Comparative behavioral effects of clorgyline and pargyline in man: A preliminary evaluation

The antidepressant and other behavioral effects of clorgyline, a preferential inhibitor of monoamine oxidase (MAO) type A, were compared with those of pargyline, a preferential inhibitor of MAO type B, in 16 depressed patients. In a subgroup of more severely depressed patients, clorgyline treatment for 4 weeks resulted in significant improvement on both observer-rated and self-rated scales, while minimal changes occurred during pargyline treatment. Similarly, in a crossover study that included 8 patients examined with multiple scales, clorgyline had generally greater antidepressant and antianxiety effects than did pargyline, although pargyline had some activating effects and also tended to produce more side effects. MAO type A inhibition may be more important than MAO type B inhibition for antidepressant efficacy.     

Treatment with clorgyline and pargyline differentially decreases clonidine-induced hypotension and bradycardia

Summary A study was made of the effects of acute and chronic treatment with monoamine-oxidase (MAO) inhibitiors on the peripheral and central cardiovascular response induced by clonidine in anaesthetized normotensive rats. Clonidine (30 nmoles · kg^–1 i.v.) produced a biphasic change in mean blood pressure; an initial transient increase was followed by a prolonged hypotensive effect, coinciding with the maximal bradycardia. Twenty-four hours after acute (single) or chronic (daily for 7 days) administration of MAO inhibitors (pargyline 10 mg · kg^–1 SC or clorgyline 0.3 mg · kg^–1 SC) there was no effect either on the basal cardiovascular parameters or on the initial pressor response induced by clonidine. Chronic but not acute treatment with clorgyline, an inhibitor of type A MAO, greatly decreased the hypotension and bradycardia induced by clonidine for as long as 5 days after its discontinuation. On the other hand, after chronic administration of pargyline (10 mg · kg^–1), a preferential type B MAO inhibitor, the hypotension and bradycardia caused by clonidine were differently affected. There was a reduction in the bradycardia up to the third day following the discontinuation of pargyline, whereas the hypotensive response induced by clonidine was only attenuated for 24 h and unaffected with a lower dose of pargyline (0.3 mg · kg^–1).It is concluded that chronic administration of the type A MAO inhibitor, clorgyline, attenuates the central responses to clonidine through the reduction in sensitivity of brain -adrenoceptors. Pargyline, that preferentially inhibits type B MAO, reduces only the bradycardia induced by clonidine. This result may indicate a different modulation of the receptors involved in this response to clonidine.     

Chronic clorgyline and pargyline increase apomorphine-induced stereotypy in the rat

The effects of monoamine oxidase inhibiting antidepressant drugs on behavioral and biochemical measures of dopamine receptor status were measured in the rat. Male Wistar rats received clorgyline (1 mg/kg/day for 21-28 days), pargyline (1 mg/kg/day for 21-28 days) or a combination of these regimens. They were then either tested for stereotypy induced by 1 mg/kg SC injection of apomorphine or were sacrificed and their striata used to measure specific [3H]spiroperidol binding. All three chronic treatment regimens produced statistically significant increases in apomorphine induced stereotypy: there was, however, no significant difference between the three drug regimens. None of the antidepressant drug treatments significantly affected [3H]spiroperidol binding in the corpus striatum. This study demonstrates that behavioral and biochemical measures of dopamine function may not always be closely correlated. It is proposed that the behavioral changes may be related to alterations in other monoaminergic systems, which are known to have fibres running into the nigrostriatal pathway.     

Effect of lamotrigine on the activities of monoamine oxidases A and B in vitro and on monoamine disposition in vivo

