- |||||||||| Remicade (infliximab) / Mitsubishi Tanabe, J&J, Stelara (ustekinumab) / J&J, Humira (adalimumab) / Eisai, AbbVie
Infliximab Drug-Induced Autoimmune Hepatitis in Patient With Crohn’s Ileocolitis (Exhibit Halls 3 and 4 (Street Level)) - Aug 8, 2019 - Abstract #ACG2019ACG_3002;
This is a rare case of infliximab-induced AIH, and it is an important consideration in patients with elevated LFTs after starting this drug. Treatment involves cessation of infliximab and treatment with steroids, which usually leads to resolution of the hepatitis.
- |||||||||| Idiopathic Thrombocytopenic Purpura: An Uncommon Extra-intestinal Manifestation of Crohn's Disease (Exhibit Halls 3 and 4 (Street Level)) - Aug 8, 2019 - Abstract #ACG2019ACG_1917;
He was started on IV methylprednisone and given platelet transfusions with only a brief response in platelet count...His platelet count had only a transient response to combined steroids and IVIg, so rituximab was given on hospital day 10...Given a history of thrombocytopenia with adalimumab and infliximab, he received ustekinumab for his CD flare on day 14...His CD has been controlled on maintenance ustekinumab and 6-mercaptopurine in the 5 months following discharge...Indeed, our literature review identified 1 case where ITP was refractory to steroids and splenectomy, but responded after bowel resection and another case where medically refractory ITP responded to bowel resection alone. These cases, as well as the one we have presented, suggest that colectomy should be considered in the treatment of medically refractory ITP among patients with concomitant CD.
- |||||||||| A Case of Hepatosplenic T-cell Lymphoma in a Patient on Vedolizumab for Crohn’s Disease (Exhibit Halls 3 and 4 (Street Level)) - Aug 8, 2019 - Abstract #ACG2019ACG_1012;
To our knowledge, there have not been reports of HSTCL associated with vedolizumab use nor is there a known mechanism by which vedolizumab could cause HSTCL. In our case, TNF-α inhibitor was stopped 5 years prior and thiopurine analog 1 year prior to diagnosis, raising the question as to how long the risk of HSTCL remains elevated after cessation of such agents.
- |||||||||| 6 Mercaptopurine / Teva
NUDT15 MUTATION: A NEW PROGNOSTIC FACTOR IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA? (Poster Area) - Aug 7, 2019 - Abstract #SIOP2019SIOP_1348;
This report supports CPIC guidelines for screening NUDT15 polymorphism before 6-MP treatment regardless patients’ origins. The impact of this polymorphism on relapse occurrence is worrying and prospective results with dose adjustments at 6-MP initiation will be crucial to understand if treatment interruptions and/or reduced dose were at risk of relapse.
- |||||||||| 6 Mercaptopurine / Teva
Clinical, Journal: MSH6 haploinsufficiency at relapse contributes to the development of thiopurine resistance in pediatric B-lymphoblastic leukemia. (Pubmed Central) - Jul 11, 2019
We knocked down MSH6 in mismatch repair proficient cell lines (697 and UOCB1) and showed significant increases in IC50s to 6-thioguanine and 6-mercaptopurine (697: 26- and 9-fold; UOCB1: 5- and 8-fold) in vitro, as well as increased resistance to 6-mercaptopurine treatment in vivo No shift in IC50 was observed in deficient cells (Reh and RS4;11)...MSH6 knockdown cells showed minimal activation of checkpoint regulator CHK1, ɣH2AX (DNA damage marker) and p53 levels upon treatment with thiopurines, consistent with intrinsic chemoresistance due to failure to recognize thioguanine nucleotide mismatching and initiate mismatch repair. Aberrant MSH6 adds to the list of alterations/mutations associated with acquired resistance to purine analogues emphasizing the importance of thiopurine therapy.
- |||||||||| 6 Mercaptopurine / Teva
Journal: Excitation-independent emission carbon nanoribbon polymer as a ratiometric photoluminescent probe for highly selective and sensitive detection of quercetin. (Pubmed Central) - Jul 11, 2019
In this study, sulfur-nitrogen co-doped carbon nanoribbon (SNCNR) polymers with stable dual-emission fluorescence were synthesized using a one-step traditional hydrothermal method of 6-mercaptopurine in an aqueous methanol solution...Meanwhile, this sensor shows high selectivity for Que over other biomolecules, most amino acids and metal ions under the same conditions. Finally, this fluorescent probe was successfully applied to the direct analysis of Que in bovine serum and some beverage samples, which showed that it has potential for use in applications in clinical diagnosis and food analysis, and may pave the way for the design of effective fluorescent probes for other biologically related targets and food protection.
