Cisplatin and Oxaliplatin Toxicity: Importance of Cochlear Kinetics as a Determinant for Ototoxicity

Background Cisplatin is a commonly used platinum anti-cancer drug. Regrettably cisplatin has dose-limiting ototoxic side effects, e.g. the drug can induce an irreversible hearing loss. The ototoxic mechanisms of cisplatin have not been elucidated in the human ear and no clinically useful oto-protectors are yet available. Cisplatin is a necessary part of many treatment regimes. Its beneficial therapeutic effects might be reduced if cisplatin was excluded from the treatment in order to protect the hearing function. In this work the ototoxic effects of cisplatin are studied with the aim to better understand the mechanisms behind the irreversible hearing loss induced by this drug. Oxaliplatin is a second generation platinum-derivative anti-cancer drug, free from ototoxic side effects in clinical practice. The effects of oxaliplatin on the inner ear have been studied in this work and the results are compared with cisplatin treatment. The two drugs differ regarding both anti-cancer effects and side effects, which could be attributed to differences in pharmacokinetic factors, cellular uptake and apoptotic mechanisms. The thioredoxin redox system with the enzyme thioredoxin reductase (TrxR) was studied in cochleae due to a suggested DNA-independent apoptotic mechanism of the hair cells. The cochlear pharmacokinetics of cisplatin was assessed and the transport protein organic cation transporter 2 (OCT2) was studied in relation to the ototoxic effect of cisplatin. Material and methods Cultured human colon carcinoma cells and cell cultures of rat organ of Corti were used for apoptosis studies in vitro following exposure to cisplatin and oxaliplatin. Cisplatin and oxaliplatin were administered i.v. to guinea pigs, followed by in vivo sampling of blood, cerebrospinal fluid (CSF) and scala tympani (ST) perilymph. Liquid chromatography with post-column derivatization was used to determine the concentration of parent drug in the samples. Electrophysiological hearing thresholds and the loss of hair cells were assessed to evaluate their ototoxic effects. Phenformin, a potential blocker of OCT2 was administered and the ototoxic side effect of cisplatin was evaluated. For immunohistochemical studies, cochlea from rat, guinea pig and pig were used, where TrxR and OCT2 were evaluated in the cochlea. TrxR-assays were used to measure the TrxR activity in cochlear tissue, both in vivo and in vitro. Results The results from the in vitro studies showed that addition of either cisplatin or oxaliplatin to the culture medium in organ of Corti cell cultures caused a similar amount of outer hair cell loss and inhibition of TrxR activity. Cisplatin exposure to cultured human colon carcinoma cells also reduced the activity of TrxR. The results from the in vivo studies showed that a considerable concentration of cisplatin was present in ST perilymph as compared with weak concentrations of oxaliplatin after high dose oxaliplatin i.v. Ten minutes after cisplatin administration, its concentration in ST perilymph was 4-fold higher in the basal turn of the cochlea as compared to the apex. Cisplatin could be analysed in ST perilymph for up to 120 min. Phenformin i.v. did not reduce the ototoxic side-effect of cisplatin. Positive immunoreactivity to TrxR was evident in both hair cells and spiral ganglion cells. Futhermore, OCT2 was expressed in the supporting cells of organ of Corti and in the spiral ganglion cells. Conclusion The transport of cisplatin to the vulnerable cells of hearing seems to be of major importance for the ototoxic effects. An early high concentration of cisplatin in the base of the cochlea and delayed elimination of cisplatin from ST perilymph may be related to the cisplatin-induced loss of outer hair cells in the basal turn of the cochlea. Cisplatin and oxaliplatin both cause similar ototoxic effects when the organ of Corti is directly exposed in vitro. The thioredoxin redox system with the TrxR enzyme may well play a critical role in cisplatininduced ototoxicity. The presence of OCT2 in the supporting cells indicates that this transport protein is primarily not involved in the uptake of cisplatin from the systemic circulation but rather from the deeper compartments of the cochlea. The knowledge elicited in this work will hopefully suggest objectives for further studies in order to develop oto-protective treatments to preserve the hearing of cisplatin treated patients

