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1.
BMJ ; 385: e078242, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38663919

RESUMO

OBJECTIVE: To determine whether the combined use of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors is associated with a decreased risk of major adverse cardiovascular events and serious renal events compared with either drug class alone among patients with type 2 diabetes, and to assess the effect of the combination on the individual components of major adverse cardiovascular events, heart failure, and all cause mortality. DESIGN: Population based cohort study using a prevalent new-user design, emulating a trial. SETTING: UK Clinical Practice Research Datalink linked to Hospital Episode Statistics Admitted Patient Care and Office for National Statistics databases. PARTICIPANTS: Two prevalent new-user cohorts were assembled between January 2013 and December 2020, with follow-up until the end of March 2021. The first cohort included 6696 patients who started GLP-1 receptor agonists and added on SGLT-2 inhibitors, and the second included 8942 patients who started SGLT-2 inhibitors and added on GLP-1 receptor agonists. Combination users were matched, in a 1:1 ratio, to patients prescribed the same background drug, duration of background drug, and time conditional propensity score. MAIN OUTCOME MEASURES: Cox proportional hazards models were fitted to estimate the hazard ratios and 95% confidence intervals of major adverse cardiovascular events and serious renal events, separately, comparing the GLP-1 receptor agonist-SGLT-2 inhibitor combination with the background drug, either GLP-1 receptor agonists or SGLT-2 inhibitors, depending on the cohort. Secondary outcomes included associations with the individual components of major adverse cardiovascular events (myocardial infarction, ischaemic stroke, cardiovascular mortality), heart failure, and all cause mortality. RESULTS: Compared with GLP-1 receptor agonists, the SGLT-2 inhibitor-GLP-1 receptor agonist combination was associated with a 30% lower risk of major adverse cardiovascular events (7.0 v 10.3 events per 1000 person years; hazard ratio 0.70, 95% confidence interval 0.49 to 0.99) and a 57% lower risk of serious renal events (2.0 v 4.6 events per 1000 person years; hazard ratio 0.43, 0.23 to 0.80). Compared with SGLT-2 inhibitors, the GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a 29% lower risk of major adverse cardiovascular events (7.6 v 10.7 events per 1000 person years; hazard ratio 0.71, 0.52 to 0.98), whereas serious renal events generated a wide confidence interval (1.4 v 2.0 events per 1000 person years; hazard ratio 0.67, 0.32 to 1.41). Secondary outcomes generated similar results but with wider confidence intervals. CONCLUSIONS: In this cohort study, the GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a lower risk of major adverse cardiovascular events and serious renal events compared with either drug class alone.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Masculino , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Pessoa de Meia-Idade , Idoso , Incidência , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/efeitos adversos , Reino Unido/epidemiologia , Estudos de Coortes , 60650
2.
BMC Med ; 22(1): 176, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664766

RESUMO

BACKGROUND: There is an urgent unmet need for effective initial treatment for acute graft-versus-host disease (aGVHD) adding to the standard first-line therapy with corticosteroids after allogeneic haematopoietic stem cell transplantation (allo-HSCT). METHODS: We performed a multicentre, open-label, randomized, phase 3 study. Eligible patients (aged 15 years or older, had received allo-HSCT for a haematological malignancy, developed aGVHD, and received no previous therapies for aGVHD) were randomly assigned (1:1) to receive either 5 mg/m2 MTX on Days 1, 3, or 8 and then combined with corticosteroids or corticosteroids alone weekly. RESULTS: The primary endpoint was the overall response rate (ORR) on Day 10. A total of 157 patients were randomly assigned to receive either MTX plus corticosteroids (n = 78; MTX group) or corticosteroids alone (n = 79; control group). The Day 10 ORR was 97% for the MTX group and 81% for the control group (p = .005). Among patients with mild aGVHD, the Day 10 ORR was 100% for the MTX group and 86% for the control group (p = .001). The 1-year estimated failure-free survival was 69% for the MTX group and 41% for the control group (p = .002). There were no differences in treatment-related adverse events between the two groups. CONCLUSIONS: In conclusion, mini-dose MTX combined with corticosteroids can significantly improve the ORR in patients with aGVHD and is well tolerated, although it did not achieve the prespecified 20% improvement with the addition of MTX. TRIAL REGISTRATION: The trial was registered with clinicaltrials.gov (NCT04960644).


