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Biomedical subjects

F P Bymaster

Publications and source records attributed to F P Bymaster.

At least 37 records · Page 2Linked to original sources
PubMed2001

The muscarinic agonist xanomeline increases monoamine release and immediate early gene expression in the rat prefrontal cortex.

BACKGROUND: The muscarinic agonist xanomeline has been shown to reduce antipsychotic-like behaviors in patients with Alzheimer's disease. Because atypical antipsychotic agents increase dopamine release in prefrontal cortex and induce immediate early gene expression in prefrontal cortex and nucleus accumbens, the effect of xanomeline was determined on these indices. METHODS: The effect of xanomeline on extracellular levels of monoamines in brain regions was determined using a microdialysis technique, and changes in expression of the immediate early genes c-fos and zif/268 in brain regions were evaluated using in situ hybridization histochemistry. RESULTS: Xanomeline increased extracellular levels of dopamine in prefrontal cortex and nucleus accumbens but not in striatum. Xanomeline increased expression of c-fos and zif/268 in prefrontal cortex and nucleus accumbens. There was no change in immediate early gene expression in striatum. CONCLUSIONS: Xanomeline increased extracellular levels of dopamine, which is similar to the effects of the atypical antipsychotics clozapine and olanzapine. The regional pattern of immediate early gene expression induced by xanomeline resembled that of atypical antipsychotic agents. Based on the antipsychotic-like activity of xanomeline in Alzheimer's patients and the similarity to atypical antipsychotic agents, we suggest that xanomeline may be a novel antipsychotic agent.

Animals↗
PubMed2001

The muscarinic receptor agonist BuTAC, a novel potential antipsychotic, does not impair learning and memory in mouse passive avoidance.

(5R,6R)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane) (BuTAC) is a novel, selective muscarinic receptor ligand with partial agonist mode of action at muscarinic M2 and M4 and antagonist mode of action at M1, M3 and M5 receptor subtypes in cloned cell lines. BuTAC exhibits functional dopamine receptor antagonism despite its lack of affinity for dopamine receptors, and parasympathomimetic effects in mice are produced only at doses well beyond the doses exhibiting the antipsychotic-like effects. In the present study we investigated the effects of BuTAC and the antipsychotic compounds clozapine, sertindole and olanzapine using one trial passive avoidance with mice as a model of learning and memory. Pharmacologically relevant doses of BuTAC and reference antipsychotics were identified, based on inhibition of apomorphine-induced climbing in mice as an assay measuring antidopaminergic potency. When ratios between the minimum effective dose (MED) for impairment of retention in passive avoidance and the MED for inhibition of apomorphine-induced climbing were calculated, BuTAC displayed a high ratio of >10, compared with clozapine (0.3), sertindole (3) and olanzapine (3). These data suggest that BuTAC is a potential novel antipsychotic which may have favourable effects on aspects of learning and memory.

Animals↗
PubMed2001

A current review of olanzapine's safety in the geriatric patient: from pre-clinical pharmacology to clinical data.

OBJECTIVE: Olanzapine (OLZ) is unique among currently available antipsychotic medications in its antagonism of a range of receptor systems including dopamine, norepinephrine, serotonin, acetylcholine, and histamine. Olanzapine's mechanistic complexity provides a broad efficacy profile in patients with schizophrenia and acute, pure or mixed mania. Patients experience symptomatic relief of mania, anxiety, hallucinations, delusions, and agitation/aggression and reduced depressive, negative, and some cognitive symptoms. This paper will review the safety profile of OLZ, focusing on the elderly, where data are available. METHOD: Preclinical and clinical studies of OLZ are reviewed, with emphasis on its possible effects on the cholinergic system and the histamine H(1) receptor. Weight change and related metabolic considerations, cardiac and cardiovascular safety, and motor function during treatment with OLZ are also reviewed. RESULTS AND CONCLUSION: In vitro receptor characterization methods, when done using physiologically relevant conditions allow accurate prediction of the relatively low rate of anticholinergic-like adverse events, extrapyramidal symptoms, and cardiovascular adverse events during treatment with OLZ. Currently available clinical data suggest olanzapine is predictably safe in treating adult patients of any age with schizophrenia and acute bipolar mania, as well as in treatment of patients with some types of neurodegenerative disorders.

Adverse Drug Reaction Reporting Systems↗
PubMed2001

Current perspectives on the development of non-biogenic amine-based antidepressants.

