The role of employers in community health care systems

The postoperative analgesia and sedation in cats given carprofen (4.0 mg/kg bodyweight by subcutaneous injection preoperatively) was compared to that in cats given pethidine (3.3 mg/kg bodyweight by intramuscular injection postoperatively) in a controlled, randomised, blinded, multicentre clinical trial. Further dosing with the particular analgesic was allowed if a cat was exhibiting unacceptable pain. In total, 57 carprofen cases and 59 pethidine cases were evaluated. Significantly fewer cats in the carprofen group required additional doses of analgesic, and mean pain scores were significantly lower from four hours after ovariohysterectomy, and at 18 to 24 hours after castration, compared to the pethidine group. In conclusion, carprofen provided as good a level of postoperative analgesia as pethidine, but of a longer duration (at least 24 hours) and was well tolerated. It thus provides an option for 'pre-emptive analgesia' in cats about to undergo surgery.     

Prescription and use of analgesics in dogs and cats in a veterinary teaching hospital: 258 cases (1983-1989)

The frequency of prescribing analgesics and administering them for the treatment of apparent postoperative pain in 243 dogs and 15 cats was evaluated. Surgeries performed on the animals evaluated included limb amputations, limb-sparing bone cancer resection, thoracotomy, cervical vertebral instability repair, and humeral fracture repair. Only 1 cat was treated once with an analgesic after surgery, and cats were not evaluated statistically. Dogs undergoing amputation, limb salvage procedure, or thoracotomy were more likely to be treated than dogs undergoing the other surgeries. Ninety-six (40%) of the 243 dogs were under the influence of an analgesic at any time during their postoperative hospital stay, and 69 dogs (28%) received 1 or more doses of an analgesic after recovery from general anesthesia. One hundred thirty-three dogs were cared for in the intensive care unit (ICU) immediately after surgery. Written instructions for treatment with an analgesic were given for 61 of those dogs, and 50 were given at least 1 dose of the prescribed analgesic. Dogs cared for in the ICU were twice as likely to be given an analgesic as dogs cared for in the surgery ward. The estimated duration of analgesic effect exceeded 8 hours in 46 (19%) of 243 dogs. Small and juvenile dogs were least likely to be treated. Interns and residents were twice as likely as faculty to administer analgesics. Most written interpretations of pain behavior observed in the ICU were made on the basis of vocalizations. Half of the dogs for which medical record comments suggested moderate to severe pain were not given an analgesic. The most frequently administered analgesic immediately following surgery was oxymorphone, followed by butorphanol and morphine. Aspirin was never administered to dogs in the ICU, but was used in 10 dogs that were in the surgery ward for > 74 hours.     

Toxicologic effects of ribavirin in cats

Ribavirin, a broad-spectrum antiviral agent active in vitro against a number of RNA and DNA viruses, has been associated with moderate toxicity in laboratory animals and humans. Clinically, ribavirin has been used effectively in persons primarily to treat life-threatening viral diseases such as acute haemorrhagic fever or viral pneumonia of infants. In order to evaluate the feasibility of using this antiviral agent in cats, the effects of oral (p.o.), intramuscular (i.m.) and intravenous (i.v.) doses of ribavirin in 27 9-month-old specific-pathogen-free cats were evaluated by haematology, clinical chemistries, bone marrow biopsies and histopathology. Ribavirin was administered once daily for 10 consecutive days at a dose of either 11, 22, or 44 mg/kg after which all cats were euthanatized and necropsied. Most cats receiving 22 or 44 mg of ribavirin/kg became anorectic and suffered some degree of weight loss (0.2 to 0.6 kg), and about one-third of the cats developed diarrhoea and/or mucous membrane pallor. Icterus or haemorrhage was not observed. The most profound and consistent haematologic change, particularly among the moderate and high dosage groups regardless of route of administration, was a significant and severe thrombocytopenia (range, 33-78% reduction in mean platelet counts vs. baseline). Other changes, particularly reductions in total WBC and neutrophils and reductions in RBC and PCV, tended to occur at lower ribavirin dosages, but generally they were not statistically significant. Cats given 44 mg of ribavirin/kg i.v. showed significant decreases in leukocyte variables, including total WBC (P = 0.016), neutrophils (P = 0.026) and lymphocytes (P = 0.047). Mild-to-moderate increases in serum alanine aminotransferase and alkaline phosphatase activities occurred at doses of 22 and 44 mg/kg. Evaluation of bone marrow biopsies before and after treatment revealed that cats given 11 mg of ribavirin/kg had mild megakaryocytic (MK) hypoplasia, whereas cats receiving 22 or 44 mg/kg had progressively severe degrees of MK hypoplasia and dysplasia, asynchronous MK maturation, and increased myeloid:erythroid ratio. Pathologic changes in ribavirin-treated cats generally were mild and included primarily enteritis (seven cats) and hepatocellular vacuolation and/or centrilobular necrosis (seven cats). Results of this study in cats indicated that daily administration of ribavirin at a dose range of 11 to 44 mg/kg induced a dose-related toxic effect on bone marrow, primarily on megakaryocytes and erythroid precursors, and at the higher dosages is suppressed numbers of circulating leukocytes.     

