Characterisation of the in vivo interactions between detomidine and methadone in horses: Pharmacokinetic and pharmacodynamic modelling.

BACKGROUND: Pharmacokinetic (PK)/pharmacodynamic (PD) modelling offers new insights to design protocols for sedation and analgesia in standing horses. OBJECTIVES: To evaluate the parameters and interactions between detomidine and methadone when given alone or combined in standing horses. STUDY DESIGN: Randomised, placebo-controlled, blinded, crossover. METHODS: Eight adult healthy horses were given six treatments intravenously: saline (SAL); detomidine (5 µg/kg bwt; DET); methadone (0.2 mg/kg bwt; MET) alone or combined with detomidine (2.5 [MLD], 5 [MMD] or 10 [MHD] µg/kg bwt). Venous blood samples were obtained at predetermined times between 0 and 360 min after drug administration. Plasma detomidine and methadone were measured using a single, liquid/liquid extraction technique by liquid chromatography coupled with a triple quadrupole mass spectrometer (LC-MS/MS). Sequential PK/PD modelling compared rival models, with and without PK and PD interaction between drugs, to fit the PD data including height of the head above the ground (HHAG), a visual analogue scale for sedation (VAS), electrical (ET), thermal (TT) and mechanical (MT) nociceptive thresholds and gastrointestinal motility (GIM) [1]. RESULTS: Two and three compartment models best described the PK of detomidine and methadone, respectively. Detomidine decreased its own clearance as well as the clearance of methadone. The interaction of methadone on the effect of detomidine revealed an infra-additive (partial antagonism) effect for HHAG (α = -1.33), VAS (α = -0.98) and GIM (α = -1.05), a positive potentiation for ET (pot = 0.0041) and TT (pot = 0.133) and a synergistic to additive effect for MT (α = 0.78). MAIN LIMITATIONS: This is a small experimental study. CONCLUSIONS: Different PK/PD interactions were demonstrated for each PD parameter and could be modelled in vivo. The modelling of our data will allow us to simulate and predict the effect of constant rate infusions of both drugs for future investigations.

Sedative and antinociceptive effects of different detomidine constant rate infusions, with or without methadone in standing horses.

BACKGROUND: Standing surgery avoids the risks of general anaesthesia in horses. OBJECTIVES: To assess sedation, antinociception and gastrointestinal motility in standing horses after a detomidine loading dose and 2-h constant rate intravenous (i.v.) infusion, with or without methadone. STUDY DESIGN: Blinded, randomised, crossover with seven healthy adult cross-bred horses, three geldings and four females (404 ± 22 kg). METHODS: Five i.v. treatments were administered to all horses with 1-week washout period: saline (SAL), detomidine low (2.5 µg/kg bwt + 6.25 µg/kg bwt/h) (DL) and high doses (5 µg/kg bwt + 12.5 µg/kg bwt/h) (DH) alone or combined with methadone (0.2 mg/kg bwt + 0.05 mg/kg bwt/h), (DLM) and (DHM), respectively. Height of head above the ground (HHAG), electrical (ET), thermal (TT) and mechanical (MT) nociceptive thresholds and gastrointestinal motility were evaluated at predetermined times between 5 and 240 min. A mixed effect model and Kruskal-Wallis test were used to analyse normally and non-normally distributed data, respectively. RESULTS: Sedation (<50% basal HHAG) was achieved for the duration of the infusion, and for an additional 15 min in DH and DHM groups. Nociceptive thresholds were higher than baseline, to the greatest degree and the longest duration, with DHM (ET and TT for 135 min and MT for 150 min). After DH, TT was significantly higher than baseline from 30 to 120 min and MT from 15 to 135 min. After DLM, ET was increased at 90 min, TT at 30 min and MT for 120 min. Gastrointestinal motility was reduced for up to 135 min after DL, 150 min after DLM and 210 min after DH and DHM. MAIN LIMITATIONS: Nociceptive thresholds are not equivalent to surgical stimuli. CONCLUSION: Methadone with the highest detomidine dose (DHM) may provide sufficient sedation and analgesia for standing surgical procedures and warrants further investigation.

Antinociceptive effects of methadone combined with detomidine or acepromazine in horses.

