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Biomedical subjects

N A Moore

Publications and source records attributed to N A Moore.

At least 19 recordsLinked to original sources
PubMed2000

Nitric oxide delivery to the lung: a model.

Dedicated nitric oxide equipped ventilators are now available commercially but are not yet common in clinical practice. With other ventilators, there is no standardized procedure for the administration or monitoring of nitric oxide. We describe the use of nitric oxide in conjunction with a simple time-cycled, pressure regulated, flow generating ventilator attached to a model infant-sized lung. The measured nitric oxide concentrations were always less than calculated. Infusion site, minute ventilation and sampling port all affected nitric oxide concentration (P < 0.05). Increasing minute ventilation lowered measured nitric oxide concentration exponentially. Mixing of gases improved when nitric oxide was infused closer to the ventilator. Acid contamination was found in water samples from humidifier, water trap and ventilator gas outlet. Acidification was reduced, without change in measured nitric oxide delivery, when infused prehumidifier. We recommend, when used as therapy, nitric oxide levels in inspired gases should always be measured.

Administration, Inhalation↗
PubMed1999

Effects of the group II metabotropic glutamate receptor agonist, LY354740 on schedule-controlled behaviour in rats.

The present study examined the effect of the novel, systemically active Group II metabotropic glutamate (mGlu) receptor agonist, LY354740, on schedule-controlled behaviour in rats. Responding for food reward was maintained by three different operant procedures; the first, a three-component conflict schedule; the second, a multiple fixed-interval 60 s/fixed-ratio 10 (FI60/FR10) schedule and the third, a differential reinforcement of low rates of responding 10 s (DRL10) schedule. In the first procedure, rats were trained to respond for food on a schedule comprising of variable-interval 30 s (food, VI30) and fixed-ratio 10 (food + shock, FR10) components separated by time-out (TO). LY354740 (1.25-5 mg/kg, i.p.) produced a dose-related reduction in responding during the VI component and increased responding during the TO component, while having no effect on responding during the punished FR10 phase. In the FI60/FR10 schedule, LY354740 produced a dose-related reduction in the high rates of responding observed during the FR10 component of the schedule. Although LY354740 (0.6-10 mg/kg, i.p.) had no effect on the overall response rates produced by the FI60 component, there was a shift in the temporal distribution of responding as measured by the quarter-life. LY354740 (10 mg/kg, i.p.) increased the low rates towards the start of the interval, while decreasing the rates of responding towards the end of the FI60 period. In the DRL10 s schedule, LY354740 (5-20 mg/kg, i.p.) had no effect on the total number of responses but produced a significant reduction in the total number of rewards, suggesting that the temporal control of responding had been disrupted. The changes in operant responding occurred at doses that decreased exploratory behaviour. In summary, LY354740 modified responding maintained by all three operant schedules at doses which suppressed spontaneous activity. These data demonstrate that stimulation of Group II mGlu receptors can produce changes in responding which are dependent on the base-line rate of responding, suggesting that mGlu 2/3 receptors may be involved in the stimulus and temporal control of behaviour.

Animals↗
PubMed1999

Olanzapine: a basic science update.

Olanzapine, an atypical antipsychotic, has a broad receptor binding profile, which may account for its pharmacological effects in schizophrenia. In vitro receptor binding studies showed a high affinity for dopamine D2, D3, and D4 receptors; all 5-HT2 receptor subtypes and the 5-HT6 receptor; muscarinic receptors, especially the M1 subtype: and alpha 1-adrenergic receptors. In vivo studies showed that olanzapine had potent activity at D2 and 5-HT2A receptors, but much less activity at D1 and muscarinic receptors, and that it inhibited dopaminergic neurons in the A10 but not the A9 tract, suggesting that this agent will not cause extrapyramidal side-effects (EPS). Microdialysis studies showed that olanzapine increased the extracellular levels of norepinephrine and dopamine, but not 5-HT, in the prefrontal cortex, and increased extracellular dopamine levels in the neostriatum and nucleus accumbens, areas of the brain associated with schizophrenia. Studies of gene expression showed that olanzapine 10 mg/kg also increased Fos expression in the prefrontal cortex, the dorsolateral striatum, and the nucleus accumbens. These findings are consistent with the effectiveness of olanzapine on both negative and positive symptoms and suggest that, with careful dosing, olanzapine should not cause EPS.

Animals↗
PubMed1999

Olanzapine: preclinical pharmacology and recent findings.