Compounds that inhibit the re-uptake and/or metabolism of biogenic amines (i.e. serotonin, norepinephrine, and dopamine) have been used to treat depression for more than 40 years. Selective re-uptake inhibitors, currently the most widely prescribed class of biogenic amine-based agents, are certainly safe and relatively easy to use, but do not exhibit either a faster onset of action or greater efficacy than their predecessors. An approach to overcome the limitations that may be inherent to these 'conventional' therapies is to circumvent the monoaminergic synapse. In this review, two potential antidepressant strategies are discussed that may converge with intracellular pathways impacted by chronic treatment with biogenic amine-based agents. Drugs emerging from these strategies may offer significant advantages over currently used antidepressants.

Animals↗
PubMed2001

Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors.

The blockade of serotonin (5-HT) and norepinephrine (NE) transporters in vitro and in vivo by the dual 5-HT/NE reuptake inhibitors duloxetine and venlafaxine was compared. Duloxetine inhibited binding to the human NE and 5-HT transporters with K(i) values of 7.5 and 0.8 nM, respectively, and with a K(i) ratio of 9. Venlafaxine inhibited binding to the human NE and 5-HT transporters with K(i) values of 2480 and 82 nM, respectively, and with a K(i) ratio of 30. Duloxetine inhibited ex vivo binding to rat 5-HT transporters and NE transporters with ED(50) values of 0.03 and 0.7 mg/kg, respectively, whereas venlafaxine had ED(50) values of 2 and 54 mg/kg, respectively. The depletion of rat brain 5-HT by p-chloramphetamine and depletion of rat hypothalamic NE by 6-hydroxydopamine was blocked by duloxetine with ED(50) values of 2.3 and 12 mg/kg, respectively. Venlafaxine had ED(50) values of 5.9 and 94 mg/kg for blocking p-chloramphetamine- and 6-hydroxydopamine-induced monoamine depletion, respectively. Thus, duloxetine more potently blocks 5-HT and NE transporters in vitro and in vivo than venlafaxine.

Animals↗
PubMed2001

A novel augmentation strategy for treating resistant major depression.

OBJECTIVE: Treatment-resistant depression is a significant public health concern; drug switching or augmentation often produce limited results. The authors hypothesized that fluoxetine could be augmented with olanzapine to successfully treat resistant depression. METHOD: An 8-week double-blind study was conducted with 28 patients who were diagnosed with recurrent, nonbipolar, treatment-resistant depression without psychotic features. Subjects were randomly assigned to one of three groups: olanzapine plus placebo, fluoxetine plus placebo, or olanzapine plus fluoxetine. RESULTS: Fluoxetine monotherapy produced minimal improvement on various scales that rate severity of depression. The benefits of olanzapine monotherapy were modest. Olanzapine plus fluoxetine produced significantly greater improvement than either monotherapy on one measure and significantly greater improvement than olanzapine monotherapy on the other measures after 1 week. There were no significant differences between treatment groups on extrapyramidal measures nor significant adverse drug interactions. CONCLUSIONS: Olanzapine plus fluoxetine demonstrated superior efficacy for treating resistant depression compared to either agent alone.

Ambulatory Care↗
PubMed2000

Muscarinic receptor agonists decrease cocaine self-administration rates in drug-naive mice.

(5R,6R)-6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[ 3.2.1]octane (PTAC) is a selective muscarinic receptor ligand. The compound exhibits high affinity for central muscarinic receptors with partial agonist mode of action at muscarinic M(2) and M(4) and antagonist mode of action at muscarinic M(1), M(3) and M(5) receptor subtypes. The compound was earlier reported to exhibit functional dopamine receptor antagonism in rodents despite its lack of affinity for dopamine receptors. In the present study, we report that PTAC, as well as the muscarinic receptor agonists pilocarpine and oxotremorine, dose-dependently decreased rates of intravenous self-administration (fixed ratio 1) of the indirect dopamine receptor agonist cocaine in drug naive mice. Similar decreases in cocaine self-administration rates were obtained with the dopamine receptor antagonists olanzapine, clozapine, risperidone, fluphenazine and haloperidol. These findings suggest that compounds with partial muscarinic receptor agonist mode of action may be used in the medical treatment of cocaine abuse.

Animals↗
PubMed2000

Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice.