REASONS FOR PERFORMING STUDY: To investigate two protocols to provide antinociception in horses. OBJECTIVES: To evaluate the antinociceptive effects of intravenous methadone combined with detomidine or acepromazine in adult horses. STUDY DESIGN: Randomised, blinded, crossover study. METHODS: Mechanical, thermal and electrical stimuli were applied to the dorsal left and right metacarpus and coronary band of the left thoracic limb, respectively. A thermal stimulus was applied caudal to the withers. The horses were treated with saline (C), a combination of methadone (0.2 mg/kg bwt) and detomidine (10 µg/kg bwt) (MD) or methadone (0.2 mg/kg bwt) and acepromazine (0.05 mg/kg bwt) (MA) at 1 week intervals. Nociceptive thresholds were measured before and at 15 min intervals until 150 min after treatment. Wilcoxon rank-sum and Wilcoxon signed rank tests were used to compare data between groups at each time point and over time within each group, followed by the Bonferroni method to adjust the P value. RESULTS: The mechanical stimulus was the most sensitive test to differentiate the antinociceptive effects of the treatments. Mechanical thresholds were greater after MD than MA between 15 and 30 min and with both MD and MA these thresholds were greater than C from 15 to 60 min. Electrical and thermal limb thresholds were greater after MD than C at 15 and 45 min and at 15, 30, 45, 75 and 105 min, respectively. Thermal limb thresholds were greater with MA than C at 30 min. Thoracic thermal threshold in MD and MA were higher than C at 45, 75, 90 and 120 min and from 30 to 75 min, respectively. CONCLUSIONS: Methadone and acepromazine produced less pronounced mechanical antinociception than MD.

Validation of mechanical, electrical and thermal nociceptive stimulation methods in horses.

REASONS FOR PERFORMING STUDY: To validate a model for investigating the effects of analgesic drugs on mechanical, thermal and electrical stimulation testing. OBJECTIVES: To investigate repeatability, sensitivity and specificity of nociceptive tests. STUDY DESIGN: Randomised experiment with 2 observers in 2 phases. METHODS: Mechanical (M), thermal (TL) and electrical (E) stimuli were applied to the dorsal metacarpus (M-left and TL-right) and coronary band of the left thoracic limb (E) and a thoracic thermal stimulus (TT) was applied caudal to the withers in 8 horses (405 ± 43 kg). Stimuli intensities were increased until a clear avoidance response was detected without exceeding 20 N (M), 60°C (TL and TT) and 15 V (E). For each set of tests, 3 real stimuli and one sham stimulus were applied (32 per animal) using a blinded, randomised, crossover design repeated after 6 months. A distribution frequency and, for each stimulus, Chi-square and McNemar tests compared both the proportion of positive responses detected by 2 observers and the 2 study phases. The κ coefficients estimated interobserver agreement in determining endpoints. Sensitivity (384 tests) and specificity (128 tests) were evaluated for each nociceptive stimulus to assess the evaluators' accuracy in detecting real and sham stimuli. RESULTS: Nociceptive thresholds were 3.1 ± 2 N (M), 8.1 ± 3.8 V (E), 51.4 ± 5.5°C (TL) and 55.2 ± 5.3°C (TT). The level of agreement after all tests, M, E, TL and TT, was 90, 100, 84, 98 and 75%, respectively. Sensitivity was 89, 100, 89, 98 and 70% and specificity 92, 97, 88, 91 and 94%, respectively. CONCLUSIONS: The high interobserver agreement, sensitivity and specificity suggest that M, E and TL tests are valid for pain studies in horses and are suitable tools for investigating antinociceptive effects of analgesics in horses.

Analgesia for cats after ovariohysterectomy with either buprenorphine or carprofen alone or in combination.

