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1.
J Enzyme Inhib Med Chem ; 38(1): 203-215, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36382444

RESUMO

The present study aimed to investigate the antitumor effect of simultaneous inhibition of dihydrofolate reductase (DHFR) enzyme. We designed some novel pyrazolo[3,4-d]pyrimidines bearing different amino acid conjugates as efficient antifolate agents attributable to their structural similarity with methotrexate (MTX) and MTX-related antifolates. All compounds were tested to screen their enzymatic inhibition against DHFR compared with the reference drug MTX and for their in vitro antitumor cytotoxicity against six MTX-resistant cancer cell lines. The flow cytometry indicated that the most potent compound 7f arrested MCF-7 cells in the S-phase and induced apoptosis. Western blot for visualisation proved the ability of compound 7f to induce the expression of proapoptotic caspases and Bax proteins in MCF-7 breast cancer cell line beside its ability to diminish the expression of antiapoptotic Bcl-2 protein. Molecular modelling studies concluded that compound 7f displayed better binding energy than that of the normal ligand MTX. HIGHLIGHTSNew pyrazolo[3,4-d]pyrimidine derivatives 7a-m which are structurally similar to the classical methotrexate (MTX) and MTX-related antifolates were synthesised as antitumor agents.Novel N-acyl amino acid compound 7f exhibited marked DHFR inhibition activity that are parralel to both the molecular docking results and cytotoxic activity.Compound 7f could induce the expression of proapoptotic caspases and Bax proteins in MCF-7 breast cancer cell line beside its ability to diminish the expression of antiapoptotic Bcl-2 protein.All prepared compounds obey Lipinski rule of five except compound 7f.


Assuntos
Antineoplásicos , Neoplasias da Mama , Antagonistas do Ácido Fólico , Humanos , Feminino , Pirimidinas/química , Proteína X Associada a bcl-2 , Metotrexato/farmacologia , Simulação de Acoplamento Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Aminoácidos , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/metabolismo , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Caspases/metabolismo
2.
Gene ; 851: 146941, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36257469

RESUMO

Methotrexate (MTX), as a folate antagonist is used for breast cancer chemotherapy, but its application due to the adverse side effects was limited. In this study, MTX were encapsulated in magnetic alginate beads coated with glutaraldehyde to control its release in order to reduce the side effects and improve its stability. The complex was characterized by physicochemical studies. The encapsulation efficiency was 75 % and the complex showed acceptable controlled release behavior. The cell cytotoxicity assessed using methylthiazol tetrazolium (MTT) method showed that magnetic alginate beads-MTX, in lower dosage has higher anticancer effect compared to the free MTX. The real-time polymerase chain reaction (PCR) was used to evaluate apoptotic factors Bcl2 associated X gene (Bax), B-cell lymphoma 2 (Bcl-2), and neuroinflammatory marker tumor necrosis factor-alpha (TNF-α) genes expression level on the treated cells. The findings demonstrated the significant increase of expression of Bax and a significant decrease in the expressions of Bcl-2 and TNF-α in Michigan cancer foundation-7 (MCF-7) cells. These results indicated that the developed drug can overcome the side effects of MTX and offer a controlled drug release for a sustained period with the long-term treatment of breast cancer.


Assuntos
Neoplasias da Mama , Metotrexato , Humanos , Feminino , Liberação Controlada de Fármacos , Metotrexato/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Alginatos/uso terapêutico , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
3.
Ann Pharmacother ; 57(1): 86-98, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35587593

RESUMO

OBJECTIVE: The objective of this article is to review abrocitinib, an oral Janus kinase (JAK) 1 inhibitor, for the treatment of patients with moderate-to-severe atopic dermatitis (AD). DATA SOURCES: A literature search of MEDLINE (PubMed) was performed for articles from inception through end-March 2022 using the following search terms: atopic dermatitis, abrocitinib, PF-04965842, methotrexate, cyclosporine, dupilumab, ruxolitinib, and JAK-STAT pathway. STUDY SELECTION AND DATA EXTRACTION: English articles relating to pharmacology, pharmacokinetics, efficacy, and safety of abrocitinib, and other conventional systemic medications for AD, were included. DATA SYNTHESIS: Across phase IIb and phase III clinical trials, abrocitinib was efficacious with an average of 47.5% patients on 200 mg abrocitinib and 32.0% on 100 mg abrocitinib achieving an Investigator's Global Assessment (IGA) of 0 or 1 at 12 weeks. In comparison with dupilumab 300 mg subcutaneously every other week, patients on abrocitinib 200 mg once daily had improved disease severity and itch response. The majority of adverse events were not severe and self-limited. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Prior to Food and Drug Administration (FDA) approval of abrocitinib, prednisone was the only FDA-approved oral medication for AD. Although biologics such as dupilumab have revolutionized care, some patients prefer oral medications. Compared with clinical trials of conventional AD treatments, abrocitinib appears more effective. CONCLUSIONS: Abrocitinib is an efficacious oral JAK 1 inhibitor recently FDA-approved for patients ≥ 18 years old with moderate-to-severe AD who have not responded to systemic medications or when contraindicated otherwise.


