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Further characterization of the discriminative stimulus effects of spiradoline.

The results of a previous study in rats indicated that spiradoline has pharmacologically selective discriminative effects that are mediated by kappa-opioid receptors. However, the training dose, 3.0 mg/kg, increased response latencies, suggesting that it was relatively high. The current study was performed to characterize further the discriminative effects of spiradoline by using a lower training dose, 1.0 mg/kg, and testing a larger number of drugs for generalization with spiradoline. Rats were trained in a discrete-trial avoidance/escape procedure to discriminate 1.0 mg/kg spiradoline, SC, from saline in an average of 19.7 sessions; response latencies after saline and spiradoline were not different from each other. The rats generalized dose dependently and completely to other kappa-opioid agonists that have relatively high efficacy: ethylketocyclazocine, U69,593, and U50,488. They generalized partially to ketocyclazocine, (-)-N-allylnormetazocine, and DuP 747, and not at all to cyclazocine, butorphanol, nalorphine, and pentazocine, discriminable opioids that have relatively low efficacy at kappa-opioid receptors, or to morphine and dextromethorphan, discriminable drugs that do not act at kappa-opioid receptors. The discriminative effects of spiradoline were unaffected by the mu-opioid antagonist beta-funaltrexamine, but were blocked completely for at least 4 weeks by the kappa-opioid antagonist nor-binaltorphimine. Thus, spiradoline-like stimulus control of behavior remains kappa-opioid selective, and continues to have a high efficacy requirement even at a training dose that does not impair performance.

Analgesics, Non-Narcotic↗

Opioid receptor blockade throughout prenatal life confers long-term insensitivity to morphine and alters mu opioid receptors.

The influence of maternal opioid receptor blockade (50 mg/kg naltrexone, NTX) or saline (controls) throughout pregnancy on nociception and brain opioid receptor characteristics of rat offspring were examined; all animals were crossfostered to untreated mothers at birth. At 21 and 30 days, NTX-exposed pups weighed 8.2-24.3% more than controls, but both NTX and control groups were of similar body weights at 48, 60, and 80 days. Rats in the NTX and control groups displayed comparable baseline reactions to the hotplate. Morphine challenge tests and nociceptive measures revealed that NTX-subjected offspring examined at 21, 30, 48, and 60 days did not react to dosages that invoked 42-132% decreases from baseline levels in controls. Animals exposed prenatally to NTX were analgesic when injected with the opioid butorphanol or the nonopioid xylazine. The binding affinity (Kd) and capacity (Bmax) of delta and kappa opioid receptors were similar in NTX and control groups at 21 and 80 days. However, the Bmax, but not the Kd, of mu opioid receptors was subnormal in NTX offspring by about 20% in contrast to control rats at 21 and 80 days. The results imply that the interactions of some endogenous opioids with opioid receptors during development are determinants of certain aspects of pain sensitivity as well as the density of particular opioid receptors in the postnatal period.

Analgesics, Opioid↗

Comparison of cizolirtine citrate and metamizol sodium in the treatment of adult acute renal colic: a randomized, double-blind, clinical pilot study.