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Metotrexato , Metilprednisolona , Humanos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Feminino , Masculino , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Adulto , Metilprednisolona/uso terapêutico , Metilprednisolona/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adulto Jovem , Resultado do Tratamento , Quimioterapia Combinada , Idoso , Adolescente , Doença Aguda
3.
Front Immunol ; 15: 1326066, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38665907

RESUMO

Introduction: Defective interleukin-2 (IL-2) production contributes to immune system imbalance in patients with systemic erythematosus lupus (SLE). Recent clinical studies suggested that low-dose IL-2 treatment is beneficial for SLE and the therapeutic effect is associated with regulatory T cell (Treg) expansion. Pharmacological calcineurin inhibition induces a reduction in the number of Tregs because they require stimulation of T cell receptor signaling and IL-2 for optimal proliferation. However, the activation of T cell receptor signaling is partially dispensable for the expansion of Tregs, but not for that of conventional T cells if IL-2 is present. Aim: We examined whether addition of IL-2 restores the Treg proportion even with concurrent use of a calcineurin inhibitor and if the follicular helper T cell (Tfh) proportion is reduced in an SLE-like murine chronic graft versus host disease model. Methods: Using a parent-into-F1 model, we investigated the effect of IL-2 plus tacrolimus on Treg and Tfh proportions and the therapeutic effect. Results: Treatment with a combination of IL-2 and tacrolimus significantly delayed the initiation of proteinuria and decreased the urinary protein concentration, whereas tacrolimus or IL-2 monotherapy did not significantly attenuate proteinuria. Phosphorylation of signal transducer and activator of transcription 3, a positive regulator of Tfh differentiation, was reduced by combination treatment, whereas phosphorylation of signal transducer and activator of transcription 5, a negative regulator, was not reduced. Conclusion: Addition of calcineurin inhibitors as adjunct agents may be beneficial for IL-2-based treatment of lupus nephritis.


Assuntos
Interleucina-2 , Nefrite Lúpica , Linfócitos T Reguladores , Tacrolimo , Animais , Tacrolimo/uso terapêutico , Tacrolimo/farmacologia , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/imunologia , Camundongos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Modelos Animais de Doenças , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Quimioterapia Combinada , Feminino , Células T Auxiliares Foliculares/imunologia , Imunossupressores/uso terapêutico , Imunossupressores/farmacologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/metabolismo , Inibidores de Calcineurina/uso terapêutico , Inibidores de Calcineurina/farmacologia , Síndrome de Bronquiolite Obliterante
4.
High Blood Press Cardiovasc Prev ; 31(2): 99-112, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38616212

RESUMO

Resistant hypertension (RHT) is characterized by persistently high blood pressure (BP) levels above the widely recommended therapeutic targets of less than 140/90 mmHg office BP, despite life-style measures and optimal medical therapies, including at least three antihypertensive drug classes at maximum tolerated dose (one should be a diuretic). This condition is strongly related to hypertension-mediated organ damage and, mostly, high risk of hospitalization due to hypertension emergencies or acute cardiovascular events. Hypertension guidelines proposed a triple combination therapy based on renin angiotensin system blocking agent, a thiazide or thiazide-like diuretic, and a dihydropyridinic calcium-channel blocker, to almost all patients with RHT, who should also receive either a beta-blocker or a mineralocorticoid receptor antagonist, or both, depending on concomitant conditions and contraindications. Several other drugs may be attempted, when elevated BP levels persist in these RHT patients, although their added efficacy in lowering BP levels on top of optimal medical therapy is uncertain. Also, renal denervation has demonstrated to be a valid therapeutic alternative in RHT patients. More recently, novel drug classes and molecules have been tested in phase 2 randomised controlled clinical trials in patients with RHT on top of optimal medical therapy with at least 2-3 antihypertensive drugs. These novel drugs, which are orally administered and are able to antagonize different pathophysiological pathways, are represented by non-steroid mineralocorticorticoid receptor antagonists, selective aldosterone synthase inhibitors, and dual endothelin receptor antagonists, all of which have proven to reduce seated office and 24-h ambulatory systolic/diastolic BP levels. The main findings of randomized clinical trials performed with these drugs  as well as their potential indications for the clinical management of RHT patients are summarised in this systematic review article.


Assuntos
Anti-Hipertensivos , Pressão Sanguínea , Resistência a Medicamentos , Quimioterapia Combinada , Hipertensão , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Hipertensão/diagnóstico , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Resultado do Tratamento , Medicina de Precisão
5.
Sci Rep ; 14(1): 8986, 2024 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-38637591

