Sublingual administration of detomidine to calves prior to disbudding: a comparison with the intravenous route.

OBJECTIVE: To study the effects of oromucosal detomidine gel administered sublingually to calves prior to disbudding, and to compare its efficacy with intravenously (IV) administered detomidine. STUDY DESIGN: Randomised, prospective clinical study. ANIMALS: Twenty dairy calves aged 12.4 ± 4.4days (mean ± SD), weight 50.5 ± 9.0 kg. METHODS: Detomidine at 80 µg kg(-1) was administered to ten calves sublingually (GEL) and at 30 µg kg(-1) to ten control calves IV (V. jugularis). Meloxicam (0.5 mg kg(-1) ) and local anaesthetic (lidocaine 3 mg kg(-1) ) were administered before heat cauterization of horn buds. Heart rate (HR), body temperature and clinical sedation were monitored over 240 minutes. Blood was collected from the V. cephalica during the same period for drug concentration analysis. Pharmacokinetic variables were calculated from the plasma detomidine concentration-time data using non-compartmental methods. Statistical analyses compared routes of administration by Student's t-test and linear mixed models as relevant. RESULTS: The maximum plasma detomidine concentration after GEL was 2.1 ± 1.2 ng mL(-1) (mean ±SD) and the time of maximum concentration was 66.0 ± 36.9 minutes. The bioavailability of detomidine was approximately 34% with GEL. Similar sedation scores were reached in both groups after administration of detomidine, but maximal sedation was reached earlier in the IV group (10 minutes) than in the GEL group (40 minutes). HR was lower after IV than GEL from 5 to 10 minutes after administration. All animals were adequately sedated, and we were able to administer local anaesthetic without resistance to all of the calves before disbudding. CONCLUSIONS AND CLINICAL RELEVANCE: Oromucosally administered detomidine is an effective sedative agent for calves prior to disbudding.

Plasma drug concentrations and clinical effects of a peripheral alpha-2-adrenoceptor antagonist, MK-467, in horses sedated with detomidine.

OBJECTIVE: To investigate plasma drug concentrations and the effect of MK-467 (L-659'066) on sedation, heart rate and gut motility in horses sedated with intravenous (IV) detomidine. STUDY DESIGN: Experimental randomized blinded crossover study. ANIMALS: Six healthy horses. METHODS: Detomidine (10 µg kg(-1) IV) was administered alone (DET) and in combination with MK-467 (250 µg kg(-1) IV; DET + MK). The level of sedation and intestinal sounds were scored. Heart rate (HR) and central venous pressure (CVP) were measured. Blood was collected to determine plasma drug concentrations. Repeated measures anova was used for HR, CVP and intestinal sounds, and the Student's t-test for pairwise comparisons between treatments for the area under the time-sedation curve (AUCsed ) and pharmacokinetic parameters. Significance was set at p < 0.05. RESULTS: A significant reduction in HR was detected after DET, and HR was significantly higher after DET + MK than DET alone. No heart blocks were detected in any DET + MK treated horses. DET + MK attenuated the early increase in CVP detected after DET, but later the CVP decreased with both treatments. Detomidine-induced intestinal hypomotility was prevented by MK-467. AUCsed was significantly higher with DET than DET + MK, but maximal sedations scores did not differ significantly between treatments. MK-467 lowered the AUC of the plasma concentration of detomidine, and increased its volume of distribution and clearance. CONCLUSIONS AND CLINICAL RELEVANCE: MK-467 prevented detomidine induced bradycardia and intestinal hypomotility. MK-467 did not affect the clinical quality of detomidine-induced sedation, but the duration of the effect was reduced, which may have been caused by the effects of MK-467 on the plasma concentration of detomidine. MK-467 may be useful clinically in the prevention of certain peripheral side effects of detomidine in horses.

Characterization of the binding properties of SIRT2 inhibitors with a N-(3-phenylpropenoyl)-glycine tryptamide backbone.

SIRT2 inhibitors with a N-(3-phenylpropenoyl)-glycine tryptamide backbone were studied. This backbone has been developed in our group, and it is derived from a compound originally found by virtual screening. In addition, compounds with a smaller 3-phenylpropenoic acid tryptamide backbone were also included in the study. Binding modes for the new compounds and the previously reported compounds were analyzed with molecular modelling methods. The approach, which included a combination of molecular dynamics, molecular docking and cluster analysis, showed that certain docking poses were favourable despite the conformational variation in the target protein. The N-(3-phenylpropenoyl)-glycine tryptamide backbone is also a good backbone for SIRT2 inhibitors, and the series of compounds includes several potent SIRT2 inhibitors.

Oxadiazole-carbonylaminothioureas as SIRT1 and SIRT2 inhibitors.

A new inhibitor for human sirtuin type proteins 1 and 2 (SIRT1 and SIRT2) was discovered through virtual database screening in search of new scaffolds. A series of compounds was synthesized based on the hit compound (3-[[3-(4-tert-butylphenyl)1,2,4-oxadiazole-5-carbonyl]amino]-1-[3-(trifluoromethyl)phenyl]thiourea). The most potent compound in the series was nearly as potent as the reference compound (6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide).

N-(3-(4-Hydroxyphenyl)-propenoyl)-amino acid tryptamides as SIRT2 inhibitors.

A series of N-(3-(4-hydroxyphenyl)-propenoyl)-amino acid tryptamides was based on a previously reported new SIRT2 inhibitor from our group, and it was designed to study if the molecular size of the compound could be reduced. The most potent compounds, N-(3-(4-hydroxyphenyl)-propenoyl)-2-aminoisobutyric acid tryptamide and N-(3-(4-hydroxyphenyl)-propenoyl)-L-alanine tryptamide, were equipotent, 30% smaller in molecular weight, and slightly more selective (SIRT2/SIRT1) than the parent compound.