Recent clinical evidence indicates that the broad spectrum anticonvulsant drug lamotrigine is effective against the depressive phase of bipolar illness and the difficult to treat rapid cycling form of the disorder. However, the molecular mechanism underlying this therapeutic action remains uncertain. Given that inhibition of the A-type of monoamine oxidase (MAO) is a proven antidepressant mechanism, we investigated the effects of lamotrigine on MAO activities in vitro and on monoamine disposition in vivo. In vitro, lamotrigine inhibited rat brain MAO activities with Ki values (MAO-A, 15 microM; MAO-B, 18 microM) potentially within the therapeutic range for this drug. The effects of lamotrigine on the MAO-A activities of rat brain and human liver preparations were almost identical suggesting minimal species or tissue variation. In contrast, there was no (MAO-A) or minimal (MAO-B) reduction in brain MAO activities when assayed ex vivo following the administration of lamotrigine to rats. In vivo brain microdialysis failed to detect meaningful alterations in extracellular hippocampal or frontal cortex monoamine concentrations. Furthermore, lamotrigine did not modulate oral tyramine-induced hypertension in rats or 5-hydroxytryptophan-induced head shaking in mice, providing strong evidence that the drug does not perturb monoamine metabolism in vivo. The absence of observable effects of lamotrigine on monoamine disposition in vivo may be explained by the competitive and highly reversible nature of the interaction of lamotrigine with MAO isoforms. Thus, altered monoamine metabolism in vivo is unlikely to account for the antidepressant action of the drug in bipolar depression.     

Lifetime monoamine oxidase inhibition and sleep

The effects of clorgyline, a type A monoamine oxidase (MAO) inhibitor, on the sleep of the rat were examined after subacute and lifetime administration. When 2 mg/kg/24 hours were given for 60 hours, type A MAO was inhibited by 92% and a significant reduction in REM sleep time was noted. When fetal rats were exposed to maternal dosage of 1 mg/kg/24 hours and then received this dose from one to 6 weeks postnatally, type A MAO was inhibited by 99%, but there were no alterations in the EEG sleep stages. In summary, subacute administration of clorgyline resulted in decreases in both Type A MAO and REM sleep; during chronic administration in a developing animal, Type A MAO was again decreased, but there was no corresponding changes in REM sleep.     

Species differences in the deamination of dopamine and other substrates for monoamine oxidase in brain

Cortex and caudate specimens from human, non-human primate and rodent brains were examined for their ability to deaminate dopamine and for their sensitivity to irreversible monoamine oxidase (MAO) inhibitors. Using inhibition curves obtained with clorgyline, deprenyl and pargyline to estimate the relative proportions of MAO-A and MAO-B activity, dopamine was found to be deaminated predominantly by MAO-A in rat cortex and caudate. In contrast, dopamine was primarily an MAO-B substrate in human and vervet cortex and caudate. When clorgyline inhibition curves with tyramine or dopamine as substrate were compared in human, vervet and rat cortex, more pronounced species differences were found with dopamine than with tyramine. In all three species caudate tended to be more sensitive to inhibition by low concentrations of clorgyline than was cortex, suggesting a higher proportion of MAO-A activity in caudate. Similar species differences were also found when MAO-A activities were estimated using serotonin (5-HT): -phenylethylamine (PEA) ratios (5-HT/5-HT + PEA). These ratios with selective substrates were highly correlated with clorgyline inhibition curves obtained with tyramine as substrate across 29 brain regions and tissues from different rodent and primate species (r=0.85, P<0.001). Data from both the substrate ratios and the clorgyline inhibition curves confirmed the relative predominance of MAO-B activity in primate brain regions (70–85%) as compared to rat brain regions (45%). Smaller species differences were observed in liver. Species differences in the proportion of brain MAO-A and B activities and in the deamination of dopamine and other substrates for MAO may have important implications in regard to the widespread use of rodent rather than primate models in the study of biogenic amine metabolism and of drugs affecting amine function.     

Binding of [H]brofaromine to monoamine oxidase A in vivo: displacement by clorgyline and moclobemide

