Tramadol ou butorfanol: modelo analgésico pós osteossíntese experimental de úmero em galos ( Gallus gallus domesticus ) / Tramadol or butorphanol: analgesic model of post experimental osteosynthesis of humerus in roosters ( Gallus gallus domesticus )

O tramadol é um fármaco opioide amplamente utilizado em medicina veterinária, porém seu uso e eficácia analgésica pós-cirúrgica não foi investigado em aves. Objetivou-se avaliar a eficácia do tramadol ou butorfanol em galos submetidos à ostessíntese de úmero. Foram utilizados 12 galos (Gallus gallus domesticus), os quais foram alocados aleatoriamente em dois grupos: grupo tramadol (GT) que recebeu como medicação pré anestésica (MPA) 5mg.Kg-1 de tramadol e o grupo butorfanol (GB) que recebeu como MPA 1mg.kg-1 de butorfanol, ambos pela via intramuscular. Em seguida a indução ocorreu com a administração do agente anestésico inalatório, isoflurano 3V% e a manutenção anestésica com o mesmo agente 1,3 V%. Avaliaram-se a pressão arterial sistólica (PAS), frequência cardíaca (FC), frequência respiratória (f) e temperatura corporal (TC). As avaliações foram realizadas: antes da MPA (M0); 15 minutos após MPA (M1); após indução anestésica (M2) e em diferentes momentos cirúrgicos (M3, M4, M5 e M6). A analgesia pós-operatória foi avaliada através da escala adaptada de dor em aves por dois avaliadores cegos aos tratamentos nos momentos: basal, e 1, 2, 4, 6, 8, 10, 12 e 24 horas pós-operatórias; sendo o resgate analgésico realizado quando uma pontuação maior ou igual a seis pontos de um total de 24 fosse observada. Observou-se redução da FC, f e da TC entre os momentos M2 e M6 em relação ao momento basal em ambos os grupos, sendo que no GB períodos de apneia foram observados entre M2 e M6, e entre grupos valores maiores na f no GT foram observados no momento M5 em relação ao GB. Houve diminuição da PAS apenas no momento M3 em relação ao momento basal no grupo GT. No pós-operatório apenas um animal do GT necessitou resgate analgésico observando-se pontuação maior no GT entre M1 e M8 e no GB entre M1 e M12 em relação ao momento basal, e entre grupos apenas T12 foi maior em GB quando comparado ao GT. Através da utilização da escala de dor em pombos submetidos à osteossíntese em membro pélvico e adaptada para avaliação álgica em galos, conclui-se que o tramadol e o butorfanol podem ser utilizados como analgésicos eficientes para o controle de dor pós-operatória em galos.(AU)

Tramadol is an opioid drug widely used in veterinary medicine, but their use and postoperative analgesic efficacy has not been investigated in birds. This study aimed to evaluate the efficacy of tramadol or butorphanol roosters submitted to osteosynthesis of humerus. Twelve roosters (Gallus gallus domesticus) randomly into two groups were used: Tramadol group (TG) received as premedication 5mg.kg-1 of tramadol and butorphanol group (GB) as premedicated with 1mg.kg-1 of butorphanol. Then the induction occurred with the administration of inhalational anesthetic, isoflurane 3V% and anesthetic maintenance with the same agent 1.3V%. We evaluated systolic blood pressure (SBP), heart rate (HR), respiratory rate (RR) and body temperature (BT). The evaluations were performed: before MPA (M0); 15 minutes after MPA (M1); after induction (M2) and different surgical times (M3, M4, M5 and M6). Postoperative analgesia was assessed by the modified scale of pain in birds by 2 reviewers blinded to the treatments in times: baseline and 1, 2, 4, 6, 8, 10, 12 and 24 hours postoperatively; being the analgesic rescue perfomed when a higher sore than or equal to six points of a total of 24 were observed. Observed reduction in HR, RR and BT between M2 and M6 moments compared to baseline in both groups, and in GB periods of apnea were observed between M2 and M6, and between groups at higher values f in GT were M5 observed when compared to GB. SBP decreased only when M3 relative to baseline in the TG group. Postoperatively only a GT animal needed analgesic rescue with a higher score on the GT between M1 and M8 and GB between M1 and M12 compared to baseline, and between groups only T12 was higher in GB when compared to the GT. It was concluded that through the evaluation scale used analgesic, butorphanol, and tramadol showed satisfactory analgesia and may be used to control pain roosters subjected to fixation of the humerus.(AU)

Butorphanol and ketamine combined in infusion solutions for patient-controlled analgesia administration: a long-term stability study.

