Influence of vesicular storage and monoamine oxidase activity on [11C]phenylephrine kinetics: studies in isolated rat heart.
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[11C]Phenylephrine (PHEN) is a radiolabeled analogue of norepinephrine that is transported into cardiac sympathetic nerve varicosities by the neuronal norepinephrine transporter and taken up into storage vesicles localized within the nerve varicosities by the vesicular monoamine transporter. PHEN is structurally related to two previously developed sympathetic nerve markers: [11C]-meta-hydroxyephedrine and [11C]epinephrine. To better characterize the neuronal handling of PHEN, particularly its sensitivity to neuronal monoamine oxidase (MAO) activity, kinetic studies in an isolated working rat heart system were performed. METHODS: Radiotracer was administered to the isolated working heart as a 10-min constant infusion followed by a 110-min washout period. Two distinctly different approaches were used to assess the sensitivity of the kinetics of PHEN to MAO activity. In the first approach, oxidation of PHEN by MAO was inhibited at the enzymatic level with the MAO inhibitor pargyline. In the second approach, the two hydrogen atoms on the a-carbon of the side chain of PHEN were replaced with deuterium atoms ([11C](-)-alpha-alpha-dideutero-phenylephrine [D2-PHEN]) to inhibit MAO activity at the tracer level. The importance of vesicular uptake on the kinetics of PHEN and D2-PHEN was assessed by inhibiting vesicular monoamine transporter-mediated storage into vesicles with reserpine. RESULTS: Under control conditions, PHEN initially accumulated into the heart at a rate of 0.72+/-0.15 mL/min/g wet. Inhibition of MAO activity with either pargyline or di-deuterium substitution did not significantly alter this rate. However, MAO inhibition did significantly slow the clearance of radioactivity from the heart during the washout phase of the study. Blocking vesicular uptake with reserpine reduced the initial uptake rates of PHEN and D2-PHEN, as well as greatly accelerated the clearance of radioactivity from the heart during washout. CONCLUSION: These studies indicate that PHEN kinetics are sensitive to neuronal MAO activity. Under normal conditions, efficient vesicular storage of PHEN serves to protect the tracer from rapid metabolism by neuronal MAO. However, it is likely that leakage of PHEN from the storage vesicles and subsequent metabolism by MAO lead to an appreciable clearance of radioactivity from the heart. (+info)
Inhibition of monoamine oxidase type A, but not type B, is an effective means of inducing anticonvulsant activity in the kindling model of epilepsy.
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The anticonvulsant activity of inhibitors of monoamine oxidase (MAO) was reported early after the development of irreversible MAO inhibitors such as tranylcypromine, but was never clinically used because of the adverse effects of these compounds. The more recently developed reversible MAO inhibitors with selectivity for either the MAO-A or MAO-B isoenzyme forms have not been studied extensively in animal models of epilepsy, so it is not known which type of MAO inhibitor is particularly effective in this respect. We compared the following drugs in the kindling model of epilepsy: 1) L-deprenyl (selegiline), i.e., an irreversible inhibitor of MAO-B, which, however, also inhibits MAO-A at higher doses, 2) the novel reversible MAO-B inhibitor LU 53439 (3,4-dimethyl-7-(2-isopropyl-1,3, 4-thiadiazol-5-yl)-methoxy-coumarin), which is much more selective for MAO-B than L-deprenyl, 3) the novel reversible and highly selective MAO-A inhibitor LU 43839 (esuprone; 7-hydroxy-3, 4-dimethylcoumarin ethanesulfonate), and 4) the irreversible nonselective MAO inhibitor tranylcypromine. Esuprone proved to be an effective anticonvulsant in the kindling model with a similar potency as L-deprenyl. In contrast to esuprone and L-deprenyl, the selective MAO-B inhibitor LU 53439 was not effective in the kindling model; this substantiates the previous notion that the anticonvulsant activity of L-deprenyl is not related to MAO-B inhibition, but to other effects of this drug, such as inhibition of MAO-A. Drugs inhibiting both MAO-A and MAO-B to a similar extent (tranylcypromine) or combinations of selective MAO-A and MAO-B inhibitors (esuprone plus LU 53439) had no advantage over MAO-A inhibition alone, but were less well tolerated. The data thus suggest that selective MAO-A inhibitors such as esuprone may be an interesting new approach for the treatment of epilepsy. (+info)
Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide and brofaromine for the treatment of depression.