Assuntos
Produtos Biológicos , Ciclosporinas , Dermatite Atópica , Humanos , Adolescente , Dermatite Atópica/tratamento farmacológico , Prednisona/uso terapêutico , Metotrexato/uso terapêutico , Janus Quinases/uso terapêutico , Resultado do Tratamento , Método Duplo-Cego , Fatores de Transcrição STAT/uso terapêutico , Transdução de Sinais , Índice de Gravidade de Doença , Produtos Biológicos/uso terapêutico , Ciclosporinas/uso terapêutico , Imunoglobulina A/uso terapêutico
4.
Int J Nanomedicine ; 17: 5153-5162, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36348765

RESUMO

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by arthrocele, cartilage damage and disability. Although several anti-RA drugs have been developed for long-term treatment, they require frequent local injection and lead to multiple adverse effects such as osteoporosis and myelosuppression. Purpose: Reducing the amount and frequency of anti-RA drugs methotrexate (MTX) and dexamethasone sodium phosphate (DSP) by local injection of phospholipid-based phase separation gel (PPSG) coloaded the two drugs, which presented PPSG-(+). Methods: First, We characterized PPSG-(+). And we used UV spectrophotometry and high performance liquid chromatography (HPLC) to detect drug concentration, which can clarify the drug release in vitro and in vivo, respectively. We also injected PPSG-(+) into the joint cavity of healthy rabbits to prove the safety of PPSG-(+). Then, we injected PPSG-(+) into the joint cavity of RA modeled rabbits to demonstrate the effect in anti-RA of PPSG-(+) including the thickness of joints, tumor necrosis factor (TNF)-α and interleukin (IL)-1ß detection, hematoxylin-eosin (H&E) staining and computed tomography (CT) of joints. Results: Suspended particles show a tight and uniform arrangement in PPSG-(+). The gel underwent a phase transition at 20 min in vitro and 8 h in vivo, and vesicular structures reflecting its degradation and phase transition were observed in vivo. PPSG-(+) released both drugs in a sustained and fixed ratio for more than 14 days, while it proved to be safe for intra-articular injection and did not induce inflammation in a rabbit. Eventually, PPSG-(+) showed a good anti-RA effect and its potency can be maintained for 3 weeks. Conclusion: PPSG-(+) is a drug delivery system offering good biocompatibility and sustained release of MTX and DSP, leading to long-lasting anti-RA effect.


Assuntos
Artrite Reumatoide , Metotrexato , Animais , Coelhos , Fosfolipídeos/química , Géis/química , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Injeções Intra-Articulares , Fator de Necrose Tumoral alfa/uso terapêutico , Dexametasona/uso terapêutico
5.
BMC Musculoskelet Disord ; 23(1): 1001, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36419049

RESUMO

BACKGROUND: Systemic sclerosis (SSc) is an incurable autoimmune disease characterized by progressive skin fibrosis and organ failure. Tenosynovitis is a common musculoskeletal manifestation, but tendon rupture has seldom reported in SSc. CASE PRESENTATION: We present a rare case of a 49-year-old female with SSc who has suffered from bilateral tendon rupture of the fourth and fifth digits with positive antinuclear antibody (ANA) and anti-centromere B antibody, but negative rheumatoid factor in serum. In the extensor tendons of the patient's hands, inflammation, edema, hypertrophy and tendon interruption were detected with ultrasound and magnetic resonance imaging(MRI). Tendon transfer repair surgery was performed and 10 mg/week methotrexate was then used in this patient. Her hand function was improved well with methotrexate and rehabilitation treatment postoperatively. CONCLUSIONS: Early detection of tenosynovitis is necessary to prevent tendon rupture in SSc patients. Ultrasound and Magnetic Resonance Imaging appear to be useful examinations for evaluating tendon pathology for early detection.


Assuntos
Escleroderma Sistêmico , Traumatismos dos Tendões , Tenossinovite , Humanos , Feminino , Pessoa de Meia-Idade , Tenossinovite/diagnóstico por imagem , Tenossinovite/etiologia , Tenossinovite/cirurgia , Metotrexato , Traumatismos dos Tendões/complicações , Traumatismos dos Tendões/diagnóstico por imagem , Ruptura Espontânea , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico por imagem , Tendões/patologia
6.
RMD Open ; 8(2)2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36410777

