Sirolimus in pediatric renal transplantation

Kasap, Belde

doi:10.1111/j.1399-3046.2011.01575.x

Cited by 30 publications

(28 citation statements)

References 120 publications

(289 reference statements)

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“…Thus, the anticonvulsant mechanisms of rapamycin may be distinct from other metabolism-based therapies. Because of the adverse effects of rapamycin and related drugs in patients [23], finding an explanation for how mTOR inhibition protects against seizures could help facilitate the design of more specific agents and minimize side effects.…”

Section: Introductionmentioning

confidence: 99%

The mTOR Inhibitor Rapamycin Has Limited Acute Anticonvulsant Effects in Mice

et al. 2012

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ObjectiveThe mammalian target of rapamycin (mTOR) pathway integrates signals from different nutrient sources, including amino acids and glucose. Compounds that inhibit mTOR kinase activity such as rapamycin and everolimus can suppress seizures in some chronic animal models and in patients with tuberous sclerosis. However, it is not known whether mTOR inhibitors exert acute anticonvulsant effects in addition to their longer term antiepileptogenic effects. To gain insights into how rapamycin suppresses seizures, we investigated the anticonvulsant activity of rapamycin using acute seizure tests in mice.MethodsFollowing intraperitoneal injection of rapamycin, normal four-week-old male NIH Swiss mice were evaluated for susceptibility to a battery of acute seizure tests similar to those currently used to screen potential therapeutics by the US NIH Anticonvulsant Screening Program. To assess the short term effects of rapamycin, mice were seizure tested in ≤6 hours of a single dose of rapamycin, and for longer term effects of rapamycin, mice were tested after 3 or more daily doses of rapamycin.ResultsThe only seizure test where short-term rapamycin treatment protected mice was against tonic hindlimb extension in the MES threshold test, though this protection waned with longer rapamycin treatment. Longer term rapamycin treatment protected against kainic acid-induced seizure activity, but only at late times after seizure onset. Rapamycin was not protective in the 6 Hz or PTZ seizure tests after short or longer rapamycin treatment times. In contrast to other metabolism-based therapies that protect in acute seizure tests, rapamycin has limited acute anticonvulsant effects in normal mice.SignificanceThe efficacy of rapamycin as an acute anticonvulsant agent may be limited. Furthermore, the combined pattern of acute seizure test results places rapamycin in a third category distinct from both fasting and the ketogenic diet, and which is more similar to drugs acting on sodium channels.

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Section: Introductionmentioning

confidence: 99%

The mTOR Inhibitor Rapamycin Has Limited Acute Anticonvulsant Effects in Mice

et al. 2012

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“…The main adverse effects include hyperlipidemia, mucositis, edema, altered wound healing, male hypogonadism, and myelosuppression. 9,14,15 Sirolimus led to rapid and significant improvement of gastrointestinal bleeding in 2 of our patients, which allowed for the discontinuation of blood transfusions for patient 2 and a decrease in transfusions for patient 3. The latter patient also showed complete resolution of skin lesions and partial response in the other involved sites.…”

Section: Discussionmentioning

confidence: 82%

Multifocal Lymphangioendotheliomatosis With Thrombocytopenia: Clinical Features and Response to Sirolimus

et al. 2015

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International audienceMultifocal lymphangioendotheliomatosis with thrombocytopenia (MLT) is a recently described glucose transporter 1-negative multifocal vascular disorder with significant morbidity and mortality. However, data are lacking on the clinical spectrum, long-term prognosis, and treatment of MLT. It is often confused with multifocal infantile hemangioma, but the conditions must be differentiated for appropriate assessment and therapeutic management. Treatments for MLT have been disappointing, and the treatments classically used for infantile hemangioma are often ineffective. We report 3 newborn cases featuring various clinical and biological phenotypes of MLT: 1 patient had severe brain involvement and died early; another had no thrombocytopenia; and the third had nearly no skin involvement. Histologically, all were negative for glucose transporter 1 and positive for the lymphatic marker lymphatic vessel endothelial hyaluronan receptor 1 or D2-40 (∼38-kDa O-linked transmembrane sialoglycoprotein podoplanin). Two cases with severe gastrointestinal bleeding were treated with sirolimus 0.1 mg/k per day, which was efficient after the first month of treatment. MLT clinically presents in various forms, and when complicated by widespread or severe extracutaneous involvement, initial aggressive therapeutic intervention is justified. The pathogenesis of MLT remains unclear, but lymphatic differentiation is widely acknowledged. Because of its antiangiogenic properties, including anti-lymphangiogenesis, sirolimus offers an adequate and targeted therapeutic approach for ML

