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A Gastroenterologist's guide to drug interactions of small molecules for inflammatory bowel disease.United European Gastroenterology Journal Jun 2024Small molecule drugs are becoming increasingly used in the treatment of inflammatory bowel diseases (IBD). However, unlike monoclonal antibody drugs, which have few... (Review)
Review
Small molecule drugs are becoming increasingly used in the treatment of inflammatory bowel diseases (IBD). However, unlike monoclonal antibody drugs, which have few interactions with other medications, the pharmacokinetics of small molecule drugs are complex and may be influenced by a myriad of drug-drug interactions (DDI) as well as by patient characteristics and food intake. This review aims to provide a concise practical guide to small molecule drug interactions for the use of IBD physicians. It starts with a brief overview of the main metabolizing enzymes and transporters involved in drug interactions and the Food and Drug Administration's (FDA) approach to determining drug-interaction hazard thresholds. It is then followed by a more detailed review of the pharmacokinetics of five novel small molecules approved in IBD: Tofacitinib, Upadacitinib, Filgotinib, Ozanimod, and Etrasimod, including their known interactions and specific warnings. This review will also inform readers on challenges in determining the actual magnitude of interactions and their clinical relevance, including the arbitrary nature of some hazard thresholds, the inference of the impact on metabolizing enzymes and transporters from single-drug assays which may not reflect poly-pharmaceutical regimens, and other challenges in this field which the IBD physician needs to be cognizant of. In practice, before administering a small molecule drug, it is advisable to evaluate any potential interactions with other medications the patient is receiving. An increased awareness by health care professionals and patients, may reduce the possible risks associated with DDI of small molecule IBD drugs.
Topics: Humans; Drug Interactions; Inflammatory Bowel Diseases; Piperidines; Pyrimidines; Gastrointestinal Agents; Gastroenterologists; United States Food and Drug Administration; Pyridines; Heterocyclic Compounds, 3-Ring; Indans; Oxadiazoles; Triazoles
PubMed: 38532266
DOI: 10.1002/ueg2.12559 -
Blood Advances Dec 2023The efficacy and safety of nilotinib in pediatric patients with imatinib/dasatinib resistant/intolerant (R/I) or newly diagnosed (ND) Philadelphia chromosome-positive...
The efficacy and safety of nilotinib in pediatric patients with imatinib/dasatinib resistant/intolerant (R/I) or newly diagnosed (ND) Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) was demonstrated in the phase 2, open-label DIALOG study. In this final analysis, long-term efficacy and safety are presented for patients who completed 66 cycles (of 28 days) of treatment with nilotinib (230 mg/m2 twice daily) or discontinued early. Overall, 59 patients were enrolled and 58 were treated (R/I, n = 33; ND, n = 25; median time on treatment: 60.5 and 51.9 months, respectively). In the R/I cohort, the cumulative major molecular response (MMR; BCR::ABL1 international scale [IS] ≤ 0.1%) rate was 60.6%, and no patients had a confirmed loss of MMR. Among ND patients, the best overall MMR rate was 76.0%; 3 patients had a confirmed loss of MMR. The cumulative molecular response MR4 (BCR::ABL1IS ≤ 0.01%) and MR4.5 (BCR::ABL1IS ≤ 0.0032%) rates by 66 cycles were 27.3% and 12.1% in the R/I cohort, and 56.0% and 44.0% in the ND cohort, respectively. The safety profile of nilotinib was consistent with those of earlier reports. No on-treatment deaths occurred. These long-term (up to ∼5 years) data support the efficacy and safety of nilotinib in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov.uk as #NCT01844765.
Topics: Humans; Child; Antineoplastic Agents; Imatinib Mesylate; Pyrimidines; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
PubMed: 37738125
DOI: 10.1182/bloodadvances.2023010122 -
Bioorganic Chemistry Nov 2023PI3Kδ inhibitors play an important role in the treatment of leukemia, lymphoma and autoimmune diseases. Herein, using our reported compounds as the lead compound, we...