RESUMO

Potassium-competitive acid blockers (P-CABs) provide potent acid inhibition, yet studies on P-CAB-based quadruple therapy for H. pylori eradication are limited. We theorized that integrating bismuth subsalicylate into a quadruple therapy regimen could enhance eradication rates. However, data on the efficacy of vonoprazan bismuth quadruple therapy are notably scarce. Therefore, the aim of this study was to evaluate the efficacy of vonoprazan-based bismuth quadruple therapy in areas with high clarithromycin and levofloxacin resistance. This was a prospective, single-center, randomized trial conducted to compare the efficacy of 7-day and 14-day vonoprazan-based bismuth quadruple therapy for H. pylori eradication between June 1, 2021, and March 31, 2022. Qualified patients were randomly assigned to the 7-day or 14-day regimen (1:1 ratio by computer-generated randomized list as follows: 51 patients for the 7-day regimen and 50 patients for the 14-day regimen). The regimens consisted of vonoprazan (20 mg) twice daily, bismuth subsalicylate (1024 mg) twice daily, metronidazole (400 mg) three times daily, and tetracycline (500 mg) four times daily. CYP3A4/5 genotyping and antibiotic susceptibility tests were also performed. Successful eradication was defined as 13negative C-UBTs 4 weeks after treatment. The primary endpoint was to compare the efficacy of 7-day and 14-day regimens as first-line treatments, which were assessed by intention-to-treat (ITT) and per-protocol (PP) analyses. The secondary endpoints included adverse effects. A total of 337 dyspeptic patients who underwent gastroscopy were included; 105 patients (31.1%) were diagnosed with H. pylori infection, and 101 patients were randomly assigned to each regimen. No dropouts were detected. The antibiotic resistance rate was 33.3% for clarithromycin, 29.4% for metronidazole, and 27.7% for levofloxacin. The CYP3A4 genotype was associated with 100% rapid metabolism. The H. pylori eradication rates for the 7-day and 14-day regimens were 84.4%, 95% CI 74.3-94.2 and 94%, 95% CI 87.4-100, respectively (RR difference 0.25, 95% CI 0.03-0.53, p value = 0.11). Interestingly, the 14-day regimen led to 100% eradication in the clarithromycin-resistant group. Among the patients in the 7-day regimen group, only two exhibited resistance to clarithromycin; unfortunately, neither of them achieved a cure from H. pylori infection. The incidence of adverse events was similar in both treatment groups, occurring in 29.4% (15/51) and 28% (14/50) of patients in the 7-day and 14-day regimens, respectively. No serious adverse reactions were reported. In conclusion, 14 days of vonoprazan-based bismuth quadruple therapy is highly effective for H. pylori eradication in areas with high levels of dual clarithromycin and levofloxacin resistance.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Compostos Organometálicos , Pirróis , Salicilatos , Sulfonamidas , Humanos , Claritromicina/farmacologia , Bismuto/uso terapêutico , Bismuto/efeitos adversos , Levofloxacino/efeitos adversos , Metronidazol/efeitos adversos , Estudos Prospectivos , Citocromo P-450 CYP3A , Antibacterianos/efeitos adversos , Infecções por Helicobacter/genética , Quimioterapia Combinada , Resultado do Tratamento
6.
BMC Med ; 22(1): 165, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38637772

RESUMO

BACKGROUND: Unresectable intrahepatic cholangiocarcinoma (iCCA) has a poor prognosis despite treatment with standard combination chemotherapy. We aimed to evaluate the efficacy and safety of radiotherapy in combination with an anti-PD-1 antibody in unresectable iCCA without distant metastases. METHODS: In this phase II study, patients with histopathologically confirmed unresectable primary or postoperative recurrent iCCA without distant metastases were enrolled. Patients received external radiotherapy with a dose of ≥45 Gy (2-2.5 Gy per fraction), followed by anti-PD-1 immunotherapy (camrelizumab 200 mg once, every 3 weeks) initiated within 7 days after completion of radiotherapy as first-line therapy. The primary endpoint was 1-year progression-free survival (PFS) rate. The secondary end points included safety, objective response rate (ORR), disease control rate (DCR), and overall survival (OS). RESULTS: From December 2019 to March 2021, 36 patients completed radiotherapy and at least one cycle of immunotherapy and were included in efficacy and safety analyses. The median follow-up was 19.0 months (IQR 12.0-24.0), and the one-year PFS rate was 44.4% (95% CI, 30.8-64.0). The median PFS was 12.0 months (95% CI, 7.5-not estimable); the median OS was 22.0 months (95% CI, 15.0-not estimable). The ORR was 61.1% and the DCR was 86.1%. Seventeen of 36 (47.2%) patients experienced treatment-related adverse effects (AEs) of any grade. The most common AE was reactive cutaneous capillary endothelial proliferation (25.0%). Five (13.9%) patients experienced grade ≥3 treatment-related AEs, including decreased lymphocyte (5.6%), bullous dermatitis (2.8%), decreased platelet count (2.8%), and deep-vein thrombosis (2.8%). CONCLUSIONS: External radiotherapy plus camrelizumab, as first-line therapy, met its primary endpoint and showed antitumor activity and low toxicity levels in patients with unresectable iCCA without distant metastases, warranting further investigation. TRIAL REGISTRATION: NCT03898895. Registered 2 April 2019.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Imunoterapia/efeitos adversos , Quimioterapia Combinada , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/radioterapia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/radioterapia , Ductos Biliares Intra-Hepáticos
7.
Korean J Gastroenterol ; 83(4): 150-156, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38659251

