A quick approach for medetomidine enantiomer determination in dog plasma by chiral liquid chromatography-tandem mass spectrometry and application to a pharmacokinetic study.

In the present study, a rapid, sensitive and high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of medetomidine enantiomers in dog plasma was developed and validated. The separation and individual quantification of chiral compounds can be a tricky task in LC. This is particularly true when target analytes have a relatively small mass, as is the case with medetomidine, a potent and highly specific α2-adrenoceptor agonist widely used in both human and veterinary medicine. The proposed approach is based on a quick liquid-liquid extraction with ethyl acetate and filtration prior to injection. The optimized mobile phase composition allowed to perfectly separate the two enantiomers of medetomidine in a short chromatographic run time, using a cellulose tris(4-methylbenzoate)-based chiral column. A lower limit of quantification of 0.1 ng/mL was reached for both analytes thanks to the high sensitivity and selectivity of MS/MS and the use of racemic medetomidine-d3 as internal standard prevented potential matrix effect. Linearity was satisfying (R2  > 0.99) over the range 0.1-25 ng/mL, as well as within- and between-session accuracy and precision, both always <15%. This method was also applied with success to a series of samples from a pharmacokinetic (PK) study aimed at comparing dex- and levomedetomidine behaviour after administration of the racemic mixture in dogs. The simple extraction procedure, which allows reduced solvent and time consumption without compromising analytical performances, makes this technique a useful tool for this kind of applications even when small animals are involved, due to the small amount of sample required.

Medetomidine hydrochloride efficiency and safety in guinea pig (Cavia porcellus), in doses estimated through allometric extrapolation / Eficiência e segurança do cloridrato de medetomidina no cobaio (Cavia porcellus), em doses calculadas por extrapolação alométrica / Eficiencia y seguridad del clorhidrato de medetomidina en cobayo (Cavia porcellus), en dosis calculadas por extrapolación alométrica

In this study, medetomidine hydrochloride, an alfa2 adrenergic receptor agonist, was administered to five adult guinea pigs (three males and two females) to verify the efficiency and safety of using doses calculated by using an allometric scale. A surgical procedure was performed to insert a polyethylene cannula that advanced 2.0 to 2.5 cm into the left carotid artery until the aorta. A minimum recovery period of two days was observed before any other manipulation or pharmacological test were performed. The cannulas were washed every two days with heparinized saline flow and remained patent for two to three weeks after insertion. After surgery, each animal was placed in an open box measuring 45x25x20cm, in a quiet room with soft lighting. The “MS” group received exactly the allometrically calculated dose, while the “2MS” group received twice the allometric dose and the “½ MS” group received half the allometric dose. Parameters were measured and analyzed at 0, 5, 10, 20, 40, 60, 90 and 120 minutes after injection. Body mass was 709.6±169g, 742±172.87g and 710±160.2g for groups 1, 2 and 3, respectively. Body temperature was 101.68±0.19ºF; respiratory rate was 85.2±4.54 strokes per minute; heart rate was 297.13±3.46 beats per minute; PaO2 at 81.7±9.43mmHg; PaCO2 at 34.49±1.59mmHg; pH was measured at 7.41±0.07; hematocrit at 38.4±1.31%; total protein was 4.33±0.29g/dL, glucose was measured at 97.13±3.75mg/dL; systolic blood pressure was 85.53±2.50mmHg; diastolic pressure at 7.,40±3.74mmHg; and mean blood pressure was 78.73±1.13mmHg. Straightening postural reaction was lost at 7.20±2.05, 12.80±3.56 and 8.67±3.06 minutes for groups “2MS, MS and ½ MS”, respectively...