- |||||||||| 6 Mercaptopurine / Teva
Preclinical, Journal: Preclinical evaluation of-guided thiopurine therapy and its effects on toxicity and anti-leukemic efficacy. (Pubmed Central) - Jul 4, 2019
Thiopurines (eg, 6-mercaptopurine [MP]) are highly efficacious antileukemic agents, but they are also associated with dose-limiting toxicities...Using leukemia-bearing mice with concordantgenotype in leukemia and host, we also confirmed that therapeutic efficacy is preserved inmice on a reduced MP dose comparedcounterparts exposed to a standard dosage. In conclusion, we demonstrated that-genotype guided MP dose individualization can preemptively mitigate toxicity without compromising therapeutic efficacy.
- |||||||||| 6 Mercaptopurine / Teva
Retrospective data, Journal: Clostridium difficile in inflammatory bowel disease. (Pubmed Central) - Jun 19, 2019
Patients with IBD with CDI in history often noted the ineffectiveness of therapy with salicylates, often require the assignment of biological therapy. IBD patients with CDI have a lower average albumin, and a higher activity of the inflammatory process.
- |||||||||| dexamethasone / generics
Clinical, Journal: Systemic Juvenile Xanthogranuloma Involving the Bone Marrow, Multiple Bones, and the Skin That Developed During Treatment of Acute Lymphoblastic Leukemia in Remission State. (Pubmed Central) - Jun 15, 2019
Symptoms have resolved since maintenance chemotherapy, which included vincristine, dexamethasone, 6-mercaptopurine, and methotrexate. Bone marrow involvement of JXG is very rare, occurring only in patients less than 1 year of age; however, this case was reported in an adolescent during acute lymphoblastic leukemia treatment.
- |||||||||| 6 Mercaptopurine / Teva
Clinical, Journal: NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia. (Pubmed Central) - Jun 15, 2019
The antileukaemic drug 6-mercaptopurine is converted into thioguanine nucleotides (TGN) and incorporated into DNA (DNA-TG), the active end metabolite...rs72846714 was not associated with relapse risk, but in a separate cohort of 180 children with relapsed ALL, rs72846714-A genotype was associated with increased occurrence of relapse-specific NT5C2 gain-of-function mutations that reduce cytosol TGN levels (P = 0.03). These observations highlight the impact of both germline and acquired mutations in drug metabolism and disease trajectory.
- |||||||||| 6 Mercaptopurine / Teva
Journal: Metal-free SERS substrate based on rGO-TiO-FeO nanohybrid: contribution from interfacial charge transfer and magnetic controllability. (Pubmed Central) - Jun 11, 2019
Exploiting these features, it could be used for the SERS detection of 4-mercaptobenzoic acid (4-MBA), 4-mercaptopyridine (4-MPy), 6-mercaptopurine monohydrate (6-MP), 1,2-di(4-pyridyl) ethylene (BPE) and p-aminobenzoic acid (PABA) with the detection limits of 1.0 × 10-10, 1.0 × 10-8, 1.0 × 10-10, 1.0 × 10-10 and 1.0 × 10-9 mol L-1, respectively; these are the highest SERS sensitivity values among those reported for semiconductor substrates and are even lower than that of noble metal substrates. Meanwhile, an SERS enhancement mechanism from the synergistic effects of the rGO, TiO2 and Fe3O4 components was proposed to explain the observed considerable SERS enhancement on rGO-TiO2-Fe3O4.
- |||||||||| 6 Mercaptopurine / Teva
Journal: Cysteine-stabilized silver nanoparticles as a colorimetric probe for the selective detection of cysteamine. (Pubmed Central) - May 14, 2019
...Significantly, other biomolecules such as arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutathione, glycine, methionine and 6-mercaptopurine did not cause any change in the colour of the AgNPs...The mechanism of the aggregation of the AgNPs induced by cysteamine has also been described. The method has been applied for the detection of cysteamine in human blood serum.