Olanzapine possesses a broad pharmacological profile, interacting with a range of different neurotransmitter receptors. Although its affinity for muscarinic receptors is relatively greater than for dopamine receptors, on schedule-controlled behaviour olanzapine displays a profile resembling a dopamine antagonist. Likewise, in a test of cognitive function, olanzapine does not produce anticholinergic-like deficits. In drug discrimination assays, olanzapine substitutes for clozapine in clozapine-trained animals and clozapine generalises to olanzapine in olanzapine-trained animals. Olanzapine also reverses the behavioural deficits produced by inhibiting N-methyl-D-aspartate receptor glutamatergic transmission. This profile suggests that olanzapine will be effective against both positive and negative symptoms of schizophrenia while producing minimal extrapyramidal side-effects.

Animals↗
PubMed1999

Behavioural pharmacology of the new generation of antipsychotic agents.

In conclusion, the newer agents all have behavioural profiles which can be clearly differentiated from those of the older, classical agents. Behavioural data indicate that to a greater or lesser extent, all the newer antipsychotics will produce fewer acute EPS than the older agents. However, the new 'atypical' agents all have distinct profiles. Olanzapine has a profile similar to that of clozapine, albeit somewhat more potent. Olanzapine, like clozapine, displays a wide margin between the doses predictive of efficacy and those which induce EPS. The compound also substitutes for clozapine in drug discrimination assays and increases punished responding in a conflict paradigm. Quetiapine also has a clozapine-like profile, although it lacks the cholinergic receptor affinity and is relatively weak in most behavioural assays. Quetiapine, like olanzapine, also reverses PCP-induced deficits, and substitutes for clozapine in drug discrimination assays. However, no data are currently available regarding quetiapine's action in anxiolytic tests. Risperidone, sertindole and ziprasidone have profiles of activity different from those of older agents, predominantly due to their 5-HT2a affinity. All these agents possess some properties similar to those of clozapine, but there are some differences: for example, risperidone and sertindole fail to substitute for clozapine in drug discrimination assays and are inactive in classical conflict models of anxiety. It is more difficult to make an accurate assessment of the behavioural profile of ziprasidone, due to a lack of published data. Given the behavioural differences exhibited by animals receiving the new antipsychotic agents, one would predict that these drugs will have distinct clinical profiles. All the agents display activity indicative of agents with a reduced propensity to induce EPS. However, significant differences may be observed in their efficacy against negative and cognitive symptoms. It will be important to assess the clinical profiles of these agents carefully if the predictive value of the pre-clinical 'models' is to be improved.

Animals↗
PubMed1997

In vitro and in vivo biochemistry of olanzapine: a novel, atypical antipsychotic drug.

BACKGROUND: Classical (typical) antipsychotic drugs are in wide use clinically, but some patients do not respond at all to treatment, while in others, negative symptoms and cognitive deficits fail to respond. Also, these drugs often cause serious motor disturbances. Clozapine, an atypical antipsychotic, appears to correct many of these deficiencies, but has a significant incidence of potentially fatal agranulocytosis. Accordingly, we attempted to develop a prototype of a new generation of antipsychotics that is both more efficacious and safe. Our strategy was to create a compound that is not only active in behavioral tests that predict antipsychotic action but also shares the rich, multifaceted receptor pharmacology of clozapine without its side effects. To this end, Eli Lilly and Co. developed olanzapine. In this article we characterize the in vitro and in vivo receptor pharmacology of olanzapine. METHOD: We evaluated olanzapine interactions with neuronal receptors using standard assays of radioreceptor binding in vitro and well-established in vivo (functional) assays. RESULTS: Binding studies showed that olanzapine interacts with key receptors of interest in schizophrenia, having a nanomolar affinity for dopaminergic, serotonergic, alpha 1-adrenergic, and muscarinic receptors. In vivo olanzapine is a potent antagonist at DA receptors (DOPAC levels; pergolide-stimulated increases in plasma corticosterone) and 5-HT receptors (quipazine-stimulated increases in corticosterone), but is weaker at alpha-adrenergic and muscarinic receptors. Olanzapine has little or no effect at other receptors, enzymes, or key proteins in neuronal function. Olanzapine has a receptor profile that is similar to that of clozapine: it is relatively nonselective at dopamine receptor subtypes and it shows selectivity for mesolimbic and mesocortical over striatal dopamine tracts (electrophysiology; Fos). CONCLUSION: The binding and functional profile of olanzapine (1) is similar to that of clozapine, (2) indicates that olanzapine is an atypical antipsychotic drug, and (3) is consistent with clinical efficacy. If olanzapine also proves to be safe, then it will have high potential to become a more ideal antipsychotic drug.

