Show simple item record Dósa, Edit Heltai, Krisztina Radovits, Tamás Molnar G Kapocsi, Judit Merkely, Béla Péter Fu R Doolittle ND Toth GB Urdang Z Neuwelt EA 2018-08-09T13:34:52Z 2018-08-09T13:34:52Z 2017
dc.identifier 85030309041
dc.identifier.citation pagination=26; journalVolume=14; journalIssueNumber=1; journalTitle=FLUIDS AND BARRIERS OF THE CNS;
dc.identifier.uri doi:10.1186/s12987-017-0075-0
dc.description.abstract BACKGROUND: Cisplatin neuro-, oto-, and nephrotoxicity are major problems in children with malignant tumors, including medulloblastoma, negatively impacting educational achievement, socioemotional development, and overall quality of life. The blood-labyrinth barrier is somewhat permeable to cisplatin, and sensory hair cells and cochlear supporting cells are highly sensitive to this toxic drug. Several chemoprotective agents such as N-acetylcysteine (NAC) were utilized experimentally to avoid these potentially serious and life-long side effects, although no clinical phase I trial was performed before. The purpose of this study was to establish the maximum tolerated dose (MTD) and pharmacokinetics of both intravenous (IV) and intra-arterial (IA) NAC in adults with chronic kidney disease to be used in further trials on oto- and nephroprotection in pediatric patients receiving platinum therapy. METHODS: Due to ethical considerations in pediatric tumor patients, we used a clinical population of adults with non-neoplastic disease. Subjects with stage three or worse renal failure who had any endovascular procedure were enrolled in a prospective, non-randomized, single center trial to determine the MTD for NAC. We initially aimed to evaluate three patients each at 150, 300, 600, 900, and 1200 mg/kg NAC. The MTD was defined as one dose level below the dose producing grade 3 or 4 toxicity. Serum NAC levels were assessed before, 5 and 15 min post NAC. Twenty-eight subjects (15 men; mean age 72.2 +/- 6.8 years) received NAC IV (N = 13) or IA (N = 15). RESULTS: The first participant to experience grade 4 toxicity was at the 600 mg/kg IV dose, at which time the protocol was modified to add an additional dose level of 450 mg/kg NAC. Subsequently, no severe NAC-related toxicity arose and 450 mg/kg NAC was found to be the MTD in both IV and IA groups. Blood levels of NAC showed a linear dose response (p < 0.01). Five min after either IV or IA NAC MTD dose administration, serum NAC levels reached the 2-3 mM concentration which seemed to be nephroprotective in previous preclinical studies. CONCLUSIONS: In adults with kidney impairment, NAC can be safely given both IV and IA at a dose of 450 mg/kg. Additional studies are needed to confirm oto- and nephroprotective properties in the setting of cisplatin treatment. Clinical Trial Registration URL: . Unique identifier: 2011-000887-92.
dc.relation.ispartof urn:issn:2045-8118
dc.title Dose escalation study of intravenous and intra-arterial N-acetylcysteine for the prevention of oto- and nephrotoxicity of cisplatin with a contrast-induced nephropathy model in patients with renal insufficiency.
dc.type Journal Article 2018-07-13T06:36:45Z
dc.language.rfc3066 en
dc.identifier.mtmt 3277048
dc.identifier.wos 000412065200001
dc.identifier.pubmed 28974245
dc.contributor.department SE/AOK/K/VAROSMAJOR_SZÍVÉRGYÓGY/Kardiológia Központ - Kardiológiai Tanszék [2017.10.31]
dc.contributor.department SE/AOK/K/I. Sz. Belgyógyászati Klinika
dc.contributor.institution Semmelweis Egyetem

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