BACKGROUND: Renal colic causes excruciating pain that provides a good clinical model of acute pain for the development of new analgesics. OBJECTIVE: The purpose of the study was to compare the analgesic efficacy and tolerability of cizolirtine citrate and metamizol sodium in adult acute renal colic. METHODS: This Phase II, randomized, double-blind, clinical pilot study was conducted in the emergency departments of 6 general hospitals in the Czech Republic between October 2000 and February 2001. Male and female patients aged 18 to 65 years and presenting with hematuria and moderate to severe pain due to suspected renal colic starting within the 24 hours before presentation were eligible. Patients were randomized to receive a single IV dose of cizolirtine 350 mg or metamizol 2,500 mg, administered by slow infusion over 15 minutes. Both doses were maximal for the respective drugs to attain adequate analgesia. Use of rescue medication with butorphanol was allowed 30 minutes after study drug administration. Pain intensity was assessed at various time points during the following 360 minutes using a 100-mm visual analog scale (VAS) and a verbal categoric scale. In addition, a specific verbal categoric scale was used to rank pain relief. Physical examinations, laboratory tests, and questioning for adverse events addressed drug tolerability. RESULTS: Sixty-four patients (50 men, 14 women; mean [SD] age, 44.21 [12.29] years; mean [SD] body mass index, 25.97 [3.38] kg/m(2)) were enrolled. Physical examination findings and mean VAS pain intensity scores at baseline (mean [SD], 79.42 [7.89] mm and 82.59 [10.50] mm in the cizolirtine and metamizol groups, respectively) were similar in both groups. After 30 minutes, the mean (SD) scores were 33.84 (25.15) mm and 25.41 (24.51) mm, respectively. This difference was not statistically significant, and the noninferiority of cizolirtine with respect to the comparator could not be established. However, the proportion of patients that showed satisfactory pain relief (ie, decrease of > or = 50% in VAS pain intensity score compared with baseline) at 30 minutes in the cizolirtine group was fairly high (64.5%), which means relevant analgesic activity. Both treatments were well tolerated; 6 adverse events were reported in 5 patients (7.8%), and all were considered as not treatment related. CONCLUSIONS: Although this limited pilot study did not include an internal measure of sensitivity, relevant pain reduction was shown in the population of patients with suspected renal colic undergoing treatment with cizolirtine, suggesting the presence of analgesic activity. However, the efficacy of cizolirtine was found to be similar to that of metamizol. Treatments were well tolerated.

Acute Disease↗

Management of osteoarthritis in cats.

OA is a disease of the geriatric cat. Clinical signs include weight loss, anorexia, depression, urinating outside the litter box, poor grooming, and lameness. Radiographs, synovial fluid analysis, and synovial biopsy are used to distinguish this disease from the various forms of inflammatory arthritis that affect the cat. Management consists mainly of environmental manipulation. Aspirin, butorphanol, corticosteroids, and nutritional supplements are used for chronic treatment of painful OA in cats.

Adrenal Cortex Hormones↗

Propofol anesthesia.

Although questions may still remain regarding the use of this unique sedative-hypnotic drug with anesthetic properties in high-risk patients, our studies have provided cardiopulmonary and neurological evidence of the efficacy and safety of propofol when used as an anesthetic under normal and selected impaired conditions in the dog. 1. Propofol can be safely and effectively used for the induction and maintenance of anesthesia in normal healthy dogs. Propofol is also a reliable and safe anesthetic agent when used during induced cardiovascular and pulmonary-impaired conditions without surgery. The propofol requirements to induce the safe and prompt induction of anesthesia prior to inhalant anesthesia with and without surgery have been determined. 2. The favorable recovery profile associated with propofol offers advantages over traditional anesthetics in clinical situations in which rapid recovery is important. Also, propofol compatibility with a large variety of preanesthetics may increase its use as a safe and reliable i.v. anesthetic for the induction and maintenance of general anesthesia and sedation in small animal veterinary practice. Although propofol has proven to be a valuable adjuvant during short ambulatory procedures, its use for the maintenance of general anesthesia has been questioned for surgery lasting more than 1 hour because of increased cost and marginal differences in recovery times compared with those of standard inhalant or balanced anesthetic techniques. When propofol is used for the maintenance of anesthesia in combination with a sedative/analgesic, the quality of anesthesia is improved as well as the ease with which the practitioner can titrate propofol; therefore, practitioners are able to use i.v. anesthetic techniques more effectively in their clinical practices. 3. Propofol can induce significant depression of respiratory function, characterized by a reduction in the rate of respiration. Potent alpha 2 sedative/analgesics (e.g., xylazine, medetomidine) or opioids (e.g., oxymorphone, butorphanol) increase the probability of respiratory depression during anesthesia. Appropriate consideration of dose reduction and speed of administration of propofol reduces the degree of depression. Cardiovascular changes induced by propofol administration consist of a slight decrease in arterial blood pressures (systolic, mean, diastolic) without a compensatory increase in heart rate. Selective premedicants markedly modify this characteristic response. 4. When coupled with subjective responses to painful stimuli, EEG responses during propofol anesthesia provide clear evidence that satisfactory anesthesia has been achieved in experimental dogs. When propofol is used as the only anesthetic agent, a higher dose is required to induce an equipotent level of CNS depression compared with the situation when dogs are premedicated. 5. The propofol induction dose requirement should be appropriately decreased by 20% to 80% when propofol is administered in combination with sedative or analgesic agents as part of a balanced technique as well as in elderly and debilitated patients. As a general recommendation, the dose of propofol should always be carefully titrated against the needs and responses of the individual patient, as there is considerable variability in anesthetic requirements among patients. Because propofol does not have marked analgesic effects and its metabolism is rapid, the use of local anesthetics, nonsteroidal anti-inflammatory agents, and opioids to provide postoperative analgesia improves the quality of recovery after propofol anesthesia. 6. The cardiovascular depressant effects of propofol are well tolerated in healthy animals, but these effects may be more problematic in high-risk patients with intrinsic cardiac disease as well as in those with systemic disease. In hypovolemic patients and those with limited cardiac reserve, even small induction doses of propofol (0.75-1.5 mg/kg i.v.) can produce profound hypotens

