Experimental and clinical studies on the catecholamine metabolism 3. Experimental and clinical studies on the peripheral aromatic amino acid decarboxylase inhibitor and catecholamine metabolism

Combined effects by L-DOPA and peripheral decarboxylase inhibitor (L-alpha-hydrazinomethyldopa: MK486) were studied in cats and eighteen parkinsonian patients, with special reference to catecholamines and amino acids metabolism. Catecholamine levels in brain tissues and plasma were measured in cats following the intraperitoneal injection of L-DOPA alone (100mg/kg b. w.) or combined with MK486 (10mg/kg b. w.) by gas chromatographic method (using an Electron Capture Detector). 1) DOPA level in cat plasma in the combination with MK486 was three-fold as high as in L-DOPA alone. Dopamine levels in caudate nucleus of cats were increased up to about six-fold in the combination. Dopamine level in plasma was markedly decreased in the combination with MK486. Norepinephrine and epinephrine levels in cat plasma were no significant change in both L-DOPA alone and combination with MK486. Norepinephrine level in the brain was no significant change except slight increase in pallidum and caudate nucleus. 2) After oral administration of L-DOPA in combination with MK486, DOPA level in plasma of the patients with parkinsonism was maintained at a higher level and for longer than after the oral administration of L-DOPA alone. Plasma dopamine level with the combination was markedly lower than with L-DOPA alone. Dopamine level in plasma at three hours after the administration tended to be decreased at a 1:5 ratio of MK486 to L-DOPA in dosage. Plasma epinephrine level was not significant change at all. Dopamine level in cerebrospinal fluid was maintained at a higher level and for longer than the oral administration of L-DOPA alone. 3) Urinary homovanillic acid level in parkinsonism was lower in the combination of MK486. 4) Plasma amino acids which might affect catecholamines metabolism was not significant change following the administration of L-DOPA alone as well as L-DOPA plus MK486. 5) In clinical studies of 18 patients with parkinsonism, the effectiveness of the combination therapy with L-DOPA and MK486 (mean dosage of L-DOPA: 750mg/day and MK486: 75mg/day) was observed in all cases. Marked improvement was noted in 10 cases out of 18 (56%) with akinesia, in 12 cases out of 18 (67%) with rigidity and in 6 cases out of 18 (33%) with tremor. Maximum plasma DOPA levels were higher in cases with marked improvement than the other, and were highest in patients with dyskinesias of a side effect. 6) Nausea and vomiting of the side effect, which were less severe than those experienced with L-DOPA alone, were noted in 5 cases (28%). Dyskinesias in extremities, face, mouth and tongue were observed in 6 cases (33%)