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.

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. Two such anti- cancer, platinum- containing drugs, cisplatin and oxaliplatin, have different side effects. Only cisplatin induces hearing loss, i.e. has an ototoxic side effect that is not seen after treatment with oxaliplatin. The objective of this study was to evaluate if TrxR is a target in the cochlea. Loss of outer hair cells was also compared when cisplatin and oxaliplatin were administered directly to the organ of Corti. Methods: Organ of Corti cell culture was used for direct exposure to cisplatin and oxaliplatin. Hair cells were evaluated and the level of TrxR was assessed. Immunohistochemical staining for TrxR was performed. An animal model was used to evaluate the effect on TrxR after treatment with cisplatin and oxaliplatin in vivo. Results: Direct exposure of cochlear organotypic cultures to either cisplatin or oxaliplatin induced comparable levels of outer hair cell loss and inhibition of TrxR, demonstrating that both drugs are similarly ototoxic provided that the cochlea becomes directly exposed.

Cisplatin during hyperthermic intraperitoneal chemotherapy (HIPEC) has not previously been measured with a selective technique. The primary aims were to examine the pharmacokinetics of active cisplatin and its monohydrated complex (MHC) during HIPEC using a specific measuring technique, to compare cisplatin’s systemic absorption with oxaliplatin, and to compare active cisplatin levels to that of total platinum.

OBJECTIVES/HYPOTHESIS:Cisplatin produces toxic lesions to outer hair cells (OHCs) in the cochlear base but not in the apex. The objective of this study was to compare the pharmacokinetic profile of cisplatin in scala tympani (ST) perilymph in the cochlear base and apex, respectively. STUDY DESIGN:In vivo animal study. METHODS:Forty-seven guinea pigs were given an intravenous bolus injection of an ototoxic dose of cisplatin. Ten to 240 minutes after cisplatin was given, blood, cerebrospinal fluid (CSF), and ST perilymph were aspirated within the same target time. ST perilymph was aspirated from the basal turn and from the apex of the cochlea by two different sampling techniques. Liquid chromatography with postcolumn derivatization was used for quantitative determination of the parent drug. RESULTS:Ten minutes after administration, the concentration of cisplatin in ST perilymph was 4-fold higher in the basal turn of the cochlea than in the apex. At 30 minutes, the drug concentrations did not differ. At 60 minutes, the level of cisplatin in ST perilymph and blood UF was equivalent. The perilymph-blood ratio increased thereafter with time. CONCLUSION:The pharmacokinetic findings of an early high concentration of cisplatin in the base of the cochlea and delayed elimination of cisplatin from ST perilymph compared to blood might correlate to the cisplatin-induced loss of OHCs in the base of the cochlea.

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. injection of cisplatin in a guinea pig model.METHODS:The release of thiosulfate (0.1 M) from HYA gel (0.5% w/w) was explored in vitro. Thiosulfate in the scala tympani perilymph of the cochlea 1 and 3 h after application of thiosulfate in HYA gel to the middle ear was quantified with HPLC and fluorescence detection. Thiosulfate in blood and CSF was also explored. The potential otoprotective effect was evaluated by hair cell count after treatment with thiosulfate in HYA gel applied to the middle ear 3 h prior to cisplatin injection (8 mg/kg b.w.).RESULTS:HYA did not impede the release of thiosulfate. Middle ear administration of thiosulfate in HYA gel gave high concentrations in the scala tympani perilymph while maintaining low levels in blood, and it protected against cisplatin-induced hair cell loss.CONCLUSION:HYA gel is an effective vehicle for administration of thiosulfate to the middle ear. Local application of a thiosulfate-containing HYA gel reduces the ototoxicity of cisplatin most likely without compromising its antineoplastic effect. This provides a minimally invasive protective treatment that can easily be repeated if necessary.

