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Effect of mycophenolate mofetil plus adriamycin on HepG-2 cells

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World Journal of Hepatology 2010年第8期2卷 311-317页

作者： Yan-Kui Chu,Yi Liu,Ji-Kai Yin,Nan Wang,Liang Cai,Jian-Guo Lu,Department of General Surgery,Tangdu Hospital, Fourth Military Medical University,Xi’an 710038,Shaanxi Province,China Yan-Kui Chu Yi Liu Ji-Kai Yin Nan Wang Liang Cai Jian-Guo Lu Department of General Surgery Tangdu Hospital Fourth Military Medical University Xi'an 710038 Shaanxi Province China.

AIM:To investigate the influence of mycophenolate mofetil(MMF)plus adriamycin(ADM)on hepatocellular carcinoma(HCC)cells. METHODS:HCC cells were treated with 100μg/ml of MMF alone(MMF group),1μg/mL of adriamycin(ADM group)alone,or a combination of the drugs(MMF+ ADM group).We performed an 3-[4,5-dimethylthiazol2-yl]-2,5-diphenyl tetrazolium bromide(MTT)assay to measure the growth inhibition rate of HCC *** cytometry was used to determine the percentage of cells in different phases of the cell cycle and the number of apoptotic *** 33258 staining revealed the morphological changes associated with apoptosis in HCC cells. RESULTS:The results of MTT assays revealed that monotherapy with ADM or MMF showed inhibition of cell growth,while MMF+ADM therapy afforded an inhibition rate of more than 90%with cell distribution in G1 and G2/M phase greater than that in S phase. MMF+ADM treatment also downregulated Bcl-2 expression *** growth of HCC cells was markedly inhibited and apoptosis was enhanced in all the 3 *** with other 2 groups,the MMF +ADM group showed more obvious apoptosis of cells. CONCLUSION:The MMF plus ADM combination exerts remarkable inhibitory effects on the growth of HCC cells.

关键词： Mycophenolate mofetil Adriamycin Hepatocellular carcinoma Cell cycle Apoptosis

Safety and Efficacy of Once-Daily Administration of Mycophenolate mofetil in Kidney Transplant Patients—A New Treatment Option for Non-Adherence

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Journal of Biomedical Science and Engineering 2014年第10期7卷 788-791页

作者： Naotsugu Ichimaru Kazuaki Yamanaka Taigo Kato Yoichi Kakuta Toyofumi Abe Jun-ya Kaimori Ryoichi Imamura Norio Nonomura Shiro Takahara Department of Advanced Technology for Transplantation Osaka University Graduate School of Medicine Suita Japan Department of Specific Organ Regulation (Urology) Osaka University Graduate School of Medicine Suita Japan

Non-adherence to immunosuppressive therapy is associated with reduced graft survival. Fifteen long-term follow up kidney transplant patients with stable post-transplant clinical courses were enrolled in the study. All patients were prescribed to tacrolimus prolonged release, mycophenolate mofetil (MMF) and corticosteroid at the time of enrolment. Twice-daily administration of MMF was then converted to a single daily dose. As a result, all immunosuppressive agents were administered simultaneously at one time in the morning. The daily total doses of the three immunosuppressants were identical during the study period. No acute rejection or adverse event was observed during the study period. Blood urea nitrogen and estimated glomerular filtration rate did not change significantly after conversion to once-daily administration. The blood tacrolimus trough level and the Mycophenolic acid (MPA) trough level also did not change significantly after conversion to once-daily administration. Interestingly, the meanmedian MPA trough level remained >3 μg/ml even after conversion to once-daily administration. A sufficient plasma MPA level was maintained after conversion to once-daily administration, and no acute rejection was observed during the study period. To our knowledge, this study is the first to report that the plasma MPA concentration can be maintained after once-daily administration of MMF in long-term kidney transplant patients. Once-daily administration of immunosuppressive agents may improve long-term graft survival because of better treatment adherence due to the reduced dosing frequency. The safety or efficacy of conversion to once-daily administration of MMF should be evaluated in a future randomized controlled large-scale clinical study.

关键词： Once-Daily Administration Mycophenolate mofetil Treatment Adherence

Mycophenolate mofetil toxicity mimicking acute cellular rejection in a small intestinal transplant

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World Journal of Transplantation 2017年第1期7卷 98-102页

作者： Ross Apostolov Khashayar Asadi Julie Lokan Ning Kam Adam Testro Australian Intestinal Transplant Service Austin Health

Mycophenolate mofetil(MMF) is an important medication used for maintenance immunosuppression in solid organ transplants. A common gastrointestinal(GI) side effect of MMF is enterocolitis, which has been associated with multiple histological features. There is little data in the literature describing the histological effects of MMF in small intestinal transplant(SIT) recipients. We present a case of MMF toxicity in a SIT recipient, with histological changes in the donor ileum mimicking persistent acute cellular rejection(ACR). Concurrent biopsies of the patient's native colon showed similar changes to those from the donor small bowel, suggesting a non-graft specific process, raising suspicion for MMF toxicity. The MMF was discontinued and complete resolution of these changes occurred over three weeks. MMF toxicity should therefore be considered as a differential diagnosis for ACR and graftversus-host disease in SITs.