RESUMO

Background/Aims: Helicobacter pylori (H. pylori) is the most prevalent infection in the world and is strongly associated with gastric adenocarcinoma, lymphoma and gastric or duodenal ulcers. Different regimens have been used for H. pylori eradication. We aimed to compare the efficacy of two different regimens as first-line H. pylori eradication regimens, in an area with high antibiotic resistance. Methods: In this RCT, we assigned 223 patients with H. pylori infection, who were naïve to treatment. They were randomly divided into two groups to receive either 12-day concomitant quadruple therapy (consisting of pantoprazole 40 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg every 12 hours) or 14-day high dose dual therapy (consisting of esomeprazole 40 mg and amoxicillin 1 g TDS). H. pylori eradication was assessed eight weeks after the end of treatment. Results: H. pylori eradication rate by PP analysis for 12-day concomitant quadruple therapy and 14-day high dose dual therapy were 90.4% and 79.1%, respectively (p=0.02). According to ITT analysis, the eradication rates were 86.2% and 76.3%, respectively (p=0.06). Adverse drug reactions were 12.3% in high dose dual therapy and 36.8% in concomitant quadruple therapy (p<0.001). Conclusions: Twelve-day concomitant therapy seems to be an acceptable regimen for first-line H. pylori eradication in Iran, a country with a high rate of antibiotic resistance. Although, high dose dual therapy did not result in an ideal eradication rate, but it had fewer drug side effects than the 12-day concomitant regimen.


Assuntos
Amoxicilina , Antibacterianos , Claritromicina , Quimioterapia Combinada , Esomeprazol , Infecções por Helicobacter , Helicobacter pylori , Metronidazol , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Claritromicina/uso terapêutico , Claritromicina/administração & dosagem , Esquema de Medicação , Esomeprazol/uso terapêutico , Esomeprazol/administração & dosagem , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/efeitos dos fármacos , Metronidazol/uso terapêutico , Pantoprazol/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêutico , Resultado do Tratamento
8.
Artigo em Inglês | MEDLINE | ID: mdl-38646606

RESUMO

Purpose: To assess patient characteristics of users and new initiators of triple therapy for chronic obstructive pulmonary disease (COPD) in Germany. Patients and Methods: Retrospective cohort study of patients with COPD and ≥1 prescription for single-inhaler triple therapy (SITT; fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI] or beclomethasone dipropionate/glycopyrronium bromide/formoterol [BDP/GLY/FOR]) or multiple-inhaler triple therapy (MITT), using data from the AOK PLUS German sickness fund (1 January 2015-31 December 2019). The index date was the first date of prescription for FF/UMEC/VI or BDP/GLY/FOR (SITT users), or the first date of overlap of inhaled corticosteroid, long-acting ß2-agonist, and long-acting muscarinic antagonist (MITT users). Two cohorts were defined: the prevalent cohort included all identified triple therapy users; the incident cohort included patients newly initiating triple therapy for the first time (no prior use of MITT or SITT in the last 2 years). Patient characteristics and treatment patterns were assessed on the index date and during the 24-month pre-index period. Results: In total, 18,630 patients were identified as prevalent triple therapy users (MITT: 17,945; FF/UMEC/VI: 700; BDP/GLY/FOR: 908; non-mutually exclusive) and 2932 patients were identified as incident triple therapy initiators (MITT: 2246; FF/UMEC/VI: 311; BDP/GLY/FOR: 395; non-mutually exclusive). For both the prevalent and incident cohorts, more than two-thirds of patients experienced ≥1 moderate/severe exacerbation in the preceding 24 months; in both cohorts more BDP/GLY/FOR users experienced ≥1 moderate/severe exacerbation, compared with FF/UMEC/VI and MITT users. Overall, 97.9% of prevalent triple therapy users and 86.4% of incident triple therapy initiators received maintenance treatment in the 24-month pre-index period. Conclusion: In a real-world setting in Germany, triple therapy was most frequently used after maintenance therapy in patients with recent exacerbations, in line with current treatment recommendations.


Triple therapy (a combination of three different respiratory inhaled medications) is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience repeated short-term symptom flare-ups when taking dual therapy (a combination of two different respiratory medications). Previously, patients had to take triple therapy using two or three separate inhalers. More recently, single-inhaler triple therapies have been developed, meaning patients can take all three different medications at the same time via one single inhaler. This study assessed the characteristics of patients who were already receiving triple therapy, or who started triple therapy (either via multiple inhalers or a single inhaler), in Germany between January 2015 and December 2019. In total, 18,630 patients who were already receiving triple therapy during the study period, and 2932 patients who newly started using triple therapy were included. The study reported that more than two-thirds of included patients had experienced at least one flare-up of COPD symptoms in the 2 years before starting triple therapy. Most patients had also received another therapy for COPD before starting triple therapy. A small proportion of patients started taking triple therapy after receiving no other therapy for COPD in the previous 2 years. The results of the study suggest that triple therapy for COPD in Germany is most often used in accordance with recommendations (patients already receiving therapy and experiencing repeated symptom flare-ups).


Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Broncodilatadores , Combinação de Medicamentos , Glicopirrolato , Antagonistas Muscarínicos , Nebulizadores e Vaporizadores , Doença Pulmonar Obstrutiva Crônica , Humanos , Masculino , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Feminino , Estudos Retrospectivos , Alemanha , Idoso , Administração por Inalação , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/efeitos adversos , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Glicopirrolato/administração & dosagem , Glicopirrolato/efeitos adversos , Clorobenzenos/administração & dosagem , Clorobenzenos/efeitos adversos , Quinuclidinas/administração & dosagem , Quinuclidinas/efeitos adversos , Resultado do Tratamento , Álcoois Benzílicos/administração & dosagem , Álcoois Benzílicos/efeitos adversos , Beclometasona/administração & dosagem , Beclometasona/efeitos adversos , Fumarato de Formoterol/administração & dosagem , Quimioterapia Combinada , Fatores de Tempo , Idoso de 80 Anos ou mais
9.
J Microbiol Biotechnol ; 34(4): 828-837, 2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38668685

RESUMO

Vancomycin (VAN) and metronidazole (MTR) remain the current drugs of choice for the treatment of non-severe Clostridioides difficile infection (CDI); however, while their co-administration has appeared in clinical treatment, the efficacy varies greatly and the mechanism is unknown. In this study, a CDI mouse model was constructed to evaluate the therapeutic effects of VAN and MTR alone or in combination. For a perspective on the intestinal ecology, 16S rRNA amplicon sequencing and non-targeted metabolomics techniques were used to investigate changes in the fecal microbiota and metabolome of mice under the co-administration treatment. As a result, the survival rate of mice under co-administration was not dramatically different compared to that of single antibiotics, and the former caused intestinal tissue hyperplasia and edema. Co-administration also significantly enhanced the activity of amino acid metabolic pathways represented by phenylalanine, arginine, proline, and histidine, decreased the level of deoxycholic acid (DCA), and downregulated the abundance of beneficial microbes, such as Bifidobacterium and Akkermansia. VAN plays a dominant role in microbiota regulation in co-administration. In addition, co-administration reduced or increased the relative abundance of antibiotic-sensitive bacteria, including beneficial and harmful microbes, without a difference. Taken together, there are some risks associated with the co-administration of VAN and MTR, and this combination mode should be used with caution in CDI treatment.


Assuntos
Antibacterianos , Clostridioides difficile , Infecções por Clostridium , Modelos Animais de Doenças , Quimioterapia Combinada , Fezes , Microbioma Gastrointestinal , Metronidazol , RNA Ribossômico 16S , Vancomicina , Animais , Metronidazol/administração & dosagem , Vancomicina/administração & dosagem , Vancomicina/farmacologia , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Clostridioides difficile/efeitos dos fármacos , Clostridioides difficile/genética , RNA Ribossômico 16S/genética , Fezes/microbiologia , Intestinos/microbiologia , Intestinos/efeitos dos fármacos , Masculino , Bactérias/classificação , Bactérias/genética , Bactérias/efeitos dos fármacos , Metaboloma/efeitos dos fármacos
10.
J Am Heart Assoc ; 13(8): e032782, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38563380

RESUMO

BACKGROUND: The VOYAGER PAD (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities) trial compared rivaroxaban (2.5 mg twice a day) plus aspirin with aspirin alone in patients with symptomatic peripheral artery disease requiring endovascular or surgical limb revascularization, with 50% receiving clopidogrel background therapy. The New Drug Indication application includes benefit-risk assessments using clinical judgment to balance benefits against risks. During its review, the US Food and Drug Administration requested additional quantitative benefit-risk analyses with formal weighting approaches. METHODS AND RESULTS: Benefits and risks were assessed using rate differences between treatment groups (unweighted analysis). To account for clinical importance of the end points, a multi-criteria decision analysis was conducted using health state utility values as weights. Monte Carlo simulations incorporated statistical uncertainties of the event rates and utility weights. Intent-to-treat and on-treatment analyses were conducted. For unweighted intent-to-treat analyses, rivaroxaban plus aspirin would result in 120 (95% CI, -208 to -32) fewer events of the primary composite end point (per 10 000 patient-years) compared with aspirin alone. Rivaroxaban caused an excess of 40 (95% CI, 8-72) Thrombolysis in Myocardial Infarction major bleeding events, which was largely driven by nonfatal, nonintracranial hemorrhage Thrombolysis in Myocardial Infarction major bleeding events. For weighted analyses, rivaroxaban resulted in the utility equivalent of 13.7 (95% CI, -85.3 to 52.6) and 68.1 (95% CI, 7.9-135.7) fewer deaths per 10 000 patient-years (intent-to-treat and on-treatment, respectively), corresponding to probabilities of 64.4% and 98.7%, respectively, that benefits outweigh risks favoring rivaroxaban per Monte Carlo simulation. CONCLUSIONS: These analyses show a favorable benefit-risk profile of rivaroxaban therapy in the VOYAGER PAD trial, with findings generally consistent between the unweighted and weighted approaches.


