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1.
Arq Bras Cir Dig ; 33(4): e1551, 2021.
Artigo em Inglês, Português | MEDLINE | ID: mdl-33503111

RESUMO

BACKGROUND: Tacrolimus and mycophenolate mofetil are immunosuppressive agents widely used on the postoperative period of the transplants. AIM: To evaluate the influence of the association of them on the abdominal wall healing in rats. METHODS: Thirty-six Wistar rats were randomly assigned in three groups of 12. On the early postoperative period, four of the control group and three of the experimental groups died. The three groups were nominated as follow: control group (GC, n=8); group I (GI, n=11, standard operation, mycophenolate mofetil and tacrolimus); group II (GII, n=10, standard operation, mycophenolate mofetil and tacrolimus). The standard operation consisted of right total nephrectomy and 20 min ischemia of the left kidney followed by reperfusion. Both NaCl 0.9% and the immunosuppressive agents were administered starting on the first postoperative day and continuing daily until the day of death on the 14th day. On the day of their deaths, two strips of the anterior abdominal wall were collected and submitted to breaking strength measurement and histological examination. RESULTS: There were no significant differences in wound infection rates (p=0,175), in the breaking strength measurement and in the histological examination among the three groups. CONCLUSION: The combination of the immunosuppressive agents used in the study associated with renal ischemia and reperfusion does not interfere in the abdominal wall healing of rats.


Assuntos
Parede Abdominal/cirurgia , Imunossupressores/farmacologia , Rim/irrigação sanguínea , Ácido Micofenólico/farmacologia , Traumatismo por Reperfusão/complicações , Tacrolimo/farmacologia , Animais , Isquemia , Ácido Micofenólico/administração & dosagem , Ratos , Ratos Wistar , Reperfusão , Tacrolimo/administração & dosagem
2.
Medicine (Baltimore) ; 100(1): e24093, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429774

RESUMO

RATIONALE: Henoch-Schönlein Purpura (HSP) is an acute small vessel vasculitis. It is the most common vasculitis in children. In majority of the cases, the disease is self-limited. Relapses can occur, in particular during the first year of the disease. There is no consensus on a specific treatment. The efficacy and safety of steroidal treatment in treating HSP is still controversial. Immunosuppressive treatment of HSP nephritis is used in patients with severe renal involvement (nephrotic range proteinuria and/or progressive renal impairment). The literature on immunosuppressive treatment of severe HSP without kidney involvement is scanty. PATIENTS CONCERNS: We report 2 case reports of 2 adolescents affected from Henoch-Schönlein Purpura and severe gastrointestinal involvement. Both patients presented a poor response to steroids treatment. DIAGNOSES: The diagnosis of HSP was made according to the diagnostic criteria published by European League against Rheumatism and Pediatric Rheumatology European Society in 2006. INTERVENTIONS: In consideration of the recurrence of the Henoch Schönlein Purpura and the gastrointestinal involvement, we decided to start Mycophenolate Mofetil treatment. OUTCOMES: In both patients all clinical manifestations resolved in few days. LESSONS: In our cases of HSP with gastrointestinal involvement Mycophenolate Mofetil treatment has been very effective. This experience teaches us that immunosuppressive agents may be very useful to induce and maintain remission not only in renal involvement, but in all cases of persistent, recurrent, or complicated Henoch Schönlein Purpura in children.


Assuntos
Trato Gastrointestinal/efeitos dos fármacos , Ácido Micofenólico/uso terapêutico , Púrpura de Schoenlein-Henoch/tratamento farmacológico , Adolescente , Criança , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Trato Gastrointestinal/fisiopatologia , Humanos , Masculino , Ácido Micofenólico/farmacologia , Púrpura de Schoenlein-Henoch/fisiopatologia , Recidiva
3.
Arch Virol ; 165(11): 2605-2613, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32770483

RESUMO

Noroviruses are the main causative agents of acute viral gastroenteritis worldwide. However, no vaccine or specific antiviral treatment is available, imposing a heavy global health burden. The nucleoside analogue 2'-fluoro-2'-deoxycytidine (2'-FdC) has been reported to have broad antiviral activity. Here, we report that 2'-FdC significantly inhibits murine norovirus replication in macrophages. This effect was partially reversed by exogenous supplementation of cytidine triphosphate. The combination of 2'-FdC with mycophenolic acid, ribavirin or favipiravir (T705) exerts synergistic antiviral effects. These results indicate that 2'-FdC is a potential candidate for antiviral drug development against norovirus infection.


