BACKGROUND: T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction. METHODS: A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models. RESULTS: In vitro , blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg -1 ·day -1 ) and Rapamycin (0.1 mg·kg -1 ·day -1 ) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression. CONCLUSIONS Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.
Animals ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Interferon Regulatory Factors/metabolism* ; Heart Transplantation/methods* ; T-Lymphocytes/immunology* ; Sirolimus/therapeutic use* ; Pyridones/therapeutic use* ; Graft Survival/drug effects* ; Pyrimidinones/therapeutic use* ; Cell Proliferation/drug effects* ; Apoptosis/drug effects* ; Male ; Signal Transduction/drug effects*

ADC189 is a novel drug of cap-dependent endonuclease inhibitor. In our study, its antiviral efficacy was evaluated in vitro and in vivo, and compared with baloxavir marboxil and oseltamivir. A first-in-human phase I study in healthy volunteers included single ascending dose (SAD) and food effect (FE) parts. In the preclinical study, ADC189 showed potent antiviral activity against various types of influenza viruses, including H1N1, H3N2, influenza B virus, and highly pathogenic avian influenza, comparable to baloxavir marboxil. Additionally, ADC189 exhibited much better antiviral efficacy than oseltamivir in H1N1 infected mice. In the phase I study, ADC189 was rapidly metabolized to ADC189-I07, and its exposure increased proportionally with the dose. The terminal elimination half-life (T_1/2) ranged from 76.69 to 98.28 hours. Of note, food had no effect on the concentration, clearance, and exposure of ADC189. It was well tolerated, with few treatment-emergent adverse events (TEAEs) reported and no serious adverse events (SAEs). ADC189 demonstrated excellent antiviral efficacy both in vitro and in vivo. It was safe, well-tolerated, and had favorable pharmacokinetic characteristics in healthy volunteers, supporting its potential for single oral dosing in clinical practice.
Humans ; Antiviral Agents/therapeutic use* ; Animals ; Male ; Adult ; Mice ; Female ; Endonucleases/antagonists & inhibitors* ; Influenza, Human/drug therapy* ; Young Adult ; Dibenzothiepins/pharmacology* ; Oseltamivir/pharmacology* ; Middle Aged ; Triazines/pharmacology* ; Thiepins/pharmacology* ; Influenza B virus/drug effects* ; Influenza A Virus, H1N1 Subtype/drug effects* ; Pyridines/pharmacology* ; Morpholines ; Pyridones

Adult ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use* ; COVID-19/drug therapy* ; Humans ; Pyridones/therapeutic use* ; Treatment Outcome

INTRODUCTIONDirect oral anticoagulants (DOACs) are establishing themselves as principle choices for the treatment of a variety of thrombotic disorders. DOACs are also known to affect common coagulation tests which are routinely performed for patients in clinical practice. An understanding of their varied effects is crucial for the appropriate ordering of coagulation tests and their interpretation.

MATERIALS AND METHODSLaboratories in public and private healthcare institutions and commercial sectors were surveyed on coagulation tests offered and their methods. A Medline and bibliography search, including a search on search engines, was performed for publications reporting the effects of dabigatran, apixaban and rivaroxaban on these coagulation tests. These papers were reviewed and summarised for consensus recommendations.

RESULTSProthrombin time (PT) and activated partial thromboplastin time (aPTT) are variably affected by the DOACs and dependent of the coagulation assays used. Clinicians must know which laboratory has performed these tests to logically interpret test results. A normal PT or aPTT does not exclude the presence of residual DOACs effect. The thrombin time is sensitive to dabigatran but not apixaban or rivaroxaban. Specialised coagulation tests such as thrombophilia tests are also variably affected by the DOACs. All laboratories in Singapore however, employ similar test methods permitting a common set of recommendations for specialised coagulation testing.

CONCLUSIONKnowledge of the effects of DOACs on coagulation testing is essential to determine the appropriateness of performing such tests and interpreting them coherently. Practical recommendations which are tests and location-specific are set out in this paper.