Anesthesia, General↗

Further evidence for a role of NMDA receptors in the locus coeruleus in the expression of withdrawal syndrome from opioids.

To examine a role of N-methyl-D-aspartate (NMDA) receptors in the locus coeruleus (LC) in the expression of the withdrawal signs from opioids, rats were continuously infused with morphine (a mu-opioid agonist, 26 nmol/microl per h) or butorphanol (a mu/delta/kappa-mixed opioid agonist, 26 nmol/microl per h) intracerebroventricularly (i.c.v.) through osmotic minipumps for 3 days. An LC injection of NMDA (0.1 and 1 nmol/5 microl) induced withdrawal signs in opioid-dependent animals. However, it did not precipitate any abnormal behaviors in saline-treated control rats. The expression of the withdrawal signs precipitated by NMDA (1 nmol/5 microl), glutamate (10 nmol/5 microl), or naloxone (an opioid antagonist, 24 nmol/5 microl) was completely blocked by pretreatment with a NMDA antagonist, MK-801 (5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5,10-imine), 0.1 mg/kg, i.p. In animals that had been infused with opioids in the same manner, naloxone (48 nmol/5 microl, i.c.v.) precipitated withdrawal signs and increased extracellular glutamate levels in the LC of opioid-dependent rats measured by in vivo microdialysis method. Pretreatment with MK-801, however, did not affect the increases of glutamate levels in the LC. These results further demonstrate that the expression of opioid withdrawal induced by an expeditious release of glutamate in the LC region of opioid-dependent animals might be mainly mediated by the postsynaptic NMDA receptors.

Animals↗

Dose ratio is important in maximizing naloxone enhancement of nalbuphine analgesia in humans.

The analgesic effect of kappa partial agonist opioids (i.e. nalbuphine, pentazocine and butorphanol) is significantly greater in women. Recent evidence suggests that this sexual dimorphism may result from a naloxone-sensitive anti-analgesic effect that is activated along with, and summates with, the analgesic effect of these agents, resulting in decreased analgesia or increased pain. For example, nalbuphine (5 mg) produces profound anti-analgesia (i.e. enhanced pain) in men, but addition of a low dose of the opioid receptor antagonist naloxone (0.4 mg, opioid antagonist) induces significant analgesia in men and enhances nalbuphine analgesia in women. To further delineate the dose-dependent relationship of nalbuphine and naloxone, we recently evaluated the effect of a lower dose of nalbuphine (2.5 mg) with and without naloxone (0.4 mg) on dental postoperative pain. In women, nalbuphine alone induced modest short duration analgesia, which was antagonized by the addition of naloxone. In men, this dose of nalbuphine alone did not produce analgesia or anti-analgesia, and naloxone did not alter the response to nalbuphine. Thus, it appeared that the 2.5 mg dose of nalbuphine was not sufficient to induce anti-analgesia while the 0.4 mg dose of naloxone was able to antagonize the analgesic effect of nalbuphine, at least in women. In the current study, we tested the hypothesis that an important determinant of naloxone enhancement of nalbuphine analgesia is the dose ratio of nalbuphine to naloxone. Since a dose ratio of 12.5:1 (i.e. 5 mg nalbuphine:0.4 mg naloxone) resulted in analgesic enhancement, but a dose ratio of 6.25:1 (2.5 mg:0.4 mg) did not, we tested the same, lower, dose of nalbuphine (2.5 mg) in combination with a lower dose of naloxone (0.2 mg) to maintain the 12.5:1 dose ratio. This lower dose of naloxone significantly prolonged the analgesic effect of nalbuphine in both men and women, suggesting that the anti-analgesic effect of nalbuphine is present in both sexes at the 2.5 mg dose and that the dose ratio of nalbuphine to naloxone is an important determinant of the analgesic efficacy of this combination.