Assuntos
Antivirais/farmacologia , Desoxicitidina/análogos & derivados , Norovirus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Amidas/farmacologia , Animais , Infecções por Caliciviridae/tratamento farmacológico , Infecções por Caliciviridae/virologia , Linhagem Celular , Desoxicitidina/farmacologia , Humanos , Camundongos , Ácido Micofenólico/farmacologia , Norovirus/fisiologia , Pirazinas/farmacologia , Células RAW 264.7 , Ribavirina/farmacologia , Replicação Viral/fisiologia
4.
Biochimie ; 177: 50-52, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32805303

RESUMO

Various interferon (IFN)-inducible transmembrane (IFITM) proteins are known to be expressed in human tissues though only IFITM 1-3 are inducible by IFN. Numerous studies have shown that activation of IFITM3 could suppress infection by influenza and coronaviruses such as the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). In view of the potential application of IFITM proteins' induction to target SARS-CoV-2 infection that causes COVID-19, this article layout insights into the known antiviral mechanisms and therapeutic agents related to IFITM. Blocking viral entry through various mechanisms and the potential application of the FDA approved immunosuppressant agent, mycophenolic acid, as inducer of IFITM3 are among those discussed.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Interferons/farmacologia , Proteínas de Membrana/efeitos dos fármacos , Ácido Micofenólico/farmacologia , Pneumonia Viral/tratamento farmacológico , Proteínas de Ligação a RNA/efeitos dos fármacos , Animais , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Humanos , Imunossupressores/farmacologia , Proteínas de Membrana/imunologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Proteínas de Ligação a RNA/imunologia
5.
PLoS One ; 15(7): e0235743, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645052

RESUMO

Granulomatosis with polyangiitis (GPA) is an autoimmune disease affecting mainly small blood vessels. B-cells are important in the GPA pathogenesis as precursors of autoantibody-producing cells but likely also contribute (auto)antibody-independently. This has been underlined by the effectiveness of B-cell-depletion (with Rituximab) in inducing and maintaining disease remission. Mycophenolate-mofetil (MMF) and azathioprine (AZA) are immunosuppressive therapies frequently used in GPA-patients. Interestingly, MMF-treated GPA-patients are more prone to relapses than AZA-treated patients, while little is known about the influence of these drugs on B-cells. We investigated whether MMF or AZA treatment (or their active compounds) alters the circulating B-cell subset distribution and has differential effects on in vitro B-cell proliferation and cytokine production in GPA-patients that might underlie the different relapse rate. Circulating B-cell subset frequencies were determined in samples from AZA-treated (n = 13), MMF-treated (n = 12), untreated GPA-patients (n = 19) and matched HCs (n = 41). To determine the ex vivo effects of the active compounds of MMF and AZA, MPA and 6-MP respectively, on B-cell proliferation and cytokine production, PBMCs of untreated GPA-patients (n = 29) and matched HCs (n = 30) were cultured for 3-days in the presence of CpG-oligodeoxynucleotides (CpG) with MPA or 6-MP. After restimulation (with phorbol myristate acetate, calcium-ionophore), cytokine-positive B-cell frequencies were measured. Finally, to assess the effect of MMF or AZA treatment on in vitro B-cell proliferation and cytokine production, PBMCs of MMF-treated (n = 18), and AZA-treated patients (n = 28) and HCs (n = 41) were cultured with CpG. The memory B-cell frequency was increased in AZA- compared to MMF-treated patients, while no other subset was different. The active compounds of MMF and AZA showed in vitro that MPA decreased B-cell proliferation in GPA-patients and HCs. B-cell proliferation in MMF- and AZA-treated patients was not different. Finally, the IL-6+ B-cell frequency was decreased by MPA compared to 6-MP. No differences in IL-10+, IL-6+ or TNFα+ B-cell proportions or proliferation were found in MMF- and AZA-treated patients. Our results indicate that MMF could be superior to AZA in inhibiting B-cell cytokine production in GPA-patients. Future studies should assess the effects of these immunosuppressive drugs on other immune cells to elucidate mechanisms underlying the potential differences in relapse rates.


