The impact of medetomidine on the protein-binding characteristics of MK-467 in canine plasma.

This study determined the unbound fraction of the peripheral α2 -adrenoceptor antagonist MK-467 alone and combined with medetomidine. MK-467 (0.1, 1 and 10 µm) was incubated in canine plasma with and without medetomidine (molar ratio 20:1), with human serum albumin (HSA) and with α1-acid glycoprotein (AGP). Rapid equilibrium dialysis was used for the measurement of protein binding. All samples were analysed by liquid chromatography and tandem mass spectrometry to obtain the unbound fraction (fu ) of MK-467. Unbound fractions (fu ) of MK-467 in canine plasma (mean ± standard deviation) were 27.6 ± 3.5%, 26.6 ± 0.9% and 42.4 ± 1.2% at 0.1, 1.0 and 10 µm concentrations, respectively. In the presence of medetomidine, fu were 27.5 ± 0.4%, 26.6 ± 0.9% and 41.0 ± 2.4%. The fu of MK-467 in HSA were 50.1 ± 2.5% at 0.1 µm, 49.4 ± 1.2% at 1.0 µm and 56.7 ± 0.5% at 10 µm. fu of MK-467 in AGP was 56.3 ± 3.7% at 0.1 µm, 54.6 ± 5.6% at 1.0 µm and 65.3 ± 0.4% at 10 µm. Protein binding of MK-467 was approximately 70% between 0.1 and 1.0 µm. Medetomidine had no apparent effect on the protein binding of MK-467.

Effects of MK-467 on the antinociceptive and sedative actions and pharmacokinetics of medetomidine in dogs.

We investigated the influence of the peripherally acting α2 -adrenoceptor antagonist MK-467 on the sedative and antinociceptive actions and plasma drug concentrations of medetomidine, an α2 -adrenoceptor agonist that is used in veterinary medicine as a sedative and analgesic agent. Eight healthy beagle dogs received intravenous medetomidine (10 µg/kg) or medetomidine with MK-467 (250 µg/kg) in a randomized crossover design. A standardized nociceptive pressure stimulus was applied to a nail bed of a hindlimb. Times for withdrawal of the limb and for head lift were measured, and sedation was scored. EEG data were collected prior to and after stimulation. Plasma drug concentrations were measured. Co-administration of MK-467 significantly attenuated medetomidine analgesia, as assessed with limb withdrawal, and also shortened the duration of sedation. The apparent plasma clearance of both enantiomers of medetomidine, dexmedetomidine and levomedetomidine, was more than doubled in the presence of MK-467. Antagonism by MK-467 of medetomidine-evoked vasoconstriction is seen as the mechanism behind this pharmacokinetic drug interaction. Thus, MK-467 attenuated the antinociceptive and sedative effects of medetomidine. This can probably be explained by increased clearance and decreased concentrations of dexmedetomidine in plasma after co-administration of MK-467 with racemic medetomidine.

Effects of vatinoxan on cardiorespiratory function and gastrointestinal motility during constant-rate medetomidine infusion in standing horses.