Aspirin synergistically potentiates isoflurane minimum alveolar concentration reduction produced by morphine in the rat

BACKGROUND: The combination of opioids and nonsteroidal antiinflammatory drugs is more analgesic than the summed effect of each drug administered separately. This synergism has been used to obtain analgesia in the postoperative period at doses at which side effects are minimal. The aim of this study is to evaluate the analgesic interaction between aspirin and morphine in the rat during isoflurane anesthesia. The reduction in minimum alveolar concentration of isoflurane (MAC(ISO)) was used as an objective measure of the analgesic potency of individual drugs and their use in combination. METHODS: Thirty-seven male Wistar rats were anesthetized with isoflurane in oxygen, and the MAC(ISO) was determined before and after the intravenous administration of aspirin and morphine. Rats were administered morphine alone (1, 3, and 10 mg/kg) or morphine (1 and 3 mg/kg) and aspirin (30 mg/kg). The MAC(ISO) was determined from alveolar gas samples at the time of tail clamp. The duration of MAC(ISO) reduction was recorded. RESULTS: Aspirin did not have an effect on MAC(ISO), (average, 1.35+/-0.1%), whereas the combination of morphine (1 and 3 mg/kg) and aspirin (30 mg/kg) produced a reduction in the dose of morphine needed to produce the same degree of MAC(ISO) reduction. Actual MAC(ISO+drug) data were as follows: 1 mg/kg morphine, 1.17+/-0.14%; 3 mg/kg morphine, 0.98+/-0.15%; 1 mg/kg morphine plus aspirin, 0.90+/-0.04%; 10 mg/kg morphine, 0.63+/-0.13%; and 3 mg/kg morphine plus aspirin, 0.64+/-0.06%. CONCLUSIONS: The synergistic effects of aspirin and morphine allow a clinically significant reduction in the requirements of isoflurane and isoflurane plus morphine, and these drug combinations may decrease the side effects associated with the use of single higher, equianalgesic doses of these drugs.     

The behaviour of healthy awake cats following intravenous and intramuscular administration of midazolam

The onset of action and behavioural effects following intravenous (i.v.) and intramuscular (i.m.) administration of 0.05, 0.5, 1.0, 2.0 and 5.0 mg/kg of midazolam were studied for 2 h in 20 awake, healthy cats. All cats, except one that received 0.05 mg/kg i.m., showed effects of the drug, whereas no effects were observed in cats administered only the vehicle in which midazolam was dissolved. The onset of action was rapid following both i.v. and i.m. administration, some cats became ataxic, while others assumed positions of sternal or lateral recumbency. Even after administration of the highest dose (5.0 mg/kg), anaesthesia was not induced, with swallowing reflexes and conscious perception of a clamp placed on the tail still present in all cats. An abnormal arousal state was observed in many cats after administration of midazolam. During the first hour, restlessness was more commonly observed, while from 1 to 2 h, sedation was more prominent in cats that received the highest dose. Ataxia occurred in all but one cat, was short-lived in cats that received the lower doses, but still present at 2 h in all cats that received 2.0 and 5.0 mg/kg. Midazolam caused some of the cats to behave differently when approached and restrained compared with behavioural patterns identified prior to administration of the drug. The cats were more likely to behave abnormally following i.v. administration rather than i.m. administration and, for the most part, abnormal behaviour was equally distributed between the two extremes; cats being easier to approach and restrain and cats being more difficult to approach and restrain. Food consumption increased significantly, during the 2 h period, following all i.m. doses and all but the highest (5.0 mg/kg) i.v. dose, with most of the food being consumed in the first hour after administration.     