Adult↗

Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomised controlled trials.

Anaesthetists, using basic scientific concepts of peripheral opioid activity, try to improve regional anaesthesia and postoperative analgesia by injecting opioids, with or without local anaesthetic, close to nerve trunks or nerve endings. To test the evidence that peripherally applied opioids (all except intra-articular) have an analgesic effect outside the knee joint. Systematic search for published reports of randomised controlled trials in the period 1966-1996 (MEDLINE, EMBASE, Oxford Data Base, reference lists) which compared efficacy of peripheral opioids with placebo, local anaesthetic, or systemic opioids in acute pain. Reports of pethidine or intra-articular opioids were not included. Data on intraoperative efficacy (onset, quality, duration of sensory block), and postoperative efficacy (pain intensity, analgesic consumption) were extracted. Statistical significance as indicated in the original reports and clinical relevance of differences between opioids and controls were taken into account to estimate qualitatively overall efficacy. Twenty-six trials with data from 952 patients were analysed. Opioids used were morphine (16 trials), fentanyl (8), alfentanil (1), buprenorphine (1), and butorphanol (1). Of four experimental pain trials, two reported a statistically significant difference in favour of the opioid. In 22 clinical trials efficacy of opioid injections into the brachial plexus (10), Bier's block (4), perineural (3), or other sites (5) was tested. Five of 10 clinical trials measuring intraoperative efficacy reported statistically significant efficacy with opioids compared with control; none of them were judged to be clinically relevant. Five of 17 clinical trials measuring postoperative efficacy reported a significant difference in favour of the opioid; none was judged to be clinical relevant. Trials of lower quality were more likely to report increased efficacy with opioids. Adverse events related to the route of administration were not reported. These trials provide no evidence for a clinically relevant peripheral analgesic efficacy of opioids in acute pain.

Analgesics, Opioid↗

Opioids in headache treatment. Is there a role?

There may be a population of patients subject to frequent headache and in whom optimal analgesic effect is obtained only by frequent but controlled use of opiate drugs and in whom adverse drug effects are minimal. It is emphasized again that the reality is that there are currently a large amount of opioids being prescribed for headache patients because of patients' demands. One of the major considerations for physicians prescribing such treatment is familiarity with the legal guidelines. The federal law requires physicians to register if they are to maintain or detoxify with opioids addicts defined as "any individual who habitually uses any narcotic drug so as to endanger the public morals, health, safety, or welfare, or is so far addicted to the use of narcotic drugs as to have lost the power of self-control with reference to his addiction." A subsequent regulation, however, stated that the law was not intended to impose any limitation on prescription of narcotics for intractable pain. There are also many different state regulations covering, for example, limitations on amounts to be prescribed and reporting of patients who are habitual narcotic users. Obviously, headache patients who request liberal amounts of opioids must be screened. There has been considerable recent effort to provide guidelines regarding which patients with nonmalignant pain might be poor candidates for opioid treatment by reason of both probable treatment failure and risk of drug overuse. Many of these guidelines are not relevant to headache patients in whom pain is rarely continuous and rarely demands scheduled analgesia, as is often the case with pain of other types. There is general agreement that any previous history of any type of substance abuse is an important indicator of danger of recurrence of such behavior. Evaluation of psychological state and personality structure is of great importance. The more evidence of emotional disturbance, the greater the danger both of poor results and of drug abuse. In the chronic daily headache population, treatment failure has been found to correlate with abnormalities on the Minnesota Multiphasic Personality Inventory (MMPI). It is possible that formal psychological testing prior to the prescription of opioid drugs will prove of value in identifying those headache patients at greatest risk for drug abuse. The importance of making opioid treatment part of a multifaceted pain program has been emphasized. Portenoy emphasizes the need for (1) careful discussion with the patient (and often family) of the potential side effects of the drugs, and (2) scrupulous monitoring of adherence to the appropriate dosage and maintenance of prescription by a single physician. The more psychological disturbance evidenced by the patient, the more the risk with failure of drug treatment and of drug abuse. Finally, the analgesic needs of the patient with frequent migraine are different from those of the patient with tension-type headache. Migraine infrequently occurs more than two or three times a week for any period and usually responds to ergotamine, dihydroergotamine, sumatriptan, or a phenothiazine. Addition of codeine or oxycodone for the occasional intractable attack may be needed. When demands in a migraine patient for opioids in amounts greater than 10 to 15 tablets per month occur, there is obvious cause for concern. The opioid agonist-antagonist butorphanol, now available in nasal inhalation form, is alleged to have low abuse potential because it tends to produce dysphoria (an unpleasant emotional state) rather than the euphoria of other opioids. It is therefore unscheduled. The drug, however, does have abuse potential, and the limits needed to be placed on its use are still uncertain. Markley recently recommended a restriction to not more than two bottles (30 treatments) per month. The population with frequent tension-type headaches presents the major problem. Large numbers of these patients use drugs--often in combination