RESUMO

BACKGROUND: Baricitinib (BARI) is approved for the treatment of rheumatoid arthritis (RA) after failure of conventional synthetic and biologic disease modifying anti-rheumatic drugs (cs/bDMARDs) in combination with methotrexate (MTX) or as monotherapy. However, real-world data are scarce regarding efficacy and drug persistence for BARI monotherapy (BARI-mono) versus its combination with MTX (BARI-combo). OBJECTIVE: To evaluate efficacy and drug persistence of BARImono compared with BARI-combo in routine clinical practice METHODS: Patients with RA who were switched to BARI were included in a prospective, monocentric cohort. Demographics, clinical outcomes, adverse events and medication were prospectively recorded every 3 months. Clinical efficacy was measured by DAS-28 ESR while drug persistence was measured as the time on drug. We estimated least-square mean DAS-28 scores over time using linear mixed effects models including time-group interactions. Kaplan-Meier method was used to estimate BARI survival and probability of remission over time. RESULTS: 139 patients (98 women; aged 58.4 (12.8) years; mean disease duration of 9.7 years) were included between 2017 and 2021. 46 patients received BARI-combo, 93 patients received BARI-mono. Mean DAS-28 ESR were not significantly but only numerically different between both groups at baseline and multiple timepoints over follow-up. DAS-28 ESR remission was attained at least once upto 48 weeks in 62% and 51% patients in BARI-combo versus BARI-mono group (log-rank p=0.64). Drug persistence was high (69 vs 67% at 48 weeks and 62% vs 56% at 96 weeks) and similar in BARI-combo-treated and BARI-mono-treated patients. b/ts DMARD naïve patients had lower mean DAS-28 scores over the follow-up and attained DAS-28 ESR remission earlier than patients with inadequate response to b/ts DMARDs (p=0.11). BARI was discontinued in 11/139 patients (7.9%) due to adverse effects. CONCLUSION: In routine practice, BARI is effective as monotherapy in case of MTX intolerance with overall high drug persistence rates. No new safety signals were observed.


Assuntos
Antirreumáticos , Artrite Reumatoide , Humanos , Feminino , Estudos Prospectivos , Quimioterapia Combinada , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/induzido quimicamente , Antirreumáticos/efeitos adversos , Metotrexato
7.
J Ayub Med Coll Abbottabad ; 34(Suppl 1)(3): S644-S648, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36414584

RESUMO

Background: Azathioprine is first line immunosuppressive agent in treatment of chronic actinic dermatitis. The role of methotrexate has been effective in different dermatosis and it seems reasonable to use it in the treatment of chronic actinic dermatitis. Aims: We sought to compare the efficacy of methotrexate versus azathioprine in treatment of chronic actinic dermatitis. Methods: Patients with chronic actinic dermatitis were randomized to receive methotrexate in group A and azathioprine in group B. The response to treatment in terms of percentage PASI reduction and side effects of medications were assessed 12 weeks follow-up. Results: In group A, the percentage PASI reduction was <25% in 2 (1.19%) patients, 25-49% in 47 (27.9%) patients, 50-74% was achieved by 35 (20.8%) patients while in group B, the percentage PASI reduction of 25% was achieved by 2 (1.19%) patients, 25-49% in 45 (26.7%) patients, 50-74% in 37 (22.0%) patients. More than or equal to 75 percentage PASI reduction was not achieved by any patient in the study. Both drugs were found efficacious in treatment of CAD. A total of 23 (27.38%) patients in group A and 22 (26.19%) patients in group B showed derangement in laboratory investigations during 12 weeks treatment. The limitation of study was inability to do photo-patch test, so patients were diagnosed clinically and biopsy was done in clinically challenging cases. Conclusion: : This study shows that methotrexate is equally effective as azathioprine in the treatment of chronic actinic dermatitis with its added benefits of being cost effective and better safety profile.


Assuntos
Azatioprina , Transtornos de Fotossensibilidade , Humanos , Azatioprina/uso terapêutico , Metotrexato/uso terapêutico , Transtornos de Fotossensibilidade/induzido quimicamente , Transtornos de Fotossensibilidade/diagnóstico , Transtornos de Fotossensibilidade/tratamento farmacológico , Imunossupressores/uso terapêutico , Resultado do Tratamento
8.
F1000Res ; 11: 1012, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405556