关键词： Small intestinal transplantation Drug toxicity Mycophenolate mofetil Acute cellular rejection Immunosuppression

Post-dose 12-hour trough concentration of mycophenolate mofetil co-administrated with cyclosporine in dog

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畜牧与兽医 2012年第S2期44卷 51-51页

作者： Yijyun Li Zheng Cao Akiyoshi Hayashi Keichiro Mie Maki Ishibashi Toshiyuki Tanaka Katsuhito SoneFumihito Ohashi Laboratory of Veterinary SurgeryGraduate School of Life and Environmental Sciences Osaka Prefecture University

Mycophenolate mofetil (MMF) is a pro-drug for mycophenolic acid (MPA) which reduces the likelihood of allograft rejection after renal transplantation. It was known that post-dose 12-hour trough concentration of MMF will be influenced by several factors including renal function and cyclosporine (CsA) co-administration and need adjustment when used in clinical renal transplanted patients,but there is still few data in dog. The objective of this study is to investigate Post-dose 12-hour trough concentration and determine the optimal dose of MMF in renal transplanted dog. Study 1: Investigate the relationship between oral dose and Post-dose 12-hour trough concentration of MPA in healthy dogs. Study 2: Investigate the changes of post-dose 12-hour trough concentration of MPA in healthy dogs when co-administrating with CsA. Study 3: Investigate the relationship between dose and Post-dose 12-hour trough concentration of MPA in low glomerular filtration rate (GFR) model dogs with CsA co-administration. 8 Adult female beagle dogs aged 1-2 years old,weight in 1. 5-13. 5kg. Study 1: After 7 days of prier oral administration of MMF (10 mg/kg,n = 4; 30 mg/kg,n = 4),MMF was oral administrated in the same dose in day 8,and MPA blood concentrations were measured at 0,20,40,60,90,120, 240,360,480,and 720 min after oral dose. Study 2: After 7 days of prier administration of 10 mg/kg MMF with (n = 4) or without (n = 4) 10 mg/kg CsA,MMF was oral administrated in the same dose with or without CsA in day 8,and post-dose 12-hour trough concentrations were measured. Study 3: Low GFR model dogs were prepared with renal artery ligation before this study. After 7 days of prier co-administration of 10 mg/kg (n = 4) or 20 mg/kg (n = 4) MMF with 10 mg/kg CsA,MMF was oral administrated in the same dose in day 8 and 12-hour trough concentrations of MPA were measured. MPA concentrations were measured by high performance liquid chromatography method. 12-hour trough concentrations of MPA of healthy do

关键词： Mycophenolate mofetil mycophenolic acid trough concentrations cyclosporine dog

Determination of the mitigating effect of colon-specific bioreversible codrugs of mycophenolic acid and aminosugars in an experimental colitis model in Wistar rats

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World Journal of Gastroenterology 2018年第10期24卷 1093-1106页

作者： Shakuntala Santosh Chopade Suneela Sunil Dhaneshwar Department of Pharmaceutical Chemistry Poona College of Pharmacy Bharati Vidyapeeth University

AIM To design colon-targeted codrugs of mycophenolic acid(MPA) and aminosugars as a safer option to mycophenolate mofetil(MMF) in the management of inflammatory bowel disease. METHODS Codrugs were synthesized by coupling MPA with aminosugars(D-glucosamine and D-galactosamine) using EDCI coupling. The structures were confirmed by infrared radiation, nuclear magnetic resonance, mass spectroscopy and elemental analysis. The release profile of codrugs was extensively studied in aqueous buffers, upper gastrointestinal homogenates, faecal matter and caecal homogenates(in vitro) and rat blood(in vitro). Anti-colitic activity was assessed in 2,4,6-trinitrobezenesulfonic acid-induced colitis in Wistar rats by the estimation of various demarcating parameters. Statistical evaluation was performed by applying one-way and two-way ANOVA when compared with the disease *** The prodrugs resisted activation in HCl buffer(pH 1.2) and stomach homogenates of rats with negligible hydrolysis in phosphate buffer(p H 7.4) and intestinal homogenates. Incubation with colon homogenates(in vitro) produced 76% to 89% release of MPA emphasizing colon-specific activation of codrugs and the release of MPA and aminosugars at the site of action. In the in vitro studies, the prodrug of MPA with D-glucosamine(MGLS) was selected which resulted in 68% release of MPA in blood. in vitro studies on MGLS revealed its colon-specific activation after a lag time of 8 h which could be ascribed to the hydrolytic action of N-acyl amidases found in the colon. The synthesized codrugs markedly diminished disease activity score and revived the disrupted architecture of the colon that was comparable to MMF but superior to MPA. CONCLUSION The significant attenuating effect of prodrugs and individual aminosugars on colonic inflammation proved that the rationale of the codrug approach is valid.