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The reversible inhibitors of monoamine oxidase type A (RIMAs) are a newer group of antidepressants that have had much less impact on clinical psychopharmacology than another contemporary class of medications, the selective serotonin reuptake-inhibitors (SSRIs). The RIMAs agents are distinguished from the older monoamine oxidase inhibitors (MAOIs) by their selectivity and reversibility. As a result, dietary restrictions are not required during RIMA therapy, and hypertensive crises are quite rare. In this article, we describe a series of meta-analyses of studies of the two most widely researched RIMAs, moclobemide (MOC; Aurorex) and brofaromine (BRO). Our findings confirm that both BRO and MOC are as effective as the tricyclic antidepressants, and they are better tolerated. However, BRO is not being studied at present for reasons unrelated to efficacy or side effects. MOC, which is available throughout much of the world (but not the United States), is significantly more effective than placebo and, at the least, comparable to the SSRIs in both efficacy and tolerability. For MOC, higher dosages may enhance efficacy for more severe depressions. We also found evidence that supports clinical impressions that MOC is somewhat less effective, albeit better tolerated, than older MAOIs, such as phenelzine or tranylcypromine. Little evidence has yet emerged to suggest that the RIMAs share older MAOIs' utility for treatment of depressions characterized by prominent reverse neurovegetative features. Based on available evidence, the RIMAs appear to have a limited, but useful, role in the differential therapeutics of the depressive disorders. (+info)
Effect of low-dose treatment with selegiline on dopamine transporter (DAT) expression and amphetamine-induced dopamine release in vivo.
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1. Chronic treatment with low doses of the selective monoamine oxidase (MAO) type B inhibitors selegiline [(-)-deprenyl] and rasagiline, causes elevation in extracellular level of 3,4-dihydroxyphenylethylamine (dopamine) in the rat striatum in vivo (Lamensdorf et al., 1996). The present study was carried out to determine whether this effect of selegiline could be the result of an inhibition of the high-affinity dopamine neuronal transport process. 2. Changes in activity of the dopamine transporter (DAT) in vivo following selegiline treatment were evaluated indirectly by microdialysis technique in the rat, from the change in striatal dopamine extracellular concentration following systemic amphetamine administration (4 mg kg(-1), i.p.). Striatal levels of the DAT molecule were determined by immunoblotting. Uptake of [3H]-dopamine was determined in synaptosomes from selegiline-treated animals. 3. Amphetamine-induced increase in striatal extracellular dopamine level was attenuated by one day and by chronic (21 days) treatment with selegiline (0.25 mg kg(-1), s.c.). 4. Striatal levels of DAT were elevated after 1 and 21 days treatment with selegiline, but were not affected by clorgyline, rasagiline, nomifensine or amphetamine. 5. The increase in DAT expression, and attenuation of amphetamine-induced dopamine release, were not accompanied by a change in [3H]-dopamine uptake in synaptosomes of selegiline-treated animals. 6. The results suggest that a reversible inhibition of dopamine uptake occurs following chronic low dose selegiline treatment in vivo which may be mediated by an increase in endogenous MAO-B substrates such as 2-phenylethylamine, rather than by the inhibitor molecule or its metabolites. Increased DAT expression appears to be a special property of the selegiline molecule, since it occurs after one low dose of selegiline, and is not seen with other inhibitors of MAO-A or MAO-B. The new DAT molecules formed following selegiline treatment appear not to be functionally active. (+info)
Treatment of atypical depression with cognitive therapy or phenelzine: a double-blind, placebo-controlled trial.
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BACKGROUND: Patients with atypical depression are more likely to respond to monoamine oxidase inhibitors than to tricyclic antidepressants. They are frequently offered psychotherapy in the absence of controlled tests. There are no prospective, randomized, controlled trials, to our knowledge, of psychotherapy for atypical depression or of cognitive therapy compared with a monoamine oxidase inhibitor. Since there is only 1 placebo-controlled trial of cognitive therapy, this trial fills a gap in the literature on psychotherapy for depression. METHODS: Outpatients with DSM-III-R major depressive disorder and atypical features (N = 108) were treated in a 10-week, double-blind, randomized, controlled trial comparing acute-phase cognitive therapy or clinical management plus either phenelzine sulfate or placebo. Atypical features were defined as reactive mood plus at least 2 additional symptoms: hypersomnia, hyperphagia, leaden paralysis, or lifetime sensitivity to rejection. RESULTS: With the use of an intention-to-treat strategy, the response rates (21-item Hamilton Rating Scale for Depression score, < or =9) were significantly greater after cognitive therapy (58%) and phenelzine (58%) than after pill placebo (28%). Phenelzine and cognitive therapy also reduced symptoms significantly more than placebo according to contrasts after a repeated-measures analysis of covariance and random regression with the use of the blind evaluator's final Hamilton Rating Scale for Depression score. The scores between cognitive therapy and phenelzine did not differ significantly. Supplemental analyses of other symptom severity measures confirm the finding. CONCLUSIONS: Cognitive therapy may offer an effective alternative to standard acute-phase treatment with a monoamine oxidase inhibitor for outpatients with major depressive disorder and atypical features. (+info)
Selegiline effects on cocaine-induced changes in medial temporal lobe metabolism and subjective ratings of euphoria.