Assuntos
Linfócitos B/imunologia , Granulomatose com Poliangiite , Imunossupressores/farmacologia , Ácido Micofenólico/farmacologia , Adulto , Idoso , Azatioprina/farmacologia , Subpopulações de Linfócitos B/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/imunologia , Humanos , Interleucina-6/metabolismo , Masculino , Mercaptopurina/farmacologia , Pessoa de Meia-Idade
6.
Gastroenterol Hepatol ; 43(8): 457-463, 2020 Oct.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32646657

RESUMO

SARS-CoV-2 infection has produced a pandemic with serious consequences for our health care system. Although liver transplant patients represent only a minority of the population, the hepatologists who follow these patients have tried to coordinate efforts to produce a protocol the management of immunosuppression during SARS-CoV-2 infection. Although there are no solid studies to support general recommendations, experiences with other viral infections (hepatitis C, cytomegalovirus) suggest that management of immunosuppression without mycophenolate mofetil or m-Tor inhibitors (drugs that are also associated with leukopenia and lymphopenia) may be beneficial. It is also important to pay attention to possible drug interactions, especially in the case of tacrolimus, with some of the treatments with antiviral effect given in the context of COVID 19 (lopinavir/ritonavir, azithromycin). Finally, the immunosuppressive effect of immunomodulating drugs (tocilizumab and similar) administered to patients with severe lung disease should be taken into account. The mechanisms of action of the different immunosuppressive drugs are reviewed in this article, as well as their potential effect on SARS-CoV-2 infection, and suggests guidelines for the management of immunosuppression.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Imunossupressão/efeitos adversos , Imunossupressores/efeitos adversos , Transplante de Fígado , Pandemias , Pneumonia Viral/epidemiologia , Imunidade Adaptativa , Antivirais/farmacologia , Betacoronavirus/imunologia , Betacoronavirus/fisiologia , Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/farmacologia , Inibidores de Calcineurina/uso terapêutico , Contraindicações de Medicamentos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Suscetibilidade a Doenças , Interações Medicamentosas , Everolimo/efeitos adversos , Everolimo/farmacologia , Everolimo/uso terapêutico , Glucocorticoides/efeitos adversos , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Imunidade Inata , Hospedeiro Imunocomprometido , Imunossupressão/métodos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/farmacologia , Ácido Micofenólico/uso terapêutico , Pneumonia Viral/imunologia , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/prevenção & controle , Sirolimo/efeitos adversos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores
7.
Microbiol Immunol ; 64(9): 635-639, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32579258

RESUMO

In this study, the anti-severe acute respiratory syndrome coronavirus-2 (anti-SARS-CoV-2) activity of mycophenolic acid (MPA) and IMD-0354 was analyzed. These compounds were chosen based on their antiviral activities against other coronaviruses. Because they also inhibit dengue virus (DENV) infection, other anti-DENV compounds/drugs were also assessed. On SARS-CoV-2-infected VeroE6/TMPRSS2 monolayers, both MPA and IMD-0354, but not other anti-DENV compounds/drugs, showed significant anti-SARS-CoV-2 activity. Although MPA reduced the viral RNA level by only approximately 100-fold, its half maximal effective concentration was as low as 0.87 µ m, which is easily achievable at therapeutic doses of mycophenolate mofetil. MPA targets the coronaviral papain-like protease and an in-depth study on its mechanism of action would be useful in the development of novel anti-SARS-CoV-2 drugs.


Assuntos
Antivirais/farmacologia , Benzamidas/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Ácido Micofenólico/farmacologia , Pneumonia Viral/tratamento farmacológico , Animais , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Vírus da Dengue/efeitos dos fármacos , Humanos , Pandemias , Pneumonia Viral/virologia , Células Vero , Replicação Viral/efeitos dos fármacos
9.
Blood Coagul Fibrinolysis ; 31(2): 132-139, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31913146

