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. A high performance liquid chromatography-ultraviolet (HPLC-UV) method was developed and validated for analysis of Tabex® and nicotine-free oral strips, two commercial products containing cytisine. A sensitive liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for the quantification of cytisine in human plasma and for the detection of cytisine in urine. Single-dose pharmacokinetics of cytisine was studied in healthy smokers. Subjects received a single 3 mg oral dose administration of cytisine. Cytisine was detected in all plasma samples collected after administration, including 15 min post-dose and at 24 h. Cytisine was renally excreted and detected as an unchanged drug. No metabolites were detected in plasma or urine collected in the study. No adverse reactions were reported.

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.Methods: Thirty subjects undergoing functional endoscopic sinus surgery for CRS were randomized to one of three groups: (1) doxycycline (100 mg daily for 7 days); (2) roxithromycin (300 mg daily for 7 days); and (3) control (no antibiotics given). Sinonasal and stool samples collected before and after treatment were analyzed using 16S ribosomal RNA (rRNA) gene-targeted amplicon sequencing and Droplet Digital polymerase chain reaction (PCR) for bacterial community composition and the quantification of bacterial DNA, respectively.Results: There were no significant major bacterial community shifts or changes to bacterial diversity and load following the treatment period in all patient groups. Non-significant trend reductions were observed in gut microbial diversity with antibiotics. For the roxithromycin group, sinonasal bacterial diversity was negatively correlated with serum drug levels and reduced overall compared to controls (p < 0.05). The relative abundance of Staphylococcus ASV129 in sinonasal samples reduced with increasing mucus doxycycline levels (p = 0.01). Conclusion:Antibiotic prescription for CRS should be further investigated because of preliminary evidence of poor sinonasal drug penetration, unproven efficacy, and the potential impact of dysbiosis in the sinuses and off-target sites. Further studies should consider distinguishing the presence of DNA from viable and nonviable bacteria.

1. Cytisine, a partial agonist for the α 4 β 2 -nAChR, is used as a smoking cessation medication. Cytisine's current dosing is complex and involves taking 1.5 mg several times a day. The aim of this study was to explore the effect of dose on the pharmacokinetics and safety of cytisine after a single dose in healthy adult smokers.A c c e p t e d M a n u s c r i p t 2. Participants were assigned to one of three groups (n=6 in each group) to receive a single oral dose of 1.5, 3 or 4.5 mg of cytisine. Blood samples were collected up to 24 hours post dose. Pulse, blood pressure and respiratory rate were measured. Adverse effects were recorded.3. Cytisine reached peak plasma concentration 1 -2 hours post dose in all participants irrespective of dose, with no dose-dependent changes in the elimination phase. Mean (SD) cytisine exposure (AUC 0-24h ) were 81.9 (15.8), 181.9 (40.8) and 254.5 (48.1) ng.h/mL following 1.5, 3 and 4.5 mg respectively.4. Cytisine appears to have predictable pharmacokinetics following a single dose of up to 4.5 mg and may be safe given as a single 4.5 mg dose, which is 3-fold greater than the recommended dose taken at one time. This study is registered in ClinicalTrials.gov (ID:NCT02585024).

Performance of cystatin C-eGFR was superior to creatinine-based GFR in patients with Type 2 diabetes with HbA(1c) >95 mmol/mol (10.8%).

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