Analgesics, Opioid↗

Analgesia.

Critical to reducing patient morbidity as well as heightened ethical awareness, alleviation of pain in animals has become integral to medical case management and surgical procedures. Pharmacotherapy is directed at peripheral nociceptors, primary and secondary spinal neurons, and pain-processing areas in the CNS. Accordingly, three primary pharmacologic strategies have evolved: drugs that bind to and activate opioid receptors, drugs that bind to and activate alpha 2 receptors, and drugs that reduce de novo prostaglandin synthesis. In horses, the two predominant types of pain encountered are musculoskeletal and visceral pain. Several factors must be considered when devising a therapeutic strategy, including the etiology of the painful event, desired duration of therapy (acute vs chronic), desire for sedation, and potential side effects and toxicity. Opioids and alpha 2 agonists are particularly effective for visceral pain associated with colic. Butorphanol remains the only commercially available opioid and provides superior visceral analgesia compared with pentazocine or flunixin meglumine but not compared with the alpha 2 agonists. The behavioral changes such the sedative effects of alpha 2 agonists and the increased locomotion and CNS excitability seen with some opioids are important considerations when these agents are used as analgesics. NSAIDs may be considered for visceral pain therapy also, especially pain associated with an inflammatory component or endotoxemia. In particular, flunixin meglumine and ketoprofen provide prolonged analgesia and suppress the effects of endotoxin. Long-term therapy of musculoskeletal diseases usually necessitates chronic NSAID use. Although many NSAIDs are now available in approved equine formulations, there remain some important differences among NSAIDs for the practitioner to consider when choosing an analgesic. NSAIDs differ in their ability to ameliorate pyrexia, affect platelet function, alleviate pain, and reduce inflammation. For ease of administration, those available for oral use include phenylbutazone, meclofenamic acid, flunixin meglumine, and naproxen. All are potentially ulcerogenic, and poor tolerance to one may necessitate switching to another with a better toleration profile or to drug from a different analgesic class.

Adrenergic alpha-Agonists↗

Simultaneous determination of in total 17 opium alkaloids and opioids in blood and urine by fast liquid chromatography-diode-array detection-fluorescence detection, after solid-phase extraction.

A fast liquid chromatographic method with tandem diode array-fluorescence detection for the simultaneous determination of in total 17 opium alkaloids and opioids is presented. Blank blood and urine samples (1 ml) were spiked with different concentrations of a standard mixture, as well as with the internal standard, butorphanol (2000 ng/ml). After solid-phase extraction, based on weak cation exchange (Bond Elut CBA SPE columns), the extracts were examined by HPLC-DAD-FL. By using a "high-speed" phenyl column (53 x 7.0 mm I.D., particle size 3 microm) eluted with a gradient system (A: water-methanol (90:10, v/v), B: methanol, both containing 25 mM triethylammoniumformate (pH(A) = 4.5)) all compounds could be baseline separated within 12 min. The method was validated and its applicability was demonstrated by the analysis of real-time forensic cases.

