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Current Pain and Headache Reports Sep 2023Gepants are small molecules that antagonize calcitonin gene-related peptide (CGRP) receptors. Due to their favorable side effect profile and versatility in treating... (Review)
Review
PURPOSE OF REVIEW
Gepants are small molecules that antagonize calcitonin gene-related peptide (CGRP) receptors. Due to their favorable side effect profile and versatility in treating headaches acutely and preventively, gepants are preferred over triptans. We will cover the indications for the four FDA-approved gepants in adults: rimegepant, atogepant, ubrogepant, and zavegepant. This review will illustrate how gepants will continue to revolutionize the acute and preventive treatment of headaches.
RECENT FINDINGS
Gepants are now available in oral tablet, dissolving tablet, and intra-nasal spray formulations. Recent studies have shown promising utility in treating the pre-headache or prodromal phase. They have favorable tolerability, no evidence for association with medication overuse, and remain a safer alternative in those who have cerebrovascular risk factors. Additional research is needed to explore occurrence of Raynaud's phenomenon in participants treated with gepants, as it has been associated with CGRP monoclonal antibodies, but are not extensively studied in gepants. Gepants are expected to play a significant role in the next generation of migraine treatments.
Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Pyridines; Pyrroles; Migraine Disorders; Raynaud Disease
PubMed: 37531032
DOI: 10.1007/s11916-023-01142-1 -
Journal of Inorganic Biochemistry Jan 2024
Topics: Heme
PubMed: 37953207
DOI: 10.1016/j.jinorgbio.2023.112423 -
Association Between Vonoprazan and the Risk of Gastric Cancer After Helicobacter pylori Eradication.Clinical Gastroenterology and... Jun 2024Potassium-competitive acid blockers (PCABs) have been increasingly used to treat upper gastrointestinal disorders, replacing proton pump inhibitors (PPIs). Whereas PPIs...
BACKGROUND & AIMS
Potassium-competitive acid blockers (PCABs) have been increasingly used to treat upper gastrointestinal disorders, replacing proton pump inhibitors (PPIs). Whereas PPIs are associated with an increased risk of gastric cancer (GC) after Helicobacter pylori (Hp) eradication, it is uncertain whether PCABs carry the same risk.
METHODS
Using a population-based claims database in Japan, we identified patients who were prescribed a clarithromycin-based first regimen of Hp eradication between 2015 and 2018. Patients who failed this regimen and those diagnosed with GC before or within 1 year after Hp eradication were excluded. We compared GC incidence between PCAB users and histamine type-2 receptor antagonist (H2RA) users, matching them on the basis of propensity scores calculated with considerations for age, sex, smoking, alcohol consumption, comorbidities, and co-administered medications. PCABs included only vonoprazan in this study.
RESULTS
Among 54,055 patients, 568 (1.05%) developed GC during the follow-up period (mean, 3.65 years). The cumulative incidence of GC was 1.64% at 3 years, 2.02% at 4 years, and 2.36% at 5 years in PCAB users and 0.71% at 3 years, 1.04% at 4 years, and 1.22% at 5 years in H2RA users. The use of PCABs was associated with a higher GC risk (matched hazard ratio, 1.92; 95% confidence interval, 1.13-3.25; P = .016). Longer PCAB use and high-dose PCAB use were significantly associated with higher incidence of GC. Sensitivity analyses showed the risk of GC incidence among PCAB users was comparable with that of PPI users.
CONCLUSIONS
The use of PCABs was associated with an increased risk of GC among Hp-eradicated patients, with duration/dose response effects.
Topics: Humans; Male; Female; Stomach Neoplasms; Helicobacter Infections; Middle Aged; Japan; Sulfonamides; Aged; Incidence; Pyrroles; Proton Pump Inhibitors; Helicobacter pylori; Histamine H2 Antagonists; Retrospective Studies; Adult; Risk Assessment; Risk Factors; Anti-Bacterial Agents
PubMed: 38354970
DOI: 10.1016/j.cgh.2024.01.037 -
Annals of the Rheumatic Diseases Dec 2023To investigate the efficacy and safety of otilimab, an antigranulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis.
Anti-GM-CSF otilimab versus tofacitinib or placebo in patients with active rheumatoid arthritis and an inadequate response to conventional or biologic DMARDs: two phase 3 randomised trials (contRAst 1 and contRAst 2).
OBJECTIVES
To investigate the efficacy and safety of otilimab, an antigranulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis.
METHODS
Two phase 3, double-blind randomised controlled trials including patients with inadequate responses to methotrexate (contRAst 1) or conventional synthetic/biologic disease-modifying antirheumatic drugs (cs/bDMARDs; contRAst 2). Patients received background csDMARDs. Through a testing hierarchy, subcutaneous otilimab (90/150 mg once weekly) was compared with placebo for week 12 endpoints (after which, patients receiving placebo switched to active interventions) or oral tofacitinib (5 mg two times per day) for week 24 endpoints.
