David KC Cooper,1 David Ayares21Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 2Revivicor, Blacksburg, VA, USAAbstract: The transplantation of organs and cells from pigs into humans could overcome the critical and continuing problem of the lack of availability of deceased human organs and cells for clinical transplantation. Developments in the genetic engineering of pigs have enabled considerable progress to be made in the experimental laboratory in overcoming the immune barriers to successful xenotransplantation. With regard to pig organ xenotransplantation, antibody- and cell-mediated rejection have largely been overcome, and the current major barrier is the development of coagulation dysregulation. This is believed to be due to a combination of immune activation of the vascular endothelial cells of the graft and molecular incompatibilities between the pig and primate coagulation–anticoagulation systems. Pigs with new genetic modifications specifically directed to this problem are now becoming available. With regard to less complex tissues, such as islets (for the treatment of diabetes), neuronal cells (for the treatment of Parkinson's disease), and corneas, the remaining barriers are less problematic, and graft survival in nonhuman primate models extends for >1 year in all three cases. In planning the initial clinical trials, consideration will be concentrated on the risk–benefit ratio, based to a large extent on the results of preclinical studies in nonhuman primates. If the benefit to the patient is anticipated to be high, eg, insulin-independent control of glycemia, and the potential risks low, eg, minimal risk of transfer of a porcine infectious agent, then a clinical trial would be justified.Keywords: infection, pigs, genetically-engineered, xenotransplantation, islets, xenotransplantation, organs
David KC Cooper,1 David Ayares21Thomas E Starzl移植研究所，匹兹堡大学医学中心，美国宾夕法尼亚州匹兹堡;摘要:将猪的器官和细胞移植到人类身上，可以克服缺乏用于临床移植的死亡人体器官和细胞这一关键和持续的问题。猪基因工程的发展使得在实验室克服免疫障碍成功进行异种移植方面取得了相当大的进展。关于猪器官异种移植，抗体和细胞介导的排斥反应已经在很大程度上被克服，目前主要的障碍是凝血功能失调的发展。这被认为是由于移植物血管内皮细胞的免疫激活和猪和灵长类动物的凝血-抗凝系统之间的分子不相容。专门针对这个问题进行新的基因改造的猪现在已经可以使用了。对于不太复杂的组织，如胰岛(用于治疗糖尿病)、神经细胞(用于治疗帕金森病)和角膜，其余的屏障问题较少，在非人类灵长类动物模型中移植物的存活时间在所有三种情况下都延长了110年。在规划最初的临床试验时，考虑将集中在风险收益比上，这在很大程度上是基于非人类灵长类动物的临床前研究结果。如果预期对患者的益处较高(如胰岛素依赖型血糖控制)，而潜在风险较低(如猪感染原转移风险最小)，则应进行临床试验。关键词:感染，猪，基因工程，异种移植，胰岛，异种移植，器官
{"title":"Potential benefits and risks of clinical xenotransplantation","authors":"D. Cooper, D. Ayares","doi":"10.2147/TRRM.S31481","DOIUrl":"https://doi.org/10.2147/TRRM.S31481","url":null,"abstract":"David KC Cooper,1 David Ayares21Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 2Revivicor, Blacksburg, VA, USAAbstract: The transplantation of organs and cells from pigs into humans could overcome the critical and continuing problem of the lack of availability of deceased human organs and cells for clinical transplantation. Developments in the genetic engineering of pigs have enabled considerable progress to be made in the experimental laboratory in overcoming the immune barriers to successful xenotransplantation. With regard to pig organ xenotransplantation, antibody- and cell-mediated rejection have largely been overcome, and the current major barrier is the development of coagulation dysregulation. This is believed to be due to a combination of immune activation of the vascular endothelial cells of the graft and molecular incompatibilities between the pig and primate coagulation–anticoagulation systems. Pigs with new genetic modifications specifically directed to this problem are now becoming available. With regard to less complex tissues, such as islets (for the treatment of diabetes), neuronal cells (for the treatment of Parkinson's disease), and corneas, the remaining barriers are less problematic, and graft survival in nonhuman primate models extends for >1 year in all three cases. In planning the initial clinical trials, consideration will be concentrated on the risk–benefit ratio, based to a large extent on the results of preclinical studies in nonhuman primates. If the benefit to the patient is anticipated to be high, eg, insulin-independent control of glycemia, and the potential risks low, eg, minimal risk of transfer of a porcine infectious agent, then a clinical trial would be justified.Keywords: infection, pigs, genetically-engineered, xenotransplantation, islets, xenotransplantation, organs","PeriodicalId":41597,"journal":{"name":"Transplant Research and Risk Management","volume":"4 1","pages":"7-17"},"PeriodicalIF":0.9,"publicationDate":"2012-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TRRM.S31481","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68495399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Although