RESUMO

: Mycophenolate mofetil (MMF) raises platelet counts in patients with primary immune thrombocytopenia. However, studies indicate that MMF inhibits collagen-induced platelet aggregation, potentially increasing bleeding risk following MMF therapy. The study evaluates the in-vitro effect of MMF on platelet function. Blood samples (n = 6) from healthy donors were incubated with vehicle, MMF or mycophenolic acid (MPA) at clinically relevant concentrations. Platelet aggregation was measured with flow cytometry and 96-well light transmission aggregometry (LTA). Using flow cytometry, we measured the expression of platelet CD49b, CD42b, CD42a, CD61 and CD41. Platelet activation was measured as the expression of P-selectin and the active form of the GPIIb/IIIa receptor following agonist stimulation. Agonists were: ADP, thrombin receptor-activating peptide, collagen, collagen-related peptide and U46619. The Platelet Function Analyzer-200 was used to measure global platelet function. MMF and MPA did not change platelet aggregation regardless of the agonist used. An exception was a significant, but minor decrease in collagen-induced platelet aggregation in samples with MMF (6 ±â€Š3%, P = 0.02) and MPA (8 ±â€Š4%, P = 0.01) compared with vehicle (22 ±â€Š11%). However, this was not observed using the lesser sensitive LTA method. Compared with vehicle, MPA led to a significantly lower relative disposition of the surface collagen-receptor GPVI (7.8 ±â€Š1.8 versus 8.8 ±â€Š2.1 mean fluorescence intensity, P < 0.001). In all other platelet-related tests, neither MMF nor MPA showed any effect. In conclusion, MMF and MPA only had a minor effect on collagen-induced platelet aggregation, with MPA reducing the relative disposition of surface GPVI receptors.


Assuntos
Plaquetas/efeitos dos fármacos , Ácido Micofenólico/farmacologia , Humanos , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Testes de Função Plaquetária , Glicoproteínas da Membrana de Plaquetas
10.
Exp Parasitol ; 210: 107831, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31926147

RESUMO

Babesia (B.) bovis is one of the main etiological agents of bovine babesiosis, causes serious economic losses to the cattle industry. Control of bovine babesiosis has been hindered by the limited treatment selection for B. bovis, thus, new options are urgently needed. We explored the drug library and unbiasedly screened 640 food and drug administration (FDA) approved drug compounds for their inhibitory activities against B. bovis in vitro. The initial screening identified 13 potentially effective compounds. Four potent compounds, namely mycophenolic acid (MPA), pentamidine (PTD), doxorubicin hydrochloride (DBH) and vorinostat (SAHA) exhibited the lowest IC50 and then selected for further evaluation of their in vitro efficacies using viability, combination inhibitory and cytotoxicity assays. The half-maximal inhibitory concentration (IC50) values of MPA, PTD, DBH, SAHA were 11.38 ± 1.66, 13.12 ± 4.29, 1.79 ± 0.15 and 45.18 ± 7.37 µM, respectively. Of note, DBH exhibited IC50 lower than that calculated for the commonly used antibabesial drug, diminazene aceturate (DA). The viability result revealed the ability of MPA, PTD, DBH, SAHA to prevent the regrowth of treated parasite at 4 × and 2 × of IC50. Antagonistic interactions against B. bovis were observed after treatment with either MPA, PTD, DBH or SAHA in combination with DA. Our findings indicate the richness of FDA approved compounds by novel potent antibabesial candidates and the identified potent compounds especially DBH might be used for the treatment of animal babesiosis caused by B. bovis.


Assuntos
Antiprotozoários/farmacologia , Babesia bovis/efeitos dos fármacos , Animais , Antiprotozoários/toxicidade , Babesia bovis/crescimento & desenvolvimento , Babesiose/tratamento farmacológico , Babesiose/parasitologia , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Doenças dos Bovinos/parasitologia , Cães , Doxorrubicina/farmacologia , Doxorrubicina/toxicidade , Aprovação de Drogas , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Concentração Inibidora 50 , Células Madin Darby de Rim Canino/efeitos dos fármacos , Ácido Micofenólico/farmacologia , Ácido Micofenólico/toxicidade , Pentamidina/farmacologia , Pentamidina/toxicidade , Bibliotecas de Moléculas Pequenas , Espectrometria de Fluorescência , Vorinostat/farmacologia , Vorinostat/toxicidade
11.
Nat Prod Res ; 34(9): 1206-1212, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-30760051

RESUMO

Mycophenolic acid (MPA) is a group of metabolite derived from several species of Penicillium, which shows potent bioactivity. In this study, a new derivative of MPA compound named penicacid D (1), was isolated from the marine derived fungus Penicillium sp. SCSIO sof101, along with seven known compounds (2-8). Their structures were elucidated based on the HR-ESI-MS and NMR data. Moreover, the 1H and 13C NMR data of compound 2 and the 13C NMR data of compound 3 are reported. Compounds 1, 4 and 6 exhibited weak activities against Escherichia coli (clinical isolation number 100385570) and Acinetobacter baumannii (clinical isolation number 100069).