Chromatography, High Pressure Liquid↗

Improved buccal delivery of opioid analgesics and antagonists with bitterless prodrugs.

Buccal delivery of opioid analgesics and antagonists is a useful way of improving bioavailability relative to the oral route. These compounds taste bitter, however. Various prodrugs of nalbuphine, naloxone, naltrexone, oxymorphone, butorphanol, and levallorphan, in which the 3-phenolic hydroxyl group was esterified, lacked a bitter taste. This taste difference was not due to differences in water solubility, suggesting that for these compounds the phenolic functional group is important for interaction with the taste receptor. In rats, nalbuphine, naloxone, and naltrexone administered buccally as prodrugs exhibited up to 90% bioavailability. In dogs, the bitter taste of buccally administered nalbuphine and naloxone caused salivation and swallowing, and bioavailability was low. Buccal dosing of the prodrugs of these compounds caused no adverse effects and the bioavailability ranged from 35 to 50%, a significant improvement relative to the oral bioavailability, which is 5% or less. The feasibility of buccal prodrug delivery using an adhesive patch formulation was demonstrated.

Administration, Buccal↗

Progressive changes in ophthalmic blood velocities in Beagles with primary open angle glaucoma.

OBJECTIVE: To measure changes in the ocular and orbital blood flow velocities by color Doppler imaging (CDI) in beagles with primary open angle glaucoma as the disease progressed from early to advanced stages. METHODS: CDI measurements were performed periodically on 13 glaucomatous Beagles during the nontreated mild, moderate and advanced stages of POAG over the course of 4 years. CDI was performed with the dogs lightly anesthetized (butorphanol 0.1 mg/kg IV, acepromazine maleate 0.02 mg/kg IV, and atropine sulfate 0.05 mg/kg) while the CD transducer was placed directly on the cornea anesthetized with 0.5% tetracaine hydrochloride. Intraocular pressure (IOP) by pneumatonography or TonoPen XL, heart rate and mean arterial blood pressure were measured at the beginning, middle and end of each study. The ophthalmic vessels examined included: external ophthalmic arteries and veins, long and short posterior ciliary arteries, anterior ciliary arteries and veins, primary retinal arteries, and vortex veins. Recordings of each vessel included peak systolic velocity (PSV), end diastolic velocity (EDV) and time averaged velocity (TAV), and when possible the resistive index (RI) and pulsatility index (PI) were computed. RESULTS: CDI abnormalities were present before intraocular pressure exceeded the normal range. As the animals aged, and the glaucoma progressed with higher levels of IOP, significant changes occurred in nearly all vessels, and generally included a major increase in RI (P < 0.001) and an increase in the PI (P < 0.001). Mean arterial blood pressure (105 +/- 18 mmHg) and heart rate (118 +/- 33/min) remained reasonably constant. The IOP gradually increased as the disease progressed (early and normotensive: 19.4 +/- 3.9 mmHg; moderate: 29.7 +/- 2 mmHg; and advanced: 44.5 +/- 6 mmHg). The ocular veins seemed most influenced early on in the disease. Late in the disease, ocular venous blood flow could not be consistently demonstrated. An increase in the PI of ocular veins occurred in the moderately and severely affected glaucomatous Beagles. As the IOP increased, there were trends of increasing resistive index and pulsatility index in most arteries, and periods of marked decreased velocities of the vortex and external ophthalmic veins in severe cases. CONCLUSION: CDI measurements in Beagles with primary open angle glaucoma during the course of 4 years indicate easily measurable and repeatable progressive blood flow abnormalities before the elevation of IOP and, thereafter, with gradually increased levels of IOP.

Animals↗

Membrane microviscosity modulates mu-opioid receptor conformational transitions and agonist efficacy.