spleen preservation surgery and non-operative management are first- line treatment options, total splenectomy is frequently performed. Splenectomy is performed for a number of indications including idiopathic thrombocytopenic purpura, high-energetic trauma, and hematological malignancy. Following splenectomy, patients are at risk for over- whelming post-splenectomy infection (OPSI), a syndrome that presents with mild symptoms at onset but irreversible multi-organ-failure occurs within hours to days. Since the spleen plays an important role in the immune response to polysaccharide antigens, encapsulated bacteria such as pneumococci are the most frequently described causative organisms of OPSI. Although the incidence of OPSI is low, the associated mortality is reported to be as high as 80%. Because of the overwhelming and frequently irreversible nature of this syndrome, prophylactic measures to prevent OPSI have been recommended. These recommendations include vaccination, use of antibiotics, and continuous patient education. After splenectomy, patients should receive immunizations against the encapsulated bacteria S. pneumoniae, H. influenza , and N. meningitidis. Antibiotic therapy should include prophylaxis as well as "on-demand" antibiotics when infection is suspected. Importantly, patients should receive ongoing education regarding the risks associated with asplenia and precautions to take when infection occurs and when traveling.
{"title":"The value of prophylactic vaccinations and antibiotic treatment in post-splenectomy patients: a review","authors":"A. Lammers","doi":"10.2147/TRRM.S25198","DOIUrl":"https://doi.org/10.2147/TRRM.S25198","url":null,"abstract":"Although spleen preservation surgery and non-operative management are first- line treatment options, total splenectomy is frequently performed. Splenectomy is performed for a number of indications including idiopathic thrombocytopenic purpura, high-energetic trauma, and hematological malignancy. Following splenectomy, patients are at risk for over- whelming post-splenectomy infection (OPSI), a syndrome that presents with mild symptoms at onset but irreversible multi-organ-failure occurs within hours to days. Since the spleen plays an important role in the immune response to polysaccharide antigens, encapsulated bacteria such as pneumococci are the most frequently described causative organisms of OPSI. Although the incidence of OPSI is low, the associated mortality is reported to be as high as 80%. Because of the overwhelming and frequently irreversible nature of this syndrome, prophylactic measures to prevent OPSI have been recommended. These recommendations include vaccination, use of antibiotics, and continuous patient education. After splenectomy, patients should receive immunizations against the encapsulated bacteria S. pneumoniae, H. influenza , and N. meningitidis. Antibiotic therapy should include prophylaxis as well as \"on-demand\" antibiotics when infection is suspected. Importantly, patients should receive ongoing education regarding the risks associated with asplenia and precautions to take when infection occurs and when traveling.","PeriodicalId":41597,"journal":{"name":"Transplant Research and Risk Management","volume":"4 1","pages":"19-24"},"PeriodicalIF":0.9,"publicationDate":"2012-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TRRM.S25198","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68495267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
B. Macdonald, Evi Vakiani, R. Yantiss, J. Lee, Robert S. Brown, S. Sigal
Brock Macdonald1 Evi Vakiani2 Rhonda K Yantiss3 Jun Lee4 Robert S Brown Jr5 Samuel H Sigal6 1Division of Gastroenterology, Department of Medicine, University of California-San Francisco, San Francisco, CA, 2Department of Pathology, Memorial Sloan–Kettering Cancer Center, New York, NY, 3Department of Pathology and Laboratory Medicine, New York Weill Cornell Medical College, New York, NY, 4Division of Nephrology, Department of Medicine, Weill Cornell Medical College, New York, NY, 5Division of Gastroenterology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, 6Division of Gastroenterology and Hepatology, Department of Medicine, New York University, New York, NY, USA
Brock麦克唐纳1 Evi Vakiani2 Rhonda K Yantiss3 Jun Lee4 Robert S Brown Jr5 Samuel H Sigal6 1加州大学旧金山分校消化病学医学系，旧金山，加利福尼亚州;2纪念斯隆-凯特琳癌症中心病理学系，纽约，纽约州;3纽约威尔康奈尔医学院病理与检验医学系，纽约，纽约州;4威尔康奈尔医学院肾内科，纽约，纽约州;5哥伦比亚大学内科和外科医学院消化内科，纽约，NY; 6纽约大学内科消化内科和肝脏内科，纽约，NY, USA