Assuntos
Ácido Micofenólico/isolamento & purificação , Penicillium/química , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Fungos/química , Estrutura Molecular , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/química , Ácido Micofenólico/farmacologia , Análise Espectral/métodos
12.
Int J Impot Res ; 32(2): 201-206, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31000815

RESUMO

The aim of the present study was to evaluate the histological, histochemical, and stereological changes caused by mycophenolate mofetil (MMF) on the tunica albuginea of rat penises submitted to an injection of transforming growth factor beta (TGF-ß) for the induction of Peyronie's disease (PD). Twenty adult male Wistar rats were divided into four groups: Control group; TGF-ß group (TGF-ß injection); MMF-7d group (treated with MMF 7 days after induction with TGF-ß); and MMF-30d group (treated with MMF 30 days after induction with TGF-ß). The steorological evaluation included the relative volume of different types of connective fibres of the tunica albuginea. The histochemical analysis revealed the fragmentation and degradation of elastin in the tunica albuginea. This process was partially reversed in the MMF-7d group and a situation very close to normality was observed in the MMF-30d group. In the collagen III/collagen I ratio it was observed increase in this ratio in the TGF-ß (59.4 ± 5.53) and MMF-7d (49 ± 18.2) groups and a decrease in the MMF-30d group (28.7 ± 4), approaching normality. The injection of TGF-ß promoted fibrotic alterations in the penile tunica albuginea in Wistar rats corresponding to PD. In this model, MMF acts as a regenerating anti-fibrotic agent.


Assuntos
Ácido Micofenólico/farmacologia , Ereção Peniana , Induração Peniana/tratamento farmacológico , Pênis/patologia , Animais , Modelos Animais de Doenças , Fibrose , Masculino , Induração Peniana/induzido quimicamente , Induração Peniana/patologia , Pênis/efeitos dos fármacos , Ratos , Ratos Wistar , Fator de Crescimento Transformador beta
13.
Mol Biol Rep ; 47(1): 123-128, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31833032

RESUMO

Dendritic cells (DCs) have a major role in the initiation of an immune response and Immunoglobulin-like transcript 3&4 (ILT3&ILT4) are inhibitory receptors that induce tolerance in DCs. Recent studies show that immunosuppressive agents affect frequency of DCs. Herein, we compared the effect of mycophenolate mofetil (MMF) and sirolimus (SRL) in tacrolimus (TAC)-based immunosuppression on DC subsets frequency and ILT3/ILT4 gene expression in kidney transplant recipients. We enrolled 24 adult transplant recipients who received MMF/TAC (n = 14) or SRL/TAC (n = 10). Peripheral blood samples were obtained from recipients, 24-48 h before transplantation and 4 months after transplantation. The frequency of DC subsets was analyzed by flow cytometry and gene expression of ILT3/ILT4 were estimated by real-time PCR. Our results showed that MMF vs. SRL treated recipient showed an increase in pDC % with increased in the expression of ILT3/ILT4 which is in favor of better allograft survival; However, for confirming the results of this preliminary study, a cohort study with larger sample size is necessary.


Assuntos
Células Dendríticas/citologia , Imunossupressores/farmacologia , Transplante de Rim , Glicoproteínas de Membrana/genética , Receptores Imunológicos/genética , Transplantados , Condicionamento Pré-Transplante , Adulto , Contagem de Células Sanguíneas , Estudos de Coortes , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Imunossupressão/efeitos adversos , Imunossupressão/métodos , Imunossupressores/uso terapêutico , Falência Renal Crônica/sangue , Falência Renal Crônica/imunologia , Falência Renal Crônica/terapia , Transplante de Rim/métodos , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Ácido Micofenólico/farmacologia , Ácido Micofenólico/uso terapêutico , Receptores Imunológicos/metabolismo , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Tacrolimo/farmacologia , Tacrolimo/uso terapêutico , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Adulto Jovem
14.
Handb Exp Pharmacol ; 261: 441-469, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31820175

RESUMO

The goal of immunosuppressive therapy post-transplantation in pediatric renal transplant recipients is to prevent acute and chronic rejection while minimizing drug side effects. Most therapies alter immune response mechanisms but are not immunologically specific, and a careful balance is required to find the dose that prevents rejection of the graft while minimizing the risks of overimmunosuppression leading to infection and cancer. While this chapter because of space constraints focuses on immunosuppressive therapy in pediatric renal transplant recipients, many aspects can be applied on pediatric recipients of other solid organ transplants such as the liver and heart. The major maintenance immunosuppressive agents currently used in various combination regimens are tacrolimus, cyclosporine, mycophenolate mofetil, azathioprine, everolimus, sirolimus, and glucocorticoids (steroids). Although data from adult renal transplantation trials are used to help guide management decisions in pediatric patients, immunosuppressive therapy in pediatric renal transplant recipients often must be modified because of the unique dosage requirements and clinical effects of these agents in children, including their impact on growth and development. The optimal immunosuppressive therapy post-transplant is not established. The goal remains to find the best combination of immunosuppressive agents that optimizes allograft survival by preventing acute rejection while limiting drug toxicities.