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: 0.22–0.52) were spiked with cisplatin (final concentrations: 2.48 × 10−7 M–9.90 × 10−6 M) and subjected to centripetal ultrafiltration. The blood ultrafiltrate was separated (loop volume: 5 μl) with a porous graphitic carbon column and a mobile phase of HEPES-buffer (pH 9.3). Prior to UV detection (344 nm), the eluate was mixed with sodium N,N-diethyldithiocarbamate (DDTC) in a microwave field (115 °C) in order to improve the UV absorptivity. Cisplatin eluted as a Pt–DDTC complex after 11.8 min. The peak area was influenced primarily by the hematocrit, the DDTC concentration, and the temperature and residence time in the microwave cavity. The method was robust and sensitive provided preparing a fresh DDTC solution each day and, at the end of a day's run, destroying DDTC remaining in the system. It offers the main advantages of high selectivity, sensitivity, and robustness, minimal sample processing, and the possibility to use small sample volumes.

Background . In selected patients with peritoneal carcinomatosis (PC) originating from colorectal cancer (CRC) the high dosage of oxaliplatin (460 mg/m 2 ) is recommended for hyperthermic intraperitoneal chemotherapy (HIPEC), which may be a health risk to those administering the drug. The aim of this study was to determine the risk of platinum (Pt) exposure for the two main people handling and administering the cytotoxic agent during HIPEC. Methods . Samples of blood and urine were collected from one male surgeon and one female perfusionist during oxaliplatin-based HIPEC treatment with open abdomen coliseum technique on six consecutive patients with PC from CRC. Results . All blood samples analysed were below the detection limit of<0.05 nmol/L Pt, and the urine samples were all below the detection limit of<0.03 nmol/L Pt. Conclusions . There appears to be little or no risk of Pt exposure during HIPEC when the recommended protective garment is used and the safety considerations are followed.

BACKGROUND:Oxaliplatin is a platinum-based chemotherapeutic drug. Neurotoxicity is the dose-limiting side effect. Previous investigations have reported that acute neurotoxicity could be mediated via voltage-gated ion channels. A possible mechanism for some of the effects is a modification of surface charges around the ion channel, either because of chelation of extracellular Ca2+, or because of binding of a charged biotransformation product of oxaliplatin to the channel. To elucidate the molecular mechanism, we investigated the effects of oxaliplatin and its chloride complex [Pt(dach)oxCl](-) on the voltage-gated Shaker K channel expressed in Xenopus oocytes. The recordings were made with the two-electrode and the cut-open oocyte voltage clamp techniques.CONCLUSION:To our surprise, we did not see any effects on the current amplitudes, on the current time courses, or on the voltage dependence of the Shaker wild-type channel. Oxaliplatin is expected to bind to cysteines. Therefore, we explored if there could be a specific effect on single (E418C) and double-cysteine (R362C/F416C) mutated Shaker channels previously shown to be sensitive to cysteine-specific reagents. Neither of these channels were affected by oxaliplatin. The clear lack of effect on the Shaker K channel suggests that oxaliplatin or its monochloro complex has no general surface-charge effect on the channels, as has been suggested before, but rather a specific effect to the channels previously shown to be affected.

Oxaliplatin is used primarily in the treatment of metastatic colorectal cancer. In this minireview, we discuss potentially important biotransformation pathways in light of its short elimination half-life in vivo. We also highlight new information achieved using a selective analytical technique to measure intact oxaliplatin in pharmacokinetic studies (comprising intravenous, intraperitoneal, and intrahepatic administration) and compare to results obtained by measurements of total platinum. The use of selective analytical techniques is strongly recommended giving kinetic parameters of the parent compound and not only to a complex mixture of platinum containing endogenous compounds. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3879–3885, 2009

OBJECTIVE:To evaluate the perfusate and systemic kinetics of oxaliplatin during hyperthermic intraperitoneal chemotherapy (HIPEC) using a selective analytical technique.METHODS:HIPEC was carried out in eight patients by the open abdomen coliseum technique for 30 min at 41.5-43 degrees C with an average of 427 mg/m(2) of oxaliplatin in 5% dextrose solution. Blood and perfusate samples were collected during the perfusion. Additional blood samples were taken up to 2 h after the end of perfusion. The analysis was performed by liquid chromatography and post-column derivatization with N,N-diethyldithiocarbamate using microwave heating.RESULTS:The mean elimination half-life of oxaliplatin in the perfusate was 29.5 min (range 21.1-41.2 min) and in the peripheral circulation 24.7 min (range 21.7-27.7 min). The ratio of the areas under the time concentration curve in perfusate and blood was 12.8 +/- 2.9.CONCLUSION:The systemic exposure of oxaliplatin measured after HIPEC using a selective analytical technique is considerably lower than previously reported results obtained by atomic absorption spectroscopy.