- |||||||||| Remicade (infliximab) / Mitsubishi Tanabe, J&J, Humira (adalimumab) / Eisai, AbbVie
Journal: Paediatric inflammatory bowel disease: review with a focus on practice in low- to middle-income countries. (Pubmed Central) - May 7, 2019
The identification and management of children with inflammatory bowel conditions often depends on the enthusiasm, skill and commitment of a few dedicated individuals. Abbreviations: ADA: Adalimumab; CD: Crohn disease; ECCO: European Crohn's and Colitis Organisation; EEN: exclusive enteral nutrition; ESPGHAN: European Society for Paediatric Gastroenterology Hepatology and Nutrition; FMT: faecal microbiota transplantation; GDP: gross domestic product; HIC: high-income countries; IBD: inflammatory bowel disease; IBDU: inflammatory bowel disease unclassified; IC: ileocolonoscopy; IFX: infliximab; IPAA: ileal pouch anal anastomosis; LMIC: low- and middle-income countries; MH: mucosal healing; OGD: oesophago-gastroduodenoscopy; PCDAI: Paediatric Crohn's Disease Activity Index; PIBD: paediatric inflammatory bowel disease; PUCAI: Paediatric Ulcerative Colitis Activity Index; UC: ulcerative colitis; UGIT: upper gastrointestinal tract; VEO-IBD: very early-onset IBD; WLE: white light endoscopy; 5-ASA: 5 aminosalicylic acid; 6-MP: 6-mercaptopurine.
- |||||||||| 6 Mercaptopurine / Teva
Journal: Photochemical and Photodynamical Properties of Sulfur-Substituted Nucleic Acid Bases. (Pubmed Central) - May 2, 2019
The most promising photodynamic agents identified thus far have been investigated in various carcinoma cell lines and shown to decrease cell proliferation upon exposure to ultraviolet-A radiation. Overarching principles have been elucidated for the impact that sulfur substitution of the carbonyl oxygen has on the photochemical properties of the nucleobases.
- |||||||||| dexamethasone / generics, tacrolimus / generics
Journal: Conventional therapy for moderate to severe inflammatory bowel disease: A systematic literature review. (Pubmed Central) - Apr 18, 2019
Efforts to vaccinate IBD patients against HBV before use of immunomodulators and anti-TNFs, infliximab specifically, and screen periodically thereafter must be reinforced. High-quality evidence assessing conventional therapy in MS-IBD treatment is scarce, especially for remission maintenance, mucosal healing and fecal calprotectin.
- |||||||||| 6 Mercaptopurine / Teva
Journal: Thiopurine-induced toxicity is associated with dysfunction variant of the human molybdenum cofactor sulfurase gene (xanthinuria type II). (Pubmed Central) - Apr 17, 2019
The identified variant c.362C˃T results in slower thiopurine metabolism caused by inhibition of 6-mercaptopurine oxidation (catabolism) to 6-thioxanthine and 6-thiouric acid, which increases the formation of the nucleotide 6-thioguanine, which is toxic. This is the first clinical case to identify the crucial role of the MOCOS gene in thiopurine intolerance and confirm the impact of genetic variability of purine enzymes on different therapeutic outcomes in patients undergoing thiopurine treatment.
- |||||||||| Afinitor (everolimus) / Novartis
Journal: Impact of Immunosuppressive Drugs on the Metabolism of TÂ Cells. (Pubmed Central) - Apr 17, 2019
These examples raise the issue of how the modulation of these metabolic checkpoints can regulate T-cell activation, differentiation, and function. In this review we highlight emerging concepts about the modulation of metabolic reprogramming in T-cell responses by immunosuppressive drugs and how potential therapeutic interventions influence T-cell fate and effector function.
- |||||||||| 6 Mercaptopurine / Teva
Journal: A New Electrochemical Sensor for Direct Detection of Purine Antimetabolites and DNA Degradation. (Pubmed Central) - Apr 16, 2019
The new sensor, labelled as GrO-IL-AuNPs-Chit/CSE, exhibited an improved electrocatalytic response to cancer drugs such as purine antimetabolites (6-thioguanine, 6-mercaptopurine, and azathioprine) in a wide concentration range with a low detection limit (20-40 nmol·L, S/N = 3), and satisfactory recoveries (97.1-103.0%). The sensor has been also successfully used for cyclic voltammetric study of a salmon sperm double-stranded DNA degradation and DNA-6-mercaptopurine interaction in aqueous solutions (pH 7.4).