Assuntos
Rejeição de Enxerto , Imunossupressores , Adulto , Criança , Ciclosporina/química , Quimioterapia Combinada , Humanos , Ácido Micofenólico/química , Ácido Micofenólico/farmacologia , Ácido Micofenólico/uso terapêutico , Tacrolimo/uso terapêutico
15.
Int J Mol Sci ; 20(24)2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31835612

RESUMO

Abnormalities in B cells play pivotal roles in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). Breach in central and peripheral tolerance mechanisms generates autoreactive B cells which contribute to the pathogenesis of SLE and LN. Dysregulation of B cell transcription factors, cytokines and B cell-T cell interaction can result in aberrant B cell maturation and autoantibody production. These immunological abnormalities also lead to perturbations in circulating and infiltrating B cells in SLE and LN patients. Conventional and novel immunosuppressive medications confer differential effects on B cells which have important clinical implications. While cyclophosphamide and mycophenolate mofetil (MMF) showed comparable clinical efficacy in active LN, MMF induction was associated with earlier reduction in circulating plasmablasts and plasma cells. Accumulating evidence suggests that MMF maintenance is associated with lower risk of disease relapse than azathioprine, which may be explained by its more potent and selective suppression of B cell proliferation. Novel therapeutic approaches targeting the B cell repertoire include B cell depletion with monoclonal antibodies binding to cell surface markers, inhibition of B cell cytokines, and modulation of costimulatory signals in B cell-T cell interaction. These biologics, despite showing improvements in serological parameters and proteinuria, did not achieve primary endpoints when used as add-on therapy to standard treatments in active LN patients. Other emerging treatments such as calcineurin inhibitors, mammalian target of rapamycin inhibitors and proteasome inhibitors also show distinct inhibitory effects on the B cell repertoire. Advancement in the knowledge on B cell biology has fueled the development of new therapeutic strategies in SLE and LN. Modification in background treatments, study endpoints and selective recruitment of subjects showing aberrant B cells or its signaling pathways when designing future clinical trials may better elucidate the roles of these novel therapies for SLE and LN patients.


Assuntos
Linfócitos B/patologia , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nefrite Lúpica/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Azatioprina/farmacologia , Azatioprina/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Ensaios Clínicos como Assunto , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Humanos , Imunossupressores/farmacologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Ácido Micofenólico/farmacologia , Ácido Micofenólico/uso terapêutico
16.
Med Sci Monit ; 25: 8242-8247, 2019 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-31677379

RESUMO

BACKGROUND It is thought that immunosuppressive treatment, besides anti-rejection properties, leads to pathological changes within the organ due to activation of mechanisms associated with oxidative stress. The aim of this study was to examine the parameters of oxidative stress in the livers of rats treated with the most commonly used transplant recipient drug regimens. MATERIAL AND METHODS The rat livers were obtained from archival material obtained from the previously performed experiment. Malondialdehyde (MDA), reduced glutathione (GSH) concentrations, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities were analyzed. RESULTS Only the group treated with tacrolimus (T), mycophenolate mofetil (M), and prednisone (P), the TMP group, showed a slight increase in lipid peroxide concentration compared to the control group, though the difference was not statistically significant. Comparison of lipid peroxide concentration between the other treatment combinations and the control group showed a significant decrease. Additionally, a difference in lipid peroxide concentrations in the livers was observed between the cyclosporine A (C) group and tacrolimus (T) group. Alterations of other oxidative stress parameters were also observed in different regimens. CONCLUSIONS Long-lasting immunosuppressive treatment does indeed affect redox status; however, the antioxidant defenses of the liver against the effects of excess hydrogen peroxide are efficient, so the superoxide dismutase/glutathione peroxidase (SOD/GPx) and superoxide dismutase/catalase (SOD/CAT) ratios were not significant.