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 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% CI = 8.8- to 9.8-fold), to 5.1-fold (95% CI = 4.4- to 5.8-fold). A guinea pig model (n = 23) was used to examine pharmacokinetics. Drug concentrations were determined by liquid chromatography with post-column derivatization. The total platinum concentration in cochlear tissue was determined by inductively coupled plasma mass spectrometry. Drug pharmacokinetics was assessed by determining the area under the concentration-time curve (AUC). Statistical tests were two-sided. RESULTS:In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold to 3.1-fold induction) (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging (from 9.3-fold, 95% CI = 8.8- to 9.8-fold, to 5.1-fold, 95% CI = 4.4- to 5.8-fold). Oxaliplatin (20 microM)-induced apoptosis was unaffected by calcium chelation (from 7.1- to 6.2-fold induction) and by superoxide scavenging (from 5.9- to 5.6-fold induction). In guinea pig cochlea, total platinum concentration (0.12 vs 0.63 microg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 microM x minute, respectively, P < .001) were lower after intravenous oxaliplatin treatment (16.6 mg/kg) than after equimolar cisplatin treatment (12.5 mg/kg). However, after a non-ototoxic cisplatin dose (5 mg/kg) or the same oxaliplatin dose (16.6 mg/kg), the AUC for perilymphatic concentrations was similar, indicating that the two drugs have different cochlear pharmacokinetics. CONCLUSION:Cisplatin- but not oxaliplatin-induced apoptosis involved superoxide-related pathways. Lower cochlear uptake of oxaliplatin than cisplatin appears to be a major explanation for its lower ototoxicity.

Conclusion. High concentrations of the antioxidant thiosulfate reach scala tympani perilymph after i.v. administration in the guinea pig. Thiosulfate concentrations in perilymph remain elevated longer than in blood. This warrants further studies on the possibility of obtaining otoprotection by thiosulfate administration several hours before that of cisplatin without compromising the anticancer effect caused by cisplatin inactivation in the blood compartment. Objective. Thiosulfate may reduce cisplatin-induced ototoxicity, presumably by oxidative stress relief and formation of inactivate platinum complexes. This study aimed to explore to what extent thiosulfate reaches scala tympani perilymph after systemic administration in the guinea pig. Materials and methods. Scala tympani perilymph (1 µl) was aspirated from the basal turn of each cochlea up to 3 h after thiosulfate administration (103 mg/kg b.w., i.v.). Blood samples were also taken. Thiosulfate was quantified by HPLC and fluorescence detection. Results. Substantial thiosulfate concentrations were found in perilymph. The area under the concentration-time curve for thiosulfate in perilymph and blood was 3100 µM×min and 6300 µM×min, respectively. The highest thiosulfate concentrations in perilymph were found at the first sampling at about 10 min. Due to a more rapid elimination from blood, perilymph concentrations exceeded those of blood towards the end of the experiment.

The anticancer drug cisplatin can cause permanent inner ear damage. We have determined the second-order degradation rate constant, kNU, 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). The degradations were evaluated by measuring the disappearance of MHC and cisplatin at 37°C and pH 7.4 in the presence of each of the nucleophiles using LC and photometric detection. The kNU of MHC and of cisplatin was 0.044 M 1sec 1 and 0.012 M 1sec 1 with N-acetyl-l-cysteine, 0.24 M 1sec 1 and 0.067 M 1sec 1 with l-cysteine methyl ester, 0.16 M 1sec 1 and 0.074 M 1sec 1 with 1,3-dimethyl-2-thiourea, 0.070 M 1sec 1 and 0.069 M 1sec 1 with d-methionine, and 3.9 M 1sec 1 and 0.091 M 1sec 1 with thiosulfate, respectively. Our results suggest that thiosulfate, as being the strongest nucleophile, is a promising candidate for local application in order to reduce the inner ear content of MHC and cisplatin. However, otoprotection is a multifactorial event, and it remains to be established how important nucleophilicity is for the effectiveness of the protecting agent.