RESUMO

Background: Methotrexate (MTX) is a chemotherapeutic drug, used mainly in many cancerous stages, inflammatory and auto-immune diseases, but its use has been limited by its nephrotoxicity. Cyanocobalamin is a water-soluble vitamin possessing nephro-protective properties. The aim of this study was to investigate the effect of cyanocobalamin on the nephrotoxicity of methotrexate. Methods: In the study 42 albino adult female rats were used, divided into six groups each containing seven rats (n=7). 1 st group: Control group (Negative control), 7 rats were injected intraperitoneally with 0.5ml/kg/day NS. Second group: 7 rats were injected intraperitoneally with a single dose of methotrexate (20 mg/kg) for 4 days. Third Group: 7 rats were given intraperitoneally cyanocobalamin at a dose (1.5 mg/kg/day) for two weeks, fourth, fifth, sixth group: 7 rats from each group were injected intraperitoneally with different concentrations of cyanocobalamin (0.5, 1, 1.5 mg/kg /day), respectively, for two weeks and MTX (20 mg/kg), which was injected only on day 11. On day 15, rats from all groups were euthanized, and blood samples were taken for biochemical tests, including evaluating serum urea and creatinine. The kidneys were extracted for histological investigation and evaluation of antioxidant (GSH) and oxidative stress (MDA) by using kidney tissue homogenates. Results: This study revealed that kidney damage, produced by the MTX (group II), is manifested by significantly elevated (P<0.05) urea and creatinine. On the contrary, the cyanocobalamin groups (IV, V, VI) significantly (P<0.05) reduced urea and creatinine. Renal antioxidant defense systems, such as reduced glutathione depleted by MTX therapy, were restored to normal levels by cyanocobalamin. Furthermore, cyanocobalamin reduced oxidative stress (MDA) and histologically reduced renal tissue injury induced by MTX. Conclusions: In conclusion, the study revealed that cyanocobalamin has a nephroprotective action upon MTX-induced renal damage in rats; cyanocobalamin may offer a protective effect, such as antioxidant action.


Assuntos
Antioxidantes , Metotrexato , Ratos , Feminino , Animais , Metotrexato/toxicidade , Antioxidantes/farmacologia , Creatinina , Ratos Wistar , Vitamina B 12/farmacologia , Ureia
9.
Curr Oncol ; 29(11): 8160-8170, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36354704

RESUMO

Primary central nervous system lymphoma (PCNSL) is a rare malignancy. Standard of care is upfront high-dose methotrexate (HD-MTX) chemotherapy, while cranial radiation is more commonly used in the salvage setting. In this retrospective study, we aimed to investigate the safety and efficacy of salvage cranial radiation in PCNSL. PCNSL patients who received upfront HD-MTX chemotherapy and salvage cranial radiation after treatment failure between 1995 and 2018 were selected. Radiological response to cranial radiation was assessed as per Response Assessment in Neuro-Oncology Criteria. Twenty one patients were selected (median age 59.9 years), with median follow-up of 19.9 months. Fourteen patients (66.7%) received a boost to the gross tumour volume (GTV). Four patients (19.0%) sustained grade ≥2 treatment-related neurotoxicity post-completion of cranial radiation. Of the 19 patients who had requisite MRI with gadolinium imaging available for Response Assessment in Neuro-Oncology (RANO) criteria assessment, 47.4% achieved complete response, 47.4% achieved partial response, and 5.3% of patients exhibited stable disease. Higher dose to the whole brain (>30 Gy) was associated with higher rate of complete response (63.6%) than lower dose (≤30 Gy, 37.5%), while boost dose to the gross disease was also associated with higher rate of complete response (61.5%) compared with no boost dose (33.3%). Median overall survival was 20.0 months. PCNSL patients who relapsed following upfront chemotherapy showed a high rate of response to salvage cranial radiation, especially in those receiving greater than 30 Gy to the whole brain and boost to gross disease.


Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma , Humanos , Pessoa de Meia-Idade , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/radioterapia , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Irradiação Craniana , Metotrexato/uso terapêutico , Linfoma/tratamento farmacológico , Linfoma/radioterapia
10.
Genes (Basel) ; 13(11)2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-36360249

RESUMO

BACKGROUND: Methotrexate (MTX) is considered the first choice among disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA) treatment. However, response to it varies as approximately 40% of the patients do not respond and would lose the most effective period of treatment time. Therefore, having a predictive biomarker before starting MTX treatment is of utmost importance. Methylation of long interspersed nucleotide element-1 (LINE-1) is generally considered a surrogate marker for global genomic methylation, which has been reported to associate with disease activity after MTX therapy. METHODS: We performed a prospective study on 273 naïve early RA (ERA) patients who were treated with MTX, followed up to 12 months, and classified according to their therapy response. The baseline LINE-1 methylation levels in peripheral blood mononuclear cells (PBMC) of cases were assessed by bisulfite pyrosequencing. RESULTS: Baseline LINE-1 methylation level per se turned out not to predict the response to the therapy, nor did age, sex, body mass index, or smoking status. However, if cases were stratified according to positivity to rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) or seronegativity, we observed an opposite association between baseline LINE-1 methylation levels and optimal response to MTX therapy among responders. The best response to MTX therapy was associated with hypermethylated LINE-1 among double-positive ERA cases (p-value: 0.002) and with hypomethylated LINE-1 in seronegative ERA patients (p-value: 0.01). CONCLUSION: The LINE-1 methylation level in PBMCs of naïve ERA cases associates with the degree of response to MTX therapy in an opposite way depending on the presence of RF and ACPA antibodies. Our results suggest LINE-1 methylation level as a new epigenetic biomarker for predicting the degree of response to MTX in both double-positive and seronegative ERA patients.