Assuntos
Fígado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Animais , Antioxidantes/farmacologia , Catalase/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Peróxido de Hidrogênio/farmacologia , Imunossupressores/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Peróxidos Lipídicos , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Ácido Micofenólico/farmacologia , Prednisona/farmacologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Tacrolimo/farmacologia
17.
Medicine (Baltimore) ; 98(43): e17457, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651849

RESUMO

The activity of p70S6 kinase located downstream of the mammalian target of rapamycin (mTOR) pathway is sensitive to mTOR inhibitors. However, the methods of assessing p70S6 kinase activity are still unclear. This study aimed to investigate p70S6 kinase activity in CD4-positive cells of liver transplant patients.Liver transplant patients treated with mTOR inhibitors were recruited from Beijing Chaoyang Hospital between October 2014 and October 2016. The influence of mycophenolic acid (MPA) derivatives and prednisone on p70S6 kinase phosphorylation in CD4-positive cells was examined in liver transplant patients and healthy controls (HCs). The phosphorylation of p70S6K in CD4 + CD25 regulatory T cells (Treg cells) and CD4 + CD25- T effector cells was analyzed by phospho-flow cytometry.The phospho-flow technique detected a significant loss of p70S6 kinase phosphorylation in CD4-positive cells of patients treated with mTOR inhibitors compared with HCs. MPA derivatives and prednisone did not affect p70S6 kinase phosphorylation significantly. No significant difference in p70S6 kinase phosphorylation was observed when the whole blood was stored within 3 hours at room temperature. The phosphorylation of p70S6K was significantly lower in CD4 + CD25 Treg cells than in CD4 + CD25-T effector cells in HCs. After liver transplant patients were treated with mTOR inhibitors, p70S6K phosphorylation was more reduced in CD4 + CD25-T effector cells than in CD4 + CD25 Treg cells.The presence of phosphorylation of p70S6 kinase in CD4-positive cells was reduced in liver transplant patients who were treated by mTOR inhibitors.


Assuntos
Linfócitos T CD4-Positivos/enzimologia , Inibidores Enzimáticos/farmacologia , Transplante de Fígado , Ácido Micofenólico/farmacologia , Fosforilação/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Resultado do Tratamento , Adulto Jovem
18.
Mol Cell Biol ; 40(1)2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31658995

RESUMO

Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil, a drug that is widely used for immunosuppression in organ transplantation and autoimmune diseases, as well as anticancer chemotherapy. It inhibits IMP dehydrogenase, a rate-limiting enzyme in de novo synthesis of guanidine nucleotides. MPA treatment interferes with transcription elongation, resulting in a drastic reduction of pre-rRNA and pre-tRNA synthesis, the disruption of the nucleolus, and consequently cell cycle arrest. Here, we investigated the mechanism whereby MPA inhibits RNA polymerase III (Pol III) activity, in both yeast and mammalian cells. We show that MPA rapidly inhibits Pol III by depleting GTP. Although MPA treatment can activate p53, this is not required for Pol III transcriptional inhibition. The Pol III repressor MAF1 is also not responsible for inhibiting Pol III in response to MPA treatment. We show that upon MPA treatment, the levels of selected Pol III subunits decrease, but this is secondary to transcriptional inhibition. Chromatin immunoprecipitation (ChIP) experiments show that Pol III does not fully dissociate from tRNA genes in yeast treated with MPA, even though there is a sharp decrease in the levels of newly transcribed tRNAs. We propose that in yeast, GTP depletion may lead to Pol III stalling.


Assuntos
Inibidores Enzimáticos/farmacologia , Imunossupressores/farmacologia , Ácido Micofenólico/farmacologia , RNA Polimerase III/antagonistas & inibidores , RNA de Transferência/genética , Transcrição Genética/efeitos dos fármacos , Animais , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Camundongos , Células RAW 264.7 , RNA Polimerase III/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores , Proteínas de Saccharomyces cerevisiae/metabolismo
19.
Drug Metab Dispos ; 47(12): 1372-1379, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31578207