BACKGROUND: Medetomidine suppresses cardiovascular function and reduces gastrointestinal motility in horses mainly through peripheral α2 -adrenoceptors. Vatinoxan, a peripheral α2 -antagonist, has been shown experimentally to alleviate the adverse effects of some α2 -agonists in horses. However, vatinoxan has not been investigated during constant-rate infusion (CRI) of medetomidine in standing horses. OBJECTIVES: To evaluate effects of vatinoxan on cardiovascular function, gastrointestinal motility and on sedation level during CRI of medetomidine. STUDY DESIGN: Experimental, randomised, blinded, cross-over study. METHODS: Six healthy horses were given medetomidine hydrochloride, 7 µg/kg i.v., without (MED) and with (MED+V) vatinoxan hydrochloride, 140 µg/kg i.v., followed by CRI of medetomidine at 3.5 µg/kg/h for 60 min. Cardiorespiratory variables were recorded and borborygmi and sedation levels were scored for 120 min. Plasma drug concentrations were measured. The data were analysed using repeated measures ANCOVA and paired t-tests as appropriate. RESULTS: Initially heart rate (HR) was significantly lower and mean arterial blood pressure (MAP) significantly higher with MED compared with MED+V. For example at 10 min HR (mean ± s.d.) was 26 ± 2 and 31 ± 5 beats/minute (P = 0.04) and MAP 129 ± 15 and 103 ± 13 mmHg (P<0.001) respectively. At 10 min, cardiac index was lower (P = 0.02) and systemic vascular resistance higher (P = 0.001) with MED than with MED+V. Borborygmi were reduced after MED; this effect was attenuated by vatinoxan (P<0.001). All horses were sedated with medetomidine, but the mean sedation scores were reduced with MED+V until 20 min (6.8 ± 0.8 and 4.5 ± 1.5 with MED and MED+V, respectively, at 10 min, P = 0.001). Plasma concentration of dexmedetomidine was significantly lower in the presence of vatinoxan (P = 0.01). MAIN LIMITATIONS: Experimental study with healthy, unstimulated animals. CONCLUSIONS: Vatinoxan administered i.v. with a loading dose of medetomidine improved cardiovascular function and gastrointestinal motility during medetomidine CRI in healthy horses. Sedation was slightly yet significantly reduced during the first 20 min.. The Summary is available in Portuguese - see Supporting Information.

Comparison of sevoflurane and isoflurane in dogs anaesthetised for clinical surgical or diagnostic procedures.

OBJECTIVES: To assess attributes of sevoflurane for routine clinical anaesthesia in dogs by comparison with the established volatile anaesthetic isoflurane. METHODS: One hundred and eight dogs requiring anaesthesia for elective surgery or diagnostic procedures were studied. The majority was premedicated with 0.03 mg/kg of acepromazine and 0.01 mg/kg of buprenorphine or 0.3 mg/kg of methadone before induction of anaesthesia with 2 to 4 mg/kg of propofol and 0.5 mg/kg of diazepam. They were randomly assigned to receive either sevoflurane (group S, n=50) or isoflurane (group I, n=58) in oxygen and nitrous oxide for maintenance of anaesthesia. Heart rate, respiratory rate, indirect arterial blood pressure, haemoglobin saturation, vaporiser settings, end-tidal carbon dioxide and anaesthetic concentration and oesophageal temperature were measured. Recovery was timed. Data were analysed using analysis of variance and non-parametric tests. RESULTS: Heart rate (85 to 140/minute), respiratory rate (six to 27/minute) and systolic arterial blood pressure (80 to 150 mmHg) were similar in the two groups. End-tidal carbon dioxide between 30 and 60 minutes (group S 6.4 to 6.6 and group I 5.8 to 5.9 per cent) and vaporiser settings throughout (group S 2.1 to 2.9 and group I 1.5 to 1.5 per cent) were higher in group S. There was no difference in time to head lift (18+/-16 minutes), sternal recumbency (28+/-22 minutes) or standing (48+/-32 minutes). No adverse events occurred. CLINICAL SIGNIFICANCE: Sevoflurane appeared to be a suitable volatile anaesthetic for maintenance of routine clinical anaesthesia in dogs.

Effects of dexmedetomidine and MK-467 on plasma glucose, insulin and glucagon in a glibenclamide-induced canine hypoglycaemia model.