Neste estudo administrou-se cloridrato de medetomidina, um agonista de receptores adrenérgicos alfa2 , a cinco cobaios adultos (três machos e duas fêmeas) para verificar a eficiência e segurança do uso de doses calculadas por meio de extrapolação alométrica. Um procedimento cirúrgico foi realizado para inserir uma cânula de polietileno que avançou 2,0 a 2,5 cm no interior da artéria carótida esquerda, até a aorta. Um período mínimo de recuperação de dois dias foi respeitado antes de qualquer outra manipulação ou teste farmacológico. As cânulas eram lavadas a cada dois dias com fluxo de solução salina heparinizada e permaneceram patentes por duas a três semanas após sua inserção. Após a cirurgia, cada animal foi colocado em uma caixa aberta medindo 45x25x20cm, em uma sala silenciosa com iluminação suave. O grupo “MS” recebeu exatamente a dose alometricamente calculada, enquanto o grupo “2MS” recebeu o dobro da dose alométrica, e o grupo “½ MS” recebeu a metade da dose alométrica. Parâmetros foram mensurados e avaliados aos 0, 5, 10, 20, 40, 60, 90 e 120 minutos após a injeção. A massa corporal foi 709,6±169g, 742±172,87g e 710±160,2g para os grupos 1, 2 e 3 respectivamente, a temperatura corporal foi 101,68±0,19ºF, a frequência respiratória foi 85,2±4,54 movimentos por minuto, a frequência cardía ca foi 297,13±3,46 batimentos per minute, a PaO2 foi 81,7±9,43mmHg, a PaCO2 foi 34,49±1,59mmHg, o pH foi 7,41±0,07, o hematócrito foi 38,4±1,31%, a proteína total foi 4,33±0,29g/dL, a glucose foi 97,13±3,75mg/dL, a pressão sistólica foi 85,53±2,50mmHg, a pressão diastólica foi 71,40±3,74mmHg, e a pressão sanguínea média foi 78,73±1,13mmHg...

En esta investigación se ha administrado clorhidrato de medetomidina, un agonista de receptores adrenérgicos alfa2 , a cinco cobayos adultos (tres machos y dos hembras) para verificar la eficacia y seguridad del uso de dosis calculadas por extrapolación alométrica. Se realizó un procedimiento quirúrgico para introducir una cánula de polietileno penetrando 2,0 a 2,5 cm en la arteria carótida izquierda, hasta la aorta. Se ha respetado un período mínimo de recuperación de dos días antes de cualquier otra manipulación o teste farmacológico. Las cánulas eran lavadas a cada dos días con flujo de solución salina heparinizada, y permanecieron patentes por dos a tres semanas después de la inserción. Después de la cirugía, cada animal fue acomodado en una caja abierta con medida de 45x25x20cm, en una sala silenciosa con iluminación suave. El grupo “MS” recibió exactamente la dosis alométricamente calculada, mientras el grupo “2MS” recibió el doble de la dosis alométrica, y el grupo “½ MS” recibió la mitad de la dosis alométrica. Parámetros fueron mensurados y evaluados a los 0, 5, 10, 20, 40, 60, 90 y 120 minutos después de la inyección. El peso corporal fue 709,6±169g, 742±172,87g y 710±160,2g para los grupos 1, 2 y 3 respectivamente, la temperatura corporal fue 101,68±0,19ºF, la frecuencia respiratoria fue 85,2±4,54 movimientos por minuto, la frecuencia cardíaca fue 297,13±3,46 batimientos por minuto, la PaO2 fue 81,7±9,43mmHg, la PaCO2 fue 34,49±1,59mmHg, el pH fue 7,41±0,07, el hematocrito fue 38,4±1,31%, la proteína total fue 4,33±0,29g/dL, la glucosa fue 97,13±3,75mg/dL, la presión sistólica fue 85,53±2,50mmHg, la presión diastólica fue 71,40±3,74mmHg, y la presión sanguínea promedia fue 78,73±1,13mmHg. La reacción postural de enderezamiento fue perdida en 7.20±2,05, 12,80±3,56 y 8,67±3,06 minutos, para los grupos “2MS, MS y ½ MS”, respectivamente...

Bioaccumulation of the new antifoulant medetomidine in marine organisms.

