DOPA Levels Research Articles

Urinary biogenic amines in idiopathic apnea of prematurity.

Urinary biogenic amines were measured in 22 preterm infants of less than 36 weeks' gestational age. Fifteen of these infants had idiopathic apnea. Although levels of urinary dopa were not significantly different, dopamine, norepinephrine and epinephrine were all significantly lower in the infants with apena. It is proposed that apnea of prematurity may be related to an immaturity of catecholamine-producing pathways, leading to inadequate physiologic responses to hypoxia, with resulting accentuation of central respiratory depression. Alternatively, urinary biogenic amines may be a reflection of some unrelated process occurring elsewhere in the body or a depletion of catechol stores resulting from the apnea itself.

Absence of relationships between L-dopa plasma levels and therapeutic effect in Parkinson's disease treated with L-dopa.

The plasma concentration of dopa was studied in 15 parkinsonian patients after a single administration of L-dopa. The study was undertaken in order to determine if correlation between plasma dopa concentration and clinical performance as a result of the tests carried out before and after a single dose of dopa, was present. Our data confirm the absolute absence of correlation between dopa levels in plasma and clinical improvement during long-term treatment. Moreover, clinical responses to the performance tests were not related to the concentration of circulating L-dopa in the plasma. Therefore dopa levels cannot be useful in clinical practice but only for the prevention of too high concentrations of plasma L-dopa which often cause a few side-effects.

Abnormal levels of urinary catecholamines in dystrophic mice and hamsters.

Twenty-four-hour urine was collected from normal and dystrophic mice and hamsters for catecholamine determinations. A new method of analysis was used whereby 3,4-dihydroxyphenylalanine (DOPA), dopamine (DA), norepinephrine (NE), and epinephrine (E) were measured simultaneously. The procedure is based on a combination of liquid-solid extraction, cation exchange chromatography, and controlled potential electrochemistry. The results of these experiments indicated that while DA levels were similar in both normal and pathological animal urine, DOPA levels decreased slightly in the dystrophic mouse but not the hamster, and NE and E levels in dystrophic groups were two and four times greater than normal in both species. The data supports the concept of biochemical alterations in tissue other than muscle. While not necessarily supportive to catecholamine abnormality as the primary cause of muscular dystrophy, the present data cast doubt that this disease is a primary muscle disease.

On‐off response

Seven parkinsonian patients who had severe on-off effects during chronic treatment with levodopa were studied. Marked swings in plasma dopa levels as well as in motor function followed each oral dose of levodopa. A constant intravenous infusion of levodopa resulted in stable plasma dopa concentrations and virtual disappearance of motor fluctuations. Notwithstanding steady plasma dopa levels, an abrupt decline in the antiparkinsonian response to levodopa attended postural tilting or cold pressore stimulation. Although these maneuvers were accompanied by a significant rise in plasma norepinephrine, the intravenous infusion of this catecholamine failed to influence the effect of levodopa on parkinsonian signs. The results suggest that central noradrenergic mechanisms as well as alterations in circulating dopa may contribute to the on-off response to levodopa.

Dopamine: A sensitive automated assay and examples of levodopa therapy

The fluorometric determination of dopamine by oxidation with potassium ferricyanide in an alkaline medium was automated using the Technicon AutoAnalyzer. The method is rapid, sensitive, and reproducible. The concentration of dopamine in whole rat brain determined by this method was 5.15 nmole/g, agreeing closely with values in the literature. Plasma levels of dopamine and dopa were determined at half-hour intervals in patients receiving levodopa therapy. Dopa and dopamine concentrations in plasma rose and fell in response to each dosage, but patients show considerable individual variations in their pattern of plasma levels. In the presence of carbidopa, a peripheral dopa decarboxylase inhibitor, dopamine concentrations could not be detected.

L-dopa therapy combined with peripheral decarboxylase inhibitor (MK-486) in Parkinsonism.

