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Biomedical subjects

L Shuster

Publications and source records attributed to L Shuster.

At least 19 recordsLinked to original sources
PubMed2004

The use of dextromethorphan to treat repetitive self-directed scratching, biting, or chewing in dogs with allergic dermatitis.

OBJECTIVE: To evaluate the efficacy of oral dextromethorphan in dogs with a repetitive behavior problem (self-licking, self-chewing, and self-biting associated with chronic allergic dermatitis). ANIMALS: Fourteen dogs with chronic allergic dermatitis were enrolled in the study. Twelve dogs completed the study. PROCEDURE: The dogs were treated for 2 weeks each with dextromethorphan (2 mg/kg BID) and placebo in a randomized, double blind, crossover designed study. A dermatology score, including an assessment of affected areas of the integument and the level of self-directed behavior, was generated before and following each 2-week phase of the study. Owners were required to record daily the amount of time they spent with their dog and the amount of time that the dog was observed to be engaged in any of the specified self-directed behaviors. RESULTS: The percent of the observed time that the dogs were reported to be involved in self-directed behaviors was significantly less during the 2-week active drug treatment phase. The pruritus score component of the dermatology score also was significantly less during the active treatment phase. In addition, a dermatologist-rated global assessment was more favorable in 11 of 12 dogs following the active treatment phase. CONCLUSIONS: Dextromethorphan significantly reduces the percentage of time that allergic dogs spend self-licking, self-chewing, and self-biting. CLINICAL RELEVANCE: Dextromethorphan may be a useful adjunct in the management of self-directed behaviors associated with allergic dermatitis and possibly in other repetitive behaviors as well.

Analgesics, Opioid↗
PubMed2001

The effect of the NMDA receptor blocker, dextromethorphan, on cribbing in horses.

Stereotypic cribbing in horses is thought to involve excess dopaminergic activity within the striatum. Various models of stress-induced stereotypies including cribbing in horses postulate that stress stimulates the release of endorphins, triggering the release of striatal dopamine. Dopamine in turn activates basal ganglia motor programs, reinforcing behavior via a reward mechanism. Furthermore, the release of dopamine by endorphins has been shown to depend on activation of NMDA receptors. In the present study, horses identified as cribbers and volunteered by their owners were treated with the NMDA receptor antagonist dextromethorphan (DM). When DM was administered via jugular injection (1 mg/kg), eight of nine horses responded with reductions in cribbing rate (CR) compared to baseline, and cribbing was suppressed completely for a period of time in almost half of the horses tested.

Animals↗
PubMed2000

Effect of dietary protein content and tryptophan supplementation on dominance aggression, territorial aggression, and hyperactivity in dogs.

OBJECTIVE: To evaluate the effect of high- and low-protein diets with or without tryptophan supplementation on behavior of dogs with dominance aggression, territorial aggression, and hyperactivity. DESIGN: Prospective crossover study. ANIMALS: 11 dogs with dominance aggression, 11 dogs with territorial aggression, and 11 dogs with hyperactivity. PROCEDURE: In each group, 4 diets were fed for 1 weeks each in random order with a transition period of not < 3 days between each diet. Two diets had low protein content (approximately 18%), and 2 diets had high protein content (approximately 30%). Two of the diets (1 low-protein and 1 high-protein) were supplemented with tryptophan. Owners scored their dog's behavior daily by use of customized behavioral score sheets. Mean weekly values of 5 behavioral measures and serum concentrations of serotonin and tryptophan were determined at the end of each dietary period. RESULTS: For dominance aggression, behavioral scores were highest in dogs fed unsupplemented high-protein rations. For territorial aggression, [corrected] tryptophan-supplemented low-protein diets were associated with significantly lower behavioral scores than low-protein diets without tryptophan supplements. CONCLUSIONS AND CLINICAL RELEVANCE: For dogs with dominance aggression, the addition of tryptophan to high-protein diets or change to a low-protein diet may reduce aggression. For dogs with territorial aggression, tryptophan supplementation of a low-protein diet may be helpful in reducing aggression.

Aggression↗
PubMed1999

Subacute cocaine treatment changes expression of mouse liver cytochrome P450 isoforms.

