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Drug Design, Development and Therapy 2019Recent advances in the understanding of the pathophysiology of ulcerative colitis (UC) have led to the expansion of our therapeutic arsenal. Conventional treatment... (Review)
Review
Recent advances in the understanding of the pathophysiology of ulcerative colitis (UC) have led to the expansion of our therapeutic arsenal. Conventional treatment options, including aminosalicylates, corticosteroids, thiopurines, and calcineurin inhibitors, fail to control the disease in a significant proportion of patients. Approximately 25-50% of the patients treated with tumor necrosis factor antibodies (anti-TNFα) are primary and secondary non-responders to therapy. Tofacitinib is a novel orally administered small synthetic molecule that inhibits a homologous family of enzymes, termed Janus kinases that modulate multiple key cytokines involved in the pathogenesis of UC. Phase II and III trials showed promising results in UC, leading the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to approve its administration for the induction and maintenance of remission in moderate-to-severe UC. Herein, we review tofacitinib for the management of UC, its mechanism of action pharmacokinetic properties, efficacy, and safety.
Topics: Administration, Oral; Colitis, Ulcerative; Humans; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles
PubMed: 31819376
DOI: 10.2147/DDDT.S182891 -
Hypertension Research : Official... Apr 2021The nonsteroidal mineralocorticoid receptor (MR) blocker esaxerenone has demonstrated good antihypertensive activity in a variety of patients, including those with... (Review)
Review
The nonsteroidal mineralocorticoid receptor (MR) blocker esaxerenone has demonstrated good antihypertensive activity in a variety of patients, including those with uncomplicated grade I-III hypertension, hypertension with moderate renal dysfunction, hypertension with type 2 diabetes mellitus with albuminuria, and hypertension associated with primary aldosteronism. Hyperkalemia has long been recognized as a potential side effect occurring during treatment with MR blockers, but there is a lack of understanding and guidance about the appropriate management of hyperkalemia during antihypertensive therapy with MR blockers, especially in regard to the newer agent esaxerenone. In this article, we first highlight risk factors for hyperkalemia, including advanced chronic kidney disease, diabetes mellitus, cardiovascular disease, age, and use of renin-angiotensin-aldosterone system inhibitors. Next, we examine approaches to prevention and management, including potassium monitoring, diet, and the use of appropriate therapeutic techniques. Finally, we summarize the currently available data for esaxerenone and hyperkalemia. Proper management of serum potassium is required to ensure safe clinical use of MR blockers, including awareness of at-risk patient groups, choosing appropriate dosages for therapy initiation and dosage titration, and monitoring of serum potassium during therapy. It is critical that physicians take such factors into consideration to optimize MR blocker therapy in patients with hypertension.
Topics: Humans; Hyperkalemia; Hypertension; Mineralocorticoid Receptor Antagonists; Pyrroles; Sulfones
PubMed: 33214722
DOI: 10.1038/s41440-020-00569-y -
Breast Cancer Research and Treatment Sep 2023In a phase II trial in patients with metastatic triple-negative breast cancer (mTNBC; NCT02978716), administering trilaciclib prior to gemcitabine plus carboplatin (GCb)... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
In a phase II trial in patients with metastatic triple-negative breast cancer (mTNBC; NCT02978716), administering trilaciclib prior to gemcitabine plus carboplatin (GCb) enhanced T-cell activation and improved overall survival versus GCb alone. The survival benefit was more pronounced in patients with higher immune-related gene expression. We assessed immune cell subsets and used molecular profiling to further elucidate effects on antitumor immunity.
METHODS
Patients with mTNBC and ≤ 2 prior chemotherapy regimens for locally recurrent TNBC or mTNBC were randomized 1:1:1 to GCb on days 1 and 8, trilaciclib prior to GCb on days 1 and 8, or trilaciclib alone on days 1 and 8, and prior to GCb on days 2 and 9. Gene expression, immune cell populations, and Tumor Inflammation Signature (TIS) scores were assessed in baseline tumor samples, with flow cytometric analysis and intracellular and surface cytokine staining used to assess immune cell populations and function.
RESULTS
After two cycles, the trilaciclib plus GCb group (n = 68) had fewer total T cells and significantly fewer CD8+ T cells and myeloid-derived suppressor cells compared with baseline, with enhanced T-cell effector function versus GCb alone. No significant differences were observed in patients who received GCb alone (n = 34). Of 58 patients in the trilaciclib plus GCb group with antitumor response data, 27 had an objective response. RNA sequencing revealed a trend toward higher baseline TIS scores among responders versus non‑responders.