New techniques of ultrasound and color Doppler in the prospective evaluation of acute renal obstruction. Do they replace the intravenous urogram?

The effects of intravenously (i.v.) administered midazolam on noxiously evoked activity of spinal wide dynamic range (WDR) neurons were investigated in decerebrate, spinal-cord-transected cats. Extracellular, single-unit recordings were measured during stimulation by pinching the receptive field on the hind paw and the effect of midazolam at doses of 0.25, 0.5, 1, 2, and 4 mg/kg were measured. Two series of experiments were performed to characterize the analgesic effects of midazolam. In the first, dose-response experiments (n = 59) demonstrated a dose-dependent suppression of the noxiously evoked activity of spinal WDR neurons after midazolam administration. This effect of midazolam was maximal at a dose of 1 mg/kg i.v.. The second series of experiments (n = 14) demonstrated that a benzodiazepine antagonist, flumazenil (n = 8), promptly reversed the effect of midazolam, while an opioid antagonist, naloxone (n = 6), had no effect on the effect of midazolam. The present study demonstrates that i.v. administered midazolam suppresses noxiously evoked activity of spinal WDR neurons that is reversible by a benzodiazepine antagonist. This is consistent with an analgesic action of midazolam.     

Perseverance of viruses]

The effects of intravenous administration of variable-dose midazolam (0, 0.05, 0.075, 0.1, 0.3 and 0.5 mg/kg) and ketamine (3 mg/kg) were studied in twenty-four healthy unmedicated cats from time of administration until full recovery. End-points were chosen to determine the optimal dose to allow a short period of restraint without noxious stimuli, a short period of restraint with noxious stimuli and endotracheal intubation. Recovery characteristics, as well as undesirable behaviours observed during recovery, were also recorded. The dose of midazolam to achieve lateral recumbency with head down was found to be 0.016 mg/kg in 50% of the population (ED50) and 0.054 mg/kg in 95% (ED95) of the population. A midazolam dose of 0.286 mg/kg was required to prevent conscious perception of a stimulus to the ulnar nerve in 50% of the population and 0.652 mg/kg in 95% of the population. The ED50 and ED95 of midazolam required to prevent swallowing in response to a laryngoscope placed on the back of the tongue were found to be 0.265 mg/kg and 0.583 mg/kg, respectively. The ED50 doses of 0.265 mg/kg for intubation and 0.286 mg/kg for restraint with noxious stimulation were close to the tested dose of 0.3 mg/kg. At that dose, the lack of responses lasted 3.67 +/- 2.27 min for laryngoscope and 2.50 +/- 2.20 min for ulnar nerve stimulation, with recovery to walking with ataxia taking 41.50 +/- 15.18 min and complete recovery taking 3.6 +/- 1.3 h. The predominant behavioural pattern during recovery was found to be normal, but some cats also exhibited abnormal behavioural patterns. Nine of the twelve cats exhibited an abnormal arousal state, with 4 being restless and 5 being sedated. Seven of the twelve cats exhibited an abnormal behaviour when approached, with three of the cats being more difficult to approach and four of the cats being easier to approach. Eight of the twelve cats exhibited an abnormal behavioural pattern when restrained, with the cats equally divided between more difficult and easier to restrain. Five of the twelve cats vocalized more during the recovery. The ED50 of 0.042 mg/kg to induce chemical restraint without a noxious stimulus is close to the tested dose of 0.05 mg/kg. At that dose, cats remained lateral with head down for 5.49 +/- 4.02 min, took 25.96 +/- 5.77 min to walk with ataxia and 1.7 +/- 0.4 h for complete recovery. The predominant behavioural patterns during recovery were normal, with several cats exhibiting some abnormal patterns. Two cats were sedated, one cat was more difficult to approach, one cat was easier to restrain and three cats were more vocal.     