Eighteen patients with parkinsonism were treated with a combination of L-dopa and peripheral decarboxylase inhibitor, L-alphahydrazinomethyldopa (MK-486). Modification of L-dopa effect by MK-486 was also studied in parkinsonian patients as well as in cats. (1) Concentrations of dopa and dopamine in plasma and brain were measured in cats following intraperitoneal injection of L-dopa alone (100 mg/kg) or combined with MK-486 (10 mg/kg). Dopa levels in plasma and brain in the combination with MK-486 were three times as high as in L-dopa alone. Dopamine levels in caudate nucleus and putamen were increased nearly fourfold with the combination. (2) Plasma dopa and dopamine levels were measured in parkinsonian patients. Clinical pharmacological studies disclosed that a 1 : 10 ratio of MK-486 to L-dopa in dosage was preferable. (3) Maximum plasma dopa levels with the combination were four times those following L-dopa alone. Plasma dopa sustained a high level over a period of five hours. MK-486 markedly reduced plasma levels of dopamine. (4) There was no significant difference in dopa and dopamine levels in cerebrospinal fluid between L-dopa alone and a combination of MK-486, but dopamine levels in the CSF were still high at four hours after the combination of MK-486. (5) In clinical studies of eighteen patients with parkinsonism, the effectiveness of the combination therapy (mean dosage of L-dopa: 750 mg/day) was observed in all cases. Marked improvement was noted in 10 cases out of 15 (67%) with akinesia, in 12 cases out of 17 (71%) with rigidity and in six cases out of 14 (43%) with tremor. Maximum plasma dopa levels were higher in those cases with marked improvement, and were highest in patients with diskinesias as a side effect. (6) An addition of vitamin B6 did not show adverse effects. (7) Transient nausea and vomiting as a side effect, less severe than those experienced with L-dopa alone, were noted in five cases (28%). Dyskinesias in extremities, face, mouth and tongue were observed in six cases (33%). These dyskinesias were seen in a high percentage of cases with marked improvement and were never observed in the extremities contralateral to the side of thalamotomy.

The effect of LSD and 2-bromo LSD on the dopa accumulation after central and peripheral decarboxylase inhibition

LSD and BOL were found to be equally potent in increasing the rat brain DOPA accumulation after decarboxylase inhibition. However, at the doses selected, the DOPA levels after haloperidol and apomorphine were increased by LSD but not BOL. It is suggested that this difference is due to LSD's activating effect on central serotoninergic receptors.

Patterns of clinical response and plasma dopa levels in Parkinson's disease.

Serial determinations of plasma dihydroxyphenylalanine (dopa) in 16 Parkinson's disease patients receiving levodopa showed a negative correlation between plasma dopa levels and disability scores among patients who exhibited daily fluctuations of signs and symptoms. This suggests that the amount of levodopa delivered to the brain from the periphery is of major importance in the production of the "on-off" phenomenon. A close relationship between plasma dopa levels and abnormal involuntary movements was present in six patients. In three a striking dissociation between control of Parkinson's disease and abnormal involuntary movements was present, suggesting that in some patients these two effects are mediated through different underlying mechanisms. Administration of levodopa in such a way as to prevent both high and low levels of dopa in plasma minimizes disability in Parkinson's disease and may lessen abnormal involuntary movements in patients with the "on-off" effect.

カテコールアミン代謝に関する基礎的ならびに臨床的研究

Combined effects by L-DOPA and peripheral decarboxylase inhibitor (L-alpha-hydrazinomethyldopa: MK 486) 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 MK 486 (10mg/kg b. w.) by gas chromatographic method (using an Electron Capture Detector).1) DOPA level in cat plasma in the combination with MK 486 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 MK 486. Norepinephrine and epinephrine levels in cat plasma were no significant change in both L-DOPA alone and combination with MK 486. 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 MK 486, 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 MK 486 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 MK 486.4) 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 MK 486.5) In clinical studies of 18 patients with parkinsonism, the effectiveness of the combination therapy with L-DOPA and MK 486 (mean dosage of L-DOPA: 750mg/day and MK 486: 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%).

Influence of L-3-methoxytyrosine on monoamine synthesis in rat brain.

Rats were injected i.p. with L-3-methoxytyrosine, 100 or 300 mg/kg. One h later brain, liver, heart and blood plasma were analyzed for catecholamines and their precursors. In brain Dopa as well as dopamine and noradrenaline levels were unchanged, while demethylation of L-3-methoxytyrosine might have occurred in peripheral organs since Dopa levels in liver and dopamine in heart were elevated. 3-Methoxytyramine could not be detected in brain and liver after treatment with L-3-methoxytyrosine. Monoamine synthesis in vivo was measured in whole brain by determining the accumulation of Dopa and 5-hydroxytryptophan 30 min after the i.p. injection of NSD 1015(3-hydroxybenzylhydrazine HC1, 100 mg/kg), an inhibitor of the aromatic amino acid decarboxylase. L-3-Methoxytyrosine attenuated the formation of Dopa and 5-hydroxytryptophan by about 25% in brain tissue. The effect was paralleled by a decrease in the brain concentration of tryptophan.