The commonly used sedative α2-adrenoceptor agonist dexmedetomidine has adverse cardiovascular effects in dogs that can be prevented by concomitant administration of the peripherally acting α2-adrenoceptor antagonist MK-467. An ancillary effect of dexmedetomidine is to decrease insulin release from the pancreas, whereas MK-467 stimulates insulin release. This study assessed the effects of co-administered dexmedetomidine and MK-467 in a canine glibenclamide-induced hypoglycaemia model. In a randomised, cross-over experiment, eight beagle dogs received five intravenous treatments, comprising two administrations of saline, with dexmedetomidine or dexmedetomidine and MK-467, and three administrations of glibenclamide, with saline, dexmedetomidine or dexmedetomidine and MK-467. Plasma concentrations of glucose, lactate, insulin, glucagon and the test drugs were monitored. Administration of glibenclamide significantly increased insulin secretion and decreased blood glucose concentrations. Dexmedetomidine counteracted glibenclamide-evoked hypoglycaemia. This was opposed by the α2-adrenoceptor antagonist MK-467, but the glibenclamide-evoked hypoglycaemia was not potentiated by co-administration of dexmedetomidine and MK-467. None of the dogs developed uncontrolled hypoglycaemia. Thus, the combination of dexmedetomidine and MK-467 appeared to be safe in this canine hypoglycaemia model. Nevertheless, when MK-467 is used to alleviate the undesired cardiovascular effects of α2-adrenoceptor agonists in dogs, it should be used with caution in animals at risk for hypoglycaemia because of its insulin-releasing and hypoglycaemic effects.

Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites.

Parathyroid hormone-related protein (PTHrP) has recently been identified in 60% of a series of primary breast cancers. The detection of a bone-resorbing factor in tumors with a propensity to metastasize to bone prompted study of PTHrP in breast cancer metastasis. PTHrP was localized by immunohistology in 12 of 13 (92%) breast cancer metastases in bone and in 3 of 18 (17%) metastases in non-bone sites. The statistical difference was highly significant (P less than 0.0001). Production of PTHrP as a bone-resorbing agent may contribute to the ability of breast cancers to grow as bone metastases.

Immunohistochemical localization of parathyroid hormone-related protein in human breast cancer.

Parathyroid hormone-related protein (PTHrP) is known to be a causative factor in humoral hypercalcemia of malignancy. A polyclonal rabbit antiserum directed against the amino-terminal region of the protein and immunoperoxidase methods have been used to locate the presence of PTHrP in a series of 102 consecutive invasive breast tumors removed surgically from normocalcemic women. Positive PTHrP staining was detected in 60% of the tumors but not in the accompanying normal breast tissue. Positive staining was related to the progesterone receptor status of the tumor (P = 0.039) and to the prognostic index of the patient (P = 0.046) and not to estrogen receptor status, patient age, tumor size, histological grade, or nodal status.

Oral contraceptive oestrogen and progestin potencies and the incidence of deep venous thromboembolism.

To assess possible differences in the incidence of venous thrombosis and pulmonary embolism associated with oral contraceptives of varying hormonal potencies, the authors conducted a retrospective cohort study in the 15-44 year old Michigan Medicaid population. Cohorts were defined by the progestin- and oestrogen-potencies of oral contraceptives in use at the time of follow-up as classified by an oral contraceptive potency scheme. Using the low-oestrogen-/low-progestin-potency formulations for reference (rate ratio = 1), adjusted rate ratios of 0.8 (95% CI: 0.5 to 1.3, P = 0.41) and 0.6 (95% CI 0.4 to 1.2, P = 0.13) were observed for intermediate-progestin-potency and high-progestin-potency formulations, respectively. Adjusted rate ratios of 1.4 (95% CI: 0.8 to 2.3, P = 0.21) and 2.6 (95% CI: 1.2 to 5.5, P = 0.01) were observed for intermediate- and high-oestrogen-potency formulations. These data suggest a dose-response relationship between oral contraceptive oestrogen potency and venous thromboembolism, whereas no such evidence for a dose-response relationship between oral contraceptive progestin potency and venous thrombo-embolism was found.

The prognostic importance of steroid receptors in endometrial carcinoma.