Animals↗
PubMed1997

Behavioral pharmacology of olanzapine: a novel antipsychotic drug.

BACKGROUND: In this paper, we review the behavioral pharmacology of olanzapine and compare it to its in vitro profile and to clozapine and a number of other antipsychotic agents, and we estimate the likelihood that olanzapine will be an effective and safe antipsychotic with fewer side effects. METHOD: Since there is no model of schizophrenia, per se, a battery of behavioral assays was used. RESULTS: Behavioral assays confirmed the in vitro results that olanzapine interacts with dopamine, serotonin, and muscarinic receptor subtypes. Moreover, olanzapine appears to have a clozapine-like atypical profile based on (1) mesolimbic selectivity, (2) blocking 5-HT receptors at a lower dose than dopamine receptors, and (3) inhibiting the conditioned avoidance response (indicative of antipsychotic efficacy) at doses that are lower than those required to induce catalepsy (indicative of extrapyramidal side effects). No only is this profile similar to that of clozapine, but olanzapine has other similarities: olanzapine substitutes for clozapine in a drug discrimination assay; like clozapine and unlike "typical" antipsychotics, olanzapine increases responding in a conflict procedure; and olanzapine, like clozapine, reverses changes induced by antagonists of the NMDA receptor. CONCLUSION: On the basis of these findings, we predict that olanzapine will be an efficacious antipsychotic, active against both positive and negative symptoms, while producing fewer extrapyramidal symptoms than existing treatments.

Animals↗
PubMed1996

Radioreceptor binding profile of the atypical antipsychotic olanzapine.

The affinities of olanzapine, clozapine, haloperidol, and four potential antipsychotics were compared on binding to the neuronal receptors of a number of neurotransmitters. In both rat tissues and cell lines transfected with human receptors olanzapine had high affinity for dopamine D1, D2, D4, serotonin (5HT)2A, 5HT2C, 5HT3, alpha 1-adrenergic, histamine H1, and five muscarinic receptor subtypes. Olanzapine had lower affinity for alpha 2-adrenergic receptors and relatively low affinity for 5HT1 subtypes, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites. The receptor binding affinities for olanzapine was quite similar in tissues from rat and human brain. The binding profile of olanzapine was comparable to the atypical antipsychotic clozapine, while the binding profiles for haloperidol, resperidone, remoxipride, Org 5222, and seroquel were substantially different from that of clozapine. The receptor binding profile of olanzapine is consistent with the antidopaminergic, antiserotonergic, and antimuscarinic activity observed in animal models and predicts atypical antipsychotic activity in man.

Animals↗
PubMed1995

Light and electron microscopic observations of epithelial shedding in stored canine small intestine.

Simple cold storage of canine small intestine is accompanied by ischemic damage to the intestinal mucosa. Progression of damage observed during cold storage is unique and has not been observed with other organs. The mucosal damage begins within 15 min after the onset of the storage, with progressive involvement of the gut as the storage period lengthens. Cytoplasmic blebs develop from the base of the epithelial cells and detach the epithelium from the basal lamina. While the process begins uniformly along the length of the villus, separation of the epithelium occurs first at the villus tip. The epithelium, which is shed into the intestinal lumen, is otherwise undamaged. Blebbing occurs in enteroendocrine and goblet cells and is not restricted to enterocytes. Early blebs occur in proximity to mucosal mast cells and subepithelial nerves. Tissue damage in cold is possibly related to enzymes that are still active at storage temperatures.

Animals↗
PubMed1993

NMDA receptor antagonists inhibit catalepsy induced by either dopamine D1 or D2 receptor antagonists.

In the present study, we investigated the ability of NMDA receptor antagonists to inhibit catalepsy induced by haloperidol, or SCH23390 and clebopride, selective dopamine D1 and D2 receptor antagonists respectively. Catalepsy was measured by recording the time the animal remained with its forepaws placed over a rod 6 cm above the bench. Pretreatment with either the non-competitive NMDA receptor antagonist, MK-801 (0.25-0.5 mg/kg i.p.) or the competitive antagonist, LY274614 (10-20 mg/kg i.p.) reduced the cataleptic response produced by haloperidol (10 mg/kg), SCH23390 (2.5-10 mg/kp i.p.) or clebopride (5-20 mg/kg i.p.). This demonstrates that NMDA receptor antagonists will reduce both dopamine D1 and D2 receptor antagonist-induced catalepsy. Muscle relaxant doses of chlordiazepoxide (10 mg/kg i.p.) failed to reduce the catalepsy induced by haloperidol, suggesting that the anticataleptic effect of the NMDA receptor antagonists was not due to a non-specific action. These results support the hypothesis that NMDA receptor antagonists may have beneficial effects in disorders involving reduced dopaminergic function, such as Parkinson's disease.