Eighty-four female cats undergoing ovariohysterectomy in a blinded, randomised, prospective clinical study were assigned to one of three groups of 28 to receive either 0.01 mg/kg buprenorphine (group B), 4 mg/kg carprofen (group C), or the same doses of both drugs (group BC). A dynamic and interactive visual analogue scale (DIVAS) from 0 to 100 mm, and a simple descriptive scale (SDS) from 0 to 4 were used to evaluate the cats' degree of analgesia and sedation for 24 hours postoperatively. There was no significant difference in the cats' sedation scores by SDS or DIVAS, and no difference in their pain scores by DIVAS. By SDS, the cats in group BC had significantly lower pain scores than the cats in group C (P<0.001) and group B (P<0.05). Nine of the cats in group B, nine in group C and five in group BC required rescue analgesia, and the cats in group C required rescue earlier than those in group B (P<0.05).

EFEITOS NEUROLÓGICOS, RESPIRATÓRIOS, COMPORTAMENTAIS E ENDÓCRINOS DECORRENTES DA CAUDECTOMIA, EM CÃES RECÉM-NASCIDOS SUBMETIDOS À ANESTESIA EPIDURAL

A caudectomia é realizada em algumas raças de cães visando prevenir traumas, além de uma questão de estética. O objetivo deste estudo foi avaliar os efeitos comportamentais, endócrinos, neurológicos e respiratórios produzidos pela caudectomia em cães recém-nascidos. Foram utilizados cinqüenta e dois filhotes de dois a sete dias de idade. A anestesia epidural sacrococígea foi realizada utilizando uma agulha 27 G x ½`` e seringa de insulina com 0,2 mL de lidocaína 0,5% com adrenalina. A caudectomia foi realizada em metade dos filhotes de cada fêmea e a outra metade foi utilizada como controle. A concentração de cortisol plasmático, ganho de peso, freqüência respiratória, vocalização, defecação, micção, movimentação, e reflexos anogenital, de sucção, magnum, flexor, vestibular e tátil foram avaliados antes e 1, 2, 3, 4, 8 e 24 horas após a caudectomia. Os resultados foram comparados utilizando ANOVA, seguidos de Student Newman Keuls, Friedman or Mann-Whitney tests. Não houve diferença em tempo ou entre os grupos em nenhuma variável. A caudectomia realizada após anestesia epidural não alterou frequência respiratória, comportamento, reflexos neurológicos e concentração de cortisol plasmático até 24 horas após a cirurgia. Deve ser considerado que a anestesia epidural pode ter mascarado um efeito prejudicial da caudectomia nestas variáveis.PALAVRAS-CHAVE: Anestesia epidural. Cães.Caud

Neurological, respiratory, behavioural and endocrine effects of tail docking in newborn dogs submitted to epidural anesthesia / Efeitos neurológicos, respiratórios, comportamentais e endocrinos decorrentes da caudectomia, em cães recém-nascidos submetidos à anestesia epidural

Tail docking is performed in some dog breeds to prevent injuries and to improve appearance. It has been forbidden in some countries for ethical reasons. The aim of this study was to investigate the behavioural, endocrine, neurological and respiratory effects produced by tail docking in newborn dogs. Fifty-two puppies ranging from 2 to 7 days of age were used. Sacrococcigeal epidural anaesthesia was performed using a 27 G x ½" needle and an insulin syringe filled with 0.2 mL of 0.5% lignocaine with adrenaline. Tail docking was performed in half of the puppies of each litter and the other half were used as controls. Plasma cortisol concentration, weight gain, respiratory rate, vocalization, defecation, urination, movement and suction, anogenital, magnum, flexor, vestibular and tactile reflexes were investigated both before and 1, 2, 3, 4, 8 and 24 hours after tail docking. Data were compared using ANOVA, followed by Student Newman Keuls, Friedman or Mann-Whitney tests where applicable. Tail docking after epidural anaesthesia did not modify respiratory rate, behaviour, neurological reflexes or plasma cortisol concentration up to 24 hours after surgery. It should be considered that epidural anaesthesia might have masked a possible harmful effect of tail docking on these variables.