PI3Kδ inhibitors play an important role in the treatment of leukemia, lymphoma and autoimmune diseases. Herein, using our reported compounds as the lead compound, we designed and synthesized a series of selenium-containing PI3Kδ inhibitors based on quinazoline and pyrido[3,2-d]pyrimidine skeletons. Among them, compound Se15 showed sub-nanomolar inhibition against PI3Kδ and strong δ-selectivity. Moreover, Se15 showed potent anti-proliferative effect on SU-DHL-6 cells with an IC value of 0.16 μM. Molecular docking study showed that Se15 was able to form multiple hydrogen bonds with PI3Kδ and was close proximity and stacking with PI3Kδ selective region. In conclusion, the Se-containing compound Se15 bearing pyrido[3,2-d]pyrimidine scaffold is a novel potent and selective PI3Kδ inhibitor. The introduction of selenium can enrich the structure of PI3Kδ inhibitors and provide a new idea for design of novel PI3Kδ inhibitors.
Topics: Humans; Hydrogen Bonding; Leukemia; Molecular Docking Simulation; Pyrimidines; Selenium; Class I Phosphatidylinositol 3-Kinases; Drug Design
PubMed: 37672953
DOI: 10.1016/j.bioorg.2023.106815 -
BMJ Case Reports Oct 2023Aspergillosis is a challenging fungal infection. Voriconazole is an antifungal drug belonging to the triazole group, commonly used for treating invasive aspergillosis,...
Aspergillosis is a challenging fungal infection. Voriconazole is an antifungal drug belonging to the triazole group, commonly used for treating invasive aspergillosis, and candida infections. We present a case of a man in his late 70s diagnosed with rhino-orbital invasive aspergillosis who developed voriconazole-induced psychosis as an idiosyncratic, adverse drug reaction (ADR); however, he responded to the cessation of intravenous voriconazole and, after starting on an oral antipsychotic, haloperidol. Clinicians need to be cognizant of this rare, idiosyncratic and iatrogenic ADR to voriconazole.
Topics: Male; Humans; Voriconazole; Pyrimidines; Aspergillosis; Antifungal Agents; Invasive Fungal Infections; Psychotic Disorders
PubMed: 37821144
DOI: 10.1136/bcr-2023-254790 -
European Journal of Heart Failure Mar 2024In VICTORIA, vericiguat compared with placebo reduced the risk of cardiovascular death (CVD) and heart failure hospitalization (HFH) in patients enrolled after a... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
In VICTORIA, vericiguat compared with placebo reduced the risk of cardiovascular death (CVD) and heart failure hospitalization (HFH) in patients enrolled after a worsening heart failure (WHF) event. We examined clinical outcomes and efficacy of vericiguat as it relates to background use of loop diuretics in patients with WHF.
METHODS AND RESULTS
We calculated the total daily loop diuretic dose equivalent to furosemide dosing at randomization and categorized these as: no loop diuretic, 1-39, 41-80, 40, and >80 mg total daily dose (TDD). The primary composite outcome of CVD/HFH and its components were evaluated based on TDD loop diuretic and expressed as adjusted hazard ratios with 95% confidence intervals. Post-randomization rates of change in TDD were also examined. Of 4974 patients (98% of the trial) with diuretic dose information available at randomization, 540 (10.8%) were on no loop diuretic, 647 (13.0%) were on 1-39, 1633 (32.8%) were on 40, 1185 (23.8%) were on 41-80, and 969 (19.4%) were on >80 mg TDD. Patients with higher TDD had a higher rate of primary and secondary clinical outcomes. There were no significant interactions with TDD at randomization and efficacy of vericiguat versus placebo for any outcome (all p > 0.5). Post-randomization diuretic dose changes for vericiguat and placebo showed similar rates of up-titration (19.6 and 20.2/100 person-years), down-titration (16.8 and 18.1/100 person-years), and stopping diuretics (22.9 and 24.2/100 person-years).
CONCLUSIONS
Loop diuretic TDD at randomization was independently associated with worse outcomes in this high-risk population. The efficacy of vericiguat was consistent across the range of diuretic doses.