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To test the effect of selegiline, a specific monoamine oxidase B (MAO-B) inhibitor, on the cerebral metabolic and euphorigenic effects of cocaine in experienced users, eight cocaine-dependent (CD) subjects were evaluated using a within-subjects design. Each subject participated in two pairs of [F-18]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans (baseline scan followed 24 h later by a second scan obtained in conjunction with a 40-mg cocaine infusion) performed before and after a 1-week period of daily treatment with 10 mg selegiline administered orally. The hippocampus and amygdala were evaluated because of their hypothesized involvement in the addiction process, and the thalamus was evaluated as a comparison region. Following 7 days of selegiline treatment, the magnitude of the subjective euphoria ("high") produced by cocaine infusion was reduced by 40% (cocaine by selegiline interaction F = 7.15, df = 1.21, p = .014). Selegiline treatment also altered glucose utilization (normalized against whole brain counts) in the two limbic regions, but not the thalamus. In the amygdala, the effects of cocaine differed, depending upon whether or not patients were being treated with selegiline (cocaine by selegiline interaction F = 4.67, df = 1,19.8, p = .043). A different effect was observed in the hippocampus, where selegiline treatment decreased metabolic activity irrespective of whether cocaine was given (main effect F = 7.70, df = 1.20, p = .012). The concomitant changes in both the subjective experience of the "high" and normalized amygdala glucose utilization after selegiline treatment, suggest that a relationship exists between cocaine-induced euphoria and limbic metabolism. The data suggest that selegiline may be a useful adjunct in the treatment of cocaine dependence. (+info)
Cellular and molecular remodeling in a heart failure model treated with the beta-blocker carteolol.
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Broad-breasted white turkey poults fed furazolidone developed dilated cardiomyopathy (DCM) characterized by ventricular dilatation, decreased ejection fraction, beta1-receptor density, sarcoplasmic reticulum (SR) Ca2+-ATPase, myofibrillar ATPase activity, and reduced metabolism markers. We investigated the effects of carteolol, a beta-adrenergic blocking agent, by administrating two different dosages (0.01 and 10.0 mg/kg) twice a day for 4 wk to control and DCM turkey poults. At completion of the study there was 59% mortality in the nontreated DCM group, 55% mortality in the group treated with the low dose of carteolol, and 22% mortality in the group treated with the high dose of carteolol. Both treated groups showed a significant decrease in left ventricle size and significant restoration of ejection fraction and left ventricular peak systolic pressure. Carteolol treatment increased beta-adrenergic receptor density, and the high carteolol dose restored SR Ca2+-ATPase and myofibrillar ATPase activities, along with creatine kinase, lactate dehydrogenase, aspartate transaminase, and ATP synthase activities, to normal. These results show that beta-blockade with carteolol improves survival, reverses contractile abnormalities, and induces cellular remodeling in this model of heart failure. (+info)
Selegiline in the treatment of Alzheimer's disease: a long-term randomized placebo-controlled trial. Czech and Slovak Senile Dementia of Alzheimer Type Study Group.
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OBJECTIVE: To evaluate the efficacy and adverse effects of the type B monoamine oxidase inhibitor selegiline (also known as I-deprenyl) in the treatment of Alzheimer's disease. DESIGN: Long-term, double-blind, placebo-controlled trial. SETTING: Seven cities (1 or 2 nursing homes in each city) in the Czech and Slovak Republics. PATIENTS: A total of 173 nursing-home residents fulfilling the DSM-III criteria for mild to moderate Alzheimer's disease. INTERVENTIONS: Selegiline (10 mg per day) or placebo (both including 50 mg ascorbic acid) administered for 24 weeks. OUTCOME MEASURES: Clinical Global Impressions scale and Nurses Observation Scale for Inpatient Evaluation at baseline and at weeks 6, 12 and 24; Clock Drawing Test at baseline and 24 weeks, results of which were evaluated as normal or pathologic, and quantitatively on a modified 6-point scale; Sternberg's Memory Scanning test at baseline and at weeks 6, 12 and 24; Mini Mental State Examination, and electroencephalogram at baseline and 24 weeks; Structured Adverse Effects Rating Scale; physical, laboratory, hematological and electrocardiographic examinations at baseline and weeks 12 and 24. RESULTS: A total of 143 subjects completed enough of the trial to be entered in the analysis. Subjects were analyzed by 2 subgroups depending on whether they had a normal or pathologic result of the Clock Drawing Test. Analysis of variance showed significant improvement with selegiline versus placebo among those with a normal result of the Clock Drawing Test on the Mini Mental Status Examination (total score and orientation-place subscale) and among those with a pathologic result of the Clock Drawing Test of Sternberg's Memory Scanning test (for both speed and accuracy), on the Clinical Global Impressions scale as well as in terms of the dominant frequency on electroencephalograms. CONCLUSION: Selegiline has a long-term beneficial effect in Alzheimer's disease on memory modalities that reflect the function of the prefrontal areas of the brain, which are rich in dopamine receptors. The delayed appearance of differences between selegiline and placebo supports the notion that the mechanism of action is through neuronal rescue or neuroprotection. The differential response of patients with normal and pathologic results of the Clock Drawing Test may reflect the fact that the evaluation methods' sensitivity to change depends on the severity of dementia. (+info)