Plasmapheresis reverses all side-effects of a cisplatin overdose – a case report and treatment recommendation

BACKGROUND: Cisplatin is widely used as an antineoplastic agent since it is effective against a broad spectrum of different tumours. Nevertheless, it has several potential side effects affecting different organ systems and an overdose may lead to life-threatening complications and even death. CASE PRESENTATION: We report on a 46-year old woman with non-small cell lung cancer who accidentally received 225 mg/m(2 )of cisplatin, which was threefold the dose as scheduled, within a 3-day period. Two days later, the patient presented with hearing loss, severe nausea and vomiting, acute renal failure as well as elevated liver enzymes. In addition, she developed a severe myelodepression. After plasmapheresis on two consecutive days and vigorous supportive treatment, the toxicity-related symptoms improved and the patient recovered without any sequelae. CONCLUSION: To date, no general accepted guidelines for the treatment of cisplatin overdoses are available. Along with the experience from other published cases, our report shows that plasmapheresis is capable of lowering cisplatin plasma and serum levels efficiently. Therefore, plasma exchange performed as soon as possible can ameliorate all side effects of a cisplatin overdose and be a potential tool for clinicians for treatment. However, additional intensive supportive treatment-modalities are necessary to control all occurring side effects

d-Methionine protects against cisplatin-induced neurotoxicity in cortical networks

Article discussing D-Methionine protecting against cisplatin-induced neurotoxicity in cortical networks

Association between long-term neuro-toxicities in testicular cancer survivors and polymorphisms in glutathione-s-transferase-P1 and -M1, a retrospective cross sectional study

<p>Abstract</p> <p>Background</p> <p>To assess the impact of polymorphisms in Glutathione S-transferase (GST) -P1, -M1, and -T1 on self-reported chemotherapy-induced long-term toxicities in testicular cancer survivors (TCSs).</p> <p>Methods</p> <p>A total of 238 TCSs, who had received cisplatin-based chemotherapy at median twelve years earlier, had participated in a long-term follow-up survey which assessed the prevalence of self-reported paresthesias in fingers/toes, Raynaud-like phenomena in fingers/toes, tinnitus, and hearing impairment. From all TCSs lymphocyte-derived DNA was analyzed for the functional A→G polymorphism at bp 304 in <it>GSTP1</it>, and deletions in <it>GST-M1 </it>and <it>GST-T1</it>. Evaluation of associations between GST polymorphisms and self-reported toxicities included adjustment for prior treatment.</p> <p>Results</p> <p>All six evaluated toxicities were significantly associated with the cumulative dose of cisplatin and/or bleomycin. Compared to TCSs with either <it>GSTP1-AG </it>or <it>GSTP1</it>-<it>AA</it>, the 37 TCSs with the genotype <it>GSTP1-GG</it>, were significantly less bothered by paresthesias in fingers and toes (p = 0.039, OR 0.46 [0.22–0.96] and p = 0.023, OR 0.42 [0.20–0.88], respectively), and tinnitus (p = 0.008, OR 0.33 [0.14–0.74]). Furthermore, absence of functional GSTM1 protected against hearing impairment (p = 0.025, OR 1.81 [1.08–3.03]).</p> <p>Conclusion</p> <p>In TCSs long-term self-reported chemotherapy-induced toxicities are associated with functional polymorphisms in <it>GSTP1 </it>and <it>GSTM1</it>. Hypothetically, absence of GST-M1 leaves more glutathione as substrate for the co-expressed GST-P1. Also intracellular inactivation of pro-apoptotic mediators represents a possible explanation of our findings. Genotyping of these GSTs might be a welcomed step towards a more individualized treatment of patients with metastatic testicular cancer.</p

Antioxidants l-carnitine and d-methionine modulate neuronal activity through GABAergic inhibition

Article on antioxidants L-carnitine and D-methionine modulate neuronal activity through GABAergic inhibition