Topics: Humans; Heart Failure; Male; Female; Stroke Volume; Aged; Sodium Potassium Chloride Symporter Inhibitors; Middle Aged; Treatment Outcome; Furosemide; Dose-Response Relationship, Drug; Hospitalization; Pyrimidines; Double-Blind Method
PubMed: 38450878
DOI: 10.1002/ejhf.3179 -
Bioorganic Chemistry Oct 2023In the present work, the anti-inflammatory effect of 30 compounds containing 3-fluorophenyl pyrimidinylimidazo[2,1-b]thiazole was investigated. All final target...
In the present work, the anti-inflammatory effect of 30 compounds containing 3-fluorophenyl pyrimidinylimidazo[2,1-b]thiazole was investigated. All final target compounds showed significant Inhibitory effect on p38α. P38α is considered one of the key kinases in the inflammatory process due to its regulatory effect on pro-inflammatory mediators. The final target compounds divided into four group based on the type of terminal moiety (amide and sulfonamide) and the linker between pyrimidine ring and terminal moiety (ethyl and propyl). Most compounds with terminal sulfonamide moiety and propyl linker between the sulfonamide and pyrimidine ring were the most potent among all synthesized final target compounds with sub-micromolar IC. Compound 24g (with p-Cl benzene sulfonamide and propyl linker) exhibited the highest activity over P38α with IC 0.68 µM. All final target compounds were tested for their ability to inhibit nitric oxide release and prostaglandin E2 production. Compounds having amide terminal moiety with ethyl linker showed higher inhibitory activity for nitric oxide release and compound 21d exhibited the highest activity for nitric oxide release with IC 1.21 µM. Compounds with terminal sulfonamide moiety and propyl linker showed the highest activity for inhibiting PGE2 production and compounds 24i and 24g had the lowest IC with value 0.87 and 0.89 µM, respectively. Compounds 21d, 22d and 24g were tested for their ability to inhibit over expression of iNOS, COX1, and COX2. In addition the ability of compounds 21d, 22d and 24g to inhibit inflammatory cytokines were determined. Finally molecular docking of the three compounds were performed on P38α crystal structure to expect their mode of binding.
Topics: Thiazoles; Nitric Oxide; Molecular Docking Simulation; Anti-Inflammatory Agents; Sulfonamides; Amides; Pyrimidines; Structure-Activity Relationship; Molecular Structure
PubMed: 37459825
DOI: 10.1016/j.bioorg.2023.106716 -
Oncogene Nov 2023The internal tandem duplication of the FMS-like tyrosine kinase 3 (FLT3-ITD) is one of the most frequent genetic alterations in acute myeloid leukemia (AML). Limited and...
The internal tandem duplication of the FMS-like tyrosine kinase 3 (FLT3-ITD) is one of the most frequent genetic alterations in acute myeloid leukemia (AML). Limited and transient clinical benefit of FLT3 kinase inhibitors (FLT3i) emphasizes the need for alternative therapeutic options for this subset of myeloid malignancies. Herein, we showed that FLT3-ITD mutant (FLT3-ITD) AML cells were susceptible toward inhibitors of DHODH, a rate-limiting enzyme of de novo pyrimidine biosynthesis. Genetic and pharmacological blockade of DHODH triggered downregulation of FLT3-ITD protein, subsequently suppressed activation of downstream ERK and STAT5, and promoted cell death of FLT3-ITD AML cells. Mechanistically, DHODH blockade triggered autophagy-mediated FLT3-ITD degradation via inactivating mTOR, a potent autophagy repressor. Notably, blockade of DHODH synergized with an FDA-approved FLT3i quizartinib in significantly impairing the growth of FLT3-ITD AML cells and improving tumor-bearing mice survival. We further demonstrated that DHODH blockade exhibited profound anti-proliferation effect on quizartinib-resistant cells in vitro and in vivo. In summary, this study demonstrates that the induction of degradation of FLT3-ITD protein by DHODH blockade may offer a promising therapeutic strategy for AML patients harboring FLT3-ITD mutation.
Topics: Animals; Humans; Mice; Autophagy; Dihydroorotate Dehydrogenase; fms-Like Tyrosine Kinase 3; Leukemia, Myeloid, Acute; Mutation; Oncogene Proteins; Protein Kinase Inhibitors; Pyrimidines
PubMed: 37752234
DOI: 10.1038/s41388-023-02848-7 -
European Journal of Immunology Aug 2023Unraveling the immune signatures in rheumatoid arthritis (RA) patients receiving various treatment regimens can aid in comprehending the immune mechanisms' role in...