Assuntos
Infarto do Miocárdio , Doença Arterial Periférica , Humanos , Aspirina/efeitos adversos , Quimioterapia Combinada , Inibidores do Fator Xa/efeitos adversos , Hemorragia/induzido quimicamente , Infarto do Miocárdio/tratamento farmacológico , Doença Arterial Periférica/tratamento farmacológico , Doença Arterial Periférica/cirurgia , Inibidores da Agregação Plaquetária/efeitos adversos , Medição de Risco , Rivaroxabana/efeitos adversos
11.
J Cardiothorac Surg ; 19(1): 213, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38616246

RESUMO

BACKGROUND: Pulmonary large-cell neuroendocrine carcinoma (pLCNEC) represents a rare malignancy characterized by its aggressive behavior and a notably high recurrence rate. Remarkably, there is currently no established standard treatment protocol for this condition. CASE DESCRIPTION: In this report, we present an intriguing case of pLCNEC diagnosed at clinical-stage IIB. This case involves a 64-year-old man with a smoking history spanning four decades. In our approach, we initiated a course of neoadjuvant chemotherapy in combination with pembrolizumab, administered for two cycles prior to surgical resection. This innovative treatment strategy resulted in a significant pathological response, culminating in a major pathological remission (MPR). As of the time of composing this report, the patient has been diligently monitored for 39 months post-surgery, exhibiting no indications of recurrence, and has demonstrated exceptional tolerance to the entire treatment regimen. CONCLUSIONS: We have first reported a clinically successful case of neoadjuvant combination chemotherapy with pembrolizumab in the treatment of pLCNEC. This case offers promising clinical insights and suggests that this therapeutic approach could be a viable option for managing pLCNEC.


Assuntos
Carcinoma Neuroendócrino , Neoplasias Pulmonares , Masculino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Carcinoma Neuroendócrino/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quimioterapia Combinada
12.
Acta Med Indones ; 56(1): 3-12, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38561891

RESUMO

BACKGROUND: Asthma is a disease characterized by chronic airway inflammation, however one-third of asthmatic cases did not respond adequately. Inhaled magnesium has been proposed as a treatment for unresponsive asthma cases. However, its role remains controversial. This review evaluates the effectiveness and safety of nebulized magnesium compared to standard therapy (Beta Agonist, Anticholinergic, Corticosteroid) in adults with acute asthma attacks. METHODS: The protocol has been registered in PROSPERO. A literature search was conducted through PubMed/MEDLINE, Cochrane, ProQuest, and Google Scholar, and using the keywords "inhaled magnesium" and "asthma". Manual searches were carried out through data portals. Journal articles included are randomized controlled trials. The assessment risk of bias was performed using Version 2 of the Cochrane risk-of-bias tool for randomized trials. RESULTS: There are five articles included in this review. There is no significant difference in readmission rate and oxygen saturation in the magnesium group compared to control (RR 1; 95% CI 0.92 to 1,08; p= 0,96 and MD 1,82; 95% CI -0.89 to 4.53; p= 0.19, respectively). There is a significant reduction of respiratory rate and clinical severity in magnesium (MD -1,72; 95% CI -3,1 to 0.35; p= 0.01, RR 0.29; 95% CI 0.17 to 0.69; p <0.001, respectively). There was a higher risk of side effects in the magnesium group (HR 1.56; 95%CI 1.05 to 2.32; p= 0.03). However, the side effects are relatively mild such as hypotension and nausea. CONCLUSION: Inhaled magnesium improves the outcome of asthmatic patients, especially in lung function, clinical severity, and respiratory rate. Moreover, inhaled magnesium is safe to be given.


Assuntos
Antiasmáticos , Asma , Adulto , Humanos , Magnésio/uso terapêutico , Antiasmáticos/efeitos adversos , Asma/tratamento farmacológico , Hospitalização , Quimioterapia Combinada
13.
BMC Bioinformatics ; 25(1): 140, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561679

RESUMO

Drug combination therapy is generally more effective than monotherapy in the field of cancer treatment. However, screening for effective synergistic combinations from a wide range of drug combinations is particularly important given the increase in the number of available drug classes and potential drug-drug interactions. Existing methods for predicting the synergistic effects of drug combinations primarily focus on extracting structural features of drug molecules and cell lines, but neglect the interaction mechanisms between cell lines and drug combinations. Consequently, there is a deficiency in comprehensive understanding of the synergistic effects of drug combinations. To address this issue, we propose a drug combination synergy prediction model based on multi-source feature interaction learning, named MFSynDCP, aiming to predict the synergistic effects of anti-tumor drug combinations. This model includes a graph aggregation module with an adaptive attention mechanism for learning drug interactions and a multi-source feature interaction learning controller for managing information transfer between different data sources, accommodating both drug and cell line features. Comparative studies with benchmark datasets demonstrate MFSynDCP's superiority over existing methods. Additionally, its adaptive attention mechanism graph aggregation module identifies drug chemical substructures crucial to the synergy mechanism. Overall, MFSynDCP is a robust tool for predicting synergistic drug combinations. The source code is available from GitHub at https://github.com/kkioplkg/MFSynDCP .