Acute administration of single high doses of cocaine (50 or 60 mg/kg) produces liver injury in mice that have been pretreated with inducers of mixed function oxidases. Multiple low doses of cocaine (10-30 mg/kg) will produce hepatotoxicity without prior induction. To establish whether cocaine can induce its own activation, mice were given three daily injections of cocaine. Total cytochrome P450 content of the liver did not change. After 3 days the amount of cytochrome P450 2B10, as measured by pentoxy resorufin-O-dealkylase activity and immunoblotting, increased 3-fold. Cytochrome P450 2A5-catalyzed coumarin 7-hydroxylase activity and immunoreactive protein increased by about 50%. Enzyme activities and Western blotting of isoforms 1A, 2E, and 3A showed no change during this time. Chronic cocaine increased N-hydroxylation of norcocaine. Immunoinhibition studies showed that cytochrome P450 2A5 was the major isoform responsible for norcocaine N-hydroxylation. These results demonstrate that chronic cocaine can induce its own metabolism. Similar increases were also observed in mice not susceptible to liver injury from chronic cocaine.

Animals↗
PubMed1996

Use of fluoxetine to treat dominance aggression in dogs.

OBJECTIVE: To evaluate fluoxetine for the treatment of owner-directed dominance aggression in dogs. DESIGN: Prospective study. ANIMALS: 9 dogs of various breeds, ages, and either sex determined to have owner-directed dominance aggression. PROCEDURE: Placebo and fluoxetine (1 mg/kg of body weight) were compared for the treatment of owner-directed dominance aggression in a single-blind crossover study. Owners were instructed to record aggressive and nonaggressive responses of their dogs daily on a canine-overt aggression chart for the 5-week duration of the study. Total aggression scores (linear and geometric) were calculated for each week of the study. The frequency of individual responses was also analyzed independently. RESULTS: Fluoxetine resulted in a significant (P = 0.01) reduction in owner-directed dominance aggression after 3 weeks of treatment. No particular aggressive response accounted for the overall reduction in aggression. CLINICAL IMPLICATIONS: Fluoxetine may be useful in the management of dominance aggression in dogs.

Aggression↗
PubMed1996

Behavioral changes associated with suspected complex partial seizures in bull terriers.

OBJECTIVES: To identify and treat a range of abnormal behavior, including tail chasing, unprovoked aggression, and extreme irrational fear, in Bull Terriers and to correlate the behavioral signs with electroencephalogram (EEG) or anatomic evidence of abnormal brain geometry or deafness. DESIGN: Prospective clinical study. ANIMALS: 8 affected and 5 unaffected (control) Bull Terriers. PROCEDURE: All dogs were examined neurologically, including use of EEG, brainstem auditory-evoked response, and computed tomography or postmortem examination of the brain. In addition, plasma concentrations of zinc, copper, and iron, and the activity of zinc- and copper-dependent enzymes (alkaline phosphatase and ceruplasmin oxidase) were measured in affected and control dogs. RESULTS: An abnormal EEG was found in 7 of 7 affected dogs and in none of the control dogs subjected to this examination. Seven of 8 affected dogs and 2 of 3 controls had various degrees of hydrocephalus. Metal ion and enzyme concentrations were not different between affected and control dogs. Treatment with phenobarbital was effective in 5 of 7 dogs. CLINICAL IMPLICATIONS: Bull Terriers with compulsive tail chasing and extreme affective disorders should be regarded as neurologically disturbed, with partial seizures perhaps underlying their behavior. Treatment with anti-convulsants is a logical first step in treatment.

Animals↗
PubMed1996

Effect of dietary protein content on behavior in dogs.

OBJECTIVE: To determine the effect that feeding diets containing a low (17%), medium (25%), or high (32%) protein content would have on behavior in dogs. DESIGN: Prospective, controlled study. ANIMALS: 12 dogs with dominance aggression, 12 dogs with hyperactivity, 12 dogs with territorial aggression, and 14 control dogs without behavioral problems. PROCEDURE: Dogs were fed each of the diets for a 2-week period, and owners were instructed to score their dogs' behavior on a daily basis. RESULTS: Behavior of the dogs with dominance aggression, dogs with hyperactivity, and control dogs was unchanged by the dietary manipulations. Territorial aggression was significantly reduced when dogs were fed the low- or medium-protein diet, compared with territorial aggression when fed the high-protein diet. Post hoc analysis indicated that this effect was attributable to a marked reduction in aggression in a subset of the group (n = 7) in which territorial aggression was a result of fear. CLINICAL IMPLICATIONS: Results of this study suggest that a reduction in dietary protein content is not generally useful in the treatment of behavior problems in dogs, but may be appropriate in dogs with territorial aggression that is a result of fear.