Animals↗
PubMed1993

Effect of L-type calcium channel modulators on stimulant-induced hyperactivity.

The present study investigated the effect of L-type calcium channel modulators on stimulant-induced locomotor activity. The L-channel activator, (+/-)BayK8644, produced a marked, long-lasting enhancement of cocaine-induced activity, while having no effect on amphetamine hyperactivity. Nicardipine reduced cocaine hyperactivity but had no effect on the amphetamine response.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

5-HT1A-mediated lower lip retraction: effects of 5-HT1A agonists and antagonists.

This study investigated the production of lower lip retraction (LLR) in the rat by the 5-hydroxytryptamine1A (5-HT1A) agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the effect of the putative 5-HT1A antagonists pindolol and (1-(2-methoxy-phenyl)-4-[4-(2-phthalimido)-butyl]-piperazine (NAN190). 8-OH-DPAT (0.125-1.0 mg/kg, IP) caused a dose-related increase in LLR. Pindolol (10-40 mg/kg, IP) and NAN190 (2.5-10 mg/kg, IP) produced a dose-related block of 8-OH-DPAT-induced LLR. Pindolol (10-40 mg/kg, IP) when administered alone was also found to cause LLR, suggesting that pindolol behaves as a partial agonist in this model. This was not the case with NAN190 (2.5-10 mg/kg, IP), which failed to produce LLR; however, NAN190 (2.5-10 mg/kg, IP) produced a dose-related block of the pindolol-induced LLR. These results clearly demonstrate that the LLR model can be used to detect 5-HT1A agonists, partial agonists, and antagonists.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1993

Haemodynamic effects and comparison of enoximone, dobutamine and dopamine following mitral valve surgery.

Mitral valve surgery may be complicated by a post-operative low output state requiring inotropic support, and a wide variety of factors may influence the choice of agents used to treat this condition. The authors have examined and compared the haemodynamic effects of the highly specific phosphodiesterase inhibitor enoximone, and the adrenergic agents dobutamine and dopamine in patients undergoing mitral valve surgery. Enoximone, 0.5 mg kg-1 bolus, followed by a continuous infusion of 5 micrograms kg-1 min-1, was compared against dobutamine, 7 micrograms kg-1 min-1, and dopamine, 5 micrograms kg-1 min-1, with the protocol allowing for an increase in the infusion rate by a factor of two if clinical and haemodynamic measurements indicated. All 25 patients receiving enoximone were successfully weaned from cardiopulmonary bypass at the first attempt, with significant increases in cardiac index and stroke index, combined with little or no change in heart rate or pulmonary artery pressures and a highly significant reduction in systemic vascular resistance, and a reduction in mean arterial pressure. Three of the 25 patients receiving dobutamine were withdrawn from the study because of inadequate haemodynamic response, while the remaining 22 patients demonstrated significant increases in heart rate, cardiac index and stroke index, with a reduction in systemic vascular resistance. Nine of the 25 patients receiving dopamine failed to respond adequately, while the remaining 16 demonstrated an increase in heart rate and cardiac index but with little change in stroke index and a modest reduction in systemic vascular resistance. Enoximone has been shown to be a highly effective first-line inotrope in patients following mitral valve surgery with significant advantages over dobutamine and dopamine.

Adult↗
PubMed1992

The behavioral pharmacology of olanzapine, a novel "atypical" antipsychotic agent.

Olanzapine (LY170053, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine) is a novel "atypical" antipsychotic agent with 5-hydroxytryptamine2.dopamine D1/D2 antagonist activity and anticholinergic properties. In behavioral studies, olanzapine (1.25-10 mg/kg, p.o.) antagonizes apomorphine-induced climbing behavior in mice, demonstrating that the compound possesses D1/D2 antagonist activity in vivo. Olanzapine (0.3-20 mg/kg, p.o.) antagonizes 5-hydroxytryptophan-induced head twitches in mice at doses much lower than those required to block the climbing response, confirming that in vivo, the compound is a more potent 5-hydroxytryptamine2 antagonist than dopamine antagonist. Olanzapine (2.5-10 mg/kg, p.o.) also antagonized oxotremorine-induced tremor in mice. In a conditioned avoidance paradigm in rats, olanzapine inhibits the avoidance response with an ED50 of 4.7 mg/kg p.o; however, unlike other antipsychotic agents, catalepsy is only observed at much higher doses (ED50 39.4 mg/kg, p.o.). These data would suggest that the compound will be less likely to produce undesirable extrapyramidal symptoms. Unlike "typical" antipsychotics, olanzapine (1.25-5 mg/kg p.o.) increases responding during the conflict component of a modified Geller Seifter test, demonstrating that the compound may also possess anxiolytic activity. In another series of experiments, olanzapine (1.25 mg/kg, i.p.) produced clozapine-appropriate responding in a drug discrimination model in which animals had been trained to discriminate clozapine (5 mg/kg, i.p.) from vehicle. On the basis of these results, it would therefore be predicted that olanzapine will have an atypical profile and will be less likely to induce undesirable extrapyramidal symptoms than currently available drugs.

