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A patient with pure akinesia, who experienced freezing only when starting to walk backward or when turning, is reported. L-DOPA, maprotiline, clonazepam, DL-threo-3,4-dihydroxyphenylserine (DOPS), and L-threo-DOPS were administered to the patient. Only DL-threo-DOPS and L-threo-DOPS were effective, but they concurrently brought on a hypomanic state. Combining carbidopa with DL (or L)-threo-DOPS did not change the effectiveness of the treatment. DL (or L)-threo-DOPS did not affect monoamine metabolites in the cerebrospinal fluid (CSF). The effectiveness of L-threo-DOPS on freezing, the induction of affective changes, and the absence of 3-methoxy-4-hydroxyphenylglycol alteration in the CSF suggest that L-threo-DOPS acts centrally but may not directly involve the noradrenergic system.
Neurogenic orthostatic hypotension is an incapacitating symptom of central and peripheral autonomic nervous system degeneration. It occurs in such clinical conditions as multiple system atrophy, pure autonomic failure, and small-fiber peripheral neuropathies. Although many treatments are available, their effects are inconsistent, unsustained, and complicated by side effects. 3,4-Dihydroxyphenylserine is a synthetic, unnatural amino acid that is an immediate norepinephrine precursor. There is theoretical and clinical evidence supporting the use of this agent in the treatment of neurogenic orthostatic hypotension in patients with peripheral and central autonomic nervous system dysfunction. We review the biochemistry, pharmacokinetics, and possible mechanisms of action and clinical utility of this agent in the treatment of neurogenic orthostatic hypotension.
Results of long-term administration of L-threo-3,4-dihydroxyphenylserine (L-DOPS), a synthetic precursor of noradrenaline, in a patient with freezing gait and pure akinesia are reported. Effects were temporal and disappeared during a 16-month treatment period. It was recognized that pure akinesia is an early symptom of progressive supranuclear palsy (PSP). Previously, we reported results of short-term (4 weeks) administration of L-DOPS in this patient. We present the further clinical course of the patient, along with results of long-term (16 months) administration of L-DOPS.
A 71-year-old woman presented with severe akinesia, frozen gait, and compromised postural reflexes, without rigidity, tremor, or vertical gaze disturbance. With a working diagnosis of pure akinesia, we administered amantadine (150 mg/d) and L-threo-3,4-dihydroxyphenylserine (DOPS) (600 mg/d), which alleviated her symptoms. When frozen gait recurred 2 months later, we increased the dose of L-threo-DOPS to 900 mg/d and added levodopa (300 mg/d) combined with carbidopa, but this failed to improve the patient's symptoms. We then combined administration of tandospirone, a serotonin (5-HT) 1A agonist with L-threo-DOPS (600 mg/d), resulting in marked clinical improvement. Tandospirone is reported to activate noradrenergic neurons via the 5-HT 1A receptor, which could account for such striking improvement in a patient previously responsive to the noradrenergic precursor L-threo-DOPS given alone.
A 72-year-old woman with Parkinson's disease and autonomic dysfunction underwent I-123 MIBG cardiac imaging to study sympathetic neuronal integrity. This revealed a defect in the infero-posterior wall. Tc-99m sestamibi myocardial perfusion imaging revealed no abnormalities. On follow-up I-123 MIBG SPECT, the defect was less prominent and the parkinsonian symptoms were ameliorated by drug therapy. Cardiac I-123 MIBG imaging may be a promising new method for evaluating drug therapy in patients with Parkinson's disease.
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Two patients with congenital dopamine beta-hydroxylase (DBH) deficiency were treated with d,l-threo-3,4-dihydroxyphenylserine (DOPS), 500 mg twice daily. In this orthostatic syndrome the functional integrity of the sympathetic noradrenergic neuron is probably intact, but dopamine instead of noradrenaline is released as the neurotransmitter. In vitro l-DOPS may serve as a substrate for aromatic-l-amino-acid decarboxylase (ALAAD) to form physiological (-)-noradrenaline. During infusion of d,l-threo-DOPS, 400 mg in 4 h, noradrenaline appeared in plasma and blood pressure rose, whereas plasma dopamine and the elevated venous:arterial ratio of plasma dopamine decreased. During chronic treatment supine blood pressure rose from 100-115/55-65 to 140-145/80-85 mmHg and orthostatic hypotension disappeared. After 12 and 6 months of treatment the patients are free of symptoms and they live a normal life. During chronic treatment, d,l-threo-DOPS, like plasma noradrenaline and dopamine, rose after standing, indicating release of the precursor after neuronal stimulation. After administration of tyramine plasma noradrenaline, dopamine and d,l-threo-DOPS and their respective venous:arterial ratios rose; this is further evidence of neuronal release. Thus, in DBH deficiency, dopamine instead of noradrenaline is released as a neurotransmitter, but the integrity of the sympathetic neuron is otherwise intact. Acting as an alternative substrate for ALAAD in the production of noradrenaline, DOPS is taken up by the neuron, restoring sympathetic control and thereby curing the orthostatic hypotension in DBH deficiency.