Unraveling the immune signatures in rheumatoid arthritis (RA) patients receiving various treatment regimens can aid in comprehending the immune mechanisms' role in treatment efficacy and side effects. Given the critical role of cellular immunity in RA pathogenesis, we sought to identify T-cell profiles characterizing RA patients under specific treatments. We compared 75 immunophenotypic and biochemical variables in healthy donors (HD) and RA patients, including those receiving different treatments as well as treatment-free patients. Additionally, we conducted in vitro experiments to evaluate the direct effect of tofacitinib on purified naïve and memory CD4 and CD8 T cells. Multivariate analysis revealed that tofacitinib-treated patients segregated from HD at the expense of T-cell activation, differentiation, and effector function-related variables. Additionally, tofacitinib led to an accumulation of peripheral senescent memory CD4 and CD8 T cells. In vitro, tofacitinib impaired the activation, proliferation, and effector molecules expression and triggered senescence pathways in T-cell subsets upon TCR-engagement, with the most significant impact on memory CD8 T cells. Our findings suggest that tofacitinib may activate immunosenescence pathways while simultaneously inhibiting effector functions in T cells, both effects likely contributing to the high clinical success and reported side effects of this JAK inhibitor in RA.
Topics: Humans; CD8-Positive T-Lymphocytes; CD4-Positive T-Lymphocytes; Arthritis, Rheumatoid; Pyrimidines
PubMed: 37179252
DOI: 10.1002/eji.202250353 -
Topics in Current Chemistry (Cham) Jan 2024Pyrimidine is a pharmacologically important moiety that exhibits diverse biological activities. This review reflects the growing significance of transition... (Review)
Review
Pyrimidine is a pharmacologically important moiety that exhibits diverse biological activities. This review reflects the growing significance of transition metal-catalyzed reactions for the synthesis of pyrimidines (with no discussion being made on the transition metal-catalyzed functionalization of pyrimidines). The effect of different catalysts on the selectivity/yields of pyrimidines and catalyst recyclability (wherever applicable) are described, together with attempts to illustrate the role of the catalyst through mechanisms. Although several methods have been researched for synthesizing this privileged scaffold, there has been a considerable push to expand transition metal-catalyzed, sustainable, efficient and selective synthetic strategies leading to pyrimidines. The aim of the authors with this update (2017-2023) is to drive the designing of new transition metal-mediated protocols for pyrimidine synthesis.
Topics: Transition Elements; Pyrimidines; Catalysis
PubMed: 38296918
DOI: 10.1007/s41061-024-00451-2 -
Hematological Oncology Jul 2024Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell malignancies. They target BTK, a key effector in the B-cell receptor (BCR)... (Review)
Review
Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell malignancies. They target BTK, a key effector in the B-cell receptor (BCR) signaling pathway, crucial for B-cell survival and proliferation. The first-in-class irreversible BTK inhibitor, ibrutinib, was approved for various B-cell malignancies but has limitations due to off-target effects. Second-generation inhibitors, such as acalabrutinib and zanubrutinib, offer improved selectivity and reduced side effects. However, resistance to BTK inhibitors, driven by BTK mutations, remains a challenge. Combinatorial therapies with PI3K inhibitors, immune checkpoint inhibitors, BH3 mimetics, and anti-CD20 antibodies show promise in overcoming resistance. Noncovalent BTK inhibitors and proteolysis-targeting chimeras (PROTACs) are emerging strategies with potential to combat resistance. Overall, advancements in BTK-targeted therapies provide hope for improved outcomes in patients with B-cell malignancies and a promising avenue to address drug resistance. Further research is needed to optimize combination therapies and identify optimal treatment regimens.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Drug Resistance, Neoplasm; Pyrazoles; Pyrimidines; Protein Kinase Inhibitors; Piperidines; Lymphoma, B-Cell; Tyrosine Kinase Inhibitors
PubMed: 38847437
DOI: 10.1002/hon.3294