Narcotic withdrawal like mouse jumping produced by amphetamine and L-DOPA

Upward jumping in mice that resembled the narcotic-withdrawal syndrome was produced by a combination of amphetamine (4 mg/kg) and L-DOPA (400 mg/kg) administration. Neither drug alone caused that jumping. Pretreatment with haloperidol (0.16 mg/kg) or pimozide (0.08 mg/kg) but not with phentolamine (10 mg/kg) effectively blocked amphetamine-dopa jumping. After DOPA there was an increase in the brain levels of DOPA, dopamine and norepinephrine. Amphetamine, ineffective in itself, enhanced DOPA-induced elevation of brain DOPA and dopamine without affecting brain norepinephrine levels.

Plasma dopa concentrations and the "on-off" effect after chronic treatment of Parkinson's disease.

Plasma concentrations 01 dopa were measured during “on” (mobile and dyskinetic) and “off” (akinetic and/or tremulous) episodes in 10 patients who had been treated chronically with levodopa for Parkinson9s disease. Dopa levels were higher during “on” than “off” spells (1.29 ± 1.08 versus 0.62 ± 0.59 mcg per milliliter; p

Brain catechol synthesis: control by train tyrosine concentration.

Brain catechol synthesis was estimated by measuring the rate at which brain dopa levels rose following decarboxylase inhibition. Dopa accumulation was accelerated by tyrosine administration, and decreased by treatments that lowered brain tyrosine concentrations (for example, intraperitoneal tryptophan, leucine, or parachlorophenylalanine). A low dose of phenylalanine elevated brain tyrosine without accelerating dopa synthesis. Our findings raise the possibility that nutritional and endocrine factors might influence brain catecholamine synthesis by controlling the availability of tyrosine.

Effects of l-dopa administration on the serotonergic system in rat brain: Correlation between levels of l-dopa accumulated in the brain and depletion of serotonin and tryptophan

Following administration of an acute dose of l-dopa (200 mg/kg i.p.), the concentration of this aminoacid increased rapidly in whole rat brain, to 10 μg/g and this new level was maintained for at least 20 min. At the same time, there was a significant ( p < 0.01) depletion of brain serotonin (5HT), which was correlated with the level of dopa in the brain. The level of brain tryptophan (TP) also decreased. If l-dopa was given orally at a dose of 250 mg/kg, an increased concentration of this drug in the brain was still seen but the levels reached were 20 times less than the levels obtained after i.p. administration. In this situation the brain levels of 5HT and TP were unchanged. The chronic administration of l-dopa did not cause accumulation of the drug in the brain nor did it affect the concentration of 5HT and TP.

Levodopa, carbidopa, and pyridoxine in Parkinson disease. Metabolic interactions.

Exogenous pyridoxine is known to antagonize the neuropharmacologic action of levodopa in Parkinson disease. The metabolic interactions of levodopa, pyridoxine, and carbidopa, a peripheral decarboxylase inhibitor, were studied in 15 long-term, levodopa-treated patients. Pyridoxine reduced plasma dopa levels 67% but enhanced homovanillic acid synthesis 49% Carbidopa potentiated plasma dopa, inhibited homovanillic acid synthesis, and minimized the effects of pyridoxine. The decarboxylase activity index following pyridoxine administration increased 483% and 136% for plasma and urine respectively. Carbidopa effected a 77% and 94% reduction. It is suggested that pyridoxine accelerates systemic metabolism of levodopa, thereby decreasing availability of the amino acid to brain parenchyma. The combination of levodopa and carbidopa prevents the loss of levodopa effect produced by exogenous pyridoxine.

"On-off" phenomenon with levodopa therapy in Parkinsonism. Clinical and pharmacologic correlations and the effect of intramuscular pyridoxine.

Five parkinsonian patients with severe “on-off” effects from levodopa therapy also were given combination carbidopa/levodopa. Serial half-hourly measurements of plasma levels of dopa, 3-O-methyldopa, and homovanillic acid showed partial concordance between clinical fluctuation and plasma dopa levels in patients receiving levodopa alone or in combination with carbidopa. The combination therapy does not lessen “on-off” effects except when administered in greater and more-frequent doses, which are permitted by the improved gastrointestinal tolerance with carbidopa/levodopa. A single intramuscular injection of pyridoxine has no clinical effect and slightly lowers subsequent plasma dopa only in the absence of carbidopa. Possible biochemical mechanisms are discussed.