Assuntos
Benchmarking , Treinamento por Simulação , Combinação de Medicamentos , Quimioterapia Combinada , Linhagem Celular
15.
J Am Coll Cardiol ; 83(17): 1627-1636, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38658101

RESUMO

BACKGROUND: Ticagrelor reduced major adverse cardiovascular events (MACE) and increased bleeding in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease. Limb events including revascularization, acute limb ischemia (ALI), and amputation are major morbidities in patients with T2DM and atherosclerosis. OBJECTIVES: This study sought to determine the effect of ticagrelor on limb events. METHODS: Patients were randomized to ticagrelor or placebo on top of aspirin and followed for a median of 3 years. MACE (cardiovascular death, myocardial infarction, or stroke), limb events (ALI, amputation, revascularization), and bleeding were adjudicated by an independent and blinded clinical events committee. The presence of peripheral artery disease (PAD) was reported at baseline. RESULTS: Of 19,220 patients randomized, 1,687 (8.8%) had PAD at baseline. In patients receiving placebo, PAD was associated with higher MACE (10.7% vs 7.3%; HR: 1.48; P < 0.001) and limb (9.5% vs 0.8%; HR: 10.67; P < 0.001) risk. Ticagrelor reduced limb events (1.6% vs 1.3%; HR: 0.77; 95% CI: 0.61-0.96; P = 0.022) with significant reductions for revascularization (HR: 0.79; 95% CI: 0.62-0.99; P = 0.044) and ALI (HR: 0.24; 95% CI: 0.08-0.70; P = 0.009). The benefit was consistent with or without PAD (HR: 0.80; 95% CI: 0.58-1.11; and HR: 0.76; 95% CI: 0.55-1.05, respectively; Pinteraction = 0.81). There was no effect modification of ticagrelor vs placebo based on PAD for MACE (Pinteraction = 0.40) or TIMI major bleeding (Pinteraction = 0.3239). CONCLUSIONS: Patients with T2DM and atherosclerosis are at high risk of limb events. Ticagrelor decreased this risk, but increased bleeding. Future trials evaluating the combination of ticagrelor and aspirin would further elucidate the benefit/risk of such therapy in patients with PAD, including those without coronary artery disease. (A Study Comparing Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes Mellitus [THEMIS]: NCT01991795).


Assuntos
Aspirina , Diabetes Mellitus Tipo 2 , Inibidores da Agregação Plaquetária , Ticagrelor , Humanos , Ticagrelor/uso terapêutico , Ticagrelor/administração & dosagem , Aspirina/uso terapêutico , Aspirina/administração & dosagem , Masculino , Feminino , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Idoso , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/administração & dosagem , Quimioterapia Combinada , Doença Arterial Periférica/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Método Duplo-Cego , Resultado do Tratamento , Isquemia/prevenção & controle
17.
J Int Med Res ; 52(4): 3000605241247702, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38661102

RESUMO

Generalized pustular psoriasis (GPP) is characterized by painful and occasionally disfiguring cutaneous manifestations with sepsis-like systemic symptoms, and is a rare severe variant of psoriasis. Currently, there is no standard treatment for GPP. Here, we report a case of a female patient with ankylosing spondylitis (AS) and mild scalp psoriasis, who developed GPP and alopecia following three courses of adalimumab therapy. The patient's condition gradually improved following cessation of adalimumab and treatment with secukinumab and acitretin. After eight weeks of treatment, the patient achieved almost complete clearance of her psoriasis, her alopecia improved, and her AS was relieved. Therefore, we believe that a combination of secukinumab with acitretin may be a rational approach for the treatment of severe GPP.


Assuntos
Acitretina , Anticorpos Monoclonais Humanizados , Quimioterapia Combinada , Psoríase , Humanos , Feminino , Psoríase/tratamento farmacológico , Psoríase/patologia , Acitretina/uso terapêutico , Acitretina/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Adulto , Espondilite Anquilosante/tratamento farmacológico , Resultado do Tratamento
18.
Proc Natl Acad Sci U S A ; 121(15): e2321116121, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38557176

