Cisplatin, a platinum-containing antineoplastic drug: perspectives on analytical chemistry and prevention of ototoxicity

The platinum-containing drug cisplatin plays a key role in the curative and palliative treatment of many solid malignancies. Unfortunately, the treatment can lead to sensorineural hearing loss, which limits the use of the drug. High single and cumulative dose levels are risk factors, but there is a large interindividual variability in the susceptibility to the ototoxic effects. The mechanisms behind the ototoxicity have not been fully elucidated, but one hallmark is oxidative stress. Moreover, the ototoxicity is dependent on the exposure of cisplatin and/or its biotransformation product MHC in the perilymphatic compartment of the cochlea. The aim of the research presented in this thesis was to contribute to the development of treatment strategies against cisplatin-induced ototoxicity. Sulfur-containing nucleophiles are attractive candidate compounds against cisplatininduced hearing loss since they are prone to chemically interact with cisplatin and MHC and could potentially reduce the exposure of these platinum species in the cochlea. A second possible mechanism may be relief of oxidative stress. The aim of the in vitro study described in Paper I was to investigate how quickly the concentrations of cisplatin and MHC can be reduced in the presence of five sulfur-containing nucleophiles. The results showed that thiosulfate was a promising candidate for future studies in vivo, since it reacted fast with cisplatin and, in particular, with MHC. This conclusion was further supported by the fact that thiosulfate is an endogenous ion, is well tolerated, and has been used clinically for decades against e.g. cyanide poisoning. Systemic administration of thiosulfate has earlier been investigated in several in vitro and in vivo studies against cisplatin-induced ototoxicity. However, it has been unknown whether thiosulfate at all reaches the cochlea. In the study described in Paper II, it was demonstrated that the distribution of thiosulfate to the perilymphatic compartment was quick and extensive after an i.v. bolus injection in guinea pigs. Unfortunately, this way of administration of thiosulfate in connection with systemic cisplatin delivery is risky, since it may lead to decreased antitumoral effects due to inactivation of cisplatin and MHC not only in the cochlea but also in tumor tissues. In the studies on which Paper III is based, it was found that the ototoxicity in cisplatin-treated guinea pigs was reduced by a local administration strategy employing a thiosulfate-containing hyaluronan gel administered into the middle ear cavity three hours prior to the systemic cisplatin injection. When quantifying cisplatin, unselective methods are almost always used, which may confound the results. In the final study, on which Paper IV is based, a sensitive, robust, and fast method using liquid chromatography and UV detection for the selective analysis of cisplatin in blood was developed. This method will be a valuable instrument in future studies exploring the role of pharmacokinetic parameters of cisplatin for the ototoxic effects

Subjective and Clinically Assessed Hearing Loss; A Cross-Sectional Register-Based Study on a Swedish Population Aged 18 through 50 Years

Objectives Questionnaire studies suggest that hearing is declining among young adults. However, few studies have examined the reliability of hearing questionnaires among young adult subjects. This study examined the associations between pure tone audiometrically assessed (PTA) hearing loss and questionnaire responses in young to middle aged adults. Materials and Methods A cross-sectional study using questionnaire and screening PTA (500 through 6000 Hz) data from 15322 Swedish subjects (62% women) aged 18 through 50 years. PTA hearing loss was defined as a hearing threshold above 20 dB in both ears at one or more frequencies. Data were analysed with chi-square tests, nonlinear regression, binary logistic regression, and the generalized estimating equation (GEE) approach. Results The prevalence of PTA hearing loss was 6.0% in men and 2.9% in women (p < 0.001). Slight hearing impairment was reported by 18.5% of the men and 14.8% of the women (p < 0.001), whereas 0.5% of men and women reported very impaired hearing. Using multivariate GEE modelling, the odds ratio of PTA hearing loss was 30.4 (95% CI, 12.7-72.9) in men and 36.5 (17.2-77.3) in women reporting very impaired hearing. The corresponding figures in those reporting slightly impaired hearing were 7.06 (5.25-9.49) in men and 8.99 (6.38-12.7) in women. These values depended on the sound stimulus frequency (p = 0.001). The area under the ROC curve was 0.904 (0.892-0.915) in men and 0.886 (0.872-0.900) in women. Conclusions Subjective hearing impairment predicted clinically assessed hearing loss, suggesting that there is cause for concern as regards the future development of hearing in young to middle-aged people