CONCLUSION
The results suggest that administering trilaciclib prior to GCb may modulate the composition and response of immune cell subsets to TNBC.
Topics: Humans; Carboplatin; Triple Negative Breast Neoplasms; Pyrimidines; Pyrroles; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37418031
DOI: 10.1007/s10549-023-07009-8 -
Bioorganic & Medicinal Chemistry Letters Mar 2022The Protein Kinase N proteins (PKN1, PKN2 and PKN3) are Rho GTPase effectors. They are involved in several biological processes such as cytoskeleton organization, cell...
The Protein Kinase N proteins (PKN1, PKN2 and PKN3) are Rho GTPase effectors. They are involved in several biological processes such as cytoskeleton organization, cell mobility, adhesion, and cell cycle. Recently PKNs have been reported as essential for survival in several tumor cell lines, including prostate and breast cancer. Here, we report the development of dihydropyrrolopyridinone-based inhibitors for PKN2 and its closest homologue, PKN1, and their associated structure-activity relationship (SAR). Our studies identified a range of molecules with high potency exemplified by compound 8 with K = 8 nM for PKN2 and 14x selectivity over PKN1. Membrane permeability and target engagement for PKN2 were assessed by a NanoBRET cellular assay. Importantly, good selectivity across the wider human kinome and other kinase family members was achieved. These compounds provide strong starting points for lead optimization to PKN1/2 development compounds.
Topics: Antineoplastic Agents; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Development; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Molecular Docking Simulation; Molecular Structure; Protein Kinase C; Protein Kinase Inhibitors; Pyridones; Pyrroles; Structure-Activity Relationship
PubMed: 35104640
DOI: 10.1016/j.bmcl.2022.128588 -
Antimicrobial Agents and Chemotherapy Sep 2022Previous studies show high agreement between MIC spectrophotometric readings and visual inspection of azoles and amphotericin B against Aspergillus fumigatus isolates....
EUCAST-Obtained Olorofim MICs against Aspergillus and Scedosporium Species and Lomentospora prolificans Showed High Agreements between Visual Inspection and Spectrophotometric Readings.
Previous studies show high agreement between MIC spectrophotometric readings and visual inspection of azoles and amphotericin B against Aspergillus fumigatus isolates. Here, we tested and compared the activity of a novel antifungal, olorofim, against Aspergillus spp., spp., and Lomentospora prolificans by visual inspection and spectrophotometric readings. Clinical isolates of Aspergillus ( = 686) and ( = 36) spp. and ( = 13) were tested. Olorofim MICs were evaluated-following the EUCAST E.Def 9.4 procedure-by visual inspection or spectrophotometric readings (combinations of either ≥90% or ≥95% fungal growth inhibition endpoints compared to drug-free control endpoints and different wavelengths [405 nm, 450 nm, 492 nm, 540 nm, and 620 nm]). We observed high activity of olorofim against all tested Aspergillus spp. (MICs up to 0.06 mg/L), except for A. calidoustus, and against and spp. (MICs up to 0.125 mg/L). The combination of ≥90% fungal growth inhibition endpoints at wavelengths of ≥492 nm resulted in high essential agreements with A. fumigatus and lesser agreement with non- Aspergillus, spp., and , although the number of isolates studied was low. This single-center study shows high agreement among olorofim MICs against A. fumigatus by visual inspection and spectrophotometric readings (≥90% fungal growth inhibition endpoints and wavelengths of ≥492 nm) and encouraging results against non- Aspergillus spp., spp., and .
Topics: Acetamides; Amphotericin B; Antifungal Agents; Aspergillus; Piperazines; Pyrimidines; Pyrroles; Scedosporium
PubMed: 35924916
DOI: 10.1128/aac.00849-22 -
BMJ Open Diabetes Research & Care Sep 2020Progressive distal symmetrical axonal neuropathy, a complication of diabetes mellitus (DM), has an unknown cause. Normal physiological metabolism and diabetic...
INTRODUCTION
Progressive distal symmetrical axonal neuropathy, a complication of diabetes mellitus (DM), has an unknown cause. Normal physiological metabolism and diabetic dysmetabolism are associated with the generation of γ-diketones. γ-Diketones form pyrroles with protein amines, notably with axonal proteins required for the maintenance of nerve fiber integrity, especially elongate, large-diameter peripheral nerve fibers innervating the extremities. We tested the hypothesis that neuropathy-associated γ-diketone pyrroles are elevated in DM.