PRIMARY ENDPOINT
proportion of patients achieving an American College of Rheumatology response ≥20% (ACR20) at week 12.
RESULTS
The intention-to-treat populations comprised 1537 (contRAst 1) and 1625 (contRAst 2) patients.
PRIMARY ENDPOINT
proportions of ACR20 responders were statistically significantly greater with otilimab 90 mg and 150 mg vs placebo in contRAst 1 (54.7% (p=0.0023) and 50.9% (p=0.0362) vs 41.7%) and contRAst 2 (54.9% (p<0.0001) and 54.5% (p<0.0001) vs 32.5%). Secondary endpoints: in both trials, compared with placebo, otilimab increased the proportion of Clinical Disease Activity Index (CDAI) low disease activity (LDA) responders (not significant for otilimab 150 mg in contRAst 1), and reduced Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Benefits with tofacitinib were consistently greater than with otilimab across multiple endpoints. Safety outcomes were similar across treatment groups.
CONCLUSIONS
Although otilimab demonstrated superiority to placebo in ACR20, CDAI LDA and HAQ-DI, improved symptoms, and had an acceptable safety profile, it was inferior to tofacitinib.
TRIAL REGISTRATION NUMBERS
NCT03980483, NCT03970837.
Topics: Humans; Antirheumatic Agents; Arthritis, Rheumatoid; Methotrexate; Biological Products; Treatment Outcome; Double-Blind Method; Pyrroles; Randomized Controlled Trials as Topic
PubMed: 37699654
DOI: 10.1136/ard-2023-224482 -
FP Essentials May 2024Peptic ulcer disease (PUD) involves ulceration of the mucosa in the stomach and/or proximal duodenum. The main causes are Helicobacter pylori infection and nonsteroidal... (Review)
Review
Peptic ulcer disease (PUD) involves ulceration of the mucosa in the stomach and/or proximal duodenum. The main causes are Helicobacter pylori infection and nonsteroidal anti-inflammatory drug (NSAID) use. PUD occurs in 5% to 10% of people worldwide, but rates have decreased by more than half during the past 20 years. This reduction is thought to be because of H pylori management, more conservative use of NSAIDs, and/or widespread use of proton pump inhibitors (PPIs). Common symptoms include postprandial abdominal pain, nausea, vomiting, and weight loss. These symptoms have broad overlap with those of other conditions, making clinical diagnosis difficult. Endoscopy is the gold standard for diagnosis, especially in older patients and those with alarm symptoms, but a test-and-treat strategy (noninvasive test for H pylori and treat if positive) can be used for younger patients with no alarm symptoms. Numerous treatment regimens are available, all of which include PPIs plus antibiotics. As an alternative to PPIs, a new triple therapy with vonoprazan (which blocks acid production) plus antibiotics has been approved and appears to be superior to conventional therapy with PPIs plus antibiotics. At least 4 weeks after treatment, repeat testing for H pylori should be obtained to confirm cure. When possible, NSAIDs should be discontinued; when not possible, antisecretory cotherapy should be considered.
Topics: Humans; Peptic Ulcer; Proton Pump Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Helicobacter Infections; Helicobacter pylori; Anti-Bacterial Agents; Drug Therapy, Combination; Sulfonamides; Pyrroles
PubMed: 38767885
DOI: No ID Found -
Molekuliarnaia Biologiia 2023Vitamin B12, or cobalamin, is essential for normal body function and is used in the therapies of different diseases. Vitamin B12 has anti-inflammatory and antioxidant... (Review)
Review
Vitamin B12, or cobalamin, is essential for normal body function and is used in the therapies of different diseases. Vitamin B12 has anti-inflammatory and antioxidant properties that can play an important role in the prevention of some diseases. On the other hand, it has been reported that vitamin B12 in combination with such reducing agents as ascorbate (vitamin C) and thiols showed prooxidant activity. This review provides information on the roles of vitamin B12 in diseases accompanied by inflammation and oxidative stress and the effects of vitamin B12 administrated alone and in combinations with different reducing agents such as ascorbate and thiols on oxidative stress. In addition, the mechanisms of prooxidant actions of combinations of vitamin B12 with these reducing agents depending on the form of vitamin B12 (hydroxocobalamin and cyanocobalamin) are discussed. Understanding the mechanisms of prooxidant action of vitamin B12 is necessary for developing strategies for therapeutic administration of vitamin B12.
Topics: Vitamin B 12; Reducing Agents; Hydroxocobalamin; Ascorbic Acid; Sulfhydryl Compounds; Oxidation-Reduction
PubMed: 38062959
DOI: No ID Found -
Cellular & Molecular Immunology Jan 2024The main challenges in the use of immune checkpoint inhibitors (ICIs) are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient...