关键词： Mycophenolic acid Mutual prodrug Inflammatory bowel disease Mycophenolate mofetil

Autoimmune hepatitis treatment in the elderly: A systematic review

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World Journal of Gastroenterology 2019年第22期25卷 2809-2818页

作者： Marilena Durazzo Giulia Lupi Michela ScANDella Arianna Ferro Gabriella Gruden Department of Medical Sciences University of Turin

BACKGROUND Autoimmune hepatitis (AIH) is a rare chronic inflammatory liver disease with a high risk of progression to liver cirrhosis. The initial treatment for AIH usually includes a steroid, with or without azathioprine. AIH can present at any age;however, the most effective and safe induction treatment for AIH in the elderly remains unclear. AIM To systematically review available data on both effectiveness and safety of AIH treatments in elderly subjects. METHODS To identify studies on AIH induction treatment in elderly patients (≥ 60 years of age), an electronic research was performed (PubMed, EMBASE and Cochrane Library databases) until February 2019. Eligible studies were selected through screening of titles and abstracts, followed by full-text critical evaluation. After risk of bias assessment, data on study designs, interventions, and outcomes were extracted and reviewed. RESULTS Among the 1736 retrieved papers, 15 studies were selected. Out of them, eight studies were excluded because of a critical risk of bias. The remaining seven studies included 789 patients and out of them 239 subjects were elders. First-line treatment was a steroid either alone or in combination with azathioprine in most patients (87.6%) and only one study investigated the effect of combined steroid and mycophenolate mofetil therapy. Standard therapy was effective in inducing remission in the elderly. Moreover, treatment failure and relapses occurred less often in the elderly compared to younger *** Treatment of AIH is challenging in elderly patients. This systematic review confirms the efficacy and safety of standard induction treatment for AIH in the elderly. Available evidence is insufficient to draw any conclusion on the effect of novel AIH treatments in elderly subjects.

关键词： Autoimmune hepatitis Elderly patients Aged Steroids Azathioprine Mycophenolate mofetil

The role of mycophenolate in the treatment of antineutrophil cytoplasmic antibody-associated vasculitis

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World Journal of Nephrology 2019年第4期8卷 75-82页

作者： Maria Koukoulaki Christos Iatrou Center for Nephrology "G.Papadakis" General Hospital of Nikaia – Piraeus "Agios Panteleimon"

Mycophenolic acid, the active metabolite for mycophenolate mofetil and mycophenolic sodium, is a strong, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase, the key enzyme in de novo synthesis of guanosine nucleotides leading to selective inhibition of lymphocyte proliferation. Mycophenolic acid has been evaluated as induction and remission maintenance agent in the treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Since the course of disease of AAV usually requires long term immunosuppression, mycophenolate has been explored as a less toxic agent compared to cyclophosphamide and azathioprine. Mycophenolate is a potent immunosuppressive agent in the therapy of AAV, non-inferior to other available drugs with comparable side effect profile. Therefore, it could be a valuable alternative in cases of toxicity with life threatening side effects or intolerance to cyclophosphamide or azathioprine, in cases with high cumulative dose of cyclophosphamide, but also in cases with insufficient response. Several studies have shown a higher relapse rate following discontinuation of mycophenolate or in mycophenolate treated subjects that raises concerns about its usefulness in the treatment of AAV. This review describes the efficacy of mycophenolate in AAV as remission induction agent, as remission maintenance agent, and as therapeutic option in relapsing AAV disease, the relapse rate following discontinuation of mycophenolate, and the adverse events related to mycophenolate treatment.