Self-reported hearing difficulties, main income sources, and socio-economic status; a cross-sectional population-based study in Sweden

BACKGROUND: Hearing difficulties constitute the most common cause of disability globally. Yet, studies on people with hearing difficulties regarding socio-economic status (SES), work, long-term unemployment, sickness absence, and disability pension are scarce. The aim of the present study was to investigate the main income sources of men and women of working ages with and without self-reported hearing difficulties and associations with gender, age, SES, type of living area, and country of birth. METHODS: A cross-sectional population-based study, using information on self-reported hearing difficulties and SES of 19 045 subjects aged 20-64 years participating in Statistics Sweden's annual Living Conditions Surveys in any of the years 2004 through 2008. The information was linked to a nationwide database containing data on demographics and income sources. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated, using binary logistic regression analysis. RESULTS: Hearing difficulties increased with age and were more common in men (age-adjusted OR: 1.42 (95% CI: 1.30-1.56)) with an overall prevalence of 13.1% in men and 9.8% in women. Using working men as reference, the OR of having hearing difficulties was 1.23 (0.94-1.60) in men with unemployment benefits and 1.36 (1.13-1.65) in men with sickness benefits or disability pension, when adjusting for age and SES. The corresponding figures in women were 1.59 (1.17-2.16) and 1.73 (1.46-2.06). The OR of having sickness benefits or disability pension in subjects with hearing difficulties was 1.36 (1.12-1.64) in men and 1.70 (1.43-2.01) in women, when adjusting for age and SES and using men and women with no hearing difficulties as reference. CONCLUSIONS: Hearing difficulties were more prevalent in men. After adjustment with age and SES as well as with type of living area and country of birth, a significant association with unemployment benefits was found only in women, and the associations with long-term sickness absence and disability pension tended to be stronger in women

Self-reported hearing difficulties, main income sources, and socio-economic status; a cross-sectional population-based study in Sweden

BACKGROUND: Hearing difficulties constitute the most common cause of disability globally. Yet, studies on people with hearing difficulties regarding socio-economic status (SES), work, long-term unemployment, sickness absence, and disability pension are scarce. The aim of the present study was to investigate the main income sources of men and women of working ages with and without self-reported hearing difficulties and associations with gender, age, SES, type of living area, and country of birth. METHODS: A cross-sectional population-based study, using information on self-reported hearing difficulties and SES of 19 045 subjects aged 20-64 years participating in Statistics Sweden's annual Living Conditions Surveys in any of the years 2004 through 2008. The information was linked to a nationwide database containing data on demographics and income sources. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated, using binary logistic regression analysis. RESULTS: Hearing difficulties increased with age and were more common in men (age-adjusted OR: 1.42 (95% CI: 1.30-1.56)) with an overall prevalence of 13.1% in men and 9.8% in women. Using working men as reference, the OR of having hearing difficulties was 1.23 (0.94-1.60) in men with unemployment benefits and 1.36 (1.13-1.65) in men with sickness benefits or disability pension, when adjusting for age and SES. The corresponding figures in women were 1.59 (1.17-2.16) and 1.73 (1.46-2.06). The OR of having sickness benefits or disability pension in subjects with hearing difficulties was 1.36 (1.12-1.64) in men and 1.70 (1.43-2.01) in women, when adjusting for age and SES and using men and women with no hearing difficulties as reference. CONCLUSIONS: Hearing difficulties were more prevalent in men. After adjustment with age and SES as well as with type of living area and country of birth, a significant association with unemployment benefits was found only in women, and the associations with long-term sickness absence and disability pension tended to be stronger in women

Hydrogen Gas Inhalation Attenuates Acute Impulse Noise Trauma : A Preclinical In Vivo Study