{"title":"Sirolimus-associated hepatotoxicity: Case report and review of the literature","authors":"B. Macdonald, Evi Vakiani, R. Yantiss, J. Lee, Robert S. Brown, S. Sigal","doi":"10.2147/TRRM.S21313","DOIUrl":"https://doi.org/10.2147/TRRM.S21313","url":null,"abstract":"Brock Macdonald1 Evi Vakiani2 Rhonda K Yantiss3 Jun Lee4 Robert S Brown Jr5 Samuel H Sigal6 1Division of Gastroenterology, Department of Medicine, University of California-San Francisco, San Francisco, CA, 2Department of Pathology, Memorial Sloan–Kettering Cancer Center, New York, NY, 3Department of Pathology and Laboratory Medicine, New York Weill Cornell Medical College, New York, NY, 4Division of Nephrology, Department of Medicine, Weill Cornell Medical College, New York, NY, 5Division of Gastroenterology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, 6Division of Gastroenterology and Hepatology, Department of Medicine, New York University, New York, NY, USA","PeriodicalId":41597,"journal":{"name":"Transplant Research and Risk Management","volume":"21 1","pages":"1-5"},"PeriodicalIF":0.9,"publicationDate":"2012-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TRRM.S21313","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68495170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Correspondence: David w Mathes Chief, Seattle veterans Affairs Hospital, University of washington Medical Center, 1959 NE Pacific Street, Box 356410, Seattle, wA 98115, USA Tel +1 206 543-5516 Fax +1 206 543-8136 Email dwmathes@u.washington.edu Abstract: The surgical history of transplantation in the modern era begins in 1956 with the successful transplantation of a kidney between identical twins. Since then the field of transplantation has seen remarkable advancements in both surgical techniques and our understanding and ability to manipulate the immune response. Composite tissue allotransplantation involves the transplantation of any combination of vascularized skin, subcutaneous tissue, blood vessels, nerves, muscle, and bone. Orthotopic hand transplantation is considered the first clinical example of CTA and has seen success at many different centers worldwide. Facial allotransplantation is a recent development in the field of CTA and the first successful case was performed as recently as November 2005. Since then there have been a number of successful facial transplants. The purpose of this paper is to examine some of the issues surrounding facial transplantation including the complex ethical issues, the surgical and clinical issues, cost and administrative issues, and future directions for this new, exciting, and controversial field.
通讯:David w Mathes主任，西雅图退伍军人事务医院，华盛顿大学医学中心，1959东北太平洋街，西雅图，wA 98115信箱356410电话+1 206 543-5516传真+1 206 543-8136电子邮件dwmathes@u.washington.edu摘要:现代移植手术的历史始于1956年同卵双胞胎肾脏移植的成功。从那时起，移植领域在手术技术和我们对操纵免疫反应的理解和能力方面都取得了显著的进步。同种异体复合组织移植包括带血管的皮肤、皮下组织、血管、神经、肌肉和骨骼的任何组合的移植。原位手移植被认为是CTA的第一个临床例子，在世界上许多不同的中心都取得了成功。面部异体移植是CTA领域的最新发展，2005年11月首次成功实施。从那时起，已经有许多成功的面部移植手术。本文的目的是探讨围绕面部移植的一些问题，包括复杂的伦理问题，手术和临床问题，成本和管理问题，以及这一新的，令人兴奋的，有争议的领域的未来方向。
{"title":"Facial transplantation: a review of ethics, progress, and future targets","authors":"J. A. Edwards, D. Mathes","doi":"10.2147/TRRM.S6883","DOIUrl":"https://doi.org/10.2147/TRRM.S6883","url":null,"abstract":"Correspondence: David w Mathes Chief, Seattle veterans Affairs Hospital, University of washington Medical Center, 1959 NE Pacific Street, Box 356410, Seattle, wA 98115, USA Tel +1 206 543-5516 Fax +1 206 543-8136 Email dwmathes@u.washington.edu Abstract: The surgical history of transplantation in the modern era begins in 1956 with the successful transplantation of a kidney between identical twins. Since then the field of transplantation has seen remarkable advancements in both surgical techniques and our understanding and ability to manipulate the immune response. Composite tissue allotransplantation involves the transplantation of any combination of vascularized skin, subcutaneous tissue, blood vessels, nerves, muscle, and bone. Orthotopic hand transplantation is considered the first clinical example of CTA and has seen success at many different centers worldwide. Facial allotransplantation is a recent development in the field of CTA and the first successful case was performed as recently as November 2005. Since then there have been a number of successful facial transplants. The purpose of this paper is to examine some of the issues surrounding facial transplantation including the complex ethical issues, the surgical and clinical issues, cost and administrative issues, and future directions for this new, exciting, and controversial field.","PeriodicalId":41597,"journal":{"name":"Transplant Research and Risk Management","volume":"3 1","pages":"113-125"},"PeriodicalIF":0.9,"publicationDate":"2011-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TRRM.S6883","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68497142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Correspondence: Alexander