Assuntos
Antirreumáticos , Artrite Reumatoide , Humanos , Metotrexato/uso terapêutico , Leucócitos Mononucleares , Estudos Prospectivos , Metilação , Elementos Nucleotídeos Longos e Dispersos/genética , Resultado do Tratamento , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Antirreumáticos/uso terapêutico , Biomarcadores , Anticorpos/uso terapêutico
11.
Ann Med ; 54(1): 3269-3285, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36382690

RESUMO

OBJECTIVE: Systematically evaluate the clinical efficacy of mifepristone combined with methotrexate therapy for ectopic pregnancy (EP), analyze the experimental designs, put forward improvement ideas. METHODS: RCTs of mifepristone combined with mifepristone for EP until January 2022 in six databases were searched. The primary outcome indicator was the cure rate. RevMan 5.4 was used to analyse and the online GRADEpro tool was used to assess the certainty of the evidence. RESULTS: Twenty-five RCTs involved 2263 patients. The cure rate was higher in the investigational group (OR = 4.09, 95%CI: [3.20, 5.22]), time of vagina stopped bleeding (MD = -11.21, 95%CI: [-11.85, -10.57]) and time of abdominal pain disappeared (MD = -6.24, 95%CI: [-6.63, -5.86]) were shorter in the investigational group, ß-HCG level (MD = -585.32, 95%CI: [-609.62, -561.03]) was lower and diameter of the mass (MD = -1.23, 95%CI: [-1.40, -106]) was smaller in the investigational group. The certainty of the evidence for most outcomes was moderate or high, and only one was low. CONCLUSIONS: The combination of mifepristone and methotrexate can improve the efficacy of ectopic pregnancy without amplifying the toxic side effects. Larger scale and better design of the randomized controlled trials are needed.KEY MESSAGESIn recent years, the increase in ectopic pregnancies and their impacts on female fertility makes physicians have to find an effective medical treatment as soon as possible that can avoid surgery.The mifepristone combined with methotrexate therapy for EP has better curative effects on improving the cure rate, lowering ß-HCG level, reducing the mass, and alleviating symptoms of abdominal pain and bleeding, without amplifying the toxic side effects.Literature with high quality is lacking, and well-designed, large-scale and high-quality multicenter randomized controlled trials are needed.


Assuntos
Mifepristona , Gravidez Ectópica , Gravidez , Humanos , Feminino , Mifepristona/uso terapêutico , Mifepristona/efeitos adversos , Metotrexato/uso terapêutico , Gravidez Ectópica/tratamento farmacológico , Gravidez Ectópica/induzido quimicamente , Dor Abdominal/induzido quimicamente , Dor Abdominal/tratamento farmacológico , Estudos Multicêntricos como Assunto
12.
Pediatr Rheumatol Online J ; 20(1): 97, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36384562

RESUMO

BACKGROUND: Evaluation of costs and short-term cost-effectiveness of infliximab plus methotrexate (IFX + MTX); triple therapy of hydroxychloquine, sulphasalazine, and methotrexate (TRIPLE); or methotrexate monotherapy (MTX) in patients with new-onset polyarticular juvenile idiopathic arthritis (JIA). METHODS: In a prospective multicenter study (ACUTE-JIA), costs and health outcomes of 60 randomized patients with new-onset disease-modifying anti-rheumatic drug (DMARD)-naïve polyarticular JIA were analyzed during the first year. A mapping algorithm was used to obtain utility values from Child Health Assessment Questionnaire (CHAQ). Wallace criteriae were used to assess clinically inactive disease (CID). Linear regression with non-parametric bootstrapping was used to adjust imbalances at baseline. RESULTS: Using prices for IFX biosimilar, adjusted annual mean (SD) costs of treatment (€) were 21,164 (4158), 12,136 (5286), and 18,300 (8635) on IFX + MTX, TRIPLE, and MTX, respectively. Incremental cost-effectiveness ratio (ICER) for IFX + MTX as compared with TRIPLE or MTX were 3442 € or 678 € per additional month spent in CID. Mean (SD) quality-adjusted life years (QALYs) for IFX + MTX, TRIPLE and MTX were 0.755 (0.065), 0.725 (0.062), and 0.686 (0.124). ICER for IFX + MTX vs TRIPLE was 294,433 €, and for IFX + MTX vs MTX 31,435 € per QALY gained. CONCLUSIONS: In short-term, biosimilar IFX + MTX can be considered cost-effective when compared with MTX alone. TRIPLE was cost-effective when compared with MTX and showed cost advantage when compared with IFX + MTX. Cost per time spent in CID showed similar results than ICER evaluations. TRIAL REGISTRATION: This trial was primarily registered with the Ethical Board of Helsinki District University Hospital ( https://www.hus.fi ), clinical trial number 211864, and later with ClinicalTrials.gov, number NCT01015547.