Three hundred forty-nine cases of primary endometrial carcinoma (endometrioid, adenosquamous, and clear-cell) were studied to investigate the relative prognostic importance of age, menopausal status, stage, histology, myometrial invasion, and estrogen and progesterone receptor content. Excluding menopausal status, all of these variables had a significant relationship to overall survival in a univariate analysis. Using a Cox multivariate regression analysis, stage, age, and an estrogen receptor value of more than 70 fmol/mg protein, combined with a progesterone receptor value of more than 30 fmol/mg protein, were independently associated with survival. The results demonstrate that for maximum prognostic information, both estrogen and progesterone content of tumors should be measured. Maximum prognostic information is obtained by using cutoff levels that are much higher than those traditionally accepted. This has particular relevance for patient stratification in clinical trials investigating receptor information and response to adjuvant or therapeutic treatment.

Cytogenetic features of twenty-six primary breast cancers.

Tumor preparations from 26 primary breast cancers were studied cytogenetically with G-banding, using a direct technique, synchronized short-term culture, or both. Two tumors had normal karyotypes, and 24 (92%) had chromosomal abnormalities. Nineteen tumors had chromosome 1 rearrangements, with 10 cases (40%) displaying distal short arm translocations (1p36). Other frequent breakpoints occurred at 3p21, 6q22-27, 11q21-25, 16q22-24, 17p, and 19q13. To seek primary rather than secondary cytogenetic changes, attention was directed toward tumors with diploid-range karyotypes (32-57 chromosomes per cell). Of four such tumors, three exhibited nonrandom involvement of chromosome 16q22. This, together with previously reported data, suggests that deletion or rearrangement of chromosome 16q21-24 may be a primary or specific event in a subset of breast cancers.

Comparison of EGFR, c-erbB-2 product and ras p21 immunohistochemistry as prognostic markers in primary breast cancer.

In a prospective study of 75 breast carcinomas, monoclonal antibodies EGFR1, Anti-serum 21N (As21N) and RAP-5 were used to assess immunohistochemically expression of Epidermal Growth Factor Receptor (EGFR), c-erbB-2 oncoprotein and ras protein p21. A careful comparison was made of their relative prognostic significance. Positive staining was seen with EGFR1 in 12/71 cancers (17%) and with As21N in 16/75 cancers (21%). Positive staining with RAP-5 occurred in all cancers and benign breast tissue, but varied in intensity. EGFR expression correlated with the number of involved lymph nodes, histological grade, estrogen and progesterone receptor (ER, PR) levels and the Melbourne Prognostic Index. C-erbB-2 and ras expression both correlated with ER levels and EGFR, but not with the Prognostic Index. Based on an immunohistochemical technique, EGFR expression emerges as the parameter with strongest prognostic associations.

Parathyroid hormone related protein in breast cancers of widely varying prognosis.

Parathyroid hormone related protein (PTHrP) is a novel calcium regulating hormone that may have a significant role in the pathophysiology of breast cancer. We have previously demonstrated a relationship between immunohistochemically detectable PTHrP in primary breast tumours and the subsequent development of bone metastases and hypercalcaemia. The aim of this study was to compare the PTHrP status in the primary tumours from three groups of patients with widely varying prognosis. (1) The favourable outcome group; all patients had a favourable prognosis and minimum 3 years disease free follow up (n = 30). (2) The unfavourable outcome group; all patients presented with localized breast cancer but developed distant disease within 3 years (n = 26). (3) The unfavourable presentation group; all had distant disease at first presentation (n = 26). No differences in PTHrP status of the primary tumour amongst the three patient groups were found (66%, 65% and 61% positive respectively). The development of bone with liver metastases and hypercalcaemia was associated with increased positive PTHrP status of the primary tumor.

Radical surgery with omental flap for uncontrolled locally recurrent breast cancer.