The influence of membrane microviscosity on mu-opioid agonist and antagonist binding, as well as agonist efficacy, was examined in membranes prepared from SH-SY5Y cells and from a C6 glioma cell line stably expressing the rat mu-opioid receptor (C6mu). Addition of cholesteryl hemisuccinate (CHS) to cell membranes increased membrane microviscosity and reduced the inhibitory effect of sodium and guanine nucleotides on the affinity of the full agonists sufentanil and [D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAMGO) for the mu-opioid receptor. Binding of the antagonists [3H]naltrexone and [3H]diprenorphine and the partial agonist nalbuphine was unaffected by CHS. The effect of CHS on agonist binding was reversed by subsequent addition of cis-vaccenic acid, suggesting that the effect of CHS is the result of increased membrane microviscosity and not a specific sterol-receptor interaction. CHS addition increased the potency of DAMGO to stimulate guanosine-5'-O-(3-[35S]thio)triphosphate binding by fourfold, whereas the potency of nalbuphine was unaffected. However, nalbuphine efficacy relative to that of the full agonist DAMGO was strongly increased in CHS-treated membranes compared with that in control membranes. Membrane rigidification also resulted in an increased efficacy for the partial agonists meperidine, profadol, and butorphanol relative to that of DAMGO as measured by agonist-stimulated GTPase activity in control and CHS-modified membranes. These findings support a regulatory role for membrane microviscosity in receptor-mediated G protein activation.

Animals↗

Effect of drugs on cholesterol crystallization in an artificial bile model and relation of this effect to drug binding to albumin.

Substances that can affect the crystallization of cholesterol from human bile and consequently the gallstone formation have been given considerable attention. We improved the model system for testing cholesterol crystallization-affecting activity (promoting or inhibiting) of substances and used it for some drugs that are excreted into bile. Besides other factors natural lipid-protein complexes isolated from the native human bile have been shown to be responsible for nucleation and fast crystal growth in cholesterol supersaturated model bile. Artificial lipid-protein complex of taurolithocholate, human serum albumin and Ca2+ (TLTC-HSA-Ca2+) exhibited a lower crystallization activity than both the artificial lipid-protein complexes of taurodeoxycholate, human serum albumin and Ca2+ and the lipid-protein complex isolated from native human bile. The model bile supplemented with this artificial lipid-protein complex (TLTC-HSA-Ca2+) formed a convenient system for testing of various substances (drugs) for their crystallization-affecting activity. From the 20 tested drugs, which could occur at least in small amounts in human bile, the highest crystallization-promoting activity was found for complexes with ampicillin, butorphanol and colchicine. Complexes with tetracycline, thioridazine and doxycycline were the strongest inhibitors. The drugs, which had some effect on cholesterol crystallization, affected somehow the artificial lipid-albumin complex by displacing its components. Interactions of different drugs with HSA and its artificial complexes with the conjugated bile salt and Ca2+ ions were followed by absorption spectroscopy to observe displacement interactions. On the basis of these experiments we could classify drugs into four groups which differ by their effects on spectral characteristics of complexes.

Bile↗

Bilateral laparoscopic ovariectomy in standing mares: 22 cases.

OBJECTIVE: To describe a technique for laparoscopic bilateral ovariectomy in standing mares and report the outcome of 22 clinical cases. STUDY DESIGN: Prospective study. ANIMALS OR SAMPLE POPULATION: A total of 22 mares between 4 and 23 years of age, weighing between 360 and 600 kg. METHODS: Mares with normal ovaries, as determined by palpation per rectum, were restrained in standing stocks and sedated with detomidine (0.01 to 0.02 mg/kg intravenously [i.v.]) and butorphanol (0.01 to 0.02 mg/kg i.v.). The laparoscope and instrument insertion sites were infiltrated with 2% lidocaine before incision. One laparoscope portal and two instrument portals were located in each paralumbar fossa. Ovariectomy was accomplished by intracorporeal dissection and ligation of the ovarian pedicles. The two instrument portals in each flank were ultimately connected resulting in a 4 to 5 cm laparotomy to facilitate ovarian removal. RESULTS: No major operative or postoperative complications occurred. Minor complications included incomplete hemostasis of an ovarian pedicle with a single ligature (three mares), transient inappetence, pyrexia and incisional infection. Owner satisfaction and cosmetic results were considered excellent. CONCLUSIONS: Standing laparoscopic ovariectomy appears to eliminate many of the potential complications associated with traditional surgical methods for ovariectomy and avoids the risk of general anesthesia. CLINICAL RELEVANCE: This technique requires minimal laparoscopic instrumentation and will provide surgeons with an alternative approach for bilateral ovariectomy in mares.

