, 0.45; P < 0.001 ) compared with male (HR, 0.73; P < 0.001 ; interaction, P = 0.004 ). Nonsmokers derived more survival benefits from combination therapy (HR, 0.29; P < 0.001 ) than smokers (HR, 0.63; P = 0.001 ; interaction, P = 0.02 ). No significant difference was found between age, ECOG PS, liver metastasis, PD-L1 expression, and OS of both PD-1/PD-L1 inhibitor monotherapy and combination therapy. Conclusions. Both PD-1/PD-L1 inhibitor monotherapy and combination therapy significantly prolonged the OS of patients with advanced malignant tumors. EGFR status for monotherapy and sex and smoking status for combination therapy were important predictors of survival benefits.

COVID-19 and hematologic diseases: Risk factors and long-term follow-up of CHRONOS19 Registry.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18715-e18715
Author(s):  
Kristina Zakurdaeva ◽  
Olga A. Gavrilina ◽  
Anastasia N. Vasileva ◽  
Sergei Dubov ◽  
Vitaly S. Dubov ◽  
...  
Keyword(s):  
Risk Factors ◽  
Mechanical Ventilation ◽  
Disease Progression ◽  
Primary Endpoint ◽  
Acute Leukemias ◽  
Risk Of Death ◽  
All Cause Mortality ◽  
Long Term Follow Up

e18715 Background: Pts with hem diseases are at high risk of COVID-19 severe course and mortality. Emerging data on risk factors and outcomes in this patient population is of great value for developing strategies of medical care. Methods: CHRONOS19 is an ongoing nationwide observational cohort study of adult (≥18 y) pts with hem disease (both malignant and non-malignant) and lab-confirmed or suspected (clinical symptoms and/or CT) COVID-19. Primary objective was to evaluate treatment outcomes. Primary endpoint was 30-day all-cause mortality. Long-term follow-up was performed at 90 and 180 days. Data from 14 centers was collected on a web platform and managed in a deidentified manner. Results: As of data cutoff on January 27, 2021, 575 pts were included in the registry, 486 of them eligible for primary endpoint assessment, n(%): M/F 243(50%)/243(50%), median age 56 [18-90], malignant disease in 452(93%) pts, induction phase/R/R/remission 160(33%)/120(25%)/206(42%). MTA in 93(19%) pts, 158(33%) were transfusion dependent, comorbidities in 278(57%) pts. Complications in 335(69%) pts: pneumonia (67%), CRS (8%), ARDS (7%), sepsis (6%). One-third of pts had severe COVID-19, 25% were admitted to ICU, 20% required mechanical ventilation. All-cause mortality at 30 days – 17%; 80% due to COVID-19 complications. At 90 days, there were 14 new deaths: 6 (43%) due to hem disease progression. Risk factors significantly associated with OS are listed in Tab 1. In multivariate analysis – ICU+mechanical ventilation, HR, 53.3 (29.1-97.8). Acute leukemias were associated with higher risk of death, HR, 2.40 (1.28-4.51), less aggressive diseases (CML, CLL, MM, non-malignant) – with lower risk of death, HR, 0.54 (0.37-0.80). No association between time of COVID-19 diagnosis (Apr-Aug vs. Sep-Jan) and risk of death. COVID-19 affected treatment of hem disease in 65% of pts, 58% experienced treatment delay for a median of 4[1-10] weeks. Relapse rate on Day 30 and 90 – 4%, disease progression on Day 90 detected in 13(7%) pts; 180-day data was not mature at the time of analysis. Several cases of COVID-19 re-infection were described. Conclusions: Thirty-day all-cause mortality in pts with hem disease was higher than in general population with COVID-19. Longer-term follow-up (180 days) for hem disease outcomes and OS will be presented. [Table: see text]

Gastroenterological emergencies

2019 ◽  
pp. 227-288
Author(s):  
Punit S. Ramrakha ◽  
Kevin P. Moore ◽  
Amir H. Sam
Keyword(s):  
Inflammatory Bowel Disease ◽  
Liver Failure ◽  
Biliary Obstruction ◽  
Gallstone Disease ◽  
Gi Bleeding ◽  
Drug Induced ◽  
Ulcer Disease ◽  
Liver Abscesses ◽  
Inflammatory Bowel ◽  
Upper Gastrointestinal

This chapter describes gastroenterological emergencies, including acute upper gastrointestinal (GI) bleeding, peptic ulcer disease, erosive gastritis/oesophagitis, variceal haemorrhage, Mallory–Weiss tear, gastroenteritis (acute, bacterial, viral), Clostridium difficile, giardiasis, travellers’ diarrhoea, bloody diarrhoea, dysentery (bacterial, amoebic), inflammatory bowel disease (IBD), jaundice, hepatitis (viral, alcoholic, drug-induced, autoimmune), acholuric jaundice, sepsis, ischaemic hepatitis, obstructive jaundice, gallstone disease, acute cholecystitis, biliary obstruction, ascites, acute liver failure, ‘acute-on-chronic’ liver failure, hepatic encephalopathy, liver abscesses, and acute pancreatitis.

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