wiseman Transplant Center, University of Colorado Denver Health Sciences Center, Mail Stop F749, AOP 7089,1635 North Aurora Court, Aurora, CO 80045, USA Tel +1 720 848 0860 Fax +1 720 848 2238 email alexander.wiseman@ucdenver.edu Abstract: Everolimus is a novel target of rapamycin (mTOR)-I analog that has recently been approved in combination with cyclosporine A and steroids for use in the prevention of organ rejection in kidney transplant recipients. Compared with rapamycin, everolimus is characterized by a shorter half-life and improved bioavailability. Prior to US Food and Drug Administration approval, a number of Phase II and III clinical trials were undertaken to evaluate the effectiveness of everolimus in combination with calcineurin inhibitors for preventing acute rejection and promoting allograft survival in kidney transplant recipients. In this report, we review the pharmacokinetic properties of everolimus, the clinical efficacy studies that led to its approval for use in kidney transplantation, as well as reported data on patient safety and tolerability associated with its use.
通讯:Alexander wiseman移植中心，科罗拉多大学丹佛健康科学中心，Mail Stop F749, AOP 7089,1635 North Aurora Court, Aurora, CO 80045, USA Tel +1 720 848 0860 Fax +1 720 848 2238 email alexander.wiseman@ucdenver.edu摘要:依维莫斯是雷帕霉素(mTOR)- 1类似物的新靶点，最近已被批准与环孢素a和类固醇联合用于预防肾移植受者的器官排斥反应。与雷帕霉素相比，依维莫司具有半衰期短、生物利用度高的特点。在美国食品和药物管理局批准之前，进行了许多II期和III期临床试验，以评估依维莫司与钙调磷酸酶抑制剂联合用于预防肾移植受者急性排斥反应和促进同种异体移植物存活的有效性。在本报告中，我们回顾了依维莫司的药代动力学特性，导致其被批准用于肾移植的临床疗效研究，以及与使用相关的患者安全性和耐受性的报告数据。
{"title":"Everolimus in kidney transplantation","authors":"J. Cooper, U. Christians, A. Wiseman","doi":"10.2147/TRRM.S13782","DOIUrl":"https://doi.org/10.2147/TRRM.S13782","url":null,"abstract":"Correspondence: Alexander wiseman Transplant Center, University of Colorado Denver Health Sciences Center, Mail Stop F749, AOP 7089,1635 North Aurora Court, Aurora, CO 80045, USA Tel +1 720 848 0860 Fax +1 720 848 2238 email alexander.wiseman@ucdenver.edu Abstract: Everolimus is a novel target of rapamycin (mTOR)-I analog that has recently been approved in combination with cyclosporine A and steroids for use in the prevention of organ rejection in kidney transplant recipients. Compared with rapamycin, everolimus is characterized by a shorter half-life and improved bioavailability. Prior to US Food and Drug Administration approval, a number of Phase II and III clinical trials were undertaken to evaluate the effectiveness of everolimus in combination with calcineurin inhibitors for preventing acute rejection and promoting allograft survival in kidney transplant recipients. In this report, we review the pharmacokinetic properties of everolimus, the clinical efficacy studies that led to its approval for use in kidney transplantation, as well as reported data on patient safety and tolerability associated with its use.","PeriodicalId":41597,"journal":{"name":"Transplant Research and Risk Management","volume":"3 1","pages":"97-112"},"PeriodicalIF":0.9,"publicationDate":"2011-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TRRM.S13782","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68494492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
K. Marfo, D. García, S. Khalique, K. Berger, A. Lu
correspondence: Kwaku Marfo Montefiore-Einstein Center for Transplantation, Department of Pharmacy, Montefiore Medical Center, The University hospital for Albert einstein college of Medicine, 111 east 210th street, Bronx, nY 10467, UsA Tel +1 718 920 3752 Fax +1 718 798 0722 email kmarfo@montefiore.org Background: Medication errors are a prime concern for all in healthcare. As such the use of information technologies in drug prescribing and administration has received considerable attention in recent years, with the hope of improving patient safety. Because of the complexity of drug regimens in renal transplant patients, occurrence of medication errors is inevitable even with a well adopted computerized physician order entering (CPOE) system. Our objective was to quantify medication error type and frequency in an inpatient renal transplant unit. Methods: Systemic evaluation of all medication errors during an initial 10-day audit and a 28-day follow-up audit in an inpatient renal transplant unit. Each error was concurrently evaluated for potential to result in adverse patient consequences (category), error type and associated medication class. Results: A total of 103 clinically significant medication errors were detected during the 10-day (43 errors) and 28-day audit (60 errors) time periods. The most common errors were wrong medication dose ordered and wrong time of drug administration. Thirty-six out of 66 prescribing/ ordering errors reached the patient. Conclusions: Even with utilization of computerized physician order entry system in an inpatient renal transplant unit, post-kidney transplant patients are at risk for adverse outcomes due to medication errors. The risk factors may be multifactorial and will require both organizational and technical approaches to resolve.