RESEARCH DESIGN AND METHODS
We measured the urinary concentration of γ-diketone pyrroles in age-matched and gender-matched elderly (60-84 years) persons with (n=267) or without (n=267) indicators of DM based in a community population (9411 community older adults aged ≥60 years) in Shenzhen city, Guangdong, China. We used statistical methods, including a generalized linear model, multivariate logistic regression analysis and restricted cubic splines, to assess linear and nonlinear relationships between urinary γ-diketone pyrroles and indicators of DM.
RESULTS
Compared with healthy controls, those with DM had significantly higher levels of fasting blood glucose, glycated hemoglobin A1c, urinary ketone bodies and urinary γ-diketone pyrroles. The median concentration of urinary γ-diketone pyrrole adducts was significantly higher (p<0.0001) in individuals with DM (7.5 (5.4) μM) compared with healthy controls (5.9 (4.3) μM). Both linear and non-linear relations were found between urinary γ-diketone pyrroles and indicators of DM.
CONCLUSIONS
Diabetic dysmetabolism includes increased generation and excretion of neuropathy-associated γ-diketone pyrroles. These findings form the foundation for studies to test whether γ-diketone pyrrole concentration correlates with quantitative sensory (vibration and temperature) and electrodiagnostic testing.
Topics: Aged; Aged, 80 and over; Axons; China; Diabetes Mellitus; Humans; Middle Aged; Peripheral Nervous System Diseases; Pyrroles
PubMed: 32912928
DOI: 10.1136/bmjdrc-2020-001575 -
United European Gastroenterology Journal Jun 2024Ustekinumab and tofacitinib have recently been approved for the management of moderate to severe ulcerative colitis (UC). However, there is no evidence on how they... (Observational Study)
Observational Study Comparative Study
BACKGROUND
Ustekinumab and tofacitinib have recently been approved for the management of moderate to severe ulcerative colitis (UC). However, there is no evidence on how they should be positioned in the therapeutic algorithm. The aim of this study was to compare tofacitinib and ustekinumab as third-line therapies in UC patients in whom anti-TNF and vedolizumab had failed.
METHODS
This was a multicenter retrospective observational study. The primary outcome was disease progression, defined as the need for steroids, therapy escalation, UC-related hospitalization and/or surgery. Secondary outcomes were clinical remission, normalization of C-reactive protein, endoscopic remission, treatment withdrawal, and adverse events.
RESULTS
One-hundred seventeen UC patients were included in the study and followed for a median time of 11.6 months (q-q 5.5-18.7). Overall, 65% of patients were treated with tofacitinib and 35% with ustekinumab. In the entire study cohort, 63 patients (54%) had disease progression during the follow-up period. Treatment with ustekinumab predicted increased risk of disease progression compared to treatment with tofacitinib in Cox regression analysis (HR: 1.93 [95% CI: 1.06-3.50] p = 0.030). Twenty-eight (68%) patients in the ustekinumab group and 35 (46%) in the tofacitinib group had disease progression over the follow-up period (log-rank test, p < 0.054). No significant differences were observed for the secondary outcomes. Six and 22 adverse events occurred in the ustekinumab and tofacitinib groups, respectively (15% vs. 31%, p = 0.11).
CONCLUSIONS
Tofacitinib was more efficacious in reducing disease progression than ustekinumab in this cohort of refractory UC patients. However, prospective head-to-head clinical trials are needed as to confirm these data.
Topics: Humans; Piperidines; Ustekinumab; Colitis, Ulcerative; Male; Female; Pyrimidines; Retrospective Studies; Adult; Middle Aged; Disease Progression; Treatment Outcome; Pyrroles; Remission Induction
PubMed: 38419274
DOI: 10.1002/ueg2.12492 -
Biomolecules Apr 2020The high sequence specificity of minor groove-binding -methylpyrrole--methylimidazole polyamides have made significant advances in cancer and disease biology, yet there... (Review)
Review
The high sequence specificity of minor groove-binding -methylpyrrole--methylimidazole polyamides have made significant advances in cancer and disease biology, yet there have been few comprehensive reports on their off-target effects, most likely as a consequence of the lack of available tools in evaluating genomic binding, an essential aspect that has gone seriously underexplored. Compared to other -heterocycles, the off-target effects of these polyamides and their specificity for the DNA minor groove and primary base pair recognition require the development of new analytical methods, which are missing in the field today. This review aims to highlight the current progress in deciphering the off-target effects of these -heterocyclic molecules and suggests new ways that next-generating sequencing can be used in addressing off-target effects.