Short duration of action, displaceability by endogenously released monoamines, and absence of cumulation of effect of the selective inhibitor of monoamine oxidase type A (MAO-A), brofaromine (CGP 11305 A), indicate reversibility of its interaction with the enzyme in vivo. However, its in vitro interaction with the enzyme showed features commonly associated with irreversible inhibition. To clarify this issue, the in vivo binding of [³H]brofaromine to MAO-A in areas of the rat brain, and in rat heart and liver was investigated. Specific binding, defined by pretreatment with the irreversible inhibitor, clorgyline, was between 15 and 75% of total binding depending on the tissue and the time elapsed after injection of radioactivity. In brain and heart tissue, unlabelled brofaromine, another reversible inhibitor of MAO-A, moclobemide and clorgyline were able to displace [³H]brofaromine when administered after the labelled compound with ED₅₀s of 1–3 mg/kg p.o., 3mg/kg p.o. and 0.3–1 mg/kg s.c., respectively. In the liver, brofaromine and moclobemide and the inhibitor of drug-metabolizing enzymes, proadifen (SK & F 525 A), were able to significantly inhibit [³H]brofaromine binding. Clorgyline was only marginally effective, suggesting that, in this organ, [³H]brofaromine binds predominantly to such enzymes. In conclusion, the binding of [³H]brofaromine to MAO-A in rat brain and heart in vivo was found to be displaceable by other MAO inhibitors and is therefore reversible. In the liver, the compound bound predominantly to other sites, probably microsomal drug-metabolizing enzymes.     

Inhibition of monoamine oxidase and semicarbazide-sensitive amine oxidase by mexiletine and related compounds

Summary The in vitro inhibition by mexiletine and related compounds of the activity of rat brain, heart and lung mono-amine oxidase-A (MAO-A), rat brain MAO-B, human platelet-poor plasma benzylamine oxidase and a clorgyline-resistant, semicarbazide-sensitive amine oxidase (SSAO) distinct from both MAO and benzylamine oxidase has been studied. The compounds were most active towards MAO-A and SSAO. IC₅₀ values for mexiletine towards rat heart MAO-A and SSAO were 10 mol/l and 320 mol/l, respectively. Replacement of the para-hydrogen atom in the mexiletine aromatic ring by bromine increased potency towards both MAO-A and SSAO. Replacement of the ortho-methyl group in the mexiletine aromatic ring by hydrogen increased the potency towards SSAO alone. FLA 1042, with both these substitutions, was found to be a reversible mixed-type inhibitor of both MAO-A (K _i ^slope 1.4 mol/l, K _i ^int 24 mol/l) and of SSAO (K _i ^slope 12 mol/l, K _i ^int 6 mol/l).     

Molecular cloning,sequence analysis,and tissue distribution of marmoset monoamine oxidases A and B

The common marmoset (Callithrix jacchus), a New World primate, is currently attracting much attention as a nonhuman primate model for pharmacological and pharmacokinetic studies in preclinical research. In this study, we newly isolated the cDNAs of marmoset monoamine oxidase A (MAO-A) and MAO-B from liver and brain, respectively. MAO-A and MAO-B cDNAs, respectively, contained open reading frames of 527 and 520 amino acids and were approximately 92% and 95% identical to their human orthologs. Marmoset MAOs were phylogenetically closer to primate MAOs, including human MAOs, than to pig, dog, or rodent MAOs. The genomic and gene structures of marmoset MAOs were similar to those of humans. Among the five marmoset tissue types analyzed, the expression levels of MAO-A mRNA were relatively abundant in lung, liver, kidney, and small intestine, whereas the expression levels of MAO-B mRNA were relatively abundant in brain, liver, kidney, and small intestine; these tissue distributions are similar to those of human MAOs. These results suggest that MAO-A and MAO-B are similar at a molecular level in marmosets and humans.     

Titration of human brain monoamine oxidase-A and-B by clorgyline andl-deprenil

Summary The interaction of clorgyline andl-deprenil with the-A and-B forms of human brain monoamine oxidase (MAO) has been studied. Both compounds inhibit cerebrocortical MAO in a manner consistent with a suicide inactivation of the enzyme. The interaction of clorgyline with the-A form of the enzyme appears to take place almost entirely at specific binding sites, and the conditions required for this inhibitor to titrate the concentrations of MAO-A have been elucidated.l-Deprenil has also been used to titrate the concentration of the-B form of MAO in cerebrocortical homogenates, but there is a considerable degree of non-specific binding of this compound. The two inhibitors have been used to titrate the concentrations of the two enzyme forms in frontal cortex homogenates from different age groups. There was a significantly higher MAO-B activity for the age range 73–95 years than for the age range 2–63 years. No significant differences between the two age groups were found for MAO-A. The activity of MAO-A in the samples correlated very well with the concentration of this enzyme form. Titration of the B-form of the enzyme withl-deprenil indicated an increased enzyme concentration with age, although other factors, such as the non-specific binding of this compound, could contribute to this effect.     