Antithrombins ; therapeutic use ; Blood Coagulation Tests ; Dabigatran ; therapeutic use ; Factor Xa Inhibitors ; therapeutic use ; Humans ; Partial Thromboplastin Time ; Practice Guidelines as Topic ; Prothrombin Time ; Pyrazoles ; therapeutic use ; Pyridones ; therapeutic use ; Rivaroxaban ; therapeutic use ; Singapore

No abstract available.
Age Factors ; Aged ; Atrial Appendage/diagnostic imaging/*drug effects ; Atrial Fibrillation/complications/diagnostic imaging/*drug therapy ; Echocardiography, Doppler, Color ; Echocardiography, Three-Dimensional ; Echocardiography, Transesophageal ; Factor Xa Inhibitors/*therapeutic use ; Female ; Humans ; Pyrazoles/*therapeutic use ; Pyridones/*therapeutic use ; Thrombosis/diagnostic imaging/etiology/*prevention & control ; Treatment Outcome

Aged ; Aged, 80 and over ; Anticoagulants ; therapeutic use ; Aspirin ; therapeutic use ; Atrial Fibrillation ; complications ; drug therapy ; Brain Ischemia ; etiology ; prevention & control ; Dabigatran ; therapeutic use ; Dipyridamole ; therapeutic use ; Female ; Guideline Adherence ; statistics & numerical data ; Humans ; Male ; Middle Aged ; Platelet Aggregation Inhibitors ; therapeutic use ; Practice Guidelines as Topic ; Primary Prevention ; statistics & numerical data ; Pyrazoles ; therapeutic use ; Pyridones ; therapeutic use ; Rivaroxaban ; therapeutic use ; Stroke ; etiology ; prevention & control ; Ticlopidine ; analogs & derivatives ; therapeutic use ; Warfarin ; therapeutic use

Besides 36 (28 single-tablets and 8 fixed-dose combinations) used antiretroviral drugs clinically, there are a number of investigational antiretroviral agents currently in phase 2-3 clinical trial. Tenofoviralafenamidefumarate (TAF) is a novel nucleoside analogue reverse transcriptase inhibitor that is potent and less toxicity than tenofovir (TDF). Doravirine is a non-nucleoside analogue reverse transcriptase inhibitor that demonstrates activity against NNRTI-resistant viral strains. GSK744 is an integrase inhibitor with a long acting preparation. In addition, several drugs with new mechanisms are also noted, for example, BMS-663 068 is a small molecule CD4 attachment inhibitors and cenicriviroc is a novel CCR5/CCR2 antagonist with antiretroviral activity and anti-inflammatory effects. Several drug classes that target known pathways in HIV latency have being developed, and leading the list are histone deacetylase inhibitors. Other agents include protein kinase C activators, positive transcription elongation factor activators, DNA methyl-transferase inhibitors and histone methyl-transferase inhibitors and so on. This review is focused on the above-mentioned drug candidates that may be used in clinical in next couple of years and those compounds that can reverse latent HIV infections.
Adenine ; analogs & derivatives ; therapeutic use ; Anti-HIV Agents ; therapeutic use ; HIV Infections ; drug therapy ; Humans ; Organophosphates ; therapeutic use ; Organophosphonates ; therapeutic use ; Piperazines ; therapeutic use ; Pyridones ; therapeutic use ; Reverse Transcriptase Inhibitors ; therapeutic use ; Tenofovir

Many Korean patients with transfusion-induced iron overload experience serious clinical sequelae, including organ damage, and require lifelong chelation therapy. However, due to a lack of compliance and/or unavailability of an appropriate chelator, most patients have not been treated effectively. Deferasirox (DFX), a once-daily oral iron chelator for both adult and pediatric patients with transfusion-induced iron overload, is now available in Korea. The effectiveness of deferasirox in reducing or maintaining body iron has been demonstrated in many studies of patients with a variety of transfusion-induced anemias such as myelodysplastic syndromes, aplastic anemia, and other chronic anemias. The recommended initial daily dose of DFX is 20 mg/kg body weight, taken on an empty stomach at least 30 min before food and serum ferritin levels should be maintained below 1000 ng/mL. To optimize the management of transfusion-induced iron overload, the Korean Society of Hematology Aplastic Anemia Working Party (KSHAAWP) reviewed the general consensus on iron overload and the Korean data on the clinical benefits of iron chelation therapy, and developed a Korean guideline for the treatment of iron overload.
Anemia, Aplastic/therapy ; Benzoates/therapeutic use ; Blood Transfusion/*adverse effects ; Chelation Therapy/*methods ; Humans ; Iron Chelating Agents/*therapeutic use ; Iron Overload/*therapy ; Myelodysplastic Syndromes/therapy ; Pyridones/therapeutic use ; Republic of Korea ; Triazoles/therapeutic use

BACKGROUNDEnoxaparin is routinely used for prevention of venous thromboembolism (VTE) after total hip or knee arthroplasty. The purpose of this study was to compare the efficacy and safety of apixaban, a newly oral direct inhibitor of factor Xa versus enoxaparin.