3-O-methyl metabolites of catecholamines: Automated fluorometric assay and their plasma levels in patients receiving levodopa and carbidopa

The fluorometric determination of homovanillic acid (HVA), 3- O-methyldopa (OMD), and 3- O-methyldopamine by oxidation with potassium ferricyanide in alkaline medium has been automated using the AutoAnalyzer of the Technicon Instruments Corporation. The method is rapid, sensitive, and reproducible and correlated well with the manual method. Plasma levels of dopa, HVA, and OMD were determined at half-hour intervals in patients receiving levodopa therapy, and also levodopa/carbidopa therapy. Dopa and HVA concentrations rise and fall in plasma in response to each dosage, but OMD remains elevated constantly. The level of HVA is drastically reduced upon the addition of carbidopa, a peripheral dopa decarboxylase inhibitor, but OMD levels are unchanged indicating a lack of inhibition of catechol- O-methyl transference by carbidopa.

VARIATIONS IN L‐DOPA ABSORPTION

Abstract. In a parkinsonian patient with a weak effect of L‐dopa on the parkinsonian symptoms, unusually high plasma levels of dopa and dopamine sulphate were noticed. The plasma concentrations of tyrosine and phenylalanine were low during the whole observation period. The urinary excretion of dopamine sulphate and the ratio of dopamine sulphate to dopamine in urine were high. The reason for this high ratio of dopamine sulphate to dopamine could not be determined. The disappearance of L‐dopa from plasma after i.v. administration was only slightly reduced. It was concluded that the L‐dopa absorption in this patient was very efficient due to a low dopa decarboxylation in the intestinal organs in spite of a normal decarboxylase activity in other peripheral tissues. Such a selective decrease in the dopa decarboxylation in the intestinal. organs is presumably unusual, but illustrates that very marked individual variations in the L‐dopa metabolism may occur in parkinsonian patients.

Studies on the Combined Effect by L-DOPA and L-alpha-hydrazinomethyldopa (MK 486) in Parkinsonism, with a Special Reference to Catecholamine Metabolism

Following oral administration of L-DOPA alone or L-DOPA in combination with extracerebral DOPA decarboxylas inhibitor (L-alpha-hydrazinomythyldopa: MK 486), catecholamines level in plasma and cerebrospinal fluid of patients with Parkinsonism were determined by gaschromatography (ECD).After oral administration of L-DOPA in combination with MK 486, DOPA level in plasma was maintained at a higher level and for longer than after the oral administration of L-DOPA alone. Dopamine level in plasma was markedly lower than with L-DOPA aloneDopamine level in cerebrospinal fluid after oral administration of L-DOPA in combination with MK 486 was maintained at a higher level than after the oral administration of L-DOPA alone.Thus, judging from DOPA and dopamine levels in plasma, a combination-ratio of L-DOPA and MK 486 of 10 to 1 was found to be desirable.

Further studies on the behavioural and biochemical interaction between caffeine and L-DOPA.

Mice, pretreated with the inhibitor of peripheral DOPA decarboxylase MK 486, were given caffeine, 25 mg/kg, or L-DOPA, 125 mg/kg, or both. The locomotor activity of the animals recorded for 2 h, doubled after caffeine whereas the effect of L-DOPA varied from depression to a slight hyperactivity. In combination the two drugs produced a tenfold increase in locomotor activity. The accumulation of dopamine in the brain, and the levels of DOPA in both brain and plasma following administration of L-DOPA, all increased when caffeine was given beforehand. However, caffeine did not modify the effects of L-DOPA on brain noradrenaline, 3-methoxytyrosine, 5-hydroxytryptamine, and 5-hydroxyindolacetic acid significantly. In some experiments3H-tyrosine was given before MK 486, caffeine and/or L-DOPA in order to label the central catecholamine stores. The disappearance of brain3H-NA and3H-DA following L-DOPA was not significantly changed by caffeine. From these and earlier data it is suggested that part of the potentiating effect of caffeine on the L-DOPA induced motility is due to the increased cerebral level of dopamine and part to a catecholamine-receptor sensitizing effect of caffeine.