BACKGROUND: Ketamine in subanesthetic dose added to butorphanol has been reported to give superior pain control when used for intravenous patient-controlled analgesia (PCA) after surgery. However, this admixture is not available commercially and stability data applicable to hospital practice are limited. MATERIAL/METHODS: The butorphanol-ketamine admixtures were prepared in polyolefin bags and stored in the dark at 4°C, 25°C, or 37°C for 15 days. The initial concentrations were 50-150 microgram/ml for butorphanol and 1-4 mg/ml for ketamine, respectively. The stabilities were determined by visual inspection, pH measurement, and high-pressure liquid chromatography (HPLC) assay of drug concentrations. RESULTS: Over the 15 days, all solutions were clear in appearance, and no color change or precipitation was observed among the three temperatures. The percentages of initial concentration of each drug were over 95% during the study period, and the pH value did not change significantly. CONCLUSIONS: The results indicate that the drug mixtures of butorphanol and ketamine in 0.9% sodium chloride injection were stable for 15 days when stored in polyolefin bags at 4°C, 25°C, or 37°C.

Stability of butorphanol-tropisetron mixtures in 0.9% sodium chloride injection for patient-controlled analgesia use.

Tropisetron is an adjuvant for butorphanol used in intravenous patient-controlled analgesia (PCA) and has been reported to provide superior pain control. It is efficacious in reducing the incidence of postoperative nausea and vomiting. However, this admixture is not available commercially and stability data applicable to hospital practice are limited. This study aimed to describe the drug compounding and evaluates the long-term (up to 14 days) stability of butorphanol and tropisetron in 0.9% sodium chloride injection for PCA use.In this study, commercial solutions of butorphanol tartrate and tropisetron hydrochloride were combined and further diluted with 0.9% sodium chloride injection to final concentrations of butorphanol tartrate 0.08 mg/mL and tropisetron hydrochloride 0.05 mg/mL. The polyolefin bags and glass bottles were stored at 4°C and 25°C for up to 14 days. The drug stabilities were determined by visual inspection, pH measurement, and high-pressure liquid chromatography assay of drug concentrations.The data obtained for admixtures prepared and stored at temperatures of 25°C and 4°C show the drugs have maintained at least 98% of the initial concentration. All solutions remained clear and colorless over the 14-day period, and the pH value did not change significantly.The results indicate that admixtures of butorphanol tartrate 0.08 mg/mL and tropisetron hydrochloride 0.05 mg/mL in 0.9% sodium chloride injection solution were stable for 14 days when stored in polyolefin bags or glass bottles at 4°C and 25°C and protected from light. The infusion is feasible for manufacturing in pharmacy aseptic units and can be stored for up to 14 days for routine use in PCA infusions.

[Chemical-toxicological analysis of butorphanol].

The conditions of butorphanol isolation from biological fluids were studied. The method of its extraction with the mix of organic solvents by pH 12 was proposed. How to identify butorphanol with the methods of thin-layer chromatography, ultraviolet spectrometry, high-performance liquid chromatography, gas chromatography with a detector of electron capture, chromato-mass spectrometry was developed. Possibility of use ultraviolet spectrometry for quantitative assessment of butorphanol was shown.

High-performance liquid chromatography of nalbuphine, butorphanol and morphine in blood and brain microdialysate samples: application to pharmacokinetic/pharmacodynamic studies in rats.

A rapid and sensitive assay for quantification of nalbuphine, butorphanol and morphine in blood (50 microL) and brain microdialysate ( approximately 40 microL) samples was developed. Blood samples were extracted with ethyl acetate. Analysis was performed with high-performance liquid chromatography (HPLC) coupled to an electrochemical detector. The mobile phase was a mixture of 0.1 M sodium phosphate buffer, methanol and octane-sulfonic acid with ratio and pH depending on compound and matrix. The limits of quantification in blood samples were 25, 50 and 25 ng/mL for nalbuphine, butorphanol and morphine, respectively and 0.5 ng/mL for morphine in microdialysate samples. Based on sample volume, sensitivity and reproducibility, these assays are particularly suitable for pharmacokinetic/pharmacodynamic studies in rodents.

Derivatization methodology for the analysis of butorphanol by gas chromatography-mass spectrometry.

Butorphanol is an opioid used as analgesic in humans and other species. In horses, it can cause locomotor stimulation at low doses. This drug is not well chromatographed by GC and so, it is necessary to transform it into a more suitable compound, which can be done by derivatization. The derivatization of a drug is used to impart volatility, masking polar groups to improve the results in gas chromatographic analysis. We have evaluated N,O-bis(trimethylsilyl)- trifluoracetamide (BSTFA)+ 1% trimethylchlorsilane (TMCS) and N-methyl-N-trimethylsilil-trifluoroacetamide (MSTFA) as derivatizing reagents for butorphanol at 30, 60 and 80 degrees C during 15, 30 and 60 min. The effects of dilution of these reagents with toluene and the evaporation before the derivatization were tested. Both reagents can be used for butorphanol derivatization and analysis and the dilution and evaporation steps did not alter the final results. The best derivatization conditions were 15 min at 80 degrees C, although 60 degrees C, although 60 degrees C during 60 min were also suitable.