The main challenges in the use of immune checkpoint inhibitors (ICIs) are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+ T cells. Transforming the tumor microenvironment (TME) from "cold" to "hot" and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer treatment. We found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+ mouse models. Using single-cell RNA sequencing, we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion, restoring T-cell function and promoting a favorable immunotherapy response. Mechanistically, we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling, thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine production. As a result, APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment, thus improving tumor immunosuppression and further enhancing antitumor T-cell immunity. Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86, p-NF-κB p65 and NLRP3 levels, accompanied by lower CD206 expression on macrophages. Collectively, these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.
Topics: Animals; Mice; Dioxanes; Immune Checkpoint Inhibitors; Nitrobenzenes; NLR Family, Pyrin Domain-Containing 3 Protein; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Tumor-Associated Macrophages; Transcription Factor RelA; Tumor Microenvironment; Cell Polarity; Lung Neoplasms; Humans; Cell Line, Tumor; Xenograft Model Antitumor Assays; Mice, Inbred C57BL; Chemokine CCL5; Chemokine CXCL10; Immunosuppression Therapy
PubMed: 38062129
DOI: 10.1038/s41423-023-01112-y -
Dermatologic Clinics Jul 2024Oral psoriasis therapies include both older traditional immunosuppressants, such as methotrexate, cyclosporine, and acitretin, as well as newer, more targeted agents,... (Review)
Review
Oral psoriasis therapies include both older traditional immunosuppressants, such as methotrexate, cyclosporine, and acitretin, as well as newer, more targeted agents, such as apremilast, deucravacitinib, and oral interleukin-23 receptor antagonists. Patients may prefer oral therapies to injectable therapies based on the route of administration. Both older and newer oral psoriasis therapies can be utilized effectively in the treatment of psoriasis. Here, we will review oral agents used in the treatment of psoriasis as well as provide commentary on their role in our current, evolving psoriasis treatment paradigm.
Topics: Humans; Psoriasis; Administration, Oral; Thalidomide; Acitretin; Immunosuppressive Agents; Methotrexate; Cyclosporine; Dermatologic Agents; Piperidines; Pyrazoles; Pyrimidines; Pyrroles; Antibodies, Monoclonal, Humanized; Keratolytic Agents; Indoles; Nicotinic Acids; Antibodies, Monoclonal
PubMed: 38796267
DOI: 10.1016/j.det.2024.02.013 -
Cell Reports. Medicine Feb 2024Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blockade has become a mainstay of cancer immunotherapy. Targeting the PD-1/PD-L1 axis with small...
Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blockade has become a mainstay of cancer immunotherapy. Targeting the PD-1/PD-L1 axis with small molecules is an attractive approach to enhance antitumor immunity. Here, we identified a natural marine product, benzosceptrin C (BC), that enhances the cytotoxicity of T cells to cancer cells by reducing the abundance of PD-L1. Furthermore, BC exerts its antitumor effect in mice bearing MC38 tumors by activating tumor-infiltrating T cell immunity. Mechanistic studies suggest that BC can prevent palmitoylation of PD-L1 by inhibiting DHHC3 enzymatic activity. Subsequently, PD-L1 is transferred from the membrane to the cytoplasm and cannot return to the membrane via recycling endosomes, triggering lysosome-mediated degradation of PD-L1. Moreover, the combination of BC and anti-CTLA4 effectively enhances antitumor T cell immunity. Our findings reveal a previously unrecognized antitumor mechanism of BC and represent an alternative immune checkpoint blockade (ICB) therapeutic strategy to enhance the efficacy of cancer immunotherapy.
Topics: Animals; Mice; B7-H1 Antigen; Programmed Cell Death 1 Receptor; Neoplasms; Lysosomes; Imidazoles; Pyrroles
PubMed: 38237597
DOI: 10.1016/j.xcrm.2023.101357 -
Journal of Comparative Effectiveness... Aug 202320 mg of vonoprazan (VPZ20) is recommended in most countries to treat erosive esophagitis (EE). Whether other doses of vonoprazan, such as 5 mg (VPZ5), 10 mg... (Meta-Analysis)
Meta-Analysis Review
20 mg of vonoprazan (VPZ20) is recommended in most countries to treat erosive esophagitis (EE). Whether other doses of vonoprazan, such as 5 mg (VPZ5), 10 mg (VPZ10), 20 mg (VPZ20), and 40 mg (VPZ40) are more effective is unknown. Three databases were electronically searched to identify studies published before November 2021. Network meta-analysis was performed using STATA 14.0. VPZ20 and VPZ40 were comparable to PPI, VPZ5 and VPZ10 in 4- and 8-week healing rates, and this was also detected in patients with refractory EE. All regimens resulted in similar treatment-emergent adverse events (TEAEs). However, VPZ40 ranked first for healing rate and TEAEs; however, VPZ20 ranked worst for TEAEs. Different doses of VPZ are comparable in efficacy and safety, but VPZ40 may be best in both effectiveness and safety.
Topics: Humans; Proton Pump Inhibitors; Esophagitis, Peptic; Network Meta-Analysis; Pyrroles; Peptic Ulcer; Treatment Outcome
PubMed: 37470274
DOI: 10.57264/cer-2022-0165