- |||||||||| 6 Mercaptopurine / Teva
Journal: Structure and Mechanisms of NT5C2 Mutations Driving Thiopurine Resistance in Relapsed Lymphoblastic Leukemia. (Pubmed Central) - Apr 11, 2019
Activating mutations in the cytosolic 5'-nucleotidase II gene NT5C2 drive resistance to 6-mercaptopurine in acute lymphoblastic leukemia...In addition, we show that the C-terminal acidic tail lost in the Q523X mutation functions to restrain NT5C2 activation. These results uncover dynamic mechanisms of enzyme regulation targeted by chemotherapy resistance-driving NT5C2 mutations, with important implications for the development of NT5C2 inhibitor therapies.
- |||||||||| 6 Mercaptopurine / Teva
Journal: Role of TPMT and ITPA variants in mercaptopurine disposition. (Pubmed Central) - Mar 27, 2019
DNA-TG may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than cytosolic metabolites. Prospective trials are needed to evaluate the usefulness of DNA-TGN for individual dose adjustments in childhood ALL maintenance therapy.
- |||||||||| Besponsa (inotuzumab ozogamicin) / Pfizer, UCB, mercaptopurine delayed release (DR6MP) / Teva, abelacimab (MAA868) / Anthos Therap, Novartis, MorphoSys, Lonza
Clinical, P2 data, Journal, Combination therapy: Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. (Pubmed Central) - Jan 29, 2019
P1/2
Inotuzumab ozogamicin plus mini-hyper-CVD chemotherapy is a safe and active first-line therapy option in older patients with newly diagnosed acute lymphoblastic leukaemia and could represent a new therapy for this population. Randomised, phase 3 trials to evaluate the efficacy of this combination compared with the current standard of care in this setting, combination chemotherapy without inotuzumab ozogamicin, are warranted.
- |||||||||| mercaptopurine delayed release (DR6MP) / Teva
Journal: Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia. (Pubmed Central) - Jul 13, 2018
Consequently, blocking guanosine synthesis by inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) induced increased cytotoxicity against NT5C2-mutant leukaemia lymphoblasts. These results identify the fitness cost of NT5C2 mutation and resistance to chemotherapy as key evolutionary drivers that shape clonal evolution in relapsed ALL and support a role for IMPDH inhibition in the treatment of ALL.
- |||||||||| mercaptopurine delayed release (DR6MP) / Teva
Journal: mTORC1 Inhibition Induces Resistance to Methotrexate and 6-Mercaptopurine in Ph+ and Ph-like B-ALL. (Pubmed Central) - May 12, 2018
Dasatinib, a tyrosine kinase inhibitor currently used in Ph patients, inhibits ABL kinase upstream of mTOR...Using xenograft models, we observed that mTOR inhibition or dasatinib increased the numbers of leukemia cells that emerge after cessation of chemotherapy treatment. These results demonstrate that inhibitors targeting mTOR or upstream signaling nodes should be used with caution when combined with chemotherapeutic agents that rely on cell cycle progression to kill B-ALL cells.
- |||||||||| mercaptopurine delayed release (DR6MP) / Teva
Journal: Comparison of self-report and electronic monitoring of 6MP intake in childhood ALL: A Children's Oncology Group study. (Pubmed Central) - Aug 12, 2017
Multivariable logistic regression technique identified the following variables associated with the over-reporter phenotype: i) non-white race: Hispanic, odds ratio (OR)=2.4, 95%CI, 1.1-5.1, p=0.02; Asian, OR=3.1, 95%CI, 1.2-8.3, p=0.02; African-American, OR=5.4, 95%CI, 2.3-12.8, p=0.0001; ii) paternal education <college (OR=1.4, 95%CI, 1.0-2.0, p=0.05); and iii) 6MP non-adherence (OR=9.4, 95%CI, 5.1-17.5, p<0.0001). Self-report of 6MP intake in childhood ALL over-estimates true intake, particularly in non-adherent patients, and should be used with caution.
- |||||||||| mercaptopurine delayed release (DR6MP) / Teva
Trial termination: Multicenter Clinical Efficacy and Safety Study of Delayed Release 6MP in Crohn's Disease (clinicaltrials.gov) - Mar 5, 2013
P1/2, N=70, Terminated,
Self-report of 6MP intake in childhood ALL over-estimates true intake, particularly in non-adherent patients, and should be used with caution. Recruiting --> Terminated; Sponsor withdrew support of study due to reorganization and project prioritization
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