Xanomeline is an M(1)/M(4) preferring muscarinic receptor agonist which decreased psychotic behaviors in patients with Alzheimer's disease, suggesting that xanomeline might be useful in the treatment of psychotic symptoms in patients with schizophrenia. The purpose of the present studies was, therefore, to compare the pharmacologic profile of xanomeline with that of known antipsychotic drugs. Electrophysiologically, xanomeline, after both acute and chronic administration in rats, inhibited A10 but not A9 dopamine cells in a manner which was blocked by the muscarinic receptor antagonist scopolamine. Behaviorally, xanomeline, like haloperidol, clozapine and olanzapine, blocked dopamine agonist-induced turning in unilateral 6-hydroxydopamine-lesioned rats, as well as apomorphine-induced climbing in mice. However, unlike the dopamine antagonist antipsychotic haloperidol, xanomeline did not produce catalepsy in rats. Moreover, xanomeline, like haloperidol, clozapine and olanzapine, inhibited conditioned avoidance responding in rats, an effect which also was blocked by scopolamine. The present results thus demonstrate that xanomeline has a pharmacologic profile which is similar to that of the atypical antipsychotics clozapine and olanzapine, thus indicating that xanomeline has the potential to be a novel approach in the treatment of psychotic symptoms in patients with schizophrenia.

Alzheimer Disease↗
PubMed2000

Decreased binding affinity of olanzapine and clozapine for human muscarinic receptors in intact clonal cells in physiological medium.

The binding affinity of olanzapine, clozapine and atropine for muscarinic receptor subtypes in clonal Chinese hamster ovary (CHO) cell lines was compared in intact cells in physiological media to disrupted cells in hypotonic buffer. The affinity of olanzapine and clozapine, but not atropine, for muscarinic receptor subtypes (M(1)-M(5)) was significantly reduced in intact cells in physiological medium compared to disrupted cells in hypotonic buffer. The affinity of olanzapine for muscarinic M(1) receptors was most affected with a reduction of K(i) value from 2.5 to 73 nM in intact cells. These data suggest that the affinity of olanzapine and clozapine for muscarinic receptors have been significantly overestimated.

Animals↗
PubMed2000

Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group.

BACKGROUND: Patients with Alzheimer disease (AD) commonly exhibit psychosis and behavioral disturbances that impair patient functioning, create caregiver distress, and lead to institutionalization. This study was conducted to assess the efficacy and safety of olanzapine in treating psychosis and/or agitation/aggression in patients with AD. METHODS: A multicenter, double-blind, placebo-controlled, 6-week study was conducted in 206 elderly US nursing home residents with AD who exhibited psychotic and/or behavioral symptoms. Patients were randomly assigned to placebo or a fixed dose of 5, 10, or 15 mg/d of olanzapine. The primary efficacy measure was the sum of the Agitation/Aggression, Hallucinations, and Delusions items (Core Total) of the Neuropsychiatric Inventory-Nursing Home version. RESULTS: Low-dose olanzapine (5 and 10 mg/d) produced significant improvement compared with placebo on the Core Total (-7.6 vs -3.7 [P<.001] and -6.1 vs -3. 7 [P =.006], respectively). Core Total improvement with olanzapine, 15 mg/d, was not significantly greater than placebo. The Occupational Disruptiveness score, reflecting the impact of patients' psychosis and behavioral disturbances on the caregiver, was significantly reduced in the 5-mg/d olanzapine group compared with placebo (-2.7 vs -1.5; P =.008). Somnolence was significantly more common among patients receiving olanzapine (25.0%-35.8%), and gait disturbance occurred in those receiving 5 or 15 mg/d (19.6% and 17.0%, respectively). No significant cognitive impairment, increase in extrapyramidal symptoms, or central anticholinergic effects were found at any olanzapine dose relative to placebo. CONCLUSION: Low-dose olanzapine (5 and 10 mg/d) was significantly superior to placebo and well tolerated in treating agitation/aggression and psychosis in this population of patients with AD.

Aged↗
PubMed2000

Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex.

To understand the mechanism of the clinical efficacy of olanzapine and fluoxetine combination therapy for treatment-resistant depression (TRD), we studied the effects of olanzapine and other antipsychotics in combination with the selective serotonin uptake inhibitors fluoxetine or sertraline on neurotransmitter release in rat prefrontal cortex (PFC) using microdialysis. The combination of olanzapine and fluoxetine produced robust, sustained increases of extracellular levels of dopamine ([DA](ex)) and norepinephrine ([NE](ex)) up to 361 +/- 28% and 272 +/- 16% of the baseline, respectively, which were significantly greater than either drug alone. This combination produced a slightly smaller increase of serotonin ([5-HT](ex)) than fluoxetine alone. The combination of clozapine or risperidone with fluoxetine produced less robust and persistent increases of [DA](ex) and [NE](ex). The combination of haloperidol or MDL 100907 with fluoxetine did not increase the monoamines more than fluoxetine alone. Olanzapine plus sertraline combination increased only [DA](ex). Therefore, the large, sustained increase of [DA](ex), [NE](ex), and [5-HT](ex) in PFC after olanzapine-fluoxetine treatment was unique and may contribute to the profound antidepressive effect of the olanzapine and fluoxetine therapy in TRD.