A caudectomia é realizada em algumas raças de cães visando prevenir traumas, além de uma questão de estética. O objetivo deste estudo foi avaliar os efeitos comportamentais, endócrinos, neurológicos e respiratórios produzidos pela caudectomia em cães recém-nascidos. Foram utilizados cinqüenta e dois filhotes de dois a sete dias de idade. A anestesia epidural sacrococígea foi realizada utilizando uma agulha 27 G x ½e seringa de insulina com 0.2 mL de lidocaína 0,5% com adrenalina. A caudectomia foi realizada em metade dos filhotes de cada fêmea e a outra metade foi utilizada como controle. A concentração de cortisol plasmático, ganho de peso, freqüência respiratória, vocalização, defecação, micção, movimentação, e reflexos anogenital, de sucção, magnum, flexor, vestibular e tátil foram avaliados antes e 1, 2, 3, 4, 8 e 24 horas após a caudectomia. Os resultados foram comparados utilizando ANOVA, seguidos de Student Newman Keuls, Friedman or Mann-Whitney tests. Não houve diferença em tempo ou entre os grupos em nenhuma variável. A caudectomia realizada após anestesia epidural não alterou frequência respiratória, comportamento, reflexos neurológicos e concentração de cortisol plasmático até 24 horas após a cirurgia. Deve ser considerado que a anestesia epidural pode ter mascarado um efeito prejudicial da caudectomia nestas variáveis.

Effects of subcutaneous methadone, morphine, buprenorphine or saline on thermal and pressure thresholds in cats.

This study compared pressure and thermal thresholds after administration of three opioids in eight cats. Pressure stimulation was performed via a bracelet taped around the forearm. Three ball-bearings were advanced against the forearm by inflation of a modified blood pressure bladder. Pressure in the cuff was recorded at the end point (leg shake and head turn). Thermal threshold was tested as previously reported using a heated probe held against the thorax [Dixon et al. (2002) Research in Veterinary Science, 72, 205]. After baseline recordings, each cat received subcutaneous methadone 0.2 mg/kg, morphine 0.2 mg/kg, buprenorphine 0.02 mg/kg or saline 0.3 mL in a four period cross-over study. Measurements were made at 15, 30, 45 min and 1, 2, 3, 4, 8, 12 and 24 h after the injection. Data were analysed by anova (P<0.05). There were no significant changes in thresholds after saline. Thermal threshold increased at 45 min after buprenorphine (maximum 2.8+/-3 degrees C), 1-3 h after methadone (maximum 3.4+/-1.9 degrees C) and 45 min to 1 h (maximum 3.4+/-2 degrees C) after morphine. Pressure threshold increased 30-45 min (maximum 238+/-206 mmHg) after buprenorphine, 45-60 min after methadone (maximum 255+/-232 mmHg) and 45-60 min and 3-6 h (maximum 255+/-232 mmHg) after morphine. Morphine provided the best analgesia, and methadone appears a promising alternative. Buprenorphines limited effect was probably related to the subcutaneous route of administration. Previously, buprenorphine has produced much greater effects when given by other routes.

Cardiorespiratory and endocrine effects of endogenous opioid antagonism by naloxone in ponies anaesthetised with halothane.

Halothane depresses cardiorespiratory function and activates the pituitary-adrenal axis, increasing beta endorphin. In horses, beta endorphin may enhance the anaesthetic-associated cardiorespiratory depression and mortality risk. The authors studied endogenous opioid effects on cardiorespiratory function and pituitary-adrenal activity in halothane-anaesthetised ponies by investigating opioid antagonism by naloxone. Six ponies were anaesthetised three times (crossover design). Anaesthesia was induced with thiopentone and maintained with 1.2 per cent halothane for 2 hours. Immediately after induction, naloxone was administered either intravenously (0.5 mg kg(-1)bolus then 0.25 mg kg(-1)hour(-1)for 2 hours) or intrathecally (0.5 mg) or was replaced by saline as control. Pulse and respiratory rates, arterial blood gases, cardiac output and plasma cortisol and adrenocorticotrophic hormone (ACTH) concentrations were measured. All groups developed cardiorespiratory depression (40 per cent decrease in cardiac output) and plasma cortisol increased. Plasma ACTH concentration was higher in ponies treated with intrathecal naloxone. Endogenous opioids may inhibit ACTH secretion, attenuating the stress response to halothane anaesthesia in equidae.

Effects of glucose infusion on the endocrine, metabolic and cardiorespiratory responses to halothane anaesthesia of ponies.