Aggression↗
PubMed1995

Spinal NMDA receptor--nitric oxide mediation of the expression of morphine withdrawal symptoms in the rat.

Previous studies in this laboratory have demonstrated that cholinergic receptors within the spinal cord play an important role in the expression of naloxone-precipitated withdrawal symptoms in the morphine-dependent rat. Related cardiovascular studies in non-dependent animals have demonstrated that this spinal cholinergic system is linked to a glutamatergic, NMDA pressor pathway which also involves the participation of a nitric oxide (NO) generating system. The purpose of this study was to determine whether spinal NMDA receptors and/or NO are involved in the expression of morphine withdrawal symptoms. Rats bearing previously implanted intrathecal (IT) catheters were dependent on morphine following chronic i.a. infusion of increasing doses over 5 days. Naloxone (0.5 mg/kg) was administered via the i.a. line to precipitate withdrawal; and both cardiovascular and behavioral symptoms were recorded over 60 min. Pretreatment 20 min before naloxone with IT injection of either of the NMDA receptor antagonists, MK-801 or AP-7 (100-200 nmol), produced a significant reduction in the expression of both the cardiovascular and behavioral symptoms of up to about 60%. IT pretreatment with the NO synthase inhibitor L-NAME--a methyl ester derivative of L-arginine, also produced a dose-dependent, L-arginine reversible inhibition of the cardiovascular (mainly the pressor) component of withdrawal, but had no significant effect on the expression of behavioral signs. In contrast, IT pretreatment with L-NOARG and L-NMMA, non-ester analogs of L-arginine, significantly inhibited the expression of the behavioral signs of withdrawal but did not alter the pressor component. A combined pretreatment with L-NAME and L-NOARG resulted in suppression of both pressor and behavioral components of withdrawal. The anti-withdrawal actions of either class of NO synthase inhibitor could not be attributed to blockade of local muscarinic receptors. These findings are consistent with a role for both spinal NMDA receptors and a NO generating system in the expression of both the behavioral and autonomic components of naloxone-precipitated withdrawal. They also suggest that different structural analogs of L-arginine have different profiles of activity in this regard--opening the possibility that different isozymes of NO synthase located within the same spinal region mediate different physiological or behavioral functions.

Animals↗
PubMed1994

Equine self-mutilation syndrome (57 cases)

Owners who believed they had a horse with self-mutilating behavior were asked to complete a questionnaire to obtain information on the signalment, clinical history, clinical signs, management, and treatment of the condition. Fifty-two owners of 59 horses responded; 2 cases were omitted because an organic cause was determined. Owners also were asked to complete information for unaffected horses on the same farm. Various breeds were affected, and of the 57 horses, 20 were stallions, 31 were geldings, and 6 were mares. Affected horses tended to develop the condition prior to sexual maturity. Clinical signs included glancing or biting at the flank or pectoral areas, bucking, kicking, vocalizing, rubbing, spinning, or rolling. Several management and environmental factors were examined, but none were found to be exclusively related to expression of the disorder. Castration was associated with improvement in 7 of 10 stallions. Medications and changes in management reduced or prevented the behavior in some horses. The syndrome appears to be similar to Tourette's syndrome of human beings.

Age Factors↗
PubMed1994

Cocaine toxicity in cultured chicken hepatocytes: role of cytochrome P450.

Cocaine (COC) causes liver damage in several species, including man. Chicken embryo hepatocyte cultures were evaluated as a model system to investigate the mechanism of cocaine-mediated hepatotoxicity. Parameters used to assess toxicity were: (1) release of lactate dehydrogenase (LDH); (2) decreased induction of 5-aminolevulinic acid synthase (ALAS), measured as porphyrin accumulation; and (3) decreased protein synthesis. Exposure of untreated cultures to COC or norcocaine (NOR) caused dose-dependent increases in LDH release, decreased protein synthesis, and eventual cell death. Pretreatment with 2-propyl-2-isopropylacetamide (PIA), a phenobarbital-like inducer of cytochrome P450, accelerated toxicity and lowered the threshold dose at which toxicity occurred. PIA pretreatment also increased rates of elimination of both COC and NOR and increased rates of formation of NOR from COC. The toxicity of COC and NOR could also be detected as decreased porphyrin accumulation. Addition of the P450 inhibitor SKF-525A concurrently with COC or NOR decreased their rates of elimination. SKF-525A also prevented the increase in LDH release as well as the decrease in protein synthesis caused by treatment with COC or N-hydroxynorcocaine (N-OH). Addition of SKF-525A up to 3 hr after COC resulted in partial prevention of the LDH increase. Exposure of the cultures to COC induced cytochrome P450 2H protein. We conclude that this hepatocyte culture system is highly sensitive to COC toxicity and that constitutive as well as induced cytochrome P450 isoforms are involved in the production of liver damage from COC.