{"title":"Evaluation of medication errors via a computerized physician order entry system in an inpatient renal transplant unit","authors":"K. Marfo, D. García, S. Khalique, K. Berger, A. Lu","doi":"10.2147/TRRM.S17819","DOIUrl":"https://doi.org/10.2147/TRRM.S17819","url":null,"abstract":"correspondence: Kwaku Marfo Montefiore-Einstein Center for Transplantation, Department of Pharmacy, Montefiore Medical Center, The University hospital for Albert einstein college of Medicine, 111 east 210th street, Bronx, nY 10467, UsA Tel +1 718 920 3752 Fax +1 718 798 0722 email kmarfo@montefiore.org Background: Medication errors are a prime concern for all in healthcare. As such the use of information technologies in drug prescribing and administration has received considerable attention in recent years, with the hope of improving patient safety. Because of the complexity of drug regimens in renal transplant patients, occurrence of medication errors is inevitable even with a well adopted computerized physician order entering (CPOE) system. Our objective was to quantify medication error type and frequency in an inpatient renal transplant unit. Methods: Systemic evaluation of all medication errors during an initial 10-day audit and a 28-day follow-up audit in an inpatient renal transplant unit. Each error was concurrently evaluated for potential to result in adverse patient consequences (category), error type and associated medication class. Results: A total of 103 clinically significant medication errors were detected during the 10-day (43 errors) and 28-day audit (60 errors) time periods. The most common errors were wrong medication dose ordered and wrong time of drug administration. Thirty-six out of 66 prescribing/ ordering errors reached the patient. Conclusions: Even with utilization of computerized physician order entry system in an inpatient renal transplant unit, post-kidney transplant patients are at risk for adverse outcomes due to medication errors. The risk factors may be multifactorial and will require both organizational and technical approaches to resolve.","PeriodicalId":41597,"journal":{"name":"Transplant Research and Risk Management","volume":"3 1","pages":"91-96"},"PeriodicalIF":0.9,"publicationDate":"2011-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TRRM.S17819","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68495125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Correspondence: Maurizio Salvadori Renal Unit, Careggi University Hospital, viale Pieraccini 18, 50139 Florence, italy Tel +39 055 794 9269 Fax +39 055 435 878 email maurizio.salvadori@unifi.it Abstract: The authors review the use of everolimus in long-term studies both in renal and heart transplantation. The pharmacokinetic and pharmacodynamic differences between everolimus and its parent drug, sirolimus are discussed. The improved pharmacokinetic, in particular the improved bioavailability, the reduced half-time and the reduced binding to plasma protein makes everolimus the first choice among the proliferation signal inhibitors. Everolimus is given in almost all studies in association with cyclosporine, but fixed doses of this drug can cause nephrotoxicity. The first studies used everolimus and CsA in fixed doses, but later studies with reduced CsA doses revealed which revealed improved outcomes. Finally, therapeutic drug monitoring became the better choice for both drugs. Recently very high everolimus exposure allowed the use of very low CsA exposure with improvement of the worse side effects linked to the CsA standard dose. The Zeus study revealed a complete and safe CsA withdrawal, thanks to everolimus and mycophenolic acid. In heart transplantation, everolimus resulted in improved outcomes with respect to antiproliferative drugs such as mycophenolic acid and azathioprine. Along with antirejection properties, everolimus provided evidence for antiproliferative effects on several cells. This resulted in fewer viral infections (mainly CMV), anti-atherosclerotic properties (mainly important in heart transplantation, and antineoplastic effect. The latter activity resulted in lower cancer incidence in transplant patients treated by everolimus. An important piece of evidence for this activity is documented by the use of everolimus in the treatment of some cancers, including renal cancer, neuroendocrine cancers and hepatocellular cancers, also outside the field of transplantation.