Glucose was infused intravenously into six ponies during halothane anaesthesia, to evaluate its effect on their endocrine response to anaesthesia. The ponies were premedicated with acepromazine, and anaesthesia was induced with thiopentone and maintained with halothane in oxygen for two hours. Glucose was infused to maintain the plasma glucose concentration above 20 mmol/litre. Anaesthesia was associated with hypothermia, a decrease in haematocrit, hypotension, hyperoxaemia, respiratory acidosis and an increase in the plasma concentrations of lactate and arginine vasopressin. The concentration of beta-endorphin in plasma increased transiently after 20 minutes but there were no changes in concentrations of adrenocorticotrophic hormone, dynorphin, cortisol or catecholamines. These data suggest that the glucose infusion attenuated the normal adrenal response of ponies to halothane anaesthesia.

Midazolam and ketamine induction before halothane anaesthesia in ponies: cardiorespiratory, endocrine and metabolic changes.

Six Welsh gelding ponies were premedicated with 0.03 mg/kg of acepromazine intravenously (i.v.) prior to induction of anaesthesia with midazolam at 0.2 mg/kg and ketamine at 2 mg/kg i.v.. Anaesthesia was maintained for 2 h using 1.2% halothane concentration in oxygen. Heart rate, electrocardiograph (ECG), arterial blood pressure, respiratory rate, blood gases, temperature, haematocrit, plasma arginine vasopressin (AVP), dynorphin, beta-endorphin, adrenocorticotropic hormone (ACTH), cortisol, dopamine, noradrenaline, adrenaline, glucose and lactate concentrations were measured before and after premedication, immediately after induction, every 20 min during anaesthesia, and at 20 and 120 min after disconnection. Induction was rapid, excitement-free and good muscle relaxation was observed. There were no changes in heart and respiratory rates. Decrease in temperature, hyperoxia and respiratory acidosis developed during anaesthesia and slight hypotension was observed (minimum value 76 +/- 10 mm Hg at 40 mins). No changes were observed in dynorphin, beta-endorphin, ACTH, catecholamines and glucose. Plasma cortisol concentration increased from 220 +/- 17 basal to 354 +/- 22 nmol/L at 120 min during anaesthesia; plasma AVP concentration increased from 3 +/- 1 basal to 346 +/- 64 pmol/L at 100 min during anaesthesia and plasma lactate concentration increased from 1.22 +/- 0.08 basal to 1.76 +/- 0.13 mmol/L at 80 min during anaesthesia. Recovery was rapid and uneventful with ponies taking 46 +/- 6 min to stand. When midazolam/ketamine was compared with thiopentone or detomidine/ketamine for induction before halothane anaesthesia using an otherwise similar protocol in the same ponies, it caused slightly more respiratory depression, but less hypotension. Additionally, midazolam reduced the hormonal stress response commonly observed during halothane anaesthesia and appears to have a good potential for use in horses.

Patterns and covariates of tobacco use in a recent sample of pregnant teenagers.

PURPOSE: Little is known about the prevalence and patterns of smoking among pregnant teenagers. We provide a comprehensive description of the prevalence, patterns and correlates of smoking from a recent sample of 199 pregnant adolescents. METHODS: We interviewed pregnant teenagers at mid-pregnancy and delivery to obtain information on tobacco and other substance use before and during pregnancy and on demographic, medical and psychosocial status. RESULTS: The average age was 16.1 years (range 12-18); 70% were African-American. Smoking was prevalent and increased from first (59%) to third (62%) trimesters. This increase was in sharp contrast to decreases in other substances. Caucasians had higher rates of smoking and heavier smoking. For Caucasians, third trimester smoking was predicted by peer smoking and early onset of sexual activity. For African-Americans, third trimester smoking was related to older age, not living with parent(s), dissatisfaction with social support, early pregnancy binge drinking, peer smoking, and early onset of sexual activity. CONCLUSIONS: The high prevalence and increasing pattern of prenatal smoking in teenagers is a major public health concern. Effective education and cessation programs must be targeted at pregnant teenagers.

Effect of prenatal marijuana exposure on the cognitive development of offspring at age three.