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“…This approach is being taken in the ongoing phase II trial of this regimen (NCT02574728) where a sirolimus trough concentration of 10‐15 ng/mL is being targeted. This concentration has shown efficacy in preclinical models and is tolerable in pediatric subjects receiving sirolimus as a single agent and in combination . The most common toxicities in this phase I trial were hematologic and were easily managed with dose modifications.…”

Section: Discussionmentioning

confidence: 99%

“…This concentration has shown efficacy in preclinical models and is tolerable in pediatric subjects receiving sirolimus as a single agent and in combination. [41][42][43][44][45] The most common toxicities in this phase I trial were hematologic and were easily managed with dose modifications. More than half of the patients experienced stable disease, some for extended durations, and one patient had a partial response, suggesting this combination can provide clinical benefit with infrequent clinic visits and manageable toxicity.…”

Section: Discussionmentioning

confidence: 99%

A phase I study of sirolimus in combination with metronomic therapy (CHOAnome) in children with recurrent or refractory solid and brain tumors

Qayed

Cash

Tighiouart

et al. 2019

Pediatric Blood & Cancer

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Background/purpose To determine the maximum tolerated dose, toxicities, and response of sirolimus combined with oral metronomic therapy in pediatric patients with recurrent and refractory solid and brain tumors. Procedure Patients younger than 30 years of age with recurrent, refractory, or high‐risk solid and brain tumors were eligible. Patients received six‐week cycles of sirolimus with twice daily celecoxib, and alternating etoposide and cyclophosphamide every three weeks, with Bayesian dose escalation over four dose levels (NCT01331135). Results Eighteen patients were enrolled: four on dose level (DL) 1, four on DL2, eight on DL3, and two on DL4. Diagnoses included solid tumors (Ewing sarcoma, osteosarcoma, malignant peripheral nerve sheath tumor, rhabdoid tumor, retinoblastoma) and brain tumors (glioblastoma multiforme [GBM], diffuse intrinsic pontine glioma, high‐grade glioma [HGG], medulloblastoma, ependymoma, anaplastic astrocytoma, low‐grade infiltrative astrocytoma, primitive neuroectodermal tumor, nongerminomatous germ cell tumor]. One dose‐limiting toxicity (DLT; grade 4 neutropenia) was observed on DL2, two DLTs (grade 3 abdominal pain and grade 3 mucositis) on DL3, and two DLTs (grade 3 dehydration and grade 3 mucositis) on DL4. The recommended phase II dose of sirolimus was 2 mg/m2 (DL3). Best response was stable disease (SD) in eight patients, and partial response (PR) in one patient with GBM. A patient with HGG was removed from the study with SD and developed PR without further therapy. Western blot analysis showed inhibition of phospho‐S6 kinase in all patients during the first cycle of therapy. Conclusion The combination of sirolimus with metronomic chemotherapy is well tolerated in children. A phase II trial of this combination is ongoing.

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Sirolimus in pediatric renal transplantation

Cited by 30 publications

References 120 publications

The mTOR Inhibitor Rapamycin Has Limited Acute Anticonvulsant Effects in Mice

The mTOR Inhibitor Rapamycin Has Limited Acute Anticonvulsant Effects in Mice

Multifocal Lymphangioendotheliomatosis With Thrombocytopenia: Clinical Features and Response to Sirolimus

A phase I study of sirolimus in combination with metronomic therapy (CHOAnome) in children with recurrent or refractory solid and brain tumors

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