Central mediation of the antihypertensive effect of pargyline in spontaneously hypertensive rats.

The monoamine oxidase (MAO) inhibitor pargyline induced a moderate (about 20 mm Hg) but persistent (48 h) decrease of systolic blood pressure in unanesthetized adult spontaneously hypertensive rats (SHR) but not in normotensive rats. The fall of blood pressure correlated with the blockade of norepinephrine (NE) deamination by brain homogenates. After an intracerebroventricular (icv) injection of 6-hydroxydopamine, which lowered brain NE content by about 70%, pargyline was unable to diminish arterial pressure. Blockade of central alpha-adrenoceptors by treatment with phentolamine (100 microgram icv) could either prevent or reverse the fall of blood pressure in SHR induced by pargylline. Moreover, a low dose of pargyline injected directly into the brain lowered arterial pressure. We conclude that the hypotensive action of pargylline in SHR appears to be the consequence of NE accumulating at an inhibitory alpha-adrenoceptor in brain.     

Inhibition of monoamine oxidases by haloperidol and its metabolites: pharmacological implications for the chemotherapy of schizophrenia

The effect of haloperidol and its metabolites on human platelet monoamine oxidase B (MAO-B) and human placenta monoamine oxidase A (MAO-A) in vitro has been investigated. We found that 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (HP⁺), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridine (HTP) and 4-chlorophenyl-1,2,3,6-tetrahydropyridine (CPTP) are potent inhibitors of MAO. HP⁺ appeared to be a reversible, uncompetitive and selective MAO-B inhibitor with a Ki of 0.83 µM. HTP was found to be an irreversible, uncompetitive and selective MAO-B inhibitor (Ki of 1.84 µM). CPTP inhibits both MAO-A and MAO-B. Some other haloperidol metabolites, i.e. 4-(4-chlorophenyl)-4-hydroxypyridine (CPHP), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridine N-oxide (HTPNO) and reduced haloperidol (RHAL), do not inhibit MAO to any appreciable degree at concentrations up to 100 µM. The results suggest that haloperidol metabolites may contribute to the reduction of platelet MAO-B activity in schizophrenic patients undergoing neuroleptic chemotherapy. An examination of the literature reveals that schizophrenic patients with low platelet MAO activity exhibit a strong association with the use of haloperidol. Other possible pharmacological implications of the inhibition of MAO activity are discussed.     

Synthesis of novel N-substituted imidazolecarboxylic acid hydrazides as monoamine oxidase inhibitors

Novel 2-alkylsulfanyl-1-benzyl-5-imidazolecarboxylic acid hydrazides (15a,b) were synthesized as analogues of isocarboxazide, which is a known nonselective irreversible monoamine oxidase inhibitor and tested for monoamine oxidase A and B inhibitory activity. Neither of the compounds showed any inhibition of MAO B activity up to a high concentration of 100 microM. An MAO A activity was only slowly inhibited at this high concentration after prolonged incubation with either compound. This suggests any observed inhibition is not very specific.     

Differential distribution of type A and B monoamine oxidase in neuronal tissue

Various neuronal tissues of the albino rabbit were assayed for type A and type B monoamine oxidase, using norepinephrine and 2-phenylethylamine as substrates, respectively. There was an apparent positive correlation between the sympathetic character of peripheral nerves and the presence of type A monoamine oxidase activity. Type A enzyme activity was 15 fold higher in the superior cervical ganglion than in the vagus nerve. Type B activity was more uniformly distributed.     