Steely hair disease, a neurodegenerative disorder, is characterized by slow growth, progressive cerebral dysfunction, kinky friable hair, x-linked inheritance, and death before three years of age. Low-serum copper has been found to play a role in steely hair disease. This article describes the role of copper, the pathophysiology of this disease, and current treatment and research. A case history and pertinent aspects of nursing care of these patients are also presented.
The effects of 3,4-dihydroxyphenylserine (DOPS), a nonnatural precursor of noradrenaline, on the sleep-wakefulness patterns of rats were studied. When the animals received an intraperitoneal injection of L-erythro-DOPS (200 mg/kg), a significant increase in slow wave sleep and a tendency to decrease wakefulness were observed during the first 2 hours after the injection. Paradoxical sleep increased 4-8 hours after the treatment. A simultaneous injection of benserazide (20 mg/kg) enhanced these effects. L-threo-DOPS (200 mg/kg, i.p.) had no effect on the sleep-wakefulness patterns. The effects of DOPS on the concentrations of brain catecholamines and serotonin in rats were also examined. An intraperitoneal injection of L-erythro-DOPS markedly increased the concentration of noradrenaline (probably the d-form) and decreased that of serotonin and dopamine. L-threo-DOPS had no effect on the brain monoamine levels of the rats in the present experimental condition. The effects of L-erythro-DOPS on the neurons containing noradrenaline in the rats were examined by fluorescence histochemistry. Fluorescence in the neuronal perikarya and fibers containing noradrenaline markedly increased in the n. coeruleus, n. paraventricularis and cerebral cortex after an intraperitoneal injection of amino acid. Fibers containing the fluorescence also increased in the second two areas.
The effect of L-threo-3, 4-dihydroxyphenylserine (DOPS) on plasma cortisol, prolactin, thyrotropin-stimulating hormone (TSH) and growth hormone concentrations was studied in nine healthy male volunteers. The drug was administered orally (300 mg or 600 mg DOPS) using a multiple crossover placebo-controlled study design. Plasma hormone concentrations were measured at 30 minute intervals for 3 hours after dosing. Plasma DOPS peak concentrations were observed between 2 and 3 hours after dosing. DOPS, however, had no effect on plasma hormone concentrations and this may be attributed to the known low brain permeability of DOPS in healthy subjects.
The effects of diastereomers of 3,4-dihydroxyphenylserine (DOPS) on the enzyme activity of monoamine oxidase (MAO) in human placenta and liver mitochondria were examined. Both L- and D-threo-DOPS were found to inhibit MAO-A in human placental mitochondria in competition with the substrate, and the Ki values for L- and D-threo-DOPS obtained were 68.3 and 125 microM, respectively. The inhibitory effect of L-threo-DOPS on both MAO-A and -B activity was confirmed in human liver mitochondria, and MAO-A was found to be more sensitive to the inhibitor. Other isomers of DOPS, L- and D-erythro-DOPS, were found to inhibit MAO activity, but the inhibition was noncompetitive with the substrate. The inhibitory effects of DOPS isomers were not affected by the presence of NSD-1055, an inhibitor of aromatic L-amino acid decarboxylase, suggesting that the inhibition is the direct effect of DOPS, and not of norepinephrine produced by the decarboxylase.
The expression vector containing the full-length cDNA of human aromatic L-amino acid decarboxylase (EC 4.1.1.28) was transfected in COS cells by a modified calcium phosphate coprecipitation method. The cells transfected with plasmids that had a true direction of the cDNA gave a major immunoreactive band at 50 kDa. This expressed enzyme catalyzed the decarboxylation of L-3,4-dihydroxyphenylalanine (L-DOPA), L-5-hydroxytryptophan (L-5-HTP) and L-threo-3,4-dihydroxyphenylserine. The optimal pH of the enzyme activity with L-DOPA as a substrate was 6.5, whereas the enzyme had a broad pH optimum when L-5-HTP was used as a substrate. Addition of pyridoxal phosphate to the incubation mixture greatly enhanced the activity for both L-DOPA and L-5-HTP.
