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Cochlear pharmacokinetics of cisplatin: An in vivo study in the guinea pig – Hellberg –


Cochlear pharmacokinetics of cisplatin: An in vivo study in the guinea pig - Hellberg -

Transient receptor potential vanilloid 1 (TRPV1) is an ion channel present on sensory neurons which is activated by heat, protons, capsaicin and a variety of endogenous lipids termed endovanilloids. Recent studies have demonstrated that the pathogenesis of NIHL is closely related to ischemia-reperfusion injury of cochlea, which is caused by blood flow decrease and free radical production due to excessive noise. In all, 169 cisplatin-treated survivors of TC provided blood samples at Survey I and reported NTX during Survey I (1998-2002) and Survey II (2007-2008). Two daily doses of up to 100mg/kg/day of D-met for 18 days. The elevations were mostly at higher frequencies (3000, 4000, 6000, 8000, 9000, 10 000, 11 200, and 12 500 Hz), and did not affect speech perception. As a young boy growing up in New York City in the late 1950s, Don Caspary tinkered with the family’s primitive television set to improve reception. Care and use of the animals reported in this study was approved in accordance with ethical standards at Karolinska Institutet and was consistent with national regulations for care and use of the animal (Ethical permits N 372/08).

The main objective was to aspirate ST perilymph, blood, and CSF from every animal within the same target time. Weekly administration of cisplatin has extensively been studied at our institution in a range of prospective clinical trials (Planting et al, 1993, 1994, 1995a, 1995b, 1997a, 1997b; van der Burg et al, 1998; van den Bent et al, 1999, 2002). In view of advances in early detection, supportive care, and treatment, the 5-year relative survival rate for all cancer patients combined is now approximately 66% (1). The current study suggests that administration of drugs that modulate dopamine do not alter the encoding temporal durations but do acutely affect the initiation of responding. CDDP primarily damages the outer and inner hair cells, induces degeneration of the stria vascularis, and remarkably reduces the number of spiral ganglion cells.4 In such cases, CDDP often causes irreversible sensorineural hearing loss and serious tinnitus in humans, mice, and other animals.5 Approximately 23–54% of adults and>50% of pediatric patients with head and neck cancer treated with CDDP develop ototoxicity.6 In addition to serving as the organ of hearing, the ears have a significant role in the control of balance. Future work should focus on the creation of a new psychometrically sound instrument for hearing outcomes in this population. Hence, the use of prophylactic antioxidants during recreational noise is unclear.

Atropine was given subcutaneously to reduce mucus in the airways and bupivacaine was administrated for local anaesthesia. Durante le prime 24 ore veniva evidenziato un recupero di circa 20 dB fino a raggiungere una elevazione di soglia di 50-70 dB; non venivano registrate ulteriori modificazioni nella settimana seguente. The patient was fit with traditional amplification and received appropriate auditory training and speech and language therapy. The right jugular vein was catheterized along the venous flow toward the heart and used for i.v. Also, he was having the smaller weekly doses of cisplatin by the time he got to radiation treatment. The left jugular vein was catheterized against the venous flow and used for blood sampling. Studies with lymphoma cells suggest that DMSO concentrations of 1−2% prevent apoptosis whereas higher concentrations induces apoptosis (Lin et al., 1995).

Therefore our classification showed a better suitability for monitoring hearing loss than the other classifications. Bepridil The serum concentration of Cisplatin can be increased when it is combined with Bepridil. Induction of Hsp70, the major inducible heat shock protein, is often used to assess activation of the heat shock response. The construction of a silicone cup on the apical part of the cochlea was previously described.[16] Clear ST perilymph was slowly filling up the silicone cup. Samples were handled and stored as described previously.[15] Liquid chromatography with postcolumn derivatization was used to determine the concentration of cisplatin and to analyze the monohydrated complex of cisplatin, MHC.[21] All samples were stored at −80°C until analysis, which occurred within 3 weeks. For descriptive data mean ± SD was used. Our previous studies have shown that ADAC can attenuate noise-induced hearing loss and ameliorate cochlear injury in instances of acute and extended noise exposure[22].

Differences for which P values were 0.05 or less were considered to be statistically significant. The mean time to aspirate 1 μl of ST perilymph from the cochlear base was about 30 seconds. Before definitive conclusions on the prevalence and associated risk factors of platinum-induced ototoxicity can be made, more high-quality research is needed. Figure 1 shows the pharmacokinetic profile and Table 1 summarizes the concentrations of cisplatin in blood-UF, CSF, and ST perilymph 10 to 30 minutes after i.v. injection. The maximum concentration of cisplatin in blood-UF is seen at 10 minutes, and after 30 minutes there is a 42% reduction. Quaranta A, Portalatini P, Henderson D.

Cochlear pharmacokinetics of cisplatin: An in vivo study in the guinea pig - Hellberg -
Whole blood EDTA samples were collected from the TCSs, lymphocyte-DNA extracted, and submitted to genetic analyses of functional polymorphisms in the genes coding for GSTT1, -M1, and -P1. At 10 minutes there is a significantly lower concentration in apex compared to the base (P = 0.02). Cisplatin in the apex increases significantly already at 20 minutes (P = 0.03). No difference in cisplatin concentration in the cochlear base and apex can be observed at 30 minutes (P = 0.79). The concentration of cisplatin is significantly lower in CSF compared to ST perilymph aspirated from the base of the cochlea at all target times. Cisplatin concentrations in blood-UF and CSF did not differ between animals in group Ia and Ib (only significant different cisplatin concentrations in blood-UF at 20 min.). The unconditioned stimulus was a 3.7 mA electric foot-shock presented for up to 30 seconds, as described by Guitton’s protocol [2], by adjusting the electric voltage with fixed copper wire resistance on the floor.

