A pharmacokinetic framework describing antibiotic adsorption to cardiopulmonary bypass devices.

Cardiopulmonary bypass (CPB) can alter pharmacokinetic (PK) parameters and the drug may adsorb to the CPB device, altering exposure. Cefazolin is a beta-lactam antibiotic used for antimicrobial prophylaxis during cardiac surgery supported by CPB. Adsorption of cefazolin could result in therapeutic failure.

CYP-catalysed cycling of clozapine and clozapine--oxide promotes the generation of reactive oxygen species .

Clozapine is an effective atypical antipsychotic indicated for treatment-resistant schizophrenia, but is under-prescribed due to the risk of severe adverse drug reactions such as myocarditis.A mechanistic understanding of clozapine cardiotoxicity remains elusive.This study aimed to investigate the contribution of selected CYP isoforms to cycling between clozapine and its major circulating metabolites, -desmethylclozapine and clozapine--oxide, with the potential for reactive species production.

Ethnic disparity in clozapine dosing and cardiotoxicity in New Zealand.

Aims: To investigate ethnic disparities in the treatment and incidence of cardiotoxicity for patients prescribed clozapine in New Zealand.

Methods: A post hoc analysis was undertaken using data from four studies investigating clozapine cardiotoxicities in New Zealand: two population studies (one prospective, one retrospective) conducted in the Auckland District Health Board (2011-2017), and two studies of coronial autopsy records (2001-2016). The relationship between ethnicity and cases (N=26) of myocarditis and/or cardiomyopathy was examined in comparison to non-cases in the rest of the study population (N=161).

Comparison of Sinus Deposition from an Aqueous Nasal Spray and Pressurised MDI in a Post-Endoscopic Sinus Surgery Nasal Replica.

Background: Optimising intranasal distribution and retention of topical therapy is essential for effectively managing patients with chronic rhinosinusitis, including those that have had functional endoscopic sinus surgery (FESS). This study presents a new technique for quantifying in vitro experiments of fluticasone propionate deposition within the sinuses of a 3D-printed model from a post-FESS patient.

Methods: Circular filter papers were placed on the sinus surfaces of the model.

Sinonasal and gastrointestinal bacterial composition and abundance are stable after 1 week of once-daily oral antibiotic treatment for chronic rhinosinusitis.

Background: Despite the widespread prescription of antibiotics for the treatment of chronic rhinosinusitis (CRS), their efficacy remains uncertain. Limited penetration of systemic antibiotics into the sinonasal mucosa has been reported previously by this group. This study aimed to investigate the short-term effects of antibiotics on the sinus and gut microbiota as well as any relationships these had with drug distribution.

Incidence and investigation of potential risk-factors for clozapine-associated myocarditis and cardiomyopathy in a New Zealand cohort.

Clozapine is a uniquely effective antipsychotic indicated for treatment-resistant schizophrenia. However, its use is underutilised and often delayed for years due to potential adverse reactions including myocarditis and cardiomyopathy. The purpose of this study was to conduct a retrospective review of the clinical records of patients initiating clozapine in the Auckland District Health Board (ADHB) region to determine the incidence of clozapine-associated myocarditis and cardiomyopathy and to identify potential risk factors associated with these cardiotoxicities.

Circulating microRNA as biomarkers of clozapine-induced cardiotoxicity.

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. Global plasma miRNA expression was analysed by microarray in patients taking CLZ, to investigate differential expression between CLZ-induced cardiotoxicity cases ( = 6) and matched control patients ( = 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 ( = 12) and an expanded cohort of CLZ-taking patients ( = 21).

Subcutaneous nicotine delivery via needle-free jet injection: A porcine model.

Subcutaneous delivery of nicotine was performed using a novel electrically-operated needle-free jet injector, and compared to hypodermic needle delivery in a porcine model. Nicotine was delivered as a single, one-milligram dose into the abdominal skin, formulated as a 50 microliter aqueous solution. Plasma levels of nicotine and cotinine, its main metabolite, were then monitored over 2 h, following which the injection site was excised for histological examination.

Ascending single dose pharmacokinetics of cytisine in healthy adult smokers.

1. Cytisine, a partial agonist for the αβ-nAChR, is used as a smoking cessation medication. Cytisine's current dosing is complex and involves taking 1.

Use of Coronial Post-mortem Tissue for Research in New Zealand.