Objective: Molecular hydrogen (H2) has shown therapeutic potential in several oxidative stress-related conditions in humans, is well-tolerated, and is easily administered via inhalation.The aim of this preclinical in vivo study was to investigate whether impulse noise trauma can be prevented by H2 when inhaled immediately after impulse noise exposure. Methods: Guinea pigs (n = 26) were subjected to impulse noise (n = 400; 156 dB SPL; 0.33/s; n = 11; the Noise group), to impulse noise immediately followed by H2 inhalation (2 mol%; 500 ml/min; 1 hour; n = 10; the Noise + H2 group), or to H2 inhalation (n = 5; the H2 group). The acoustically evoked ABR threshold at 3.15, 6.30, 12.5, 20.0, and 30.0 kHz was assessed before and 4 days after impulse noise and/or H2 exposure. The cochleae were harvested after the final ABR assessment for quantification of hair cells. Results: Noise exposure caused ABR threshold elevations at all frequencies (median 35, 35, 30, 35, and 35 dB SPL, the Noise group; 20, 25, 10, 13, and 20 dB SPL, the Noise + H2 group; P < .05) but significantly less so in the Noise + H2 group (P < .05). Outer hair cell (OHC) loss was in the apical, mid, and basal regions 8.8%, 53%, and 14% in the Noise group and 3.5%, 22%, and 1.2% in the Noise + H2 group. The corresponding inner hair cell (IHC) loss was 0.1%, 14%, and 3.5% in the Noise group and 0%, 2.8%, and 0% in the Noise + H2 group. The difference between the groups was significant in the basal region for OHCs (P = .003) and apical (P = .033) and basal (P = .048) regions for IHCs. Conclusions: Acute acoustic trauma can be reduced by H2 when inhaled immediately after impulse noise exposure

Inhalation of Molecular Hydrogen, a Rescue Treatment for Noise-Induced Hearing Loss

Noise exposure is the most important external factor causing acquired hearing loss in humans, and it is strongly associated with the production of reactive oxygen species (ROS) in the cochlea. Several studies reported that the administration of various compounds with antioxidant effects can treat oxidative stress-induced hearing loss. However, traditional systemic drug administration to the human inner ear is problematic and has not been successful in a clinical setting. Thus, there is an urgent need to develop rescue treatment for patients with acute acoustic injuries. Hydrogen gas has antioxidant effects, rapid distribution, and distributes systemically after inhalation.The purpose of this study was to determine the protective efficacy of a single dose of molecular hydrogen (H-2) on cochlear structures. Guinea pigs were divided into six groups and sacrificed immediately after or at 1 or 2 weeks. The animals were exposed to broadband noise for 2 h directly followed by 1-h inhalation of 2% H-2 or room air. Electrophysiological hearing thresholds using frequency-specific auditory brainstem response (ABR) were measured prior to noise exposure and before sacrifice. ABR thresholds were significantly lower in H-2-treated animals at 2 weeks after exposure, with significant preservation of outer hair cells in the entire cochlea. Quantification of synaptophysin immunoreactivity revealed that H-2 inhalation protected the cochlear inner hair cell synaptic structures containing synaptophysin. The inflammatory response was greater in the stria vascularis, showing increased Iba1 due to H-2 inhalation.Repeated administration of H-2 inhalation may further improve the therapeutic effect. This animal model does not reproduce conditions in humans, highlighting the need for additional real-life studies in humans

Improving clinical outcomes in cochlear implantation using glucocorticoid therapy: A review

Cochlear implant surgery is a successful procedure for auditory rehabilitation of patients with severe to profound hearing loss. However, cochlear implantation may lead to damage to the inner ear, which decreases residual hearing and alters vestibular function. It is now of increasing interest to preserve residual hearing during this surgery because this is related to better speech, music perception, and hearing in complex listening environments. Thus, different efforts have been tried to reduce cochlear implantation-related injury, including periprocedural glucocorticoids because of their anti-inflammatory properties. Different routes of administration have been tried to deliver glucocorticoids. However, several drawbacks still remain, including their systemic side effects, unknown pharmacokinetic profiles, and complex delivery methods. In the present review, we discuss the role of periprocedural glucocorticoid therapy to decrease cochlear implantation-related injury, thus preserving inner ear function after surgery. Moreover, we highlight the pharmacokinetic evidence and clinical outcomes which would sustain further interventions

Age distribution of the study population stratified by sex.

<p>Age distribution of the study population stratified by sex.</p

Prevalence of a pure tone hearing threshold above 20 dB in both ears versus age, stratified by frequency and sex.

<p>Prevalence of a pure tone hearing threshold above 20 dB in both ears versus age, stratified by frequency and sex.</p