BACKGROUND: Uncontrolled chest wall disease due to breast cancer is a highly morbid condition causing pain, ulceration, malodour and the need for frequent dressings. Aggressive surgical approaches are rarely justified because most patients will succumb to metastatic breast cancer within a short period. A highly selected group of patients with minimal or no evidence of metastatic disease and good performance status may benefit from radical chest wall surgery. Omental transposition flaps are ideal for reconstructing extensive surgical defects following chest wall surgery. METHODS: A retrospective review was carried out of 61 female patients treated consecutively between 1980 and 1995. The surgical technique is described herein. RESULTS: All patients were symptomatic preoperatively. Symptoms included ulceration (80%), pain (44%) and malodour (40%). Twenty-nine patients had uncontrolled local recurrence following initial treatment for locally advanced breast cancer and 32 patients developed uncontrolled recurrence after treatment for operable breast cancer by mastectomy or conservation surgery. Median survival following chest wall surgery was 21 months and the median local recurrence-free interval was 20 months. Morbidity was -limited. There were no cases of major flap loss. Twenty-nine patients (48%) had no further local disease. Eighteen patients (30%) developed soft-tissue recurrence at the edge of the omental flap or in surrounding skin and 14 (23%) developed recurrence beneath the flap. CONCLUSION: In a highly selected group of patients with symptomatic uncontrolled chest wall recurrence who are fit and have an expectation of at least moderate-term survival, radical chest wall surgery and omental flap transposition offers excellent palliation and local control in the majority of patients

Comparison of detomidine and romifidine as premedicants before ketamine and halothane anesthesia in horses undergoing elective surgery.

OBJECTIVE: To compare detomidine hydrochloride and romifidine as premedicants in horses undergoing elective surgery. ANIMALS: 100 client-owned horses. PROCEDURE: After administration of acepromazine (0.03 mg/kg, IV), 50 horses received detomidine hydrochloride (0.02 mg/kg of body weight, IV) and 50 received romifidine (0.1 mg/kg, IV) before induction and maintenance of anesthesia with ketamine hydrochloride (2 mg/kg) and halothane, respectively. Arterial blood pressure and blood gases, ECG, and heart and respiratory rates were recorded. Induction and recovery were timed and graded. RESULTS: Mean (+/- SD) duration of anesthesia for all horses was 104 +/- 28 minutes. Significant differences in induction and recovery times or grades were not detected between groups. Mean arterial blood pressure (MABP) decreased in both groups 30 minutes after induction, compared with values at 10 minutes. From 40 to 70 minutes after induction, MABP was significantly higher in detomidine-treated horses, compared with romifidine-treated horses, although more romifidine-treated horses received dobutamine infusions. In all horses, mean respiratory rate ranged from 9 to 11 breaths/min, PaO2 from 200 to 300 mm Hg, PaCO2 from 59 to 67 mm Hg, arterial pH from 7.33 to 7.29, and heart rate from 30 to 33 beats/min, with no significant differences between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Detomidine and romifidine were both satisfactory premedicants. Romifidine led to more severe hypotension than detomidine, despite administration of dobutamine to more romifidine-treated horses. Both detomidine and romifidine are acceptable alpha2-adrenoceptor agonists for use as premedicants before general anesthesia in horses; however, detomidine may be preferable when maintenance of blood pressure is particularly important.

Incidence and toxicological aspects of cannabis and ethanol detected in 1394 fatally injured drivers and pedestrians in Ontario (1982-1984).

A comprehensive epidemiological study of the involvement of cannabis and ethanol in motor vehicle fatalities in the Province of Ontario, Canada, is described. The study is based on toxicological analyses of blood and, when available, urine specimens. Ethanol was determined by headspace gas chromatography (GC). For cannabis, the methods employed were radioimmunoassays (RIAs) for screening and gas chromatography/mass spectrometry (GC/MS) for the determination of delta-9-tetrahydrocannabinol (THC) in blood. The study sample consisted of 1169 drivers and 225 pedestrians. THC was detected in the blood of 127 driver victims (10.9%) in concentrations ranging from 0.2 to 37 ng/mL, with a mean of 3.1 +/- 5.0 ng/mL. Ethanol was found in 667 driver victims (57.1%), in concentrations ranging from 9 to 441 mg/100 mL, with a mean of 165.8 +/- 79.5 mg/100 mL. For pedestrians, the incidence of THC and ethanol in the blood was 7.6 and 53.3%, respectively. The incidence of THC in the driver victims in this study constitutes an approximately threefold increase over the results of an Ontario study completed in 1979. At least a part of the increase may be attributed to interstudy differences in analytical methodology for cannabinoids.

