We have previously shown that adenosine amine congener (ADAC), a selective A 1 adenosine receptor agonist, can ameliorate noise- and cisplatin-induced cochlear injury. Here we demonstrate the dose-dependent rescue effects of ADAC on noise-induced cochlear injury in a rat model and establish the time window for treatment. Methods . ADAC (25–300 μg/kg) was administered intraperitoneally to Wistar rats (8–10 weeks old) at intervals (6–72 hours) after exposure to traumatic noise (8–16 kHz, 110 dB sound pressure level, 2 hours). Hearing sensitivity was assessed using auditory brainstem responses (ABR) before and 12 days after noise exposure. Pharmacokinetic studies investigated ADAC concentrations in plasma after systemic (intravenous) administration. Results . ADAC was most effective in the first 24 hours after noise exposure at doses>50 μg/kg, providing up to 21 dB protection (averaged across 8–28 kHz). Pharmacokinetic studies demonstrated a short (5 min) half-life of ADAC in plasma after intravenous administration without detection of degradation products. Conclusion . Our data show that ADAC mitigates noise-induced hearing loss in a dose- and time-dependent manner, but further studies are required to establish its translation as a clinical otological treatment.
Dapsone undergoes N-acetylation to monoacetyl dapsone as well as N-hydroxylation to a hydroxylamine which is responsible for the haemotoxicity (i.e. methaemoglobinaemia; Met Hb) of the drug. Since dapsone is always given chronically, we have investigated the ability of cimetidine to inhibit Met Hb formation caused by repeated dapsone administration. The drug was given (i.p.) to four groups (n = 6 per group) of male Wistar rats, 300-360 g. Group I received 10 mg kg-1 at 1, 24, 48 and 72 h. Group II received 10 mg kg-1 at 1, 8, 24, 32, 48, 56, 72 and 80 h. Groups III and IV received the drug as for groups I and II, respectively, as well as cimetidine (50 mg kg-1) 1 h before each dose of dapsone. Twice daily dapsone administration (Group II) resulted in a significantly greater (P less than 0.05) Met Hb AUC (757 +/- 135 vs 584 +/- 115% Met Hb h), dapsone AUC (140 +/- 17.5 vs 113 +/- 13.0 micrograms h mL-1) and monoacetyl dapsone AUC (48.2 +/- 18.3 vs 10.8 +/- 4.6 micrograms h mL-1) compared with a single daily dapsone dose (group I). The administration of cimetidine before the once daily dose of dapsone (group III) resulted in a significant (P less than 0.05) fall in Met Hb (302 +/- 179 vs 584 +/- 115% Met Hb h) and an increase in both the dapsone (151 +/- 22.2 vs 113 +/- 13.0 micrograms h mL-1) and monoacetyl dapsone AUC values (33.6 +/- 5.8 vs 10.8 +/- 4.0 micrograms h mL-1) compared with a single daily dose of dapsone (group I).(ABSTRACT TRUNCATED AT 250 WORDS)
Forensic pathology is remarkably under-represented in research: considering the obstacles a researcher must overcome to obtain post-mortem tissue for research, it is perhaps not surprising. We are investigating whether there is any role for altered drug metabolism in potentially fatal clozapine-associated myocarditis and/or cardiomyopathy. As part of this research, the use of post-mortem tissue taken during a coronial autopsy from individuals who have died from, or with, these clozapine-associated cardiotoxicities was considered fundamental. Currently, there is no clear pathway for using coronial post-mortem tissue for research in New Zealand. We have worked through the Coroners Act 2006 NZ, the Human Tissue Act 2008 NZ and the medico-legal death investigation process in New Zealand to use coronial post-mortem tissue for research. The process to obtaining tissue(s) in New Zealand is probably representative of pathways in other coronial systems.
The dinitrobenzamide mustards are a class of bioreductive nitro-aromatic anticancer prodrugs, of which a phosphorylated analog (PR-104) is currently in clinical development. They are bioactivated by tumor reductases to form DNA cross-linking cytotoxins. However, their biotransformation in normal tissues has not been examined. Here we report the aerobic in vitro metabolism of three N-(2 hydroxyethyl)-3,5-dinitrobenzamide 2-mustards and the corresponding nonmustard analog in human, mouse, rat, and dog hepatic S9 preparations. These compounds have a range of mustard structures (–N(CH2CH2X)2 where X = H, Cl, Br, or OSO2Me). Four metabolic routes were identified: reduction of either nitro group, N-dealkylation of the mustard, plus O-acetylation, and O-glucuronidation of the hydroxyethyl side chain. Reduction of the nitro group ortho to the mustard resulted in intramolecular alkylation and is considered to be an inactivation pathway, whereas reduction of the nitro group para to the mustard generated potential DNA cross-linking cytotoxins. N-Dealkylation inactivated the mustard moiety but may result in the formation of toxic acetaldehyde derivatives. Increasing the size of the nitrogen mustard leaving group abrogated the ortho-nitroreduction and N-dealkylation routes and thereby improved overall metabolic stability but had little effect on aerobic para-nitroreduction. All four compounds underwent O-glucuronidation of the hydroxyethyl side chain and further studies to elucidate the relative importance of this pathway in vivo are in progress.
Purpose: This work investigated the utility of circulating microRNA (miRNA) as biomarkers of clozapine (CLZ)-induced cardiotoxicities: serious adverse events with an unusually high incidence in Australia and New Zealand.Methods: Global plasma miRNA expression was analysed by microarray in patients taking CLZ, to investigate differential expression between CLZ-induced cardiotoxicity cases (n = 6) and matched control patients (n = 12). The results were validated by RT-qPCR using a panel of 17 miRNA, and their expression was examined in both CLZ-naïve healthy volunteers (n = 12) and an expanded cohort of CLZ-taking patients (n = 21). Temporal changes were also examined in two healthy volunteers and two CLZ-induced cardiotoxicity patients.Results: No miRNA were differentially expressed between cases of CLZ-induced cardiotoxicity and control patients. Circulating levels of several miRNA were significantly altered in CLZ-taking patients compared to healthy volunteers, with miR-16-5p, miR-25-3p, miR-92a-3p, miR-320a-3p, and miR-486-3p upregulated and miR-22-3p, miR-126-3p, and miR-142-3p downregulated in the patients. Five of these (miR-16-5p, miR-22-3p, miR-92a-3p, miR-126-3p, miR-142-3p) were stably expressed over time in both CLZ-induced cardiotoxicity patients and CLZ-naïve healthy volunteers.Conclusions: Plasma miRNA are not useful biomarkers of CLZ-induced cardiotoxicity, however patients taking CLZ have significantly altered circulating miRNA compared to healthy volunteers.
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