Animals↗

Laparoscopic closure of the renosplenic space in standing horses.

OBJECTIVE: To report a technique for laparoscopic ablation of the renosplenic space in standing horses. STUDY DESIGN: Development of a technique to perform laparoscopic renosplenic space ablation in standing horses. ANIMALS: Five healthy horses, aged 3 to 13 years, weighing 380 to 520 kg. METHODS: Horses were restrained in standing stocks and sedated with detomidine (0.01 mg/kg intravenously [IV]) and butorphanol (0.01 mg/kg IV). Portal sites in the left paralumbar fossa were infiltrated with 2% mepivacaine. A laparoscopic portal was placed between the 17th and the 18th ribs. Two instrument portals were located caudal to the 18th rib. Closure of the renosplenic space was accomplished by apposing the dorsomedial splenic capsule to the dorsal portion of the renosplenic ligament with 1 polyglactin 910 in a continuous pattern. All horses had repeat laparoscopy 3 weeks after initial surgery. RESULTS: Laparoscopic closure of the renosplenic space required 35 minutes (range, 20-65 minutes) and was successful without intraoperative or postoperative complications. On laparoscopic re-examination at 3 weeks, there was smooth connecting fibrous-like tissue between the dorsal splenic capsule and the dorsal portion of the renosplenic ligament. CONCLUSIONS: Laparoscopic closure of the renosplenic space can be efficiently and safely performed in standing horses. CLINICAL RELEVANCE: Laparoscopic-assisted closure of the renosplenic space can be performed in standing horses and may be useful in preventing recurrent incarceration of viscera in this space.

Animals↗

Reduction and stabilization of hip luxation by the transposition of the ligamentum sacrotuberale in dogs: an in vivo study.

OBJECTIVES: To evaluate the effectiveness of transposition of the sacrotuberous ligament (LST) for the treatment of coxofemoral luxation in the dog. STUDY DESIGN: In vivo experimental study. SAMPLE POPULATION: Ten mixed-breed dogs (weighing 12 to 26 kg). METHODS: After general anesthesia, the LST was exposed and released from the sacrum with a sacral bone fragment. Coxofemoral luxation was created by capsulotomy and transection of the ligament of the head of the femur. Suture was passed through 2 small holes in the bone fragment to guide transposition of the LST through a tunnel drilled through the acetabulum and femoral head and neck. The suture material was pulled tight and an interference screw was placed into the femoral tunnel to lock the sacral bone fragment and LST securely in the tunnel. Butorphanol was administered for pain relief and dogs were allowed unrestricted activity. Coxofemoral radiographs were obtained at 15-day intervals. Two dogs were euthanatized for macroscopic and histopathologic examinations at 3 months. RESULTS: Release of the sacral bone was moderately difficult. The transposed ligament and bone fragment were of an appropriate length and were easily and securely fixed by a interference screw method. Visible severe lameness, during the first 7 to 10 days improved to mild lameness within 10 to 21 days. Gait was subjectively normal after 5 weeks. No radiographic abnormalities were observed at any time point. Grossly, the LST was intact and apparently viable and functional. On histopathology, the space in the bone tunnel was filled with new tissue and a hyaline-like layer surrounded the LST. The sacral bone fragment attached to the LST was united with the femoral bone. CONCLUSIONS: Transposition of the LST reduced and stabilized experimentally induced coxofemoral luxation in 10 dogs. Survival of the LST up to 3 months and its adaptation to transposition suggest that this surgical technique could be considered as a permanent treatment option for hip luxations. Transposition and fixation of the LST was easy, but releasing the sacral edge of the LST was difficult because of its deep location and division of the origin into 2 branches in some dogs. CLINICAL RELEVANCE: Results of this experimental study suggest that the technique may be satisfactorily used in dogs with coxofemoral luxation.

Animals↗