Allylisopropylacetamide↗
PubMed1994

Chronic cocaine administration is associated with behavioral sensitization and time-dependent changes in striatal dopamine transporter binding.

Chronic cocaine administration has been associated with sensitization (an increase in drug effect) rather than the tolerance observed with many psychotropic compounds. Because cocaine acts at the presynaptic dopamine transporter, we evaluated sensitization and striatal dopamine transporter binding in vivo in several mouse strains. All strains of mice evaluated showed increased activity after cocaine compared with after saline injections. BALB/cByJ, DBA/2J, B6AF1/J and C57BL6/J mice exhibited sensitization when assayed 72 hr after five daily injections of cocaine at 20 and 40 mg/kg/day, whereas B6AF1/J mice showed sensitization at 20 but not at 40 mg/kg/day. CD-1 mice did not exhibit sensitization at either dose. Striatal dopamine transporter binding in vivo was increased in DBA/2J and B6AF1/J mice when determined 72 hr after five injections of 40 mg/kg/day cocaine. In contrast, a continuous infusion of cocaine at the same dose and duration did not produce sensitization or binding changes in DBA/2J mice. The time course of transporter binding alterations after intermittent cocaine exposure indicated no change at 1 day, increased binding at 3 days, a return to control levels at 7 days and decreased binding at 14 days. These data indicate that both sensitization and alterations in dopamine transporter binding occur after chronic cocaine injection but that these changes are unlikely to be directly related.

Animals↗
PubMed1993

Norcocaine and N-hydroxynorcocaine formation in human liver microsomes: role of cytochrome P-450 3A4.

Cocaine was metabolized to norcocaine by microsomes prepared from lymphoblastoid cells expressing transfected human P-450 3A4. The specific activities of norcocaine formation by microsomes prepared from three human liver samples correlated with the amount of P-450 3A immunoreactive protein detected by immunoblot. Triacetyloleandomycin, a specific inhibitor of P-450 3A isoforms, inhibited formation of norcocaine from cocaine, but not formation of N-hydroxynorcocaine from norcocaine. The chemical identity of the norcocaine and N-hydroxynorcocaine produced by human liver microsomes was established by combination of gas chromatography and mass spectrometry. Thus, human P-450 3A4 is a cocaine demethylase, and P-450 isoforms of the 3A family are responsible for the majority of norcocaine production by human hepatic microsomes.

Cells, Cultured↗
PubMed1993

Reexamination of the microsomal transformation of N-hydroxynorcocaine to norcocaine nitroxide.

Cocaine is known to be associated with hepatotoxicity in laboratory animals, and there is recent evidence that it also induces liver damage in humans. In both cases an N-oxidative pathway is responsible. Cocaine (NCN) is first N-demethylated to norcocaine, followed by oxidation to N-hydroxynorcocaine (NCNOH) and norcocaine nitroxide (NCNO.). On the basis of ESR studies of NCNOH with rat liver microsomes, it has been proposed that NCNO. induces hepatotoxicity by futile redox cycling between NCNO. and NCNOH at the expense of NADPH. The reaction is reported to be accompanied by formation of superoxide and lipid peroxyl radicals. It has also been reported that the same toxic sequence occurs with rat brain microsomes, leading to the formation of reactive free radicals in the brain. We have reexamined the microsomal metabolism of NCNOH to investigate the mechanism more thoroughly. Spin traps [5,5-dimethyl-1-pyrroline N-oxide and alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone] were used to investigate the formation of reactive free radicals, including superoxide, in liver and brain microsomal incubations. In agreement with the literature, we detected a six-line spectrum of a radical adduct of alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone from liver microsome incubations. In contrast, our results showed that brain microsomes were completely inactive, contrary to the literature. In addition, we did not find any NCNO.- or NCNOH-dependent formation of superoxide with either brain or liver microsomes.

Animals↗
PubMed1992

Phenobarbital-responsive episodic dyscontrol (rage) in dogs.