Cisplatin induced ototoxicity : Pharmacokinetics, prediction and prevention

Cisplatin is an anticancer drug used against a number of malignancies e.g. testicular cancer, ovarian cancer and some paediatric malignancies. The main dose limiting side effects of cisplatin are oto- and neurotoxicity. Cisplatin is regarded as the most common cause of ototoxicity in Sweden today. Cisplatin ototoxicity manifests clinically as a hearing loss beginning in the high frequency region and involving successively lower frequencies. Tinnitus is another common complaint. There is a high interindividual variability in susceptibility to the ototoxic effect, a rough dose dependence and indications that the mode of administration affects the toxic effects. The aim of the thesis has been to study cisplatin ototoxicity especially as related to the pharmacokinetics of the drug and to prediction and prevention of ototoxicity. The first hypothesis was that mode of administration affects the side effect profile of cisplatin. The pharmacokinetics of cisplatin and the monohydrated complex of cisplatin (MHC) a toxic biotransformation product of cisplatin were determined after a bolus injection or a one-hour infusion of cisplatin to guinea pigs. It was found that the interindividual variability in susceptibility to the ototoxic effect was far greater than the variability in pharmacokinetics, suggesting that other factors are more important for the degree of hearing loss. MHC has been suggested as the major cause of cisplatin side effects but has previously not been purified in sufficient amounts for animal studies of toxicity. This was effected by separation on a porous graphitic column. MHC caused an ABR thresholds shift, an increase in creatinine and a weight loss in the animals similar to those seen after administration of cisplatin in the double dose. Thus, MHC is approximately twice as toxic as cisplatin. The antitumour effect of cisplatin is often assumed to be proportional to the systemic exposure to the drug. D-methionine has recently been advocated as a protectant against cisplatin toxicity. However, i.v. administration of D-methionine 1 hour before cisplatin caused a 30% decrease in the systemic exposure to cisplatin and an even greater reduction in MHC exposure. Our results indicate that the previously observed protection from cisplatin ototoxicity by systemic D-methionine can be explained by a lowered systemic exposure to cisplatin. Local administration of a cytoprotective agent to the inner ear offers a possibility to prevent cisplatin-induced ototoxicity without risk of interference with the antitumour effect. Thiourea (TU) has unique properties that make it an interesting candidate for local protection against cisplatin ototoxicity. Ears administered TU by a direct intracochlear infusion demonstrated significantly lower OHC loss as compared to untreated ears but similar ABR. Thus, TU demonstrates partial protection against cisplatin-induced ototoxicity. A trial was initiated to test the efficacy of high dose cisplatin treatment (125 mg/m2) with amifostine (Ethyol®) protection in 15 patients with metastatic malignant melanoma. The most prominent side effects were ototoxic and in spite of amifostine treatment ototoxicity was unacceptable. After the second treatment all but one patient reported auditory symptoms and three patients ultimately required a hearing aid. No correlation was found on the individual level between subsequent hearing loss and plasma pharmacokinetics during the first course. An effect of amifostine on cisplatin pharmacokinetics was suggested as the analysis of platinum levels showed higher values than those obtained by selective analysis of cisplatin, corroborating the findings in the D-methionine study

Like an empowering micro-home : A qualitative study of women's experience of giving birth in water

OBJECTIVE: To describe women´s experiences and perceptions of giving birth in water. DESIGN: A qualitative study with in-depth interviews three to five months after the birth. A content analysis of the interviews was made. SETTING: One city-located hospital in Stockholm, offering waterbirth to low risk women. PARTICIPANTS: 20 women, 12 primiparas and 8 multiparas, aged 27-39. MEASUREMENTS AND FINDINGS: The overall theme emerging from the analysis was, "Like an empowering micro-home", which describes the effect of being strengthened, enabled and authorized in the birth process. Three categories were found: "Synergy between body and mind", "Privacy and discretion", and "Natural and pleasant". KEY CONCLUSIONS: The immersion in warm water provided the women with conditions that helped them to cope and feel confident during labour and birth. The homelike and limited space of a bathtub helped give a relaxed feeling of privacy, safety, control and focus for the women. IMPLICATIONS FOR PRACTICE: This study contributes to a deeper understanding of what waterbirth offers to women. For some women, waterbirth may be a way to accomplish an empowering and positive birth experience, and could work as a tool that preserves the normality of, and increases self-efficacy in, childbirth