Marijuana is the most commonly used illicit substance among pregnant women. Although there has been substantial concern about the effects of substance use during pregnancy, few studies have assessed the effects of prenatal exposure to marijuana and even fewer have provided longitudinal data on the developmental outcome of offspring. This is a report from a longitudinal study of substance use during pregnancy. The women in the cohort were of lower socioeconomic status, most were single, half were white and half were African-American. Women were interviewed at the fourth and seventh prenatal months, and women and children were assessed at delivery, 8, 18, and 36 months. Pediatric assessment included physical and cognitive development. At each study phase, mothers were interviewed about life style, living situation, current substance use, sociodemographic, and psychological status. Findings are reported on 655 women and children who were assessed at the third year. There were significant negative effects of prenatal marijuana exposure on the performance of 3-year-old children on the Stanford-Binet Intelligence Scale. The effects were associated with exposure during the first and second trimesters of pregnancy. Among the offspring of white women, these effects were moderated by the child's attendance at preschool/day-care at age three.

The clinical diagnosis of dapsone resistant leprosy

For the early recognition of dapsone resistance, it is essential to regularly examine patients at risk for suspicious new lesions, backed by regular clinical treatment records including smear results. The earlier the recognition and starting on alternative treatment, the better is the response. However, it is not advisable to change treatment without attempting at least clinical confirmation, and endorsing the chart so that the problem is not missed on subsequent occasions.

Neonatal asphyxia. I. Relationship of obstetric and neonatal complications to neonatal mortality in 38,405 consecutive deliveries.

The requirement of greater than one minute of positive pressure ventilation was prospectively used to identify infants suffering from asphyxia at birth in 38,405 consecutive deliveries. Multivariate analysis of high-risk factors associated with increased risk of asphyxia showed the prematurity was the most significant predictor of asphyxia. Asphyxia occurred in 62.3% of infants less than 27 weeks' gestation and decreased to 0.4% in infants greater than 38 weeks' gestation. Presence of asphyxia was associated with significant increase in neonatal mortality of infants greater than 36 weeks' gestation. Of the asphyxiated neonates, growth retardation, hypothermia, hyaline membrane disease, and seizures were significantly associated with an increased risk of death.

Neonatal asphyxia. II. Neonatal mortality and long-term sequelae.

Neonatal asphyxia, defined in this study as delay of greater than 1 minute in onset of spontaneous respiration at birth, occurred in 1% of 13,221 live-born infants of birth weight greater than 500 gm between 1970 and 1971. Seventy-five (56%) of 133 asphyxiated infants survived the neonatal period. Survival was directly related to gestational age. The 65 survivors of asphyxia available for study were seen at a mean age of 4.8 years to determine the incidence and extent of neurologic and developmental abnormalities. Twelve children (18.5%) had severe impairment: nine had both neurologic and intellectual handicaps, two had neurologic impairment alone, and one had intellectual impairment alone. The incidence and severity of impairment were not related to gestational age. Postasphyctic seizures were associated with poor outcome.

The significance of changes in the nasal mucosa in indeterminate, tuberculoid and borderline leprosy

A study of nasal biopsies from 137 leprosy patients classified on the basis of clinical, microbiological and skin biopsy as Indeterminate, Tuberculoid, Borderline-tuberculoid and Borderline-leproma was undertaken. Changes suggestive of leprosy viz., nerve and smooth muscle inflammation with a few acid fast bacilli in a proportion of the biopsies were seen in all groups of patients examined. This suggests, that even in Indeterminate and Tuberculoid leprosy the disease becomes generalised by the time clinical manifestations appear in skin. Tuberculoid granuloma was seen in two nasal biopsies from Borderline-tuberculoid leprosy patients, one of which was located in the wall of a vein, suggesting the possibility of intravascular dissemination of the disease even in non-lepromatous leprosy. 33 of the patients were children 15 years and below and they also showed changes such as nerve and smooth muscle inflammation but bacilli were seen only in the Borderline group. These findings suggest involvement of the nasal mucosa early in the course of the disease as 70% of the children had the skin lesion for less than one year. The nasal mucosa offers favourable conditions for the growth of the organisms and is readily accessible to infection by droplets, and therefore, it could be one of the primary sites of involvement in leprosy.