The metabolism of the hypolipidaemic drug sultosilic acid in rat, dog and man

1. Single oral doses of the hypolipidaemic drug [35S]sultosilic acid to rats (40 mg/kg), dogs (40 mg/kg) and man (7 mg/kg) were well absorbed. During three days, means of 59.2%, 58.8% and 61.8% in urine and 37.7%, 31.9% and 19.7% in faeces, were excreted by these species respectively. Most of the dose was excreted during the first 24 h. 2. Peak plasma levels of 35S were generally reached during 1-2 h after oral doses in rats (12 micrograms equiv./ml), dogs (45 micrograms equiv./ml) and two human subjects (15.2 and 10.3 micrograms equiv./ml). In humans, peak plasma levels of unchanged drug (at 1-1.5 h) were 10.5 and 6.3 micrograms/ml. Plasma concentrations of 35S increased almost proportionately to dose in rats following oral doses of 400 and 1200 mg/kg, although in dogs, concentrations were similar at these two dose levels but several times higher than at 40 mg/kg. 3. Tissue concn. of 35S were generally higher in rats than in dogs. Highest concn. occurred at 3 h in rats and 1 h in dogs. Apart from those in the liver and kidneys, tissue concn. were appreciably lower than the corresponding plasma levels. 4. The major radioactive component in dog urine was sultosilic acid. Rat and human urine contained sultosilic acid and also two more polar major metabolites. In male and female rat urine, the proportions of these excretory products differed and the proportions in male rat urine were similar to those in human urine. Sultosilic acid was also the only component detected in dog plasma, whereas rat and human plasma also contained the two urine metabolites. Dog bile contained a conjugate of sultosilic acid. 5. The two metabolites have been identified by mass spectrometry and nuclear magnetic resonance spectroscopy as products resulting from oxidation of the methyl in the p-toluenesulphonyl group. The structures assigned are the corresponding carboxylic acid and the hydroxymethyl derivatives.     

Species differences in pharmacokinetics of a hepatoprotective agent, YH439, and its metabolites, M4, M5, and M7, after intravenous and oral administration to rats, rabbits, and dogs

Pharmacokinetic parameters of YH439 and its metabolites, M4, M5, and M7, were compared after iv administration of YH439 to rats (1-10 mg/kg), rabbits (1-10 mg/kg), and dogs (1-20 mg/kg) and oral administration of YH439 to rats (50-500 mg/kg) and dogs (0.5-2 g per whole body weight). After oral administration of YH439 to rats, the F values were 3.67, 1.33, and 0.859% for YH439 oral doses of 100, 300, and 500 mg/kg, respectively. However, the F value increased significantly, 21.2%, after oral administration of YH439-contained mixed micelles (10 mg as free YH439) to rats due to increased water solubility of YH439. Species differences in the pharmacokinetics of YH439 and its metabolites were found. First, M7 was detected in both plasma and urine after both iv and oral administration of YH439 to dogs, whereas it was detected neither in rats nor in rabbits, indicating that considerable amount of M7 was formed from YH439 only in dogs. Second, the AUC (or AUC0-->t) ratios of M4 to YH439 after iv administration of YH439 were 24.6-31.3, 42.2-49.2, and 2200-7640% for rats, rabbits, and dogs, respectively, indicating that formation of M4 after iv administration of YH439 was maximal in dogs. Third, the AUC (or AUC0-->t) ratios of M5 to YH439 after iv administration of YH439 were 103-127, 2.93-3.31, and 92.4-158% for rats, rabbits, and dogs, respectively, indicating that formation of M5 after iv administration of YH439 was minimal in rabbits.     

Cerivastatin: pharmacology of a novel synthetic and highly active HMG-CoA reductase inhibitor

The pyridine derivative cerivastatin is a new entirely synthetic and enantiomerically pure inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. As a sodium salt cerivastatin is present in the active, open ring form. Cerivastatin inhibited the membrane-bound (non-solubilized) HMG-CoA reductase of the native microsomal fraction isolated from rat liver with a Ki value of 1.3 x 10(-9) M. The reference compound lovastatin was 100-fold less potent and exhibited a Ki value of 150 x 10(-9) M. Cerivastatin inhibited the cholesterol synthesis in the human hepatoma cell line HepG2 cells with a similar IC50 value of 1.0 x 10(-9) M. In vivo studies reflected its high in vitro activity. In both rats and dogs, cerivastatin inhibited the hepatic [14C]cholesterol synthesis from [14C]acetate with an oral ED50 value of 0.002 mg/kg body weight, while lovastatin exhibited an oral ED50 value of 0.3 mg/kg in rats, showing again the ratio of 100 or more between cerivastatin and lovastatin. In the small intestine and testes, cerivastatin was at least 50-fold less active with oral ED50 values higher than 0.1 mg/kg, which is indicative for a high liver selectivity of cerivastatin. In cholestyramine-primed dogs cerivastatin dose-dependently lowered the serum cholesterol concentrations by up to 59% with 0.1 mg/kg after 20 days. Interestingly, the serum triglycerides were markedly reduced by 53 and 76% with 0.03 and 0.1 mg/kg, respectively. In normal chow fed dogs the low density lipoprotein (LDL) concentrations were reduced by up to 75% after 0.1 mg cerivastatin/kg. The ratio of HDL/LDL increased by 81% compared with a change of only 14% in the placebo treated control group. The antiatherogenic effect of cerivastatin was shown in rabbits fed a diet enriched with 0.2% cholesterol. After 9 weeks on diet 0.1 mg cerivastatin/kg decreased the accumulation of cholesterol ester in the arterial tissue by 73%. In summary, these data as compared to published data on other HMG-CoA reductase inhibitors demonstrate cerivastatin to be the most active compound in this class. Vastatins used in therapy are effective in mg doses, while cerivastatin offers a new low dose therapy in the microg range.     