Incidence and toxicological aspects of drugs detected in 484 fatally injured drivers and pedestrians in Ontario.

Results are presented of a comprehensive drug study carried out on specimens from drivers and pedestrians fatally injured in Ontario. Toxicological analyses were regularly performed on blood and urine and occasionally on vitreous humor, stomach contents, and liver. The analytical procedures could detect and quantitate a wide variety of drugs including such illicit drugs as Cannabis. With respect to drivers, alcohol was found in 57% of the study sample and drugs other than alcohol, in 26%. However, in only 9.5% of the drivers were psychoactive drugs (other than alcohol) detected in the blood in concentrations that may adversely affect driving skills. Delta-9-Tetrahydrocannabinol and diazepam accounted for a majority of the findings in this category.

Comparison of detomidine/ketamine and guaiphenesin/thiopentone for induction of anaesthesia in horses maintained with halothane.

This prospective clinical study compared the physiological effects of two commonly used anaesthetic induction techniques in horses maintained with halothane. One hundred horses admitted for elective surgery were randomly allocated to receive either guaiphenesin (to effect) and thiopentone (5 mg/kg), or detomidine (20 microg/kg) and ketamine (2 mg/kg) for the induction of anaesthesia after acepromazine premedication. Anaesthesia was maintained with halothane in oxygen. There were no significant differences in breed, age, sex, weight, type of surgery and duration of anaesthesia between the groups. Immediately after induction of anaesthesia heart rate was higher after guaiphenesin and thiopentone, and arterial blood pressure was higher after detomidine and ketamine. Thereafter hypotension, often necessitating an infusion of dobutamine, developed in both groups. Arterial blood gases and respiratory rates were similar in the two groups. There were no significant differences between the groups in the subjectively scored quality of induction and recovery, or in recovery time.

The role of surgery in advanced carcinoma of the breast.

The role of surgery in the management of advanced carcinoma of the breast is controversial. Locally advanced carcinoma may present as a primary tumour or as recurrent disease. Treatment should be the result of a multi-disciplinary approach and may involve one or more different modalities. Minor surgery is usually meddlesome and often followed by local recurrence which is hard to control. Major resection does have a place, often in association with other modalities of treatment, and its use in carefully selected patients is described in this paper.

Tension pneumothorax secondary to nasojejunal feeding tube misplacement in a mechanically ventilated dog.

CASE REPORT: An 11-year-old female terrier-cross underwent general anaesthesia and mechanical ventilation for insulinoma resection. Following tumour removal, three consecutive but unsuccessful attempts were made to place a wire-guided nasojejunal feeding tube (NJFT), using both nostrils, with one tube eventually left in situ in the right nostril. A final successful attempt using a smaller NJFT was made via the left nostril. On withdrawal of the previously, unsuccessfully placed NJFT, the dog developed an acute tension pneumothorax. Severe cardiorespiratory dysfunction ensued, including decreasing arterial haemoglobin O2 saturation, increasing end-tidal CO2, hypotension and tachycardia. Immediate thoracocentesis with air evacuation from the pleural cavity followed by continuous air drainage through bilateral thoracostomy tubes produced marked improvement of cardiorespiratory function. During exploratory thoracotomy performed 1 day later, two lung lesions were identified and over sewn, one in the right middle lobe and the other in the accessory lobe. CONCLUSIONS: This is the first case report to describe in an anaesthetised and mechanically ventilated dog the occurrence and management of a tension pneumothorax as a life-threatening complication secondary to parenchymal injury after NJFT misplacement into the tracheobronchial tree. It illustrates that presence of a cuffed endotracheal tube does not protect against passing a NJFT into the bronchial system.