{"title":"Long-term outcome of everolimus treatment in transplant patients","authors":"M. Salvadori, E. Bertoni","doi":"10.2147/TRRM.S12212","DOIUrl":"https://doi.org/10.2147/TRRM.S12212","url":null,"abstract":"Correspondence: Maurizio Salvadori Renal Unit, Careggi University Hospital, viale Pieraccini 18, 50139 Florence, italy Tel +39 055 794 9269 Fax +39 055 435 878 email maurizio.salvadori@unifi.it Abstract: The authors review the use of everolimus in long-term studies both in renal and heart transplantation. The pharmacokinetic and pharmacodynamic differences between everolimus and its parent drug, sirolimus are discussed. The improved pharmacokinetic, in particular the improved bioavailability, the reduced half-time and the reduced binding to plasma protein makes everolimus the first choice among the proliferation signal inhibitors. Everolimus is given in almost all studies in association with cyclosporine, but fixed doses of this drug can cause nephrotoxicity. The first studies used everolimus and CsA in fixed doses, but later studies with reduced CsA doses revealed which revealed improved outcomes. Finally, therapeutic drug monitoring became the better choice for both drugs. Recently very high everolimus exposure allowed the use of very low CsA exposure with improvement of the worse side effects linked to the CsA standard dose. The Zeus study revealed a complete and safe CsA withdrawal, thanks to everolimus and mycophenolic acid. In heart transplantation, everolimus resulted in improved outcomes with respect to antiproliferative drugs such as mycophenolic acid and azathioprine. Along with antirejection properties, everolimus provided evidence for antiproliferative effects on several cells. This resulted in fewer viral infections (mainly CMV), anti-atherosclerotic properties (mainly important in heart transplantation, and antineoplastic effect. The latter activity resulted in lower cancer incidence in transplant patients treated by everolimus. An important piece of evidence for this activity is documented by the use of everolimus in the treatment of some cancers, including renal cancer, neuroendocrine cancers and hepatocellular cancers, also outside the field of transplantation.","PeriodicalId":41597,"journal":{"name":"Transplant Research and Risk Management","volume":"3 1","pages":"77-90"},"PeriodicalIF":0.9,"publicationDate":"2011-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TRRM.S12212","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68494791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Spencer T. Martin, D. Tsapepas, S. Gabardi, A. Chandraker
Belatacept (LEA29Y) is an intravenous biologic for long-term maintenance immunosuppressive therapy in renal transplant recipients. It is currently being reviewed by the United States Food and Drug Administration (FDA) as a prophylactic therapy against acute cellular rejection (ACR) in de novo renal transplant recipients. To provide an in-depth review of the pharmacology, clinical efficacy, safety, and applications of belatacept, a MEDLINE database search was performed for all English-language articles evaluating the pharmacology and efficacy of belatacept, as well as abstracts from recent scientific meetings. Belatacept is a potent inhibitor of B7 binding to CD28, a potent T-cell co-stimulatory signal. The B7 ligands are found on the surface of antigen-presenting cells, specifically B7-1 (CD80) and B7-2 (CD86). CD80 and CD86 are essential ligands for CD28, a critical component of costimulation in the three-signal transplant model of T-cell activation. Belatacept has proven noninferiority compared with calcineurin-inhibitor (CNI)-based regimens in the incidence of patient and allograft survival. However, the incidence and severity of ACR has been shown to be increased in patients receiving belatacept therapy. Although rates of ACR are increased in patients receiving belata- cept, an overall improvement in allograft function has been described with average improve- ments in glomerular filtration rates of up to 12-15 mL/min higher than CNI-based regimens. The side-effect profile of belatacept has been shown to be similar or improved compared with CNI therapy; however, the risk of malignancy, specifically post-transplant lymphoproliferative disorder is notably higher. Because of the marked increase in the risk of malignancy and ACR, approval of belatacept by the FDA will rely on more robust data from long-term follow-up of currently available data.