Topics: Amides; Animals; DNA; Genomics; Humans; Imidazoles; Pyrroles
PubMed: 32260120
DOI: 10.3390/biom10040544 -
Journal For Immunotherapy of Cancer Jan 2022Combination treatments with immune-checkpoint inhibitor and antiangiogenic therapy have the potential for synergistic activity through modulation of the microenvironment...
Antitumor activity and safety of camrelizumab plus famitinib in patients with platinum-resistant recurrent ovarian cancer: results from an open-label, multicenter phase 2 basket study.
BACKGROUND
Combination treatments with immune-checkpoint inhibitor and antiangiogenic therapy have the potential for synergistic activity through modulation of the microenvironment and represent a notable therapeutic strategy in recurrent ovarian cancer (ROC). We report the results of camrelizumab (an anti-programmed cell death protein-1 antibody) in combination with famitinib (a receptor tyrosine kinase inhibitor) for the treatment of platinum-resistant ROC from an open-label, multicenter, phase 2 basket trial.
METHODS
Eligible patients with platinum-resistant ROC were enrolled to receive camrelizumab (200 mg every 3 weeks by intravenous infusion) and oral famitinib (20 mg once daily). All patients had disease progression during or <6 months after their most recent platinum-based chemotherapy. Primary endpoint was confirmed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 based on investigator's assessment. Secondary endpoints included disease control rate (DCR), duration of response (DoR), time to response (TTR), progression-free survival (PFS), overall survival (OS), 12-month OS rate and safety profile.
RESULTS
Of the 37 women enrolled, 11 (29.7%) patients had primary platinum resistant, 15 (40.5%) patients had secondary platinum resistant and 11 (29.7%) patients had primary platinum refractory disease. As the cut-off date of April 9, 2021, nine (24.3%) patients had achieved a confirmed objective response, the ORR was 24.3% (95% CI, 11.8 to 41.2) and the DCR was 54.1% (95% CI, 36.9 to 70.5). Patients with this combination regimen showed a median TTR of 2.1 months (range, 1.8-4.1) and a median DoR of 4.1 months (95% CI, 1.9 to 6.3). Median PFS was 4.1 months (95% CI, 2.1 to 5.7), and median OS was 18.9 months (95% CI, 10.8 to not reached), with the median follow-up duration of 22.0 months (range, 12.0-23.7). The estimated 12-month OS rate was 67.2% (95% CI, 49.4 to 79.9). The most common ≥grade 3 treatment-related adverse events were hypertension (32.4%), decreased neutrophil count (29.7%) and decreased platelet count (13.5%). One (2.7%) patient died of grade 5 hemorrhage that was judged possibly related to study treatment by investigator.
CONCLUSION
The camrelizumab with famitinib combination appeared to show antitumor activity in heavily pretreated patients with platinum-resistant ROC with an acceptable safety profile. This combination might provide a novel alternative treatment strategy in platinum-resistant ROC setting and warranted further exploration.
TRIAL REGISTRATION NUMBER
NCT03827837.
Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Pharmacological; Carcinoma, Ovarian Epithelial; Female; Humans; Indoles; Middle Aged; Pyrroles
PubMed: 35017154
DOI: 10.1136/jitc-2021-003831 -
Chemistry (Weinheim An Der Bergstrasse,... Jan 2020Dearomatisation of indole derivatives to the corresponding isatin derivatives has been achieved with the aid of visible light and oxygen. It should be noted that isatin...
Dearomatisation of indole derivatives to the corresponding isatin derivatives has been achieved with the aid of visible light and oxygen. It should be noted that isatin derivatives are highly important for the synthesis of pharmaceuticals and bioactive compounds. Notably, this chemistry works excellently with N-protected and protection-free indoles. Additionally, this methodology can also be applied to dearomatise pyrrole derivatives to generate cyclic imides in a single step. Later this methodology was applied for the synthesis of four pharmaceuticals and a pesticide called dianthalexin B. Detailed mechanistic studies revealed the actual role of oxygen and photocatalyst.
Topics: Catalysis; Imides; Indoles; Light; Pesticides; Pharmaceutical Preparations; Pyrroles
PubMed: 31596010
DOI: 10.1002/chem.201904168