Comparison of the fatty acid compositions in intraepithelial and infiltrating lesions of the cervix: part II, free fatty acid profiles

Clinical studies report a low incidence of intestinal side effects with transdermally administered fentanyl (TTS-fentanyl) in comparison with oral morphine. To support these clinical data, analgesic and intestinal effects of both opioids were compared in rats. After subcutaneous injection, analgesia in the tail withdrawal reaction test was obtained at a peak effect dose of 0.032 mg/kg with fentanyl and 8.0 mg/kg with morphine. This analgesic dose exceeded the ED50 for inhibition of castor oil-induced diarrhea only slightly (1.1 x) in the case of fentanyl (0.028 mg/kg) but markedly (36 x) in the case of morphine (0.22 mg/kg). To reverse completely the antidiarrheal effect of equivalent analgesic doses of the opioids (their ED50S for analgesia lasting 2 hours), much more naloxone was required in the case of morphine (5.4 mg/kg) than in the case of fentanyl (0.19 mg/kg). After oral administration, the difference between both opioids was less pronounced. Analgesia was obtained at 0.85 mg/kg with fentanyl and 32 mg/kg with morphine. This analgesic dose only slightly (1.7 x) exceeded the antidiarrheal dose in the case of fentanyl (0.49 mg/kg) but significantly (6.2 x) in the case of morphine (5.2 mg/ kg). To reverse completely the antidiarrheal effect of equivalent analgesic oral doses of the opioids (their ED50S for analgesia lasting 2 hours), more naloxone was required in the case of morphine (11 mg/kg) than in the case of fentanyl (2.0 mg/kg). Rapid penetration of fentanyl into the brain is thought to be responsible for small dissociation between the analgesic and intestinal effect of this lipophilic opioid. The present data provide preclinical evidence to support the relatively low incidence of intestinal side effects observed clinically with the use of TTS-fentanyl in comparison with orally administered morphine.     

MS-551 and KCB-328, two class III drugs aggravated adrenaline-induced arrhythmias

We investigated the proarrhythmic effects of MS-551 and KCB-328, class III antiarrhythmic drugs using adrenaline-induced arrhythmia models in halothane anaesthetized, closed-chest dogs. In the control period, adrenaline, starting from a low dose of 0.25 to up to 1.0 microg/kg/50 s i.v., was injected to determine the arrhythmia inducing dose and the non-inducing dose. After MS-551 or KCB-328 administration, the adrenaline injection was repeated and the interval between the injection and the occurrence of arrhythmia (latent interval), the changes in arrhythmic ratio (as calculated by dividing the number of ventricular premature contraction by the number of the total heart rate) and the severity of arrhythmia were observed. MS-551 infusion, 1 mg/kg/30 min, decreased the heart rate (HR) by 16% (P<0.01) and prolonged the QTc interval by 20% (P<0.01). During the 30 min of MS-551 infusion, arrhythmias occurred in three out of seven dogs (torsades de pointes (TdP) type VT in one dog). After these arrhythmias disappeared, MS-551 decreased the latent interval of the adrenaline arrhythmias produced by the inducing dose (30+/-2 s compared with 43+/-3 s of the control interval, P < 0.05), increased the arrhythmic ratio (P<0.05) and induced arrhythmias by non-inducing adrenaline doses (P<0.05). Effect of a new class III drug KCB-328 infusion, 0.3 mg/kg/30 min, was compared witih MS-551 using the same model. KCB-328 decreased the HR by 21% (P<0.01) and prolonged the QTc interval by 25% (P<0.01). During the 30 min of infusion, arrhythmias occurred in five out of seven dogs (TdP in two dogs). KCB-328 also decreased the latent interval of the adrenaline arrhythmias produced by the inducing doses (31+/-3 s compared with 49+/-7 s of the control period, P<0.05), but did not significantly alter the arrhythmic ratio. Adrenaline induced TdP only after MS-551 or KCB-328 was administered, i.e. after MS-551, 1 mg/kg/30 min, 3/7 versus 0/7 in the control; KCB, 0.3 mg/kg/30 min, 3/7 versus 0/7 in the control. To examine the direct arrhythmogenic effect of MS-551 and whether an adrenergic mechanism plays some role on this arrhythmogenesis, a bolus injection of MS-551, 3 mg/kg, was injected either without pre-treatment or after pre-treatment with propranolol 0.3 mg/kg. MS-551 induced arrhythmias in five out of seven dogs (TdP in one dog). Also in the propranolol pre-treated dogs, MS-551 induced arrhythmias in five out of seven dogs (TdP in 1 dog). In conclusion, these observations indicate that MS-551 and KCB-328 induced arrhythmias and intensified proarrhythmic effects of adrenaline, MS-551 being stronger than KCB-328 at the same QTc prolonging doses. The direct arrhythmogenic effect of MS-551 was not influenced by beta-blocker treatment.     