{"title":"Critical appraisal of belatacept for prophylaxis of rejection in kidney transplant patients","authors":"Spencer T. Martin, D. Tsapepas, S. Gabardi, A. Chandraker","doi":"10.2147/TRRM.S11538","DOIUrl":"https://doi.org/10.2147/TRRM.S11538","url":null,"abstract":"Belatacept (LEA29Y) is an intravenous biologic for long-term maintenance immunosuppressive therapy in renal transplant recipients. It is currently being reviewed by the United States Food and Drug Administration (FDA) as a prophylactic therapy against acute cellular rejection (ACR) in de novo renal transplant recipients. To provide an in-depth review of the pharmacology, clinical efficacy, safety, and applications of belatacept, a MEDLINE database search was performed for all English-language articles evaluating the pharmacology and efficacy of belatacept, as well as abstracts from recent scientific meetings. Belatacept is a potent inhibitor of B7 binding to CD28, a potent T-cell co-stimulatory signal. The B7 ligands are found on the surface of antigen-presenting cells, specifically B7-1 (CD80) and B7-2 (CD86). CD80 and CD86 are essential ligands for CD28, a critical component of costimulation in the three-signal transplant model of T-cell activation. Belatacept has proven noninferiority compared with calcineurin-inhibitor (CNI)-based regimens in the incidence of patient and allograft survival. However, the incidence and severity of ACR has been shown to be increased in patients receiving belatacept therapy. Although rates of ACR are increased in patients receiving belata- cept, an overall improvement in allograft function has been described with average improve- ments in glomerular filtration rates of up to 12-15 mL/min higher than CNI-based regimens. The side-effect profile of belatacept has been shown to be similar or improved compared with CNI therapy; however, the risk of malignancy, specifically post-transplant lymphoproliferative disorder is notably higher. Because of the marked increase in the risk of malignancy and ACR, approval of belatacept by the FDA will rely on more robust data from long-term follow-up of currently available data.","PeriodicalId":41597,"journal":{"name":"Transplant Research and Risk Management","volume":"3 1","pages":"65-75"},"PeriodicalIF":0.9,"publicationDate":"2011-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TRRM.S11538","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68494423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pirfenidone is a pyridine-derived, double-ringed molecule that has a number of biologic effects including anti-inflammatory and antifibrotic properties in rodent models of acute lung injury and fibrosis, in addition to scavenging reactive oxygen species. These effects are clinically relevant, because idiopathic pulmonary fibrosis (IPF) is a progressive and increasingly prevalent disease characterized by diffuse lung scarring due to alveolar epithelial cell injury, which typically leads to death 3-5 years after diagnosis. No proven therapy for IPF exists, and many IPF patients eventually require lung transplantation, making the need for pharmacologic therapy great. Pirfenidone is rapidly distributed in body water and metabolized by the liver. Several clinical trials have tested pirfenidone in patients with IPF and found it well-tolerated with acceptable side effects. Pirfenidone in clinical trials has been found to improve progression-free survival and pulmonary function of IPF patients. Although the specific mechanism accounting for its benefits is not known, pirfenidone decreases collagen synthesis and fibroblast prolifera- tion, and it may down-regulate inflammation by virtue of its effects on mitogen-activated protein kinases. Pirfenidone has gained regulatory approval for marketing in Japan and in the European Union. It could prove to be a useful therapeutic agent for patients with IPF.