Assuntos
Antirreumáticos , Artrite Juvenil , Medicamentos Biossimilares , Criança , Humanos , Metotrexato , Infliximab/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Análise Custo-Benefício , Medicamentos Biossimilares/uso terapêutico , Estudos Prospectivos , Quimioterapia Combinada , Resultado do Tratamento
13.
Drug Des Devel Ther ; 16: 3877-3891, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36388083

RESUMO

Purpose: We designed this study to investigate the potential correlations between gut microbiota compositions and hepatic metabolomic disorders in mice with methotrexate (MTX)-induced hepatoxicity. Methods: We used MTX to induce hepatoxicity in healthy Kunming mice, and we determined plasma ALT and AST levels and assessed the liver tissue histopathology. We applied an integrated gas chromatography-mass spectrometry (GC-MS) and 16S ribosomal RNA (rRNA) gene sequencing approach to evaluate the effects of MTX on the gut microbiota and hepatic metabolic profiles of mice. We uncovered correlations between the gut microbiota and hepatic metabolomic profiles by calculating the Spearman correlation coefficient. Results: MTX caused ALT and AST level elevations and hepatoxicity in our mouse model. MTX disrupted amino acid metabolic pathways (including biosyntheses of valine, leucine, and isoleucine; and arginine; and, metabolism of alanine, aspartate, and glutamate; histidine; beta-alanine; and glycine, serine, and threonine); biosyntheses of aminoacyl-tRNA; and pantothenate, and CoA; and, metabolic pathways of energy, glutathione, and porphyrin; and chlorophyll. In addition, MTX increased the abundances of Staphylococcus, Enterococcus, Collinsella, Streptococcus, and Aerococcus, but decreased the amounts of Lactobacillus, Ruminococcus, norank_f_Muribaculaceae, unclassified_f_Lachnospiraceae, norank_f_Lachnospiraceae, A2, Eubacterium_xylanophilum_group, Phascolarctobacterium, Bifidobacterium, and Faecalibaculum. Our correlation analyses showed that different flora abundance changes including those of Phascolarctobacterium, Faecalibaculum, norank_f_Muribaculaceae, Streptococcus, Enterococcus, Staphylococcus, and Collinsella were associated with liver injury. Conclusion: We present evidence supporting the notion that MTX causes hepatoxicity by altering the gut microbiota and hepatic metabolite profiles, our findings provide new venues for the management of MTX-induced hepatoxicity.


Assuntos
Microbioma Gastrointestinal , Hepatopatias , Microbiota , Camundongos , Animais , Metotrexato/efeitos adversos , Metaboloma , Metabolômica/métodos , Firmicutes
14.
Medicine (Baltimore) ; 101(45): e31527, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36397392

RESUMO

Psoriasis is a disease of immunological origin that damages the skin and mucous membranes. Biological therapies with systemic medications are effective in treating moderate and severe psoriasis. Our objective was to evaluate the effects of methotrexate and etanercept treatment in this disease and to verify their response to the Psoriasis area and severity index (PASI) index in the initial and control phase. The number of patients treated at the Military Hospital in Guayaquil was 2.620 corresponding from July 2020 to July 2021; the selected sample according to the inclusion criteria was 94 patients with moderate and severe psoriasis. The method was retrospective, observational, descriptive, cross-sectional, correlational differential analytical, and approved by the Human Subjects Ethics Committee of the Specialties Hospital "Dr Teodoro Maldonado Carbo" of Guayaquil, Ecuador. In this study, the prevalence was 3.58%, and the body mass index was 28.13 corresponding to overweight and obesity. The PASI index in the initial stage before treatment was 10.8% and in the control phase, it decreased to 2.99%, showing a decrease in lesions and good improvement in the treatment of moderate and severe psoriasis. Student´s T, the combination of etanercept with methotrexate was compared with the response with the PASI index in the initial and control phases, presenting a value lower than 0.001, P = .05, which was very significant. In our study, treatment with etanercept and methotrexate in moderate and severe psoriasis had is a favorable response in reducing this disease. It is expected that, in Ecuador, the health authorities would implement the biologics for the treatment of moderate and several psoriasis and including them in the basic list of medicines of the Public Health Ministry.