Biofouling is a huge problem globally and new alternative antifoulants are presently being investigated. One candidate is medetomidine, a commonly used sedative in veterinary medicine, which has been shown to effectively prevent settlement of barnacles. The purpose of this study was to measure uptake, elimination and bioconcentration of medetomidine in Mytilus edulis, Abra nitida, Crangon crangon and periphyton communities to evaluate the risk of bioaccumulation in the marine environment. Bioconcentration factors (BCF) and bioaccumulation factors (BAF) were used to assess the bioaccumulation. The calculations of these factors were based on the distribution of the radiolabelled medetomidine. BCF for C. crangon was 2.8 while M. edulis had a BCF of 134 and the periphyton communities' BCF was 1195 l/kg fresh weight (FW). The concentration of medetomidine in the animals reached steady state after 24-48 h for all test systems except for A. nitida, which never stabilised enough to calculate a bioaccumulation factor (BAF). Elimination from the organism's tissues was rapid for three of the test systems with half-lives between 1 and 24 h. A. nitida had a half-life of 96-120 h. This study demonstrates that the bioconcentration and bioaccumulation of medetomidine differs between aquatic organisms and that microalgal communities in the form of periphyton have the highest bioconcentration factor of the organisms tested.

Effects of a candidate antifouling compound (medetomidine) on pheromone induced mate search in the amphipod Corophium volutator.

Environmental hazards associated with traditional, toxic antifouling coatings based on heavy metals calls for the development of alternative, environmentally acceptable antifouling compounds. Medetomidine ((+/-)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole) is a candidate antifouling biocide which impedes settlement of barnacles in the nanomolar range. Prior to introducing novel biocides it is of great importance to consider potential effects on non-target organisms. This study is the first to investigate the effects of medetomidine on the amphipod Corophium volutator, specifically effects on male mate search behaviour. In a laboratory, Y-maze bioassay, C. volutator males were allowed to follow female pheromones after 24 h exposure to 0 (control), 0.01 and 0.1 microg mL(-1) medetomidine. We found that exposure to medetomidine at both concentrations significantly reduced pheromone induced mate search (by 42-71%), with fewer males crawling towards female odour. The results obtained indicate that medetomidine may impair the reproductive fitness of non-target crustaceans, an aspect that needs to be considered before further commercialisation.

Efeitos sedativos das associações xilazina/midazolam e medetomidina/midazolan no gato (Felis catus) / Sedative effects of xylazine/midazolam and medetomidine/midazolam in cats

Vinte gatos, machos, sem raça definida, com 1 a 2 anos de idade, hígidos, foram divididos em dois grupos iguais. Em ambos os grupos utilizou-se como medicação pré-anestésica o sulfato de atropina, na dose de 0,03 mg/k, por via intramuscular, 20 minutos antes da administração da associação dos alfa-2 agonistas e do midazolam. O primeiro grupo (x/m) foi submetido à administração intramuscular da associação xilazinal midazolam, nas doses de 1 mg/kg e 0,2 mg/kg e o segundo grupo (m/m) à associação medetomidinal midazolam, nas doses de 0,08 mg/kg, e 0,2 mg/kg, respectivamente. A administração simultânea de alfa-2 agonistas e midazolam induziu a uma rápida e profunda depressão do SNC, que foi mais rápida com a combinação medetomidina/midazolam. O efeito sedativo máximo ocorreu entre 20-30 min. com ambas as combinações. A recuperação foi tranquila sem alterações expressivas.

Twenty healthy tom cats, from 1 to 2 years of age and weighting between 3,5 and 5 kg were used in the study. The animais were divided into two groups and were premedicated with 0,03mg/kg of atropine sulfate i.m. 20 min prior to the administration of 1 mg/kg xykazine and 0,2 mg/kg midazolam (group m/m - n = 1 O) i.m .. The combination of alfa2 agonists and midazolam induced a rapid CNS depression. The onset of sedation was earlier with m/m than x/m. The maximal sedative effect occurred at 20 to 30 min with the two combinations and recovery was uneventful.