Disease relevance of Milacemide

• These observations suggest that milacemide could enhance dopaminergic activity in the brain and could be used as therapy for Parkinson's disease in association with L-3,4-dihydroxyphenylalanine [1].
• A therapeutic trial of milacemide in myoclonus and the stiff-person syndrome [2].
• We performed a therapeutic trial with the glycine precursor, milacemide, on 10 patients with intractable movement disorders [3].
• These results confirm the existence of an abnormal glial Na+,K(+)-ATPase in cold-induced focal epilepsy and suggest that the antiepileptic activity of milacemide might be secondary to an activation of glial Na+,K(+)-ATPase, contributing to antagonize ictal transformation and seizure spread [4].
• The results of this study using an in vivo/in vitro approach clearly show potential hepatotoxic properties of Milacemide, an effect not observed in conventional toxicity studies [5].

Psychiatry related information on Milacemide

• The reaction-time functions for milacemide and placebo were similar, suggesting arousal was not diminished under milacemide and could not account for the cognitive decrements [6].
• Milacemide: a placebo-controlled study in senile dementia of the Alzheimer type [7].
• Experiment 2 demonstrated that the same dose of milacemide could also attenuate spontaneous forgetting of passive avoidance learning, thereby ruling out nonspecific effects as an explanation for the enhancement of performance following pretesting drug administration [8].
• Acute and subacute CNS effects of milacemide in elderly people: double-blind, placebo-controlled quantitative EEG and psychometric investigations [9].

High impact information on Milacemide

• Milacemide (100-600 mg/kg, i.v.) dose-dependently inhibited the heart rate and pressor responses (ED50 = 398 mg/kg; 95%CI = 196-873) and the motor responses (ED50 = 404 mg/kg; 95%CI = 275-727) [10].
• Inactivation of monoamine oxidase B by analogues of the anticonvulsant agent milacemide (2-(n-pentylamino)acetamide) [11].
• The inhibitory activity of milacemide is significantly greater for MAO-B [1].
• The apparent Km (30-90 microM) for milacemide oxidation by mitochondrial MAO-B preparations is significantly lower than that for milacemide oxidation by mitochondrial MAO-A (approximately 1,300 microM) [12].
• In vitro MAO-B (l-deprenyl and AGN 1135) rather than MAO-A (clorgyline) selectively inhibited the oxidation of milacemide [12].

Chemical compound and disease context of Milacemide

• Body weight and food intake were recorded and at day 7 of exposure, Milacemide concentration, glucose, urea, triglycerides and cholesterol levels and alanine (ALT) and aspartate aminotransferase (AST) activities were measured in plasma [5].

Biological context of Milacemide

• Antiepileptic drug pharmacokinetics and neuropharmacokinetics in individual rats by repetitive withdrawal of blood and cerebrospinal fluid: milacemide [13].
• Despite our negative findings for milacemide, other strategies for facilitating NMDA-mediated neural transmission in schizophrenia might be worth pursuing [14].
• Milacemide had a specific inhibitory effect on xenobiotic biotransformation: ECOD activity decreased to 60% of the control value for both Milacemide doses, PROD activity remained unaffected whereas EROD activity decreased to 65% of the control value [5].
• Because NMDA receptor activation appears involved in induction of long-term potentiation, it was hypothesized that milacemide administration would be involved in task acquisition [15].
• Milacemide has a low toxicity (LD50: 2585 mg/kg in the mouse) and alters the behaviour of mouse, rat and monkey, only at high doses (greater than or equal to 1000 mg/kg) [16].

Anatomical context of Milacemide

• 4. The combined effects of milacemide (10(-4) M) and acetycholine (10(-4) M) on catecholamine secretion from chromaffin cells is additive, suggesting that milacemide does not act through the normal nicotinic receptor release mechanism [17].
• After degeneration of the striato-nigral GABA-ergic pathway, milacemide no longer enhances the content of GABA in the substantia nigra [18].
• 1. The effect of milacemide, a glycine percursor known to increase gamma-aminobutyric acid (GABA) and glycine content in the brain, and to have anticonvulsant properties, was tested by ionophoresis on 247 neurones situated in the cerebral cortex and in deeper structures of cats and rats anaesthetized with urethane [19].
• After milacemide administration (400 or 800 mg/kg i.p.), glycinamide concentrations rose linearly and dose-dependently in both hippocampus and frontal cortex [20].
• At 500 mg Milacemide kg/day, hepatocyte triglycerides levels increased 3.1-fold while cholesterol and phospholipid levels remained unaffected [5].

Associations of Milacemide with other chemical compounds

• Analogues of the anticonvulsant agent milacemide (1,2-(n-pentylamino)acetamide), in which the carboxamide group is changed to a nitrile (2), a carbethoxy group (3), a carboxylic acid (4), a cyanomethyl group (5), and a trifluoromethyl group (6), were synthesized and tested as substrates and inactivators of monoamine oxidase B (MAO B) [11].
• Purification of the ox liver MAO-B did not significantly affect its interactions with milacemide and alpha-methylmilacemide [21].
• The application of the procedure to assay the oxidation of benzylamine, tyramine and 2-n-pentylaminoacetamide (milacemide) by a crude mitochondrial preparation from rat liver and purified ox liver MAO-B is demonstrated [22].
• A high-performance liquid chromatographic technique is described for the determination of milacemide and its primary metabolite glycinamide in rat plasma and cerebrospinal fluid [23].
• A concomitant increase (20-25%) in serine and taurine and a decrease in alanine cerebrospinal fluid values were observed at the highest milacemide dose [24].

Gene context of Milacemide

• 5. The results are explicable in terms of an inhibition by milacemide of MAO-A [25].
• Oxidation of the anticonvulsant drug milacemide [2-n-(pentylamino)acetamide] by monoamine oxidase-B (MAO-B) has been reported to be important in terminating its activity [21].
• 1. The kinetics and metabolism of milacemide have been studied in an animal model which allows the simultaneous investigation of the temporal inter-relationships of drugs and metabolites in blood (pharmacokinetics) and cerebrospinal fluid (CSF, neuropharmacokinetics) in individual freely moving rats [13].
• Double-blind study of milacemide in hospitalized therapy-resistant patients with epilepsy [26].
• On the other hand, the glutamate decarboxylase activity measured ex vivo 3 hr after 100 mg/kg of milacemide is significantly increased by 11% in homogenates of the whole rat brain [18].

Analytical, diagnostic and therapeutic context of Milacemide

• Milacemide had no effect on the percent synchrony in the EEG [10].
• After repeated oral administration of milacemide a comparable effect to acute administration is obtained [18].
• A microdialysis study of glycinamide, glycine and other amino acid neurotransmitters in rat frontal cortex and hippocampus after the administration of milacemide, a glycine pro-drug [20].
• Trials of milacemide in doses ranging from 400-1,200 mg once daily in Alzheimer's disease (AD) for 4 weeks have been disappointing, but milacemide has increased the accuracy and speed of word retrieval in human volunteers [27].

References