Assuntos
Metotrexato , Psoríase , Humanos , Etanercepte/uso terapêutico , Metotrexato/uso terapêutico , Receptores do Fator de Necrose Tumoral , Estudos Retrospectivos , Estudos Transversais , Imunoglobulina G/uso terapêutico , Índice de Gravidade de Doença , Psoríase/tratamento farmacológico , Psoríase/patologia
16.
Ther Adv Respir Dis ; 16: 17534666221135314, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36346076

RESUMO

BACKGROUND: Studies on the risk and protective factors for lung function decline and mortality in rheumatoid arthritis-related interstitial lung disease (RA-ILD) are limited. OBJECTIVES: We aimed to investigate clinical factors and medication uses associated with lung function decline and mortality in RA-ILD. METHODS: This retrospective cohort study examined the medical records of patients with RA-ILD who visited Severance Hospital between January 2006 and December 2019. We selected 170 patients with RA-ILD who had undergone at least one spirometry test and chest computed tomography scan. An absolute decline of ⩾10% in the functional vital capacity (FVC) was defined as significant decline in pulmonary function. Data for analysis were retrieved from electronic medical records. RESULTS: Ninety patients (52.9%) were female; the mean age was 64.0 ± 10.2 years. Multivariate logistic regression showed that a high erythrocyte sediment rate level at baseline [odds ratio (OR) = 3.056; 95% confidence interval (CI) = 1.183-7.890] and methotrexate (MTX) use (OR = 0.269; 95% CI = 0.094-0.769) were risk and protective factors for lung function decline, respectively. Multivariate Cox regression analysis indicated that age ⩾65 years (OR = 2.723; 95% CI = 1.142-6.491), radiologic pattern of usual interstitial pneumonia (UIP) or probable UIP (OR = 3.948; 95% CI = 1.522-10.242), baseline functional vital capacity (FVC) % predicted (OR = 0.971; 95% CI = 0.948-0.994), and MTX use (OR = 0.284; 95% CI = 0.091-0.880) were predictive of mortality. CONCLUSION: We identified risk and protective factors for lung function decline and mortality in patients with RA-ILD. MTX use was associated with favorable outcome in terms of both lung function and mortality in our cohort.


Assuntos
Artrite Reumatoide , Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Masculino , Metotrexato/uso terapêutico , Estudos Retrospectivos , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Pulmão/diagnóstico por imagem , Estudos de Coortes
17.
Artigo em Inglês | MEDLINE | ID: mdl-36361110

RESUMO

Ectopic pregnancy, that is, a blastocyst occurring outside the endometrial cavity of the uterus, affects nearly 2% of pregnancies. The treatment of ectopic pregnancy is surgical or pharmacological. Since surgical management is associated with numerous serious side effects, conservative treatment is sought. The treatment of choice in the majority of cases is based on pharmacotherapy with methotrexate (MTX) in a single- or multi-dose regimen. Although the efficacy of methotrexate reaches between 70 and 90%, its use requires specific conditions regarding both the general condition of the patient and the characteristic features of the ectopic pregnancy. Moreover, MTX can cause severe adverse effects, including stomatitis, hepatotoxicity and myelosuppression. Therefore, clinicians and researchers are still looking for a less toxic, more effective treatment, which could prevent surgeries as a second-choice treatment. Some studies indicate that other substances might constitute a good alternative to methotrexate in the management of ectopic pregnancies. These substances include aromatase inhibitors, especially letrozole. Another promising substance in EP treatment is gefitinib, an inhibitor of EGFR tyrosine domain which, combined with MTX, seems to constitute a more effective alternative in the management of tubal ectopic pregnancies. Other substances for local administration include KCl and absolute ethanol. KCl injections used in combination with MTX may be used when foetal heart function is detected in cervical ectopic pregnancies, as well as in heterotopic pregnancy treatment. Absolute ethanol injections proved successful and safe in caesarean scar pregnancies management. Thus far, little is known about the use of those substances in the treatment of ectopic pregnancies, but already conducted studies seem to be promising.


Assuntos
Abortivos não Esteroides , Gravidez Ectópica , Gravidez , Feminino , Humanos , Abortivos não Esteroides/uso terapêutico , Metotrexato/uso terapêutico , Gravidez Ectópica/tratamento farmacológico , Gravidez Ectópica/induzido quimicamente , Resultado do Tratamento , Etanol , Estudos Retrospectivos
18.
Int J Mol Sci ; 23(21)2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36361584

RESUMO

Methotrexate (MTX) is a potent anti-cancer drug, commonly associated with nephrotoxicity via the induction of oxidative stress and apoptosis with alteration of renal water channel proteins, namely aquaporins (AQPs). Omega-3 long-chain polyunsaturated fatty acids (LC-PUFA) have shown cytoprotective effects through their anti-oxidant and antiapoptotic activities. The present study aims for the first time to explore the role of LC-PUFA against MTX-induced nephrotoxicity. Rats were divided into the following groups: saline control, LC-PUFA control, MTX, MTX + LC-PUFA (150 mg/kg), or MTX + LC-PUFA (300 mg/kg). Then, H&E staining and immunohistochemical staining for the anti-apoptosis marker B-cell lymphoma 2 (BCL-2), the apoptosis marker BCL2-Associated X Protein (BAX), the proinflammatory marker Nuclear factor kappa B (NF-kB), AQPs 1 and 2 were performed in kidney sections with an assessment of renal oxidative stress. The MTX caused a renal histopathological alteration, upregulated renal BAX and NF-kB, downregulated Bcl-2 and AQP1, altered the distribution of AQP2, and caused oxidative stress. The LC-PUFA attenuated the pathological changes and decreased renal BAX and NF-kB, increased BCL-2 and AQP1, restored the normal distribution of AQP2, and decreased the oxidative stress. Therefore, LC-PUFA is a good adjuvant to MTX to prevent its adverse effects on kidneys through its antiapoptotic, antioxidant, and anti-inflammatory effect and its role in the restoration of the expression of AQPs 1 and 2.