Animals↗
PubMed1990

The role of multiple dopamine receptors in apomorphine and N-n-propylnorapomorphine-induced climbing and hypothermia.

Apomorphine and N-n-propylnorapomorphine (NPA) were compared for their ability to induce stereotyped cage climbing and hypothermia in mice. Climbing behavior was produced by similar doses of apomorphine and NPA (0.625-2.5 mg/kg s.c.), whereas NPA was 43 times more potent than apomorphine in inducing a hypothermic response. SKF38393 caused a shift to the left in the dose-response curve for NPA-induced climbing, the ED50 changing from 0.98 to 0.014 mg/kg. SKF38393 had no effect on apomorphine-induced climbing behaviour. The climbing response produced by apomorphine was antagonised by both D-1 and D-2 antagonists. Climbing behaviour induced by NPA (2.5 mg/kg) could be antagonised by SCH23390 but not by clebopride, however climbing behaviour induced by a low dose of NPA (0.06 mg/kg) plus SKF38393 could be blocked by both D-1 and D-2 receptor antagonists. The hypothermic responses produced by either apomorphine or NPA could only be reversed by the selective D-2 antagonist, clebopride. These results demonstrate that dopamine agonist-induced stereotyped cage climbing requires both D-1 and D-2 receptor stimulation, whereas the hypothermic response is D-2-mediated. The results also show that it is possible to assess the relative activity of a dopamine agonist at D-1 or D-2 receptors in vivo by comparing the ability of the compound to induce hypothermia and climbing behaviour.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Production of climbing behaviour in mice requires both D1 and D2 receptor activation.

The ability of SKF38393 (a D1 agonist), quinpirole (a D2 agonist), and apomorphine (a mixed D1/D2 agonist) to induce stereotyped climbing behaviour in mice was investigated. Apomorphine produced a dose-related increase in stereotyped cage climbing which lasted for up to 60 min. SKF38393 and quinpirole failed to produce climbing when administered alone. When given in combination intense apomorphine-like cage climbing was observed which lasted for up to 2 h. Apomorphine or the combination of SKF38393 and quinpirole also produced biting of the cage. The climbing behaviour produced by either apomorphine or SKF38393/quinpirole combinations was antagonised by either the D1 antagonist, SCH23390 or the D2 antagonist clebopride. These results demonstrate that both D1 and D2 receptor activation is necessary to produce apomorphine-like cage climbing in mice.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

A solid phase enzyme immunoassay (ELISA) for the detection and quantitation of anticardiolipin antibody.

A solid-phase enzyme-linked immunoabsorbent assay (ELISA) is described for the detection and quantitation of anticardiolipin antibodies (ACAs) IgG and IgM in sera. In these assays, non-specific binding was controlled by using antigen-negative wells for all serum dilutions tested. Quadruplicate 100-microliters serum samples diluted 1:20 for ACA-IgG and 1:40 for ACA-IgM were incubated for two hours, after which alkaline phosphatase-conjugated antihuman IgG or IgM was added. A standard serum was used on each plate to provide reproducibility of the assay. Upper limits of normal for ACA-IgG and IgM were established by testing 161 sera from normal persons. Sixty-one selected patients with SLE were tested; and, from these results, categories of positivity were defined from negative to 4+. All screen-positive sera (greater than or equal to 1+) were assayed in a quantitative ELISA assay for ACAs, using multiple dilutions of the unknowns. These data were fit on a standard curve generated with dilutions of a reference serum on each plate using a computerized data reduction system based on the 2 Plus 2 model. The standard curves were compared with the international standards for IgG and IgM anticardiolipin. The ability to quantitate ACA concentrations allows better definition of positive sera, as well as the opportunity to accurately evaluate and follow this antibody in a variety of patient groups.

Autoantibodies↗