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.

A systematic review of clozapine-induced myocarditis.

Background: Clozapine is an atypical antipsychotic that is beneficial to some patients who failed to have an adequate clinical response to other antipsychotic drugs. Its clinical use is limited due to several potentially fatal adverse reactions including myocarditis. Careful monitoring of patients on clozapine is required.

Plasma concentrations of cytisine, a commercially available plant-based alkaloid, in healthy adult smokers taking recommended doses for smoking cessation.

1. Cytisine is a plant alkaloid that is a partial agonist for the αβ -nAChRs and is used as an aid to smoking cessation. To date, there are no published data on cytisine concentrations in humans following multiple dosing.

Indirect regulation of CYP2C19 gene expression via DNA methylation.

1. Despite speculation that the CYP2C19 gene may contain CpG islands, there has been little direct assessment of the role for epigenetics in the regulation of this pharmacogene. The effect of 5-aza-2'-deoxycytidine (5azaDC), a DNA methyltransferase inhibitor, and trichostatin A (TSA), an inhibitor of histone deacetylases, on the expression of CYP2C19 and five of its known transcription factors (TF) has been assessed in cell lines derived from neoplastic liver and intestine.

Pharmacokinetic Properties of Adenosine Amine Congener in Cochlear Perilymph after Systemic Administration.

Noise-induced hearing loss (NIHL) is a global health problem affecting over 5% of the population worldwide. We have shown previously that acute noise-induced cochlear injury can be ameliorated by administration of drugs acting on adenosine receptors in the inner ear, and a selective A adenosine receptor agonist adenosine amine congener (ADAC) has emerged as a potentially effective treatment for cochlear injury and resulting hearing loss. This study investigated pharmacokinetic properties of ADAC in rat perilymph after systemic (intravenous) administration using a newly developed liquid chromatography-tandem mass spectrometry detection method.

Varenicline improves motor and cognitive deficits and decreases depressive-like behaviour in late-stage YAC128 mice.

Objective: Studies in the post mortem human brain and in genetic mouse model suggest that dysfunctional cholinergic neurotransmission, through a loss of agonist rather than receptors may be a significant contributing factor to HD pathology. If correct, pharmacological replacement may therefore be a potential treatment strategy. We have investigated whether chronic administration of the selective nicotinic partial agonist varenicline improved motor, cognitive and affective symptoms in a transgenic mouse model of Huntington's disease.

Varenicline improves motor and cognitive symptoms in early Huntington's disease.

The aim of this study was to describe the effects of varenicline, a smoking cessation aid that acts as a nicotinic agonist, on cognitive function in patients with early clinical Huntington's disease (HD) who were current smokers. Three gene-positive patients transitioning to symptomatic HD were evaluated using the Unified Huntington's Disease Rating Scale part I and III (motor and behavioral subscales) at baseline and after 4 weeks of treatment. Cognitive function was assessed using a touch screen computer-based neurocognitive test battery (IntegNeuro).

Adenosine amine congener as a cochlear rescue agent.

Unlabelled: We have previously shown that adenosine amine congener (ADAC), a selective A1 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).

Pharmacokinetics of cytisine, an α4 β2 nicotinic receptor partial agonist, in healthy smokers following a single dose.

Cytisine, an α4 β2 nicotinic receptor partial agonist, is a plant alkaloid that is commercially extracted for use as a smoking cessation medication. Despite its long history of use, there is very little understanding of the pharmacokinetics of cytisine. To date, no previous studies have reported cytisine concentrations in humans following its use as a smoking cessation agent.

Synthesis and methemoglobinemia-inducing properties of benzocaine isosteres designed as humane rodenticides.

A number of isosteres (oxadiazoles, thiadiazoles, tetrazoles and diazines) of benzocaine were prepared and evaluated for their capacity to induce methemoglobinemia-with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed within each series, with 1,2,4-oxadiazole 3 (metHb%=61.0±3.

Synthesis and methemoglobinemia-inducing properties of analogues of para-aminopropiophenone designed as humane rodenticides.

A number of structural analogues of the known toxicant para-aminopropiophenone (PAPP) have been prepared and evaluated for their capacity to induce methemoglobinemia--with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed for alkyl analogues of PAPP (aminophenones 1-20; compound 6 metHb% = 74.1 ± 2).