Assuntos
Ácidos Graxos Ômega-3 , Metotrexato , Ratos , Animais , Metotrexato/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , NF-kappa B/metabolismo , Aquaporina 2/metabolismo , Estresse Oxidativo , Rim/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/metabolismo , Suplementos Nutricionais
19.
Int J Mol Sci ; 23(21)2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36361779

RESUMO

This study aimed to evaluate the role of microRNAs (miRNA) as biomarkers of treatment response in rheumatoid arthritis (RA) patients through a systematic review of the literature. The MEDLINE and Embase databases were searched for studies including RA-diagnosed patients treated with disease-modifying antirheumatic drugs (DMARDs) that identify miRNAs as response predictors. Review inclusion criteria were met by 10 studies. The main outcome of the study was the response to treatment, defined according to EULAR criteria. A total of 839 RA patients and 67 healthy donors were included in the selected studies. RA patients presented seropositivity for the rheumatoid factor of 74.7% and anti-citrullinated C-peptide antibodies of 63.6%. After revision, 15 miRNAs were described as treatment response biomarkers for methotrexate, anti-tumour necrosis factor (TNF), and rituximab. Among treatments, methotrexate presented the highest number of predictor miRNAs: miR-16, miR-22, miR-132, miR-146a and miR-155. The most polyvalent miRNAs were miR-146a, predicting response to methotrexate and anti-TNF, and miR-125b, which predicts response to infliximab and rituximab. Our data support the role of miRNAs as biomarkers of treatment response in RA and point to DMARDs modifying the miRNAs expression. Nevertheless, further studies are needed since a meta-analysis that allows definitive conclusions is not possible due to the lack of studies in this field.


Assuntos
Antirreumáticos , Artrite Reumatoide , MicroRNAs , Humanos , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Biomarcadores , Epigênese Genética , Metotrexato/uso terapêutico , MicroRNAs/genética , MicroRNAs/uso terapêutico , Rituximab/uso terapêutico , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa/genética
20.
Int J Mol Sci ; 23(21)2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36362183

RESUMO

Rheumatoid arthritis (RA) is a common disease worldwide and is treated commonly with methotrexate (MTX). CS12192 is a novel JAK3 inhibitor discovered by Chipscreen Biosciences for the treatment of autoimmune diseases. In the present study, we examined the therapeutic effect of CS12192 against RA and explored if the combinational therapy of CS12192 and MTX produced a synergistic effect against RA in rat collagen-induced arthritis (CIA). Arthritis was induced in male Sprague-Dawley rats by two intradermal injections of bovine type II collagen (CII) and treated with MTX, CS12192, or the combination of CS12192 and MTX daily for two weeks. Effects of different treatments on arthritis score, X-ray score, pathology, and expression of inflammatory cytokines and biomarkers were examined. We found that treatment with either CS12192 or MTX produced a comparable therapeutic effect on CIA including: (1) significantly lowering the arthritis score, X-ray score, serum levels of rheumatic factor (RF), C-reactive protein (CRP), and anti-nuclear antibodies (ANA); (2) largely alleviating histopathological damage, reducing infiltration of Th17 cells while promoting Treg cells; (3) inhibiting the expression of inflammatory cytokines and chemokines such as IL-1ß, TNF-α, IL-6, CCL2, and CXCL1. All these inhibitory effects were further improved by the combinational therapy with MTX and CS12192. Of importance, the combinational treatment also resulted in a marked switching of the Th17 to Treg and the M1 to M2 immune responses in synovial tissues of CIA. Thus, when compared to the monotherapy, the combination treatment with CS12192 and MTX produces a better therapeutic effect against CIA with a greater suppressive effect on T cells and macrophage-mediated joint inflammation.


Assuntos
Artrite Experimental , Artrite Reumatoide , Inibidores de Janus Quinases , Ratos , Masculino , Bovinos , Animais , Metotrexato/uso terapêutico , Ratos Sprague-Dawley , Artrite Experimental/patologia , Citocinas/metabolismo , Inibidores de Janus Quinases/efeitos adversos
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