The nature of the inhibition of rat liver monoamine oxidase types A and B by the acetylenic inhibitors clorgyline,l-deprenyl and pargyline

The kinetics of inhibition of rat liver mitochondrial monoamine oxidase by clorgyline, l-deprenyl and pargyline are consistent with a mechanism whereby a reversible interaction between the inhibitor and the enzyme active site under conditions of thermodynamic equilibrium is followed by a time-dependent formation of the covalently-bound enzyme-inhibitor adduct. The K_i value for the reversible interaction between clorgyline and monoamine oxidase A is about 1000 times lower than that towards the B-form of the enzyme, and this difference is sufficient to account for most, but not all, of the selectivity of the inhibition caused by this compound. The K_i value of the monoamine oxidase B selective inhibitor l-deprenyl towards that form of the enzyme is only about 40-fold lower than that towards the A-form. However, in this case, the rate of formation of the irreversible adduct is considerably faster for the B-form than for the A-form and this makes a major contribution to the selectivity of this compound. Pargyline shows a K_i value towards monoamine oxidase B that is only 8 times lower than that towards the A-form and in this case the rates of formation of the enzyme-inhibitor adducts are similar. The significance of these results are discussed in terms of the selective inhibition of monoamine oxidase.     

乙型肝炎患者血清单胺氧化酶的检测

目的:探讨乙肝患者血清单胺氧化酶水平及其临床意义。方法:用快速比色法检测急性乙肝、慢性乙肝、重型乙肝、肝硬化患者血清MAO水平。结果:乙肝患者血清MAO为(46.68±20.64)u,而正常对照组MAO为(23.25±12.40)u,差异具显著性(P<0.01),且慢性乙肝、重型乙肝、肝硬化血清MAO值均高于正常对照组。急性、慢性、重型乙肝、肝硬化患者血清MAO阳性率依次为45%、50%、65%、82.5%,差异显著(P<0.01)。结论:MAO与肝纤维化密切相关,是反映肝纤维化程度及肝损害的重要指标。     

Conditioned taste aversion induced in rats by intracerebral or systemic administration of monoamine oxidase inhibitors

Conditioned taste aversion (CTA) elicited by systemic or intracerebral application of the monoamine oxidase inhibitors clorgyline (C), pargyline (P) or deprenyl (D) was studied in 402 rats. Water-deprived animals were allowed 15 min access to 0.1% sodium saccharin (CS) followed 10 min later by IP or by intracerebral injection of the drug. In the latter case, the animals were anesthetized 5 min after saccharin drinking with pentobarbital and the drug was stereotaxically injected (1 l/min, 1–2 l) into the target structure. CTA was assessed in a two-choice retention test performed 2 days later. A geometric progression of three to six dosages applied to groups of rats (n=10) was employed to establish the effective doses of the drugs which were 4, 20 and 32 mg/kg with IP and 2.5, 10 and 80 g per rat with intracerebral (n. raphé magnus) injections of C, P, and D, respectively. The ratios of intracerebral to systemic dosages eliciting comparable CTA were 1:300 for C, 1:800 for P and 1:100 for D. Injections of 2.5 g C and 10 g P into the mesencephalic reticular formation, medial hypothalamus and cerebral cortex were ineffective, as were injections of 10 g P into the nucleus of the solitary tract and cerebellum. The results indicate that CTA is elicited more efficiently by inhibition of monoamine oxidase A (selectively inhibited by C) than of monoamine oxidase B (selectively inhibited by D).     

单胺氧化酶抑制剂及其药物相互作用研究

目的了解单胺氧化酶抑制剂(MAOIs)及其与其他药物的相互作用。方法调查本院及其他医疗机构的药品说明书,检索中英文文献数据库,对涉及MAOIs的重点记录,进行整理归纳、分析总结。结果有11种常用药品属于MAOIs,近40种药品与MAOIs存在药物相互作用。结论上述药品应尽可能避免与M AOIs合用,或合用时减少用药剂量,以避免或减轻药物不良反应。     

Longitudinal studies of the effect of monoamine oxidase inhibitors on sleep in man

Summary Monoamine oxidase inhibitors suppressed REM sleep during longitudinal sleep studies in four subjects. While the REM suppression occurred during maximum dosages, one normal subject showed an increase in REM time during the initial phase of drug administration. One patient had a marked REM compensation after the drug was discontinued. There were no consistent changes in Non-REM sleep. Monoamine oxidase inhibition was measured by plasma and platelet studies, as well as by 24-hour urinary tryptamine levels.We wish to thank Dr. William Bunney and Dr. David Anderson for their assistance