Auxiliary Liver Allografting and Xenografting in the Nonhuman Primate

Mieles, Luis; Ye, Y.; Luo, Yanhui; Kobayashi, Takaaki; Li, S. F.; Niekrasz, Marek; Kosanke, Stanley D.; Smith, Donald; Cooper, David K. C.

doi:10.1097/00007890-199506270-00005

Cited by 23 publications

(9 citation statements)

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“…In all studies reported to date there seems to be no difference between cynomolgus-and rhesus monkeys in pharmacokinetics and efficacious dose levels. In contrast, baboons generally require a higher exposure, so that even cyclosporine had to be given at 20-30 mglkg body weight by intravenous route to induce survival of liver- [16] or heart-lung [4] allografts. Trough levels in the therapeutic range were claimed to be around 2,000 ng/ml in this species.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of cyclosporine in monkeys after oral and intramuscular administration: relation to efficacy in kidney allografting

Schuurman

Slingerland

Mennninger

et al. 2001

Transplant International

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In cynomolgus and rhesus monkeys, the dose-normalized exposure of cyclosporine administered orally as microemulsion preconcentrate (Neoral) was lower than that upon intramuscular administration. For oral administration, mean values ( f SD) of C,,,, 24-h area-under-the curve (AUC) and 24-h trough level, all normalized for a 1 mg/kg dose, were 20 k 9 ng kgfmg ml, 210 k 70 ng h kg/mg ml and 2.6 * 0.9 ng kg/mg ml, respectively.For intramuscular administration, levels were about 5.5-fold, 9-fold and 22-fold higher. Based on pharmacokinetic data, the efficacy of oral cyclosporine treatment (without any other immunosuppressant) was evaluated in life-supporting cynomolgus monkey kidney allotransplantation. Rej ection-free kidney allograft survival could be achieved using oral cyclosporine monotherapy with average 24-h trough concentrations above 100 ng/ml during maintenance treatment. Typically, daily oral doses of 100 mg/ kg-150 mg/kg during the first two weeks post-transplantation, followed by daily 30 mgfkg-100 mg/kg dose levels during subsequent maintenance can result in long-term allograft survival, with 24-h average trough levels in individual animals during maintenance between 110 ngfml and 700 ngtml.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of cyclosporine in monkeys after oral and intramuscular administration: relation to efficacy in kidney allografting

Schuurman

Slingerland

Mennninger

et al. 2001

Transplant International

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“…A theoretical alternative in those with prolonged, but potentially reversible, liver dysfunction would be temporary auxiliary (heterotopic) liver xenotransplantation, which would provide support until the native liver had recovered, at which time the pig liver could be excised. 51,52 …”

Section: Liver Xenotransplantationmentioning

confidence: 99%

Selection of Patients for Initial Clinical Trials of Solid Organ Xenotransplantation

et al. 2017

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Several groups have reported extended survival of genetically-engineered pig organs in nonhuman primates, varying from almost 10 months for life-supporting kidney grafts and >2 years for nonlife-supporting heart grafts to less than 1 month for life-supporting liver and lung grafts. We have attempted to define groups of patients who may not have an option to wait for an allograft. These include kidney, heart, and lung candidates who are highly-allosensitized. In addition, some kidney candidates (who have previously lost at least 2 allografts from rapid recurrence of native kidney disease) have a high risk of further recurrence and will not be offered a repeat allotransplant. Patients with complex congenital heart disease, who may have undergone previous palliative surgical procedures, may be unsuitable for ventricular assist device implantation. Patients dying of fulminant hepatic failure, for whom no alternative therapy is available, may be candidates for a pig liver, even if only as a bridge until an allograft becomes available. When the results of pig organ xenotransplantation in nonhuman primates suggest a realistic potential for success of a pilot clinical trial, highly-selected patients should be offered participation.

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“…Following studies of monkey and pig liver Tx in baboons [49], in the early 1990s, we seriously considered using a baboon liver as a bridge to alloTx in patients with fulminant liver failure. I called the offices of the US Food and Drug Administration to inquire what they thought about this approach.…”

Section: Oklahoma Citymentioning

confidence: 99%

Outwitting evolution*

Cooper¹

2010

Xenotransplantation

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The author pays tribute to those who stimulated him to follow a career in clinical cardiothoracic surgery and experimental transplantation. Highlights of his career have been in contributing to (i) the first hypothermic perfusion storage of the donor heart to be used successfully in clinical practice, (ii) hormonal therapy in the management of the brain-dead potential organ donor, (iii) the identification of Gal alpha 1,3Gal as the major antigenic target for primate natural anti-pig antibodies, (iv) the 2- to 6-month survival of alpha1,3-galactosyltransferase gene-knockout hearts transplanted into baboons, and (v) the 3- to 12-month normoglycemia following the transplantation of islets from CD46-transgenic pigs into diabetic monkeys. Many friends have been made through a mutual interest in transplantation, particularly through the activities of the International Xenotransplantation Association (IXA). The author thanks the many mentors, colleagues, and research fellows with whom it has been his great privilege and pleasure to work during the past several decades, and readily acknowledges that it is largely their contributions that have enabled him to receive the honor of Honorary Membership of the IXA.

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Auxiliary Liver Allografting and Xenografting in the Nonhuman Primate

Cited by 23 publications

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Pharmacokinetics of cyclosporine in monkeys after oral and intramuscular administration: relation to efficacy in kidney allografting

Pharmacokinetics of cyclosporine in monkeys after oral and intramuscular administration: relation to efficacy in kidney allografting

Selection of Patients for Initial Clinical Trials of Solid Organ Xenotransplantation

Outwitting evolution*

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