{"title":"Development and utility of pirfenidone in the treatment of idiopathic pulmonary fibrosis: review of preclinical science and recent clinical trials","authors":"R. Jackson, O. Gómez-Marín","doi":"10.2147/TRRM.S16205","DOIUrl":"https://doi.org/10.2147/TRRM.S16205","url":null,"abstract":"Pirfenidone is a pyridine-derived, double-ringed molecule that has a number of biologic effects including anti-inflammatory and antifibrotic properties in rodent models of acute lung injury and fibrosis, in addition to scavenging reactive oxygen species. These effects are clinically relevant, because idiopathic pulmonary fibrosis (IPF) is a progressive and increasingly prevalent disease characterized by diffuse lung scarring due to alveolar epithelial cell injury, which typically leads to death 3-5 years after diagnosis. No proven therapy for IPF exists, and many IPF patients eventually require lung transplantation, making the need for pharmacologic therapy great. Pirfenidone is rapidly distributed in body water and metabolized by the liver. Several clinical trials have tested pirfenidone in patients with IPF and found it well-tolerated with acceptable side effects. Pirfenidone in clinical trials has been found to improve progression-free survival and pulmonary function of IPF patients. Although the specific mechanism accounting for its benefits is not known, pirfenidone decreases collagen synthesis and fibroblast prolifera- tion, and it may down-regulate inflammation by virtue of its effects on mitogen-activated protein kinases. Pirfenidone has gained regulatory approval for marketing in Japan and in the European Union. It could prove to be a useful therapeutic agent for patients with IPF.","PeriodicalId":41597,"journal":{"name":"Transplant Research and Risk Management","volume":"3 1","pages":"55-63"},"PeriodicalIF":0.9,"publicationDate":"2011-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TRRM.S16205","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68495050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Correspondence: Matthew Cooper Division of Transplantation, University of Maryland School of Medicine, Baltimore, MD, USA Tel +1 410 328 7336 Fax +1 410 328 6343 email mcooper@smail.umaryland.edu Abstract: Addition of mycophenolate mofetil (MMF) to calcineurin-based immunosuppressive therapy has led to a significant improvement in graft survival and reduction of acute rejection in renal transplant recipients. However, in clinical practice, MMF dose reduction, interruption, or discontinuation due to hematological and gastrointestinal (GI) side-effects occurred in up to 50% of the patients. Large retrospective analyses have demonstrated that patients requiring MMF dose manipulation due to adverse events experienced a higher rate of rejection and graft loss. Enteric-coated mycophenolate sodium (EC-MPS) was developed with the goal of improving upper GI side-effects. Here, we review the efficacy and safety of EC-MPS in de novo kidney transplant recipient, and in stable renal transplant patients who were converted from MMF. The changes in GI-related adverse events using patient-reported outcome instruments are also reviewed.
{"title":"Mycophenolic acid agents: is enteric coating the answer?","authors":"Wana Manitpisitkul, Sabrina Lee, M. Cooper","doi":"10.2147/TRRM.S12210","DOIUrl":"https://doi.org/10.2147/TRRM.S12210","url":null,"abstract":"Correspondence: Matthew Cooper Division of Transplantation, University of Maryland School of Medicine, Baltimore, MD, USA Tel +1 410 328 7336 Fax +1 410 328 6343 email mcooper@smail.umaryland.edu Abstract: Addition of mycophenolate mofetil (MMF) to calcineurin-based immunosuppressive therapy has led to a significant improvement in graft survival and reduction of acute rejection in renal transplant recipients. However, in clinical practice, MMF dose reduction, interruption, or discontinuation due to hematological and gastrointestinal (GI) side-effects occurred in up to 50% of the patients. Large retrospective analyses have demonstrated that patients requiring MMF dose manipulation due to adverse events experienced a higher rate of rejection and graft loss. Enteric-coated mycophenolate sodium (EC-MPS) was developed with the goal of improving upper GI side-effects. Here, we review the efficacy and safety of EC-MPS in de novo kidney transplant recipient, and in stable renal transplant patients who were converted from MMF. The changes in GI-related adverse events using patient-reported outcome instruments are also reviewed.","PeriodicalId":41597,"journal":{"name":"Transplant Research and Risk Management","volume":"3 1","pages":"45-53"},"PeriodicalIF":0.9,"publicationDate":"2011-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TRRM.S12210","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68494582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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