Analgesic and anti-inflammatory activity of saponins of Argania spinoza

We studied analgesic and antiinflammatory actions of saponins of Argania spinosa cakes in mice and rats. With oral doses of 50 to 300 mg/kg, we found peripheric analgesic actions equivalent to the acetyl salicylic acid ones. The maximum protection was obtained with 500 mg/kg per os. There is no morphine-like central analgesic effect. Antiinflammatory studies were done in vivo using oedema due to carrageenine or experimental trauma in rats. There was a decrease in the paw swelling at doses of 10 mg/kg per os. At doses of 50 to 100 mg/kg per os, the antiinflammatory effect was similar to the one of indomethacin at doses of 10 to 20 mg/kg per os. In vitro, there was an inhibition of beef synovial fluid degradation by OH. radicals. The inhibition action is evaluated with an IC20 > or = 6 microM. Argania spinosa saponins have also an antiradical action against DPPH (IC25 = 85 mM) and against OH. radicals (IC25 = 0.56 M). Since they do not have any inhibition effect on PGE2 synthesis, their antiinflammatory activity can be explained by their action on leucotriens in the metabolic pathway of arachidonic acid.     

Effects of a prostaglandin E1 analogue, misoprostol, on renal function in dogs receiving nephrotoxic doses of gentamicin

OBJECTIVE: To determine whether the prostaglandin E1 analogue, misoprostol, could preserve renal function in dogs receiving nephrotoxic doses of gentamicin. ANIMALS: 12 (6/group) healthy sexually intact male dogs. PROCEDURE: All dogs were given high doses of gentamicin (10 mg/kg of body weight, i.v., q 8 h, for 8 consecutive days). Six dogs (treatment group) received misoprostol (3 microgram/kg, p.o., q 8 h for the duration of the study) and 6 dogs (control group) received vehicle (1 capsule, p.o., q 8 h). Renal function was assessed before treatment (day 0) and on days 3, 6, 9, and 11 after initiation of treatment by measurement of serum biochemical variables, urine specific gravity, and exogenous creatinine clearance. Serum electrolyte and protein concentrations and presence of proteinuria, glycosuria, and cylindruria were also determined. At the end of the study, renal histopathologic changed were evaluated. RESULTS: Dogs receiving misoprostol had significant reduction in exogenous creatinine clearance with time, compared with dogs receiving vehicle (P = 0.0264). Dogs receiving misoprostol tended to develop more severe azotemia, hyperphosphatemia, and renal histopathologic changes; however, results were not significantly different between groups. CONCLUSION: Misoprostol (3 microgram/kg, p.o., q 8 h) did not preserve renal function and may have exacerbated gentamicin-induced nephrotoxicosis in this group of dogs. CLINICAL RELEVANCE: Supplementation of vasodilatory prostanoids may exacerbate renal dysfunction in dogs receiving high doses of gentamicin.     