RESUMO

Multidrug resistance (MDR) is a major factor in the failure of many forms of tumor chemotherapy. Development of a specific ligand for MDR-reversal would enhance the intracellular accumulation of therapeutic agents and effectively improve the tumor treatments. Here, an aptamer was screened against a doxorubicin (DOX)-resistant human hepatocellular carcinoma cell line (HepG2/DOX) via cell-based systematic evolution of ligands by exponential enrichment. A 50 nt truncated sequence termed d3 was obtained with high affinity and specificity for HepG2/DOX cells. Multidrug resistance protein 1 (MDR1) is determined to be a possible recognition target of the selected aptamer. Aptamer d3 binding was revealed to block the MDR of the tumor cells and increase the accumulation of intracellular anticancer drugs, including DOX, vincristine, and paclitaxel, which led to a boost to the cell killing of the anticancer drugs and lowering their survival of the tumor cells. The aptamer d3-mediated MDR-reversal for effective chemotherapy was further verified in an in vivo animal model, and combination of aptamer d3 with DOX significantly improved the suppression of tumor growth by treating a xenograft HepG2/DOX tumor in vivo. This work demonstrates the feasibility of a therapeutic DNA aptamer as a tumor MDR-reversal agent, and combination of the selected aptamer with chemotherapeutic drugs shows great potential for liver cancer treatments.


Assuntos
Antineoplásicos , Resistencia a Medicamentos Antineoplásicos , Animais , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Resistência a Múltiplos Medicamentos , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Quimioterapia Combinada , Linhagem Celular Tumoral
19.
Circ Cardiovasc Interv ; 17(4): e013000, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38626080

RESUMO

BACKGROUND: Oncological patients with coronary artery disease face an elevated risk of hemorrhagic and ischemic events following percutaneous coronary intervention. Despite medical guidelines recommending minimal dual antiplatelet therapy (DAPT) duration for patients with cancer, dedicated data on abbreviated DAPT in this population is lacking. This study aims to evaluate the occurrence of ischemic and hemorrhagic events in patients with cancer compared with other high-bleeding risk individuals. METHODS: Patient-level data from 4 high-bleeding risk coronary drug-eluting stent studies (ONYX One, LEADERS FREE, LEADERS FREE II, and SENIOR trials) treated with short DAPT were analyzed. The comparison focused on patients with high-bleeding risk with and without cancer, assessing 1-year rates of net adverse clinical events (all-cause death, myocardial infarction, stroke, revascularization, and Bleeding Academic Research Consortium [BARC] types 3 to 5 bleeding) and major adverse clinical events (all-cause death, myocardial infarction, stroke). RESULTS: A total of 5232 patients were included, of whom 574 individuals had cancer, and 4658 were at high-bleeding risk without previous cancer. Despite being younger with fewer risk factors, patients with cancer had higher net adverse clinical event (HR, 1.25; P=0.01) and major adverse clinical event (HR, 1.26; P=0.02), primarily driven by all-cause mortality and major bleeding (BARC 3-5), but not myocardial infarction, stroke, stent thrombosis, or repeat revascularization. Cancer was an independent predictor of net adverse clinical event (P=0.005), major adverse clinical event (P=0.01), and major bleeding (P=0.03). CONCLUSIONS: The present work is the first report on abbreviated DAPT dedicated to patients with cancer. Cancer is a major marker of adverse outcomes and these events had high lethality. Despite short DAPT, patients with cancer experienced higher rates of major bleeding compared with patients without cancer with high-bleeding risk, which occurred mainly after DAPT discontinuation. These findings reinforce the need for a more detailed and individualized stratification of those patients. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03344653, NCT01623180, NCT02843633, NCT0284.


Assuntos
Stents Farmacológicos , Infarto do Miocárdio , Neoplasias , Intervenção Coronária Percutânea , Acidente Vascular Cerebral , Humanos , Inibidores da Agregação Plaquetária , Stents Farmacológicos/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Resultado do Tratamento , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Infarto do Miocárdio/etiologia , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Quimioterapia Combinada , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Neoplasias/terapia
20.
Nat Commun ; 15(1): 3178, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38609378

RESUMO

Chemo-immunotherapy combinations have been regarded as one of the most practical ways to improve immunotherapy response in cancer patients. In this study, we integrate the transcriptomics data from anti-PD-1-treated tumors and compound-treated cancer cell lines to systematically screen for chemo-immunotherapy synergisms in silico. Through analyzing anti-PD-1 induced expression changes in patient tumors, we develop a shift ability score to measure if a chemotherapy or a small molecule inhibitor treatment can shift anti-PD-1 resistance in tumor cells. By applying shift ability analysis to 41,321 compounds and 16,853 shRNA treated cancer cell lines transcriptomic data, we characterize the landscape of chemo-immunotherapy synergism and experimentally validated a mitochondrial RNA-dependent mechanism for drug-induced immune activation in tumor. Our study represents an effort to mechanistically characterize chemo-immunotherapy synergism and will facilitate future pre-clinical and clinical studies.


Assuntos
Imunoterapia , Neoplasias , Humanos , Quimioterapia Combinada , Linhagem Celular , Perfilação da Expressão Gênica , Neoplasias/tratamento farmacológico , Neoplasias/genética
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