关键词： Mycophenolic acid Mycophenolate mofetil Mycophenolate sodium Antineutrophil cytoplasmic antibody-associated vasculitis Microscopic polyangiitis Granulomatosis with polyangiitis, induction Remission Relapse

Psoriasis treatment: Unconventional and non-standard modalities in the era of biologics

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World Journal of Dermatology 2016年第1期5卷 17-51页

作者： Vikram K Mahajan Department of Dermatology Venereology and LeprosyDr. R. P. Govt. Medical College

Psoriasis is a potentially debilitating inflammatory dermatosis affecting 0.2%-4.8% of the population worldwide causing a significant occupational, personal or psychosocial morbidity to these patients for life. The basic aim of psoriasis therapy is to control the disease to maximum possible extent and improve the patient's quality of life. Management of triggers for flareups, lifestyle modifications, and dietary supplements are often recommended. Intermittent or rotational therapy with frequent alterations in treatment options is usually needed to reduce toxicity of anti-psoriatic drugs in the absence of safer alternatives. Currently, several biological agents categorized as either T-cell targeted(e.g., Alefacept, Efalizumab) or cytokine modulating(e.g., Adalimumab, Infliximab, Etanercept) are available for treating severe psoriasis. However, their high cost is often precluding for most patients. The usefulness of systemic(methotrexate, cyclosporine, acitretin or several other therapeutic agents) or topical(tar, anthralin, corticosteroids or calcipotriol ointments, phototherapy with or without psoralens) therapies has been well established for the management of psoriasis. The literature is also replete with benefits of less used non-standard and unconventional treatment modalities(hydroxycarbamide, azathioprine, leflunomide, mycophenolate mofetil, isotretinoin, fumarates, topical calcineurin inhibitors, peroxisome proliferator-activated receptors agonists, statins, sulfasalazine, pentoxifylline, colchicine, grenz ray therapy, excimer laser, climatotherapy and balneophototherapy, peritoneal dialysis, tonsillectomy, ichthyotherapy, etc.). These can be used alternatively to treat psoriasis patients who have mild/minimal lesions, are intolerant to conventional drugs, have developed side effects or achieved recommended cumulative dose, where comorbidities pose unusual therapeutic challenges, or may be as intermittent, rotational or combination treatment alternatives.

关键词： Acetretin Azathioprine Balneophototherapy Calcineurin inhibitors Calcipotriol Calcium dobesilate Climatotherapy Colchicine Cyclosporine Dapsone Excimer laser Fumarates Grenz ray therapy Hydroxycarbamide Ichthyotherapy Isotretinoin Leflunamide Methotrexate Mycophenolate mofetil Pentoxifylline Peritoneal dialysis Phototherpy Plaque psoriasis Peroxisome proliferator-activated receptors agonists Statins Sulfasalazine Tonsillectomy

Mycophenolic Acid Absorption Profiles in Patients with Kidney or Combined Pancreas-Kidney Transplantation

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Open Journal of Nephrology 2012年第4期2卷 116-122页

作者： Jan M. Fertmann Helmut P. Arbogast Wolf-D. Illner Walter Land Karl-W. Jauch Johannes N. Hoffmann Department of Surgery Klinikum Grosshadern Ludwig-Maximilians University of Munich Munich Germany Department of Surgery Klinikum Grosshadern Ludwig-Maximilians University of Munich Munich Germany Department of Surgery University of Duisburg-Essen Duisburg and Essen Germany

Background: Mycophenolate mofetil (MMF) is widely used in organ transplant patients to avoid calcineurine inhibittor-associated side effects. Therapeutic monitoring of MMF is up to now perform by using trough level measurements (measurements before drug administration). The present study was designed to characterize potential differences in MMF absorption kinetics between patients with allogenic kidney transplantation [kidney Tx] and simultaneous pancreas kidney transplantation [PK Tx], which might for example occur due to diabetic gastrointestinal atony. Methods: A total of 64 pharmacokinetic profiles were prospectively studied in 44 adult kidney Tx and 20 PK Tx patients. To calculate AUC by the trapezoidal rule, mycophenolic acid (MPA) levels were measured in EDTA-plasma by an EMIT assay at 0, 0.5, 1, 2, 3, 4 6, and 12h after oral MMF administration between postoperative day 14 to 28 instable patients. Results: Substantial differences between kidney Tx and PK Tx patients were evident concerning: donor age, recipient age, number of mismatches, and kidney function (serum creatinine). Despite these dissimilarities pharmacokinetic absorption profiles did not significantly differ between patient groups as measured by AUC, C2, maximum MPA concentration (Cmax), and time until maximum absorption (Tmax). Astonishingly, concomitant cyclosporine and tacrolimus medication did not influence adsorption profiles. Only MPA concentrations 6h post administration correlated closely with AUC in both patient groups, whereas trough levels failed to be predictive for AUC. Conclusions: In our study population, MMF absorption kinetics did not differ between kidney and PK Tx patients and did not seem influenced by concomitant immunosuppressive medication. Therefore, MPA measurements during the absorption phase could be useful to better estimate AUC in patients with kidney Tx and PK Tx.

关键词： Mycophenolate mofetil Mycophenolic Acid Pharmacokinetics Kidney Transplantation Pancreas-Kidney Transplantation