A modifying locus for familial adenomatous polyposis may be present on chromosome 1p35-p36

Sixteen healthy male dogs were used at random in this protocol. The dogs were anaesthetized with isoflurane in oxygen. Eight of the dogs received 0.25 mg/kg of butorphanol (group B) and the others an equal volume of isotonic saline (group S) administered by a catheter inserted in the lumbosacral epidural space. Butorphanol concentrations in plasma and cerebrospinal fluid (CSF) were measured using high-performance liquid chromatography with electrochemical detection. Maximum concentration of butorphanol and time to obtain this concentration were 42.28 ng/mL at 13.88 min in blood, and 18.03 ng/mL at 30 min in CSF. Volume of distribution, clearance, mean distribution and elimination half-lives were respectively 4.39 L/kg, 2.02 L/h.kg, 16.5 min and 189.1 min. Mean isoflurane minimal alveolar concentration values for group B obtained following hind- or forelimb stimulation decreased by 31% after epidural butorphanol. Cutaneous analgesia (to pin-prick test) persisted for 3 h after the end of isoflurane anaesthesia in group B and was in correlation with the plasmatic analgesic dose of butorphanol (9 ng/mL). These results suggested that analgesia was predominantly obtained by action of butorphanol on the supraspinal structures following its vascular systemic absorption.     

Effects of systemic atropine sulfate administration on the frequency content of the cat sensorimotor EEG during sleep and waking.

Sensorimotor electroencephalogram (EEG) frequencies in cats were evaluated with power spectral analysis before and after 3 doses of atropine sulfate. All doses of atropine tested caused enhanced EEG slow waves (0–7 Hz) and spindles (8–25 Hz) during waking immobility, and postdrug frequency profiles during slow-wave sleep and waking immobility were identical. With 0.75 mg/kg atropine, movement (head movement, locomotion) resulted in EEG desynchronization and reduced power in all frequencies less than 24 Hz. After 1.5 or 3.0 mg/kg atropine, power in low frequencies remained elevated during movement, but power in spindle frequencies was significantly reduced compared with other states. During active REM sleep after 1.5 mg/kg atropine, power in spindle frequencies was significantly lower than that during quiet REM sleep. These results indicate that the sensorimotor cortical EEG in cats is under the control of multiple systems. At least 1 of these systems is active during movement, and its actions are resistant to muscarinic receptor blockade. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

K-ATP-blocking diuretic PNU-37883A reduces plasma renin activity in dogs

We determined the effects of the K-adenosine triphosphate (ATP)-blocking diuretic PNU-37883A on plasma renin activity (PRA) in conscious and anesthetized dogs. In conscious dogs, oral PNU-37883A (6-60 mg/kg) was less potent than hydrochlorothiazide (0.15-1.5 mg/kg) and furosemide (FURO; 0.3-3.0 mg/kg) but exhibited high natriuretic efficacy with little kaliuresis. Unlike the standard diuretics, PNU-37883A reduced PRA by 46-76%, and its high dose minimally affected 24-h urinary aldosterone excretion. PNU-37883A, 1 mg/kg i.v., also blunted the hyperreninemia induced by 1 mg/kg i.v. FURO. In cannulated dogs, 10 mg/kg i.v. PNU-37883A maximally increased fractional Na+ clearance 140% and reduced PRA 76%, but these effects were accompanied by a mean 13 mm Hg pressor effect. In anesthetized dogs, renal artery-infused PNU-37883A (3 mg/kg/h i.r.a.) increased Na+ excretion and reduced renal venous PRA independent of hemodynamics, whereas half this dosage selectively reduced renal venous PRA and renin release, independent of hemodynamics and natriuresis. These data demonstrate that the K-ATP blocker diuretic PNU-37883A reduces PRA in dogs after oral, i.v., and i.r.a. administration and could be a useful pharmacologic agent for exploring the role of K-ATP channels in regulating renin release.     

Antihypertensive activity and pharmacokinetics of KD3-671, a nonpeptide AT1-receptor antagonist, in renal hypertensive dogs