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. A questionnaire to physicians and nurses was used to evaluate their experiences of the pharmacist’s contribution to the oncology ward. Results. In total, 114 DRPs were identified in 58 patients. For each DRP, the pharmacist gave proposals for solutions. Sixty-eight suggestions out of 114 (59.6%) were implemented by the physician. Two suggestions (1.8%) were partly followed. For 32 suggestions (28.0%) it was unclear if they had caused any change in medication. Twelve suggestions (10.5%) were not followed. Most of the physicians and nurses acknowledged the pharmacist’s contribution to improved drug use in the ward. Conclusion. A pharmacist can improve drug use in an oncology ward as a member of the health-care team. The pharmacist contributes with a systematic focus on the patient from a drug perspective.

Oxaliplatin undergoes extensive non-enzymatic chemical transformation in the body. Complexes with sulphur-containing compounds have previously been found in plasma from patients treated with oxaliplatin. We have studied the kinetics for the reactions between oxaliplatin and cysteine, methionine, and glutathione, by determination of the degradation of oxaliplatin using liquid chromatography with UV-detection. We also studied the degradation of oxaliplatin in plasma ultrafiltrate (PUF). For the degradation of oxaliplatin in the presence of glutathione, methionine, and cysteine, the second-order rate constants were 4.7M−1min−1 (95% confidence interval [C.I.], 4.4–5.0M−1min−1), 5.5M−1min−1 (95% C.I., 5.2–5.7M−1min−1), and 15M−1min−1 (95% C.I., 14–17M−1min−1), respectively. The reaction rate was much faster than previously reported kinetics for cisplatin. The degradation rate of oxaliplatin in PUF was biphasic. The rate constant for the first phase varied from 9.5×10−3 to 0.13min−1 and for the second phase from (1.7 to 1.8)×10−3min−1 in PUF from five healthy volunteers. The first hours of the degradation of oxaliplatin in PUF are accounted for by the degradation of oxaliplatin in a cocktail of sodium chloride and sulphur-containing compounds at physiological plasma concentrations. In conclusion, the rate of the reaction of oxaliplatin with three sulphur-containing compounds was faster for oxaliplatin than what is previously known for cisplatin. This may be important with respect to differences in the cellular effects of cisplatin and oxaliplatin treatment.

BACKGROUND:The efficacy of oxaliplatin combined with capecitabine (XELOX) as second-line therapy in patients with advanced colorectal cancer (ACRC) resistant to irinotecan is not well established. Oxaliplatin induces acute, cold-induced neuropathy in most patients. The incidence is claimed to be infusion rate-dependent and therefore a 2-h infusion is recommended.PATIENTS AND METHODS:For practical and economic reasons, but also for patient's convenience, we performed a phase II study to examine XELOX30 (capecitabine 1000 mg/m2 orally twice daily on days 1-14 and oxaliplatin 130 mg/m2 as a 30 min infusion on day 1) in patients with ACRC resistant to irinotecan. In addition the pharmacokinetics of oxaliplatin was studied.RESULTS:From November 2002 to September 2003, 70 patients with ACRC were treated with XELOX30. Median age was 62 (range 33-74 years) years and median performance status was 1 (range 0-2). The median number of courses was four (range 1-12) and median cumulative dose of oxaliplatin was 530 (range 125-1560) mg/m2. The response rate was 17% (95% CI 10-23), median time to progression (TTP) was 5.4 months (95% CI 4.6-6.4) and median survival 9.5 months (95% CI 8.5-11.2). White blood cell count (WBC) and performance status were significantly correlated to TTP. Neurotoxicity was moderate: grade 1 56%, grade 2 17% and grade 3 6%. Other grade 3 toxicities were nausea/vomiting 9%, diarrhoea 14% and PPE 8%. The maximum blood concentration and total body clearance of oxaliplatin was higher than previously reported in studies examining 2-h infusions, but the volume of distribution and terminal half-life was in close agreement with previous results.CONCLUSION:XELOX30 is a very convenient second-line regimen in ACRC with an activity and safety profile similar to other oxaliplatin schedules.