Animals↗
PubMed1999

1-(1,2,5-Thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2,6)]heptanes as new potent muscarinic M1 agonists: structure-activity relationship for 3-aryl-2-propyn-1-yloxy and 3-aryl-2-propyn-1-ylthio derivatives.

Two new series of 1-(1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2, 6)]heptanes were synthesized and evaluated for their in vitro activity in cell lines transfected with either the human M1 or M2 receptor. 3-Phenyl-2-propyn-1-yloxy and -1-ylthio analogues substituted with halogen in the meta position showed high functional potency, efficacy, and selectivity toward the M1 receptor subtype. A quite unique functional M1 receptor selectivity was observed for compounds 8b, 8d, 8f, 9b, 9d, and 9f. Bioavailability studies in rats indicated an oral bioavailability of about 20-30%, with the N-oxide as the only detected metabolite.

Animals↗
PubMed1999

Antagonism by olanzapine of dopamine D1, serotonin2, muscarinic, histamine H1 and alpha 1-adrenergic receptors in vitro.

The atypical antipsychotic olanzapine has relatively high affinity for a number of neuronal receptors in radioreceptor binding assays. The ability of olanzapine to activate or antagonize a number of neuronal receptors was investigated in vitro, in cell lines transfected selectively with receptor subtypes and in receptor-selective isolated tissue studies. Olanzapine had no agonist activity at any of the receptors examined. However, olanzapine was a potent antagonist of 5-HT-stimulated increases in IP3 in cell lines transfected with 5-HT2A or 5-HT2B receptors with IC50 values of 30-40 nM. Olanzapine weakly blocked 5-HT-induced formation of IP3 in cell lines transfected with 5-HT2c receptors, but in this cell line potently inhibited 5-HT-stimulated [35S]GTP gamma S binding with a Ki value of 15 nM. Olanzapine blocked dopamine-stimulated adenylyl cyclase in rat retina with modest potency (Ki = 69 nM), consistent with its relatively low affinity for dopamine D1 receptors. Olanzapine blocked agonist-induced activities at the muscarinic receptor subtypes M1, M2, M3, and M5 with Ki values of 70, 622, 126, and 82 nM, respectively. In studies using cell lines transfected with muscarinic M4 receptors, olanzapine and the atypical antipsychotic clozapine did not have agonist activities as determined with cAMP inhibition and stimulation assays, arachidonic acid release and [35S]GTP gamma S binding assays. However, olanzapine antagonized agonist-induced effects in muscarinic M4 cells with a Ki value of 350 nM. In isolated tissue studies, olanzapine potently blocked agonist-induced effects at alpha 1-adrenergic and histamine H1 receptors (KB = 9 and 19 nM, respectively). Thus, olanzapine was an antagonist at all receptors investigated and was a particularly potent antagonist at 5-HT2A, 5-HT2B, 5-HT2C, alpha 1-adrenergic and histamine H1 receptors. Olanzapine was a weaker antagonist at muscarinic and dopamine D1 receptors.

Adenylyl Cyclases↗
PubMed1999

The in vivo effects of olanzapine and other antipsychotic agents on receptor occupancy and antagonism of dopamine D1, D2, D3, 5HT2A and muscarinic receptors.