The antihypertensive activity and pharmacokinetics of KD3-671 (previously named KT3-671), a nonpeptide AT1-receptor antagonist, were investigated in renal hypertensive dogs with normal or high plasma renin activity (PRA). A single administration of KD3-671 at 3 and 10 mg/kg, p.o., to the hypertensive dogs with high PRA dose-dependently reduced mean blood pressure (MBP), which was not correlated with plasma KD3-671 concentration. Significant increases in PRA and plasma angiotensin (Ang) II occurred 2 h after KD3-671 dosing. Enalapril at 3 mg/kg, p.o., also reduced MBP. Neither KD3-671 nor enalapril affected heart rate. When given orally once a day for 29 days to the hypertensive dogs with normal PRA, KD3-671 at 3 and 10 mg/kg/day dose-dependently reduced MBP, which was smaller than that in the dogs with high PRA. This was the case for enalapril. The hypotension induced by the first dose of KD3-671 or enalapril was consistently observed after doses 8, 15, 22, and 29. After cessation of repeated dosing, no rebound phenomenon in MBP was observed. Pharmacokinetic parameters of KD3-671 were not influenced by repeated dosing. KD3-671 markedly increased both PRA and plasma Ang II concentration at 2 h after dosing. These results suggest that KD3-671 may be useful for the treatment of hypertension.     

Antilipidemic drugs. Part 4: The metabolic fate of the hypolipidemic agent isopropyl-[4'-(p-chlorobenzoyl)-2-phenoxy-2-methyl]-protionate (LF 178) in rats, dog and man

The excretion and plasma concentrations of radioactivity and chromatographic patterns of radioactive components in plasma and excreta have been compared in rats, dogs and man after oral doses of the hypolipidemic agent isopropyl-[4'-(p-chlorobenzoyl)-2-phenoxy-2-methyl]-propionate (LF 178; procetofene; Lipanthyl?). 2. In rats, 48.1% of a single dose of 25 mg/kg was excreted in the urine, and 48.6% in the faeces. In dogs, 23.1% of a single dose at the same level was excreted in the urine, and 71.8% in the faeces, but 88.1% of a dose of 300 mg to man was excreted in the urine, and only 5.1% in the faeces. Peak levels of radioactivity in the plasma of all three species studied were similar (20--30 mug/ml) after doses at these levels and concentrations declined thereafter with half-lives of 7--24 h in rats and dogs, and 7 h in man. The half-life of radioactivity concentrations in rat plasma was not altered by repeated daily doses for 7 days. 3. Whole-body autoradiography of rats showed that radioactivity was largely associated with the liver, kidneys and gut, which are the organs of biotransformation and excretion, although relatively high levels were present in lungs and blood, and small amounts of radioactivity had a widespread distribution into some peripheral tissues during 2--7 h after dosing. 4. The available chromatographic evidence indicated that the most important biotransformation pathway appeared to be ester hydrolysis to LF 178 acid and formation of water soluble conjugates of this acid. This pathway appeared similar to that of the related drug clofibrate (ethyl p-chlorophenoxyisobutyrate).     

Endobronchial tumours in childhood

Like psychomotor stimulants, a weak amphetamine-like agent, such as phenylpropanolamine, enhances the analgesic effects of morphine (MOR). Thus, it is possible that full psychomotor stimulant potency is not required to increase the analgesic action of opiates. The validity of this assumption is here tested by studying the ability of (-)-norpseudoephedrine (NPE), an enantiomer of phenylpropanolamine and a metabolite of cathinone, to influence both the analgesic effects of MOR and its discriminative stimulus properties. In mice NPE (5.6-10.0-17.0 mg/kg i.p.) did not prolong the latency to lick or to remove paws from a plate warmed at 54 degrees C. However, it significantly potentiated the analgesic effect of 3.2 mg/kg of MOR. These results were replicated in rats by use of the formalin test, which measures the numbers of hind paw flinches produced by injecting 50 microl of formalin into the dorsal surface of the paw. The higher dose of NPE (17 mg/kg) increased the effect of sub-analgesic doses of MOR (0.56 and 1.0 mg/kg). In rats trained to discriminate between 0.5 mg/kg of amphetamine and solvent in a two-lever operant behavior reinforced by water access. NPE induced a dose-dependent increment of drug lever responding from 0% at 1.0 mg/kg to 100% at 32.0 mg/kg. In contrast, NPE did not generalize for the MOR cue up to the dose of 56.0 mg/kg, which produced a substantial reduction of the response rate. However, when given in combination, NPE attenuated the discriminative effects of MOR and potentiated its inhibitory action on the response rate. These results exclude a direct action of NPE on the mu opiate system. In conclusion, NPE preserves amphetamine-like properties and these properties are probably responsible for the interaction of the drug with the analgesic and discriminative effects of MOR. Therefore, this study contradicts the assumption that the analgesic effects of MOR can be enhanced by a sympathomimetic drug that lacks significant psychostimulant actions.