Episodic dyscontrol (rage) was diagnosed from the clinical history, electroencephalographic findings, and response to oral treatment with phenobarbital in 3 dogs. Clinical features included a mood change heralding aggressive incidents, explosive aggression directed at people or objects, and a postaggressive phase characterized by lethargy and lack of responsiveness. Abnormal electroencephalographic findings included spike activity in the temporal recordings. All 3 dogs responded well to anticonvulsant medication with phenobarbital.

Aggression↗
PubMed1992

Hepatic morphologic and biochemical changes induced by subacute cocaine administration in mice.

The initial event and site of cocaine-induced hepatic injury have not been elucidated. In an attempt to identify the minimal effective dose and the site of injury, we have examined the livers of mice exposed to small daily doses of cocaine, using morphological and biochemical methods. All doses of cocaine greater than 5 mg/kg were able to cause significant elevation of serum glutamic pyruvic transaminase. Light microscopy revealed a progression of centrilobular necrosis as the dose increased from 10-30 mg/kg. The initial morphologic changes observed prior to necrosis included aggregation of intermediate filaments and dilation of rough endoplasmic reticulum with loss of ribosomes. Immunohistochemistry, using antibodies to cytokeratins, showed staining of individual hepatocytes in livers from cocaine-treated animals but not in controls. In contrast to earlier reports, we found little, if any, disruption of mitochondria. In vitro, the direct application of cocaine, norcocaine, and N-hydroxynorcocaine on isolated mitochondria had no effect on the ADP:O or respiratory control ratios, at concentrations up to 2.0 mM. Our studies demonstrate that any early cellular alterations in cocaine-induced hepatic injury are manifested in intermediate filaments and endoplasmic reticulum with no evidence of mitochondrial involvement.

Alanine Transaminase↗
PubMed1990

Cocaine-induced liver cell injury: comparison of morphological features in man and in experimental models.

Although investigative research of animal models in cocaine metabolism and associated liver cell injury has been fairly extensive during the past 10 yr, little evidence of hepatotoxicity has been documented in man. We report a case of fulminant hepatic failure and acute rhabdomyolysis resulting from cocaine use. Coagulative-type perivenular and midzonal necrosis and periportal microvesicular fatty change were the predominant morphological features throughout all lobules of the liver, in contrast to periportal necrosis described in the only previous case report with biopsy. Differences in zonal necrosis caused by the same drug are not typically seen in man experiencing direct or indirect intrinsic hepatotoxicity. However, experimental models have shown cocaine to have this ability, dependent on enzyme induction or inhibition, sex and dose. Therapeutic approaches for prevention of possible liver cell injury by cocaine toxicity are discussed.

Adult↗
PubMed1990

Cocaine and lidocaine interfere with epinephrine-induced changes in intracellular calcium concentration and glucose efflux from rat hepatocytes.

The mechanism of cocaine-induced hepatotoxicity is not clearly understood. Recent studies show that fluctuations in intracellular Ca2+ ([Ca2+]i) and/or cyclic-AMP ([cAMP]) concentration play a major role in hormone action, and sustained elevations in [Ca2+]i may be involved in the initiation of hepatocellular damage. To evaluate the possible involvement of intracellular Ca2+ and/or cAMP, we investigated effects of cocaine and lidocaine on basal, epinephrine and dibutyryl cyclic-AMP (DBcAMP)-induced changes in [Ca2+]i and glucose efflux from isolated rat hepatocytes. [Ca2+]i was monitored continuously using a Ca2(+)-selective fluorescence indicator, Quin-2, and was calculated after correcting for autofluorescence. Neither cocaine nor lidocaine (0.1-5 mmol/l) affected basal [Ca2+]i, yet both agents decreased epinephrine (10 mumol/l) and DBcAMP (100 mumol/l)-induced increases in [Ca2+]i in a dose-dependent fashion. Half-maximal inhibition occurred at 0.75 mmol/l cocaine and 1.7 mmol/l lidocaine. Cocaine and lidocaine also decreased epinephrine and DBcAMP-induced glucose efflux. The dose-dependent effect on epinephrine-induced glucose efflux was similar to that of both anesthetics on epinephrine-induced increases in [Ca2+]i. However, 5 mmol/l cocaine or lidocaine decreased DBcAMP-induced glucose efflux by less than 50%, and [Ca2+]i by more than 80%. Taken together, these results indicate that cocaine and lidocaine decrease the ability of epinephrine to stimulate glucose efflux by interfering with the Ca2(+)-mediated, and not the cAMP-mediated intracellular pathway. It is therefore speculated that alterations in metabolic endocrine regulation may contribute to cocaine's hepatotoxic effect.

Animals↗