METHODSWe performed a meta-analysis of relevant randomized-controlled trials (RCTs) identified in PubMed, Cochrane Library, Embase China Biological Medical Literature database, Countries Journal full-text database, VIP database, and WanFang database. The primary efficacy outcome for our meta-analysis was all VTE and all-cause mortality. The secondary efficacy outcomes included major VTE, non-fatal pulmonary embolism, and mortality. The primary safety outcome was bleeding events, categorized as major, clinically relevant non-major, or minor events.

RESULTSFour RCTs, involving 14 065 patients, were included in our meta-analysis. Compared to enoxaparin, thromboprophylaxis with apixaban was associated with significantly fewer VTE and all-cause mortality (8346 patients, risk ratio (RR): 0.63, 95%CI 0.42 - 0.95) and similar incidence of bleeding events (major bleeding, 11 525 patients, RR 0.76, 95%CI 0.43 - 1.33; clinically relevant non-major bleeding, 11 525 patients, RR 0.83, 95%CI 0.69 - 1.01; and minor bleeding, 11 828 patients, RR 0.93, 95%CI 0.79 - 1.09). However, our meta-analysis revealed similar effects of apixaban with enoxaparin for thromboprophylaxis with regard to the secondary efficacy outcomes.

CONCLUSIONSApixaban was more effective than recommended dose of enoxaparin and had a similar safety profile for thromboprophylaxis after hip and knee arthroplasty. But more evidence, especially well designed head-to-head RCTs, is needed to confirm the superior efficacy of apixaban.

Arthroplasty, Replacement, Hip ; adverse effects ; methods ; Arthroplasty, Replacement, Knee ; adverse effects ; methods ; Enoxaparin ; therapeutic use ; Humans ; Pyrazoles ; therapeutic use ; Pyridones ; therapeutic use ; Randomized Controlled Trials as Topic ; Venous Thromboembolism ; etiology ; prevention & control

OBJECTIVETo study the curative effects of pirfenidone (PF) on pulmonary fibrosis induced by paraquat (PQ) in mice and to provide the theoretical basis for clinical treatment.

METHODSNinety adult healthy male ICR mice were randomly divided into six groups: control group, PQ group, 2 mg/kg Dexamethasone group, 25 mg/kg PF group, 50 mg/kg PF group and 100 mg/kg PF group, there were 15 mice in each group. The corresponding volume of normal saline was given to the each mouse in control group according to the weight, after 2 h 0.1% CMC was given to the each mouse of control group one time by intragastric administration, then the CMC was administrated at regular time until sacrifice. All mice for other 5 groups were exposed to 100 mg/kg PQ by intragastric administration. At 2 h after exposure to PQ, 0.02 ml/10 g dexamethasone and 25, 50, 100 mg/kg PF were given to mice for dexamethasone group and for 3 PF groups by intragastric administration each day for 49 days, respectively. The lung coefficient was calculated and pathological changes of lung tissue were observed by HE staining for each mouse. The hydroxyproline (HYP) level in lung tissue was measured for each mouse. The mRNA level of and the protein level of TGF-β(1) in lung tissue for each mouse were determined, and the protein level of TGF-β(1) in the bronchus-alveolus lavage fluid (BALF) of each mouse was detected.

RESULTSThe survival rates on the 3rd day in PQ group, 3 PF groups and dexamethasone group were 53.33%, 46.67%, 73.33%, 86.67% and 80%, respectively. The survival rates on the 3rd day in dexamethasone group, 50 mg/kg and 100 mg/kg PF groups were significantly higher than those of PQ group and 25 mg/kg PF group (P < 0.05). The lung coefficients of 3 PF groups were significantly lower than that of the PQ group (P < 0.05). The lung tissue HYP levels of dexamethasone group and 3 PF groups were 50.95 ± 11.65, 44.52 ± 9.48, 43.27 ± 6.01 and 40.82 ± 5.90 mg/g respectively, which were significantly lower than that (74.27 ± 3.68) of PQ group (P < 0.01). The TGF-β(1) protein levels of BALF in dexamethasone group, 50 and 100 mg/kg PF groups were 22.03 ± 7.27, 27.75 ± 5.84 and 21.31 ± 6.82 ng/ml respectively, which were significantly lower than that (52.52 ± 15.51) ng/ml of PQ group (P < 0.01) The expression level of TGF-β(1) mRNA in 100 mg/kg PF group decreased significantly, as compared with PQ group (P < 0.01).

CONCLUSIONPF could reduce the collagen deposition and pulmonary fibrosis induced by PQ in mice lungs.

Animals ; Disease Models, Animal ; Lung ; metabolism ; pathology ; Male ; Mice ; Mice, Inbred ICR ; Paraquat ; poisoning ; Pulmonary Fibrosis ; chemically induced ; drug therapy ; pathology ; Pyridones ; therapeutic use ; Transforming Growth Factor beta ; metabolism