Profiling impurities and degradants of butorphanol tartrate using liquid chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry substructural techniques.

A rapid and systemic strategy based on liquid chromatography/mass spectrometry (LC/MS) profiling and liquid chromatography/tandem mass spectrometry (LC/MS/MS) substructural techniques was utilized to elucidate the degradation products of butorphanol, the active ingredient in stadol NS. This strategy integrates, in a single instrumental approach, analytical HPLC, UV detection, full-scan electrospray mass spectrometry, and tandem mass spectrometry to rapidly and accurately elucidate structures of impurities and degradants. In these studies, several low-level degradation products were observed in long-term storage stability samples of bulk butorphanol. The resulting analytical profile includes information on five degradants including molecular structures, chromatographic behavior, molecular weight, UV data, and MS/MS substructural information. The degradation products formed during long-term storage of butorphanol tartrate included oxidative products proposed as 9-hydroxy-and 9-keto-butorphanol, norbutorphanol, a ring-contraction degradant, and delta 1, 10 a-butorphanol. These methodologies are applicable at any stage of the drug product cycle from discovery through to development. This library of butorphanol degradants provides a foundation for future development work regarding product monitoring, as well as a useful diagnostic tool for new degradation products.

[The pharmacokinetic and pharmacodynamic characteristics of moradol in parturients during obstetrical analgesia]. / Osobennosti farmakokinetiki i farmakodinamiki moradola u rozhenits na protiazhenii obezbolivaniia rodov.

Pharmacokinetic and pharmacodynamic monitoring of moradol (2 mg) given to 16 somatically healthy parturients during analgesia of spontaneous labor has identified 2 groups of patients who significantly differed in kinetic characteristics and in the drug's ability to penetrate through the placenta barrier. At the same time there were no significant differences in autonomic nervous function and central hemodynamics after intravenous moradol analgesia. The newborns from the two groups had identical high scores (8-9). Moradol produced an adequate analgesic effects in all parturients, reaching its peak at min 30-45 and lasting up to 2 hours. There was a high correlation between the plasma drug concentration and pharmacodynamic indices in parturients.

Pharmacokinetics and milk residues of butorphanol in dairy cows after single intravenous administration.

The pharmacokinetics of butorphanol tartrate were investigated following intravenous administration of 0.25 mg/kg of body weight to six healthy non-lactating Jersey cows. Three lactating Holstein cows also received 0.045 mg of butorphanol/kg of body weight intravenously to determine the extent and duration of drug transfer into milk. A radioimmunoassay technique was used to measure butorphanol concentrations in plasma and milk. The disposition of butorphanol following intravenous administration was characterized by rapid and extensive distribution followed by a slower elimination phase. Apparent volume of distribution was 4.178 +/- 1.145 (mean +/- SD) 1/kg, mean elimination half-life was 82 min, and clearance was 34.6 +/- 7.7 ml/min/kg. Trace quantities of butorphanol were detected in the cow's milk for up to 36 h following administration. These pharmacokinetic data were compared with pharmacokinetic and pharmacodynamic data for butorphanol in other species and for three other potent opioids in related ruminant species.

Polarographic determination of butorphanol tartrate.

A new indirect polarographic method is proposed for the determination of butorphanol tartrate in the injectable solution form (Stadol). Direct-current polarography and differential pulse polarography (DPP) were applied for the study of authentic butorphanol and its injectable solution form in alkaline medium after nitration with 1 M potassium nitrite in presence of 1 M hydrochloric acid. The standard addition method was employed for the evaluation of the results and the mean percentage found for the injectable solution form was 99.2 +/- 1.0.

Human perinatal distribution of butorphanol.

The perinatal distribution of butorphanol was demonstrated in relation to maternal-neonatal transfer and colostrum/milk excretion in obstetric patients. Parenteral butorphanol passed the placental barrier and was found in neonatal cord serum. The mean neonatal serum concentration of butorphanol was not different from the mean maternal serum concentration of butorphanol, following a 1 or 2 mg intramuscular dose. Butorphanol was detected in the milk of lactating women following oral and intramuscular administration. Serum and milk concentrations appeared to be parallel with time. This observation was confirmed by the constancy of the mean milk-to-serum concentration ratio (0.7 intramuscular, 1.9 oral). We calculated that 4 micrograms would be the maximum amount of butorphanol, which would be expected to be present in the full daily milk output (1 L) following administration four times a day of 2 mg intramuscular or of 8 mg oral doses. An oral dose of 4 micrograms to an infant weighing 4 kg corresponds to the negligible oral dose of 0.7 mg to a 70 kg adult. The demonstrated safety and efficacy of butorphanol as an obstetric analgesic and the characteristics of the maternal-neonatal transfer and milk excretion are indicative of the potential excellence of this agent for obstetric use.