1. The actions of dihydroxyphenylalanine (DOPA) and dihydroxyphenylserine (DOPS) were assessed on the sleep-wakefulness cycle of male Wistar rats. 2. In comparative studies the extracerebral decarboxylase was inhibited with serinetrihydroxybenzylhydrazide (RO 4-4602) before injection of DOPA or DOPS. 3. DOPA (80-160 mg/kg, i.p.) with or without previous inhibition of the peripheral decarboxylase gave rise to an initial significant increase of slow wave activity, which may be related to a release of 5-hydroxytryptamine. 4. During the subsequent 8 h sessions, DOPA significantly decreased slow wave sleep and rapid eye movement sleep (REM) and increased wakefulness. 5. DOPS (80-160 mg/kg, i.p.) did not significantly modify the sleep-wakefulness cycle apart from a decrease of the latency for the first REM episode after 160 mg/kg in the RO 4-4602 pretreated animals.
L-threo-3,4-dihydroxyphenylserine (L-DOPS, droxydopa) is a synthetic catecholamino acid. When taken orally, L-DOPS is converted to the sympathetic neurotransmitter, norepinephrine (NE), via decarboxylation catalyzed by L-aromatic-amino-acid decarboxylase (LAAAD). Plasma L-DOPS levels peak at about 3 h, followed by a monoexponential decline with a half-time of 2 to 3 h. Plasma levels of NE and of its main neuronal metabolite, dihydroxyphenylglycol (DHPG) peak approximately concurrently but at much lower concentrations. The relatively long half-time for disappearance of L-DOPS from plasma, compared to that of NE, explains their very different attained plasma concentrations. In patients with neurogenic orthostatic hypotension, L-DOPS increases blood pressure and ameliorates orthostatic intolerance. Inhibition of LAAAD, such as by treatment with carbidopa, which does not penetrate the blood-brain barrier, prevents the blood pressure effects of the drug, indicating that L-DOPS increases blood pressure by augmenting NE production outside the brain. Patients with pure autonomic failure (which usually entails loss of sympathetic noradrenergic nerves), and patients with multiple system atrophy (in which noradrenergic innervation remains intact) have similar plasma NE responses to L-DOPS. This suggests mainly non-neuronal production of NE from L-DOPS. L-DOPS is very effective in treatment of deficiency of dopamine-beta-hydroxylase (DBH), the enzyme required for conversion of dopamine to NE in sympathetic nerves. L-DOPS holds promise for treating other much more common conditions involving decreased DBH activity or NE deficiency, such as a variety of syndromes associated with neurogenic orthostatic hypotension.
We report the case of an elderly woman with severe dysautonomic orthostatic hypotension in whom a deficit in dopamine B hydroxylase has been established. In the literature, such a deficit has been described in six young adults with long standing symptoms of postural hypotension. This enzyme catalyses the conversion of dopamine to noradrenaline. In our elderly patient, noradrenaline and adrenaline were undetectable in the plasma, but plasma dopamine was detectable. Treatment with the synthetic amino acid, DL-threo-dihydroxyphenylserine, which is converted to noradrenaline by dopa-decarboxylase, resulted in a significant increase in blood pressure. The mechanism of this acquired deficit is not elucidated.
The case is reported of a 57-year-old woman with familial amyloidotic polyneuropathy and concomitant orthostatic hypotension for which L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) was clinically effective. Testing of autonomic function under telemetric intra-arterial pressure monitoring before and during L-threo-DOPS treatment clearly demonstrated the pathophysiology of the sympathetic nervous system and its modification by L-threo-DOPS.
The effects of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS), an unnatural norepinephrine precursor, on alpha 2-adrenergic receptors in platelet membranes were investigated in a patient with familial amyloidotic polyneuropathy, two patients with multiple system atrophy, and two patients with Parkinson's disease. Each patient was treated for at least six months. While L-threo-DOPS alone, or in combination with decarboxylase inhibitor benserazide hydrochloride, produced sustained increase in plasma norepinephrine and clinical improvement, it did not induce a change in the number of alpha 2-adrenergic receptors in platelet membranes.