Figure 2 shows a more detailed presentation of the pharmacokinetic profile of cisplatin in the sequential perilymph samples aspirated from the cochlear apex. The time for sampling capillaries 1 through 10 was 5.08 ± 1.26 minutes. At 10 minutes there is a significant difference in concentration gradient between sample number 1 and the mean of sample numbers 4 and 5 (P = 0.02). This gradient is absent at 20 and 30 minutes (P = 0.98, P = 0.57, respectively). At the end of the study period, a total of 51 patients who received cisplatin-based chemotherapy were monitored for adverse reactions till their discharge from hospital. Establishing the optimal ototoxic dose of cisplatin. A significant difference in concentration is seen at 10 and 20 minutes (P = 0.01, P = 0.02, respectively).

Since lactate is a part of Ringer solution, safely used in human subjects, and has the smallest molecular weight among other antioxidants which facilitates transport across the round window membrane, a further study was conducted to prove its otoprotective effect against cisplatin ototoxicity when injected intratympanically, before intraperitoneal cisplatin administration. Late phase changes in cisplatin concentration demonstrate delayed elimination of cisplatin from the base of the cochlea. Figure 3 shows the pharmacokinetic profile of cisplatin in blood-UF, CSF, and ST perilymph aspirated from the basal turn of the right cochlea 30 to 120 minutes after cisplatin was given. showed that sertraline seems to have a protective effect on cisplatin ototoxicity, and could be used to prevent the ototoxicity and also to treat the depression that occurred in cancer patients together. Figure 4 shows an increase in ST perilymph/blood-UF ratio of cisplatin after 60 minutes, displaying slow elimination of cisplatin from ST perilymph. The ratio between ST perilymph and blood-UF concentration increases from 0.4 to 5.8 during the sampling period (30–120 min.). High frequency audiometric thresholds are initially affected.

At 60 minutes, the concentrations of cisplatin in ST perilymph and blood-UF were similar. i.v. Cisplatin and gemcitabine pharmacokinetics were studied for all schedules. Seventeen samples of ST perilymph aspirated from the basal turn of the left cochlea of group II animals were analyzed for the concentration of MHC. All samples had a concentration of MHC below the level of detection (1 μM). In the present study, the pharmacokinetic profile of cisplatin in ST perilymph along the cochlear duct is shown for the first time. By using two different techniques to sample ST perilymph, cisplatin could be analyzed both from the basal turn and the apex of the cochlea within approximately the same target time.

Enhanced early transport to the basal ST perilymph was displayed; the concentration of cisplatin in the ST perilymph at the base of the cochlea was more than four-fold higher than the concentration of cisplatin in apical samples at 10 minutes. This difference might reflect a difference in uptake of cisplatin from blood to ST perilymph, that is, transport mechanisms involving a blood-perilymph barrier along the cochlear duct. After 30 minutes, an equivalent concentration of cisplatin was seen in the base and apex of the cochlea. We found no correlation between age and hearing loss or between baseline hearing level and cisplatin-induced hearing loss. With the use of a sequential sampling technique to aspirate ST perilymph from the apex of the cochlea, a gradient of cisplatin in ST perilymph could be further studied during the distribution phase to the deeper compartments of the cochlea. The tip impedance of each electrode was 0.4 MΩ. A limitation of the study was the obvious risk of CSF contamination to the ST perilymph aspirated from the base of the cochlea.

It has been documented that 1 μl of ST-perilymph aspirated from the basal turn has a 15% contamination of CSF.[37] This study, which shows a lower concentration of cisplatin in CSF compared to ST perilymph sampled from the basal turn, excludes a false, too high concentration of cisplatin in the cisplatin basal ST perilymph results. It can be speculated, if the initial high concentration of cisplatin in the basal turn that gives a longer exposition time to high levels of the drug might favor the loss of OHC in the base of the cochlea. Signal averaging was carried out after 500 presentations of either 100 microsecond alternating polarity clicks or 5 msec pure-tone bursts (1 msec rise/fall) of 8, 16 and 32 kHz delivered at a rate of 21/sec. The basolateral parts of the OHCs are connected to the perilymphatic compartment,[40] and the uptake of cisplatin to OHCs is believed in part to be mediated via transport proteins.[22] The most studied transport proteins in relation to cisplatin ototoxicity are the membrane protein organic cation transporters (OCTs)[41] and the copper transporter (Ctrl).[42, 43] In an attempt to display the concentration of the more toxic biotransformation product MHC in ST perilymph, a total of 17 samples were analyzed. The concentration of MCH in ST perilymph was below the level of detection in all samples. The DCN was uncovered as described in a previous study (Finlayson and Kaltenbach 2009). Nevertheless, it cannot be excluded that even the low level of MHC in ST perilymph can be involved in the ototoxic side effect of cisplatin.

One microgram of total RNA was converted to cDNA using an iScript cDNA Synthesis Kit (Bio-Rad, Hercules, CA). Such treatment might be given locally to the inner ear, and several ways of administration have been evaluated.[49] Two findings from the present study can be of interest for developing a novel therapeutic approach to protect against cisplatin ototoxicity. First, OHCs in the base of the cochlea have a longer exposition time to high concentrations of cisplatin compared to OHCs in the apex. Second, elimination of cisplatin from ST perilymph is slower compared to the clearance of the drug from the blood. Equalization to correct for the system response was performed on the digital waveforms in the frequency domain. Although compared with Group 1 (50 mg/m 2 ), less increase in the hearing threshold was observed at a frequency but ototoxic effect was widespread at 80 mg/m 2 . Cisplatin could be analyzed in ST perilymph up to 120 minutes after administration, and delayed elimination of the drug from ST perilymph compared to blood was observed.