Synergistic effects of RAD and Neoral in inhibition of host‐vs.‐graft and graft‐vs.‐host immune responses in rat small‐bowel transplantation

Johnson, Stephane; Qi, S.; Xu, Dakang; Jolicoeur, Marc; Liu, Dingyi; Barama, Azemi; Busque, S.; Smeesters, C; Daloze, Pierre; Chen, Huifang

doi:10.1002/micr.10167

Cited by 7 publications

(6 citation statements)

References 18 publications

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“…The doses tested in our study are similar to those used, almost invariably, to elicit immunosuppressive effects in rats (23)(24)(25). A daily oral dose of 2.5 mg/kg reportedly leads to trough levels of approximately 20 ng/mL (23).…”

Section: Discussionmentioning

confidence: 90%

Everolimus Interferes With Healing of Experimental Intestinal Anastomoses

Vliet

Willems²,

Man³

et al. 2006

Transplantation

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Section: Discussionmentioning

confidence: 90%

Everolimus Interferes With Healing of Experimental Intestinal Anastomoses

Vliet

Willems²,

Man³

et al. 2006

Transplantation

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“…The doses of everolimus we have chosen are based on the dose range used in our previous study 10 and similar to those used to elicit immunosuppressive effects in rats 13–15 . Daily oral doses of 1 or 2.5 mg/kg are expected to result in trough levels approximating 6 and 8 ng/mL, respectively 16,17 .…”

Section: Discussionmentioning

confidence: 99%

“…The doses of everolimus we have chosen are based on the dose range used in our previous study 10 and similar to those used to elicit immunosuppressive effects in rats. [13][14][15] Daily oral doses of 1 or 2.5 mg/kg are expected to result in trough levels approximating 6 and 8 ng/mL, respectively. 16,17 In patient studies, target trough levels are usually between 3 and 15 ng/mL, 18 although an upper therapeutic concentration limit is likely to exceed 15 ng/ mL.…”

Section: Discussionmentioning

confidence: 99%

Persistent effects of everolimus on strength of experimental wounds in intestine and fascia

Willems¹,

Vliet²,

Man³

et al. 2010

Wound Repair and Regeneration

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The introduction of mTOR-inhibitors in transplantation surgery has been associated with an increase in wound complications. We have previously reported a massive negative effect of everolimus on anastomotic strength in rat intestine at 7 days postoperatively. Because it is clinically important to know if this effect persists and occurs generally, repair in both intestine and abdominal wall has been investigated over a period of 4 weeks. Wistar rats received a daily dose of 1 or 2 mg/kg everolimus orally, from the operation day onwards. Controls received saline. In each rat a resection of ileum and colon was performed, and endto-end anastomoses were constructed. On day 7, 14, and 28 the animals were killed and anastomoses and abdominal wall wounds were analyzed, wound strength being the primary parameter. Breaking strength of ileum, colon, and fascia was consistently and significantly reduced in the experimental groups at all time points. Anastomotic bursting pressures followed the same pattern. Loss of strength was accompanied by a decrease in hydroxyproline content after 7 days. Thus, the negative effect of everolimus on wound repair persists for at least 4 weeks after operation in this rodent model. This protracted effect may have clinical consequences and cause surgical morbidity.The number of patients receiving solid organ transplantation is ever increasing. As a consequence, there is a growing number of people who depend on immunosuppressive drugs for transplant survival, not only immediately after operation but also in the long term. Therefore, efforts are aimed at improving immunosuppressive drugs and establish optimal regimens for both purposes.Sirolimus is a lipophilic macrocyclic lactone antibiotic produced from Streptomyces hygroscopicus, 1 which binds to the mammalian target of rapamycin (mTOR) and blocks its function. Inhibition of mTOR-mediated pathways results in arrest of the cell cycle at the G1 phase in various cell types, including T-and B-lymphocytes, and thus constitutes a potent immunosuppressive tool. Everolimus, a more recently developed mTOR inhibitor, is very similar to sirolimus in its pharmacodynamic effects. 2Although rapamycin (sirolimus) was already discovered in the 1970s, interest in its use in transplantation surgery originated only a decade ago. The purpose of using mTOR inhibitors was minimizing cyclosporine exposure and avoidance of steroids, because of the relatively strong side effects of the latter drugs. Addition of an mTOR inhibitor to the polydrug posttransplantation regimen seemed promising, but now that sufficient clinical experience has been gathered, they appear to induce their own specific adverse effects. The most important clinical side effect recognized so far is a negative influence of mTOR inhibitors on wound repair. For instance, wound healing disorders were seen in 7-53% of renal transplantation patients and rapamycin derivatives (e.g., sirolimus) seem to play an important role.3-7 The same phenomenon is noted in cardiac transplant recipients. 8,9 Fo...

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“…The doses of 1 and 2 mg/kg everolimus have been chosen according to the dose range used in previous studies . Others have used similar doses to elicit immunosuppressive effects in rats . Daily oral doses of 1 or 2.5 mg/kg have been shown to result in trough levels approximating 6 and 8 ng/mL in rats .…”

Section: Discussionmentioning

confidence: 99%

Everolimus‐induced loss of wound strength can be prevented by a short postoperative delay in its administration

Willems

Hendriks

Man

et al. 2011

Wound Repair Regeneration

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The use of mammalian target of rapamycin inhibitors coincides with an increased incidence of surgical complications. In previous experiments, serious negative effects of postoperative everolimus on anastomotic strength were found. This study aims to investigate if delayed drug administration can prevent loss of wound strength. Ten groups of Wistar rats each received daily oral doses of 1.0 or 2.0 mg/kg everolimus, starting the day of anastomotic construction in both ileum and colon, or 1, 2, 3, or 4 days later. The 11th group received saline. Seven days later, wound strength in anastomoses and in the abdominal wall and wound hydroxyproline levels were measured. Mean wound strength was significantly and dose-dependently reduced if everolimus was started on the day of operation. In ileum and colon, strength was not affected if drug administration was delayed until the third or second day, respectively. In abdominal fascia, this was the case only if everolimus was withheld until day 4. In general, changes in wound hydroxyproline content showed similarities to changes in wound strength. Thus, delaying administration of everolimus for 2-4 days after operation can prevent a serious loss of wound strength, both in the intestine and in the abdominal fascia.

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Synergistic effects of RAD and Neoral in inhibition of host‐vs.‐graft and graft‐vs.‐host immune responses in rat small‐bowel transplantation

Cited by 7 publications

References 18 publications

Everolimus Interferes With Healing of Experimental Intestinal Anastomoses

Everolimus Interferes With Healing of Experimental Intestinal Anastomoses

Persistent effects of everolimus on strength of experimental wounds in intestine and fascia

Everolimus‐induced loss of wound strength can be prevented by a short postoperative delay in its administration

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