RESUMO

Ginseng is known to have inhibitory effects on UGT1A9 activity. However, little is known about the inhibitory effects of ginsenosides, the major active compounds in ginseng, on UGT1A9 activity. In vitro investigation of UGT1A9 inhibition by ginsenosides was carried out using human liver microsomes (HLMs). Among 10 ginsenosides, ginsenoside Rc was the strongest inhibitor of UGT1A9-mediated mycophenolic acid glucuronidase activity. Further inhibition kinetic studies using HLMs suggested that ginsenoside Rc competitively and noncompetitively inhibited UGT1A9-mediated propofol and mycophenolic acid glucuronidation activities, with K i values of 2.83 and 3.31 µM, respectively. Next, to investigate whether the inhibitory effect of ginsenoside Rc is specific to the UGT1A9 isoform, we studied the inhibitory potency of ginsenoside Rc on nine human uridine diphospho-glucuronosyltransferase (UGT) activities using recombinant human UGT isoforms. Ginsenoside Rc exhibited a 12.9-fold selectivity (which was similar to niflumic acid at 12.5-fold) for UGT1A9 inhibition. Ginsenoside Rc at 50 µM also inhibited none of the other UGT isoform-specific activities above 12.0%, except for UGT1A9 (>91.5%) in HLMs, indicating that ginsenoside Rc might be used as a selective UGT1A9 inhibitor in reaction phenotyping studies of new chemical entities. Considering lower plasma concentrations (0.01 µM) of ginsenoside Rc in healthy subjects and no induction potential on UGT isoforms, ginsenoside Rc does not cause pharmacokinetic drug interactions with other coadministered drugs metabolized by UGT1A9. SIGNIFICANCE STATEMENT: Ginsenoside Rc selectively inhibited UGT1A9-mediated propofol and mycophenolic acid glucuronidation activities in human liver microsomes and recombinant uridine diphospho-glucuronosyltransferase (UGT) isoforms. It exhibited a 12.9-fold selectivity for UGT1A9 inhibition. Therefore, ginsenoside Rc might be used as a selective UGT1A9 inhibitor in reaction phenotyping studies of new chemical entities, such as niflumic acid.


Assuntos
Inibidores Enzimáticos/farmacologia , Ginsenosídeos/farmacologia , Glucuronosiltransferase/antagonistas & inibidores , Microssomos Hepáticos/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Inibidores Enzimáticos/química , Ginsenosídeos/química , Glucuronídeos/metabolismo , Humanos , Técnicas In Vitro , Isoenzimas , Cinética , Microssomos Hepáticos/enzimologia , Estrutura Molecular , Ácido Micofenólico/farmacologia , Propofol/farmacologia
20.
Can J Vet Res ; 83(4): 279-284, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31571728

RESUMO

A lack of understanding of specific immune defects underlying canine immune-mediated diseases hampers optimal therapy. Failure to tailor treatment to an individual's immune abnormality can result in lack of efficacy, secondary complications, added expense, and drug-potentiated adverse effects. We adopted a small-volume whole-blood flow cytometric assay to determine the effect of immunosuppressant drugs on T-lymphocyte proliferation. Using healthy dogs in this proof-of-principle study, we hypothesized that there would be dose-dependent suppression of T-lymphocyte proliferation in response to dexamethasone, cyclosporine, mycophenolic acid, and the active metabolite of leflunomide (A77 1726). Whole blood was collected from 6 healthy pet dogs and incubated for 4 d with or without the mitogens concanavalin A and lipopolysaccharide and with increasing concentrations of immunosuppressant. Samples were subsequently stained with viability dye and with antibodies against the pan-T-lymphocyte marker CD5 and the cell proliferation marker Ki67. Percentages of proliferating T-lymphocytes were determined by flow cytometry, and the 50% inhibitory concentration (IC50) was calculated. Inhibition of T-lymphocyte proliferation by the panel of immunosuppressants was shown to be dose-dependent, with marked variability among the dogs. The mean IC50 was 394.8 ± 871 (standard deviation) µM for dexamethasone, 18.89 ± 36.2 ng/mL for cyclosporine, 106.3 ± 157.7 nM for mycophenolic acid, and 3.746 ± 6.8 µM for A77 1726. These results support the use of this assay for detecting the efficacy of individual immunosuppressants used to diminish T-lymphocyte proliferation. In future, the assay may be applied to pet dogs with spontaneous immune-mediated disease to help tailor individual treatment.


Assuntos
Ciclosporina/farmacologia , Dexametasona/farmacologia , Cães , Leflunomida/metabolismo , Ácido Micofenólico/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Anti-Inflamatórios , Antibióticos Antineoplásicos/farmacologia , Antígenos CD5/genética , Antígenos CD5/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Células Cultivadas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Imunossupressores/farmacologia , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Leflunomida/química , Leflunomida/farmacologia , Linfócitos T/fisiologia
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