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Drug exposure and clinical effect of transdermal mirtazapine in healthy young cats: a pilot study
Objectives The objective of this study was to measure drug exposure and clinical effects after administration of transdermal mirtazapine (TMZ) in healthy cats. Methods Phase I: seven healthy research cats received (1) 3.75 mg and 7.5 mg TMZ once aurally with 48 h serum sampling (serum samples were obtained via the jugular catheter at 0, 0.5, 1, 2, 5, 9, 12, 24, 36 and 48 h); (2) 7.5 mg TMZ and placebo daily aurally for 6 days then 48 h serum sampling; (3) 1.88 mg mirtazapine orally once with serum sampling at 1, 4 and 8 h. Phase II: 20 client-owned cats were enrolled in a randomized, double-blind, placebo-controlled, three-way crossover clinical effect study. Treatments consisted of 6 days of aural 7.5 mg TMZ or placebo gel at home, and 1.88 mg mirtazapine orally once in the clinic. Owners documented appetite, rate of food ingestion, begging activity and vocalization daily at home. On day 6, food consumed, activity and vocalization were documented in hospital, and trough and peak serum mirtazapine levels were obtained. Serum mirtazapine and gel concentrations were measured using liquid chromatography/tandem mass spectrometry. Results Phase I: administration of TMZ achieved measureable serum mirtazapine concentrations. Area under the curve0-48 of multidose 7.5 mg TMZ was significantly higher than single-dose 1.88 mg oral mirtazapine (OMZ) ( P = 0.02). Phase II: client-owned cats administered TMZ had a significant increase in appetite ( P = 0.003), rate of food ingestion ( P = 0.002), activity ( P = 0.002), begging ( P = 0.002) and vocalization ( P = 0.002) at home. In hospital there was a significant increase in food ingested with both TMZ and OMZ compared with placebo ( P <0.05). Gel concentrations ranged from 87%-119% of target dose. Conclusions and relevance TMZ 7.5 mg daily achieves measureable serum concentrations and produces significant appetite stimulation despite variance in compounded gel concentrations, but side effects denote a lower dose is indicated
Neuroprotective Efficacy and Pharmacokinetic Behavior of Novel Anti-Inflammatory Para-Phenyl Substituted Diindolylmethanes in a Mouse Model of Parkinson's Disease s
ABSTRACT There are currently no registered drugs that slow the progression of neurodegenerative diseases, in part because translation from animal models to the clinic has been hampered by poor distribution to the brain. The present studies examined a selected series of para-phenyl-substituted diindolylmethane (C-DIM) compounds that display anti-inflammatory and neuroprotective efficacy in vitro. We postulated that the pharmacokinetic behavior of C-DIM compounds after oral administration would correlate with neuroprotective efficacy in vivo in a mouse model of Parkinson's disease. Pharmacokinetics and metabolism of 1,1-bis(39-indolyl)-1-(p-methoxyphenyl)methane (C-DIM5), 1,1-bis(39-indolyl)-1-(phenyl)methane, 1,1-bis(39-indolyl)-1-(p-hydroxyphenyl)methane (C-DIM8), and 1,1-bis(39-indolyl)-1-(p-chlorophenyl)methane (C-DIM12) were determined in plasma and brain of C57Bl/6 mice after oral and intravenous administration at 10 and 1 mg/Kg, respectively. Putative metabolites were measured in plasma, liver, and urine. C-DIM compounds given orally displayed the highest area under the curve, C max , and T max levels, and C-DIM12 exhibited the most favorable pharmacokinetics of the compounds tested. Oral bioavailability of each compound ranged from 6% (C-DIM8) to 42% (C-DIM12). After pharmacokinetic studies, the neuroprotective efficacy of C-DIM5, C-DIM8, and C-DIM12 (50 mg/Kg per oral) was examined in mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid for 14 days, a model of progressive neurodegeneration with a strong neuroinflammatory component. C-DIM5 and C-DIM12 given orally once daily after one week of exposure to MPTP and probenecid prevented further loss of dopaminergic neurons in the substantia nigra pars compacta and striatal dopamine terminals, indicating that these compounds could be effective therapeutic agents to prevent neurodegeneration