The atypical antipsychotic olanzapine was compared to other atypical as well as typical antipsychotic agents for in vivo occupancy of D1, D2, D3, 5HT2, and muscarinic receptors in rat brain. Blockade of D2 receptors was determined by measuring the levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). To assess the interaction with phosphoinositide (PI)-coupled 5HT2A and muscarinic receptors in vivo, we used a novel radiometric technique to measure in vivo PI hydrolysis. The antagonism of olanzapine and other antipsychotic agents on 5HT2A and muscarinic receptors was determined by in vivo blockade of PI hydrolysis, stimulated by the 5HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) or the muscarinic agonist pilocarpine. Olanzapine inhibited 5HT2, D2, and D3 in vivo binding with high potency (ID50=0.15, 0.6 and 1.2 mg/kg, IP, respectively), while inhibiting D1 and muscarinic in vivo binding with much less potency (ID50 > 10 mg/kg, IP). The binding of olanzapine to D2 receptors in neostriatum was well correlated with the increase of DOPAC (ED200 = 0.8 mg/kg, IP) in vivo, indicating dopamine D2 antagonism. In vivo PI hydrolysis was increased by DOI in frontal cortex and by pilocarpine in hippocampus up to 2- and 7-fold above the basal level, respectively. The agonist-induced increases in PI hydrolysis were fully blocked by the 5HT2A antagonist MDL100907 and the muscarinic antagonist scopolamine, indicating the mediation by 5HT2A receptors in frontal cortex and PI-coupled muscarinic receptors (ml, m3, and m5) in hippocampus, respectively. Olanzapine was about 8-fold more potent in vivo in blocking DOI-induced stimulation of PI hydrolysis (ID50 = 0.1 mg/kg, IP) than pilocarpine-induced stimulation of PI hydrolysis (ID50 = 0.8 mg/kg, IP). In conclusion, olanzapine is more potent in blocking the 5HT2A receptor than D1, D2, D3 and muscarinic receptors in vivo, consistent with its favorable clinical profiles. In addition, the novel in vivo PI hydrolysis assay proved to be a useful and reliable in vivo method to assess the functional efficacy of compounds that interact with the 5HT2 and muscarinic receptors.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Potential role of muscarinic receptors in schizophrenia.

The role of muscarinic receptors in schizophrenia was investigated using the muscarinic agonist PTAC. PTAC was highly selective for muscarinic receptors, was a partial agonist at muscarinic M2/M4 receptors and an antagonist at M1, M3 and M5 receptors. PTAC was highly active in animal models predictive of antipsychotic behavior including inhibition of conditioned avoidance responding in rats and blockade of apomorphine-induced climbing behavior in mice. d-Amphetamine-induced Fos expression in rat nucleus accumbens was inhibited by PTAC, thus directly demonstrating the ability of PTAC to modulate DA activity. In electrophysiological studies in rats, PTAC acutely inhibited the firing of A10 DA cells and after chronic administration decreased the number of spontaneously firing DA cells in the A10 brain area. However, PTAC did not appreciably alter the firing of A9 DA cells. Thus, PTAC appears to have novel antipsychotic-like activity and these data suggest that muscarinic compounds such as PTAC may represent a new class of antipsychotic agents.

Animals↗
PubMed1999

Direct pharmacological comparison of the muscarinic receptors mediating relaxation and contraction in the rabbit thoracic aorta.

The purpose of the present studies was to directly compare the pharmacology of the muscarinic cholinergic receptors coupled to carbachol-induced relaxation and contraction of the intact and the endothelium-denuded rabbit thoracic aorta, respectively. The order of potencies of agonists for producing relaxation in the intact aorta was similar to that for producing contraction in the denuded aorta. In both preparations, the partial agonists pilocarpine, McN-A-343, and RS86 functioned as antagonists, indicating a lack of receptor reserve in both preparations. Further, the pA2 values for antagonists in both tissues were virtually identical and were consistent with the pharmacology of M3 receptors.

Animals↗
PubMed1999

Arachidonic acid release in cell lines transfected with muscarinic receptors: a simple functional assay to determine response of agonists.

Muscarinic agonists stimulated arachidonic acid release from 10- to 32-fold in Chinese hamster ovary (CHO) cells transfected with muscarinic M1, M3 and M5 receptor subtypes. Muscarinic agonists liberated arachidonic acid from the cAMP-coupled M2 and M4 cells only in the presence of ATP. Partial agonists were less efficacious at liberating arachidonic acid than full agonists. The ability of muscarinic agonists to liberate arachidonic acid and stimulate phosphoinositide hydrolysis in the same CHO M1, M3 and M5 cells was well correlated; however, partial agonists were more efficacious at stimulating phosphoinositide hydrolysis than arachidonic acid release. The efficacy and potency of 13 muscarinic agonists to liberate arachidonic acid was characterised. Influx of external calcium was required for arachidonic acid release even after initiation of agonist-induced release. It is concluded that arachidonic acid release is a simple assay suitable for evaluation of muscarinic agonists, antagonists and the flux of external calcium into cells.

Animals↗