Immunohistochemical localization of OCT2 in the cochlea of various species.

Objective: To locate the organic cation transporter 2 (OCT2) in the cochlea of three different species and to modulate the ototoxicity of cisplatin in the guinea pig by pretreatment with phenformin, having a known affinity for OCT2.

Study Design: Immunohistochemical and in vivo study.

Methods: Sections from the auditory end organs were subjected to immunohistochemical staining in order to identify OCT2 in cochlea from untreated rats, guinea pigs, and a pig.

Cisplatin and oxaliplatin are toxic to cochlear outer hair cells and both target thioredoxin reductase in organ of Corti cultures.

Conclusion: Inhibition of thioredoxin reductase (TrxR) may be a contributing factor in cisplatin-induced ototoxicity. Direct exposure of organ of Corti to cisplatin and oxaliplatin gives equal loss of hair cells.

Objectives: Platinum-containing drugs are known to target the anti-oxidant selenoprotein TrxR in cancer cells.

Quantitative liquid chromatographic determination of intact cisplatin in blood with microwave-assisted post-column derivatization and UV detection.

The anticancer agent cisplatin (cis-diamminedichloroplatinum(II), cis-[PtCl₂(NH₃)₂]) easily undergoes ligand-exchange reactions, resulting in mainly inactive Pt complexes. This paper presents a method for selective analysis of intact cisplatin in blood using LC and UV detection. Blood samples (hematocrit: 0.

Prevention of cisplatin-induced hearing loss by administration of a thiosulfate-containing gel to the middle ear in a guinea pig model.

Purpose: Thiosulfate may reduce cisplatin-induced ototoxicity, most likely by relieving oxidative stress and by forming inactive platinum complexes. This study aimed to determine the concentration and protective effect of thiosulfate in the cochlea after application of a thiosulfate-containing high viscosity formulation of sodium hyaluronan (HYA gel) to the middle ear prior to i.v.

Cimetidine as an organic cation transporter antagonist.

This Correspondence relates to “Organic transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions” (Am J Pathol 2010, 176:1169–1180).

Cisplatin and oxaliplatin toxicity: importance of cochlear kinetics as a determinant for ototoxicity.

Background: Cisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference has not been explained.

Methods: In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.

High concentrations of thiosulfate in scala tympani perilymph after systemic administration in the guinea pig.

Conclusion: High concentrations of the antioxidant thiosulfate reach scala tympani perilymph after i.v. administration in the guinea pig.

Kinetics of Cisplatin and its monohydrated complex with sulfur-containing compounds designed for local otoprotective administration.

The anticancer drug cisplatin can cause permanent inner ear damage. We have determined the second-order degradation rate constant, k(Nu), of cisplatin and its more toxic monohydrated complex (MHC) in the presence of each of the sulfur-containing nucleophiles N-acetyl-l-cysteine, l-cysteine methyl ester, 1,3-dimethyl-2-thiourea, d-methionine, and thiosulfate, compounds that are under evaluation for local administration to prevent cisplatin-induced ototoxicity. MHC was isolated from a hydrolysis solution of cisplatin using liquid chromatography (LC).

An evaluation of pharmacist contribution to an oncology ward in a Swedish hospital.

Aim: The aim of this project was to establish the importance of a pharmacist in the health-care team in improving drug use in an oncology ward in the Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.

Methods And Patients: The pharmacist participated in the medical round in the mornings and worked as a member of the health-care team. Drug-related problems (DRPs) were identified by drug chart reviews based on data from medical files, laboratory tests and interviews with patients and/or relatives.

Inhibition of thioredoxin reductase but not of glutathione reductase by the major classes of alkylating and platinum-containing anticancer compounds.

Mammalian thioredoxin reductase (TrxR) is important for cell proliferation, antioxidant defense, and redox signaling. Together with glutathione reductase (GR) it is the main enzyme providing reducing equivalents to many cellular processes. GR and TrxR are flavoproteins of the same enzyme family, but only the latter is a selenoprotein.

High-dose Cisplatin with amifostine: ototoxicity and pharmacokinetics.

Objectives/hypothesis: Ototoxicity is a common side effect of high-dose cisplatin treatment. Thiol-containing chemoprotectors ameliorate cisplatin ototoxicity under experimental conditions. The trial was initiated to test the efficacy of amifostine protection in high-dose cisplatin treatment (125-150 mg/m) for metastatic malignant melanoma, to correlate the ototoxic outcome with cisplatin pharmacokinetics, and to evaluate the importance of using a selective analytical method for the quantification of cisplatin.

Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo.

The novel alkylating dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) was evaluated for acute toxicity and antitumor activity in mice, with melphalan as a reference. To determine a safe and tolerable dose for efficacy studies the acute toxicity following intravenous injection in the tail vein was monitored using a 14-day schedule with up to four doses. The highest tested dose, 25 micromoles/kg, was considered close to this level, with minor effects on body weight gain but significant effects on hematological parameters.

Oxaliplatin degradation in the presence of chloride: identification and cytotoxicity of the monochloro monooxalato complex.

Purpose: To study the degradation of oxaliplatin in chloride media and evaluate the cytotoxicity of oxaliplatin in normal and chloride-deficient medium.

Methods: The products of the reaction of oxaliplatin with chloride were separated on a Hypercarb S column with a mobile phase containing 40% methanol in 0.05 M ammonia and subjected to electrospray ionization mass spectrometry.

Antitumor activity of the novel melphalan containing tripeptide J3 (L-prolyl-L-melphalanyl-p-L-fluorophenylalanine ethyl ester): comparison with its m-L-sarcolysin analogue P2.

Peptichemio (PTC), a mixture of six oligopeptides all containing m-L-sarcolysin, has previously shown impressive results in clinical trials. The tripeptide P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester) has been suggested as the main contributor to PTC activity. In contrast to its analogue melphalan, m-L-sarcolysin never reached clinical use.

Liquid chromatographic determination of oxaliplatin in blood using post-column derivatization in a microwave field followed by photometric detection.

Oxaliplatin ([(1R,2R)-1,2-cyclohexanediamine-N,N']oxalato(2-)-O,O'-platinum) is the first platinum drug with significant activity for metastatic colon cancer. The analysis of oxaliplatin has previously almost exclusively been based on the determination of the platinum content in plasma or ultrafiltrate using flameless atomic absorption spectroscopy (FAAS) or inductively coupled plasma mass spectrometry (ICPMS). A new method for quantitative determination of the free fraction of the intact drug in blood ultrafiltrate is presented here.