THE RELATIONSHIP OF BLOOD CONCENTRATIONS OF RAPAMYCIN AND CYCLOSPORINE TO SUPPRESSION OF ALLOGRAFT REJECTION IN A RABBIT HETEROTOPIC HEART TRANSPLANT MODEL1
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Heterotopic heart transplants were performed on 50 New Zealand white rabbits. Groups of 5 rabbits were randomly assigned to receive, through an intravenous route, rapamycin (RAPA) or cyclosporine at the following doses: RAPA (0.05, 0.1, 0.5, and 1.0 mg/kg/day); CsA (5.0, 10.0, and 15.0 mg/kg/day). Drug vehicle and saline controls were also included. Trough blood concentrations were monitored in both RAPA- and CsA-treated groups on a weekly basis throughout the study. Biochemical assessment of renal and liver function was performed at the beginning and end of the study. Animals receiving RAPA exhibited excellent allograft survival; only two animals in the lowest dosage group (0.05 mg/kg/day) rejected their grafts. In contrast, no rejection occurred in the CsA-treated groups. Animals that rejected their grafts were maintained on the drug until the endpoint of the study was reached at 60 days posttransplant to monitor drug induced side-effects. In some instances animals were sacrificed prior to this time due to infectious and other complications. No significant changes in renal or liver function were noted in the RAPA-treated group, while in the group of animals receiving the highest dose of CsA (15.0 mg/kg/day) a significant decrease in creatinine clearance was noted. A correlation was shown to exist between dose and the trough concentrations of both drugs. The whole-blood concentrations of RAPA that resulted in maximal efficacy with minimal toxicity was in the range of 10–60 μg/L. Rabbits having trough whole-blood concentrations of <10 μg/L rejected their grafts. A much wider therapeutic range for CsA (50–300 μg/L) was noted. The results suggest that RAPA is as efficacious as CsA in prevention of allograft rejection in the animal model tested. The therapeutic monitoring of trough blood concentrations of RAPA, as with CsA, may be useful in guiding dosage adjustments to maximize the immunosuppressive efficacy while minimizing drug-induced side-effects.Keywords:
Rabbit (cipher)
Graft rejection
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Seperti pada dewasa, teknik regional anestesi pada pediatrik kini makin popular digunakan oleh ahli anestesikarena keuntungannya. Namun demikian selalu ada risiko dan kemungkinan timbulnya komplikasi dari setiap tindakan yang dilakukan, termasuk tindakan anestesi regional pada pediatrik. Insidensi komplikasi anestesi regional pada pediatrik tidak banyak, dan kalaupun terjadi komplikasi adalah minor. Komplikasi bisa diakibatkan dari identifikasi ruang saraf, alat, obat, teknis tindakan anestesi regionalnya dan komplikasi lainnya.Walaupun tidak banyak kejadian komplikasi regional anestesi yang dilaporkan pada pediatrik, dan bukanlah komplikasi yang fatal, teknik regional anestesi pada pediatrik harus dilakukan dengan lebih hatihati, pertimbangan risiko dan keuntungannya untuk menghindari terjadinya komplikasi, terlebih karena kebanyakan komplikasi dapat dihindari dengan mempelajari teknik yang benar, menggunakan peralatan yang sesuai, dan sangat menerapkan prinsip keamanan pada pasien dengan baik.
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Genentech is partnering with the German cancer company Affimed to develop immunotherapies for multiple kinds of solid and blood cancers. Affimed is developing therapies that engage natural killer cells of the innate immune system to help direct them to attack cancer cells. Genentech will pay Affimed $96 million up front and up to $5 billion more in potential payments.
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The role of antibody-mediated rejection in predicting survival among heart recipients has been studied in clinical transplantology for over 20 years. This condition is a significant risk factor for heart failure and graft vasculopathy. Antibody-mediated rejection results from activation of the humoral immune system and production of donorspecific antibodies that cause myocardial injury through the complement system. The presence of donor-specific antibodies is associated with lower allograft survival. Treatment of antibody-mediated rejection should take into account the rejection category and the presence or absence of graft dysfunction. The main principle of treatment is to suppress humoral immunity at different levels. World clinical practice has made significant inroads into the study of this issue. However, further research is required to identify and develop optimal treatment regimens for patients with humoral rejection in cardiac transplantation.
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Organ transplantation has kindled the human imagination since the beginning of time. Prehistorically, transplantation appeared as mythological stories: from creatures with body parts from different species, the heart transplant between two Chinese soldiers by Pien Ch’iao, to the leg transplant by physician Saints Cosmas and Damian. By 19th century, the transplantation concept become possible by extensive contributions from scientists and clinicians whose works had taken generations. Although Alexis Carrel is known as the founding father of experimental organ transplantation, many legendary names had contributed to the experimental works of heart transplantation, including Guthrie, Mann, and Demikhov. The major contribution to experimental heart transplantation before the clinical era were made by a team lead by Richard Lower and Norman Shumway at Stanford University in the early 1960s. They played the vital role in developing experimental and clinical heart transplantation as it is known today. Using Shumway biatrial technique Christiaan Barnard started a new era of clinical heart transplantation, by performing the first in man human-to-human heart transplantation in 1967. The techniques of heart transplant have evolved since the first heart transplant. This chapter will summarize the techniques that have been used in clinical heart transplantation.
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Among patients undergoing heart transplantation, a fundamental clinical concern is the risk of rejection of the new organ. Although modern immunosuppressive regimens have reduced the incidence of rejection substantially, about one quarter of recipients will still have a rejection episode requiring treatment during the first year after transplantation.1 Acute rejection is the cause of 12% of deaths occurring between 1 month and 1 year after transplantation.1 There is no established noninvasive marker of rejection available for heart-transplant recipients; instead they must undergo serial endomyocardial biopsies with histologic evaluation of myocardial tissue to monitor for rejection. Endomyocardial biopsy is an invasive . . .
Endomyocardial Biopsy
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Heart transplants
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In 1905, Carrel and Guthrie reported the heterotopic heart transplantation on dogs for the first time. In the same year, Shone advanced the transplantation immunity theory which provided a basis for organ transplantation. In 1964, Hardy and his colleagues performed the first human chimpanzee heart transplantation. In 1967, Barnard performed the first human-to-human orthotopic heart transplantation in the world. In 1968 - 1971, 56 hospitals performed 180 heart transplantations world-wide. But because of the poor survival rate after operation, heart transplantations became less frequent. In 1972, Castaneda and Reitz summed up the experiences of heart-lung experimental transplantation, which laid a foundation for human heart-lung transplantation. In 1973, Caves invented myocardium biopsy for rejection surveillance after heart transplantation, which solved the problem of diagnosis for early rejection. In 1981, Stanford University first took cyclosporin A into clinical practice. The acute rejection after heart transplantation was effectively controlled and the long-term survival rate was significantly increased. Heart transplantation entered the second peak period. The launching of Asian heart transplantation began in 1968. Juro·Wada with his medical team performed the first heart transplantation in Japan. In 1978, Zhang Shize in Shanghai performed the first heart transplantation in China.
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