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PubMed1976

Effects of drugs that modify brain biogenic amine concentrations on thyroid activation induced by exposure to cold.

L-Dihydroxphenylalanine (L-DOPA) significantly inhibited intrathyroidal colloid droplet formation induced by exposure to cold in the rat. Diethyldithiocarbamate (DDC) also inhibited colloid droplet formation in response to cold. The combined administration of L-DOPA and DDC produced an additive inhibition of the thyroidal endocytotic response to exposure to cold. Pretreatment with chlorpromazine (CPZ) ameliorated the inhibitory effect of L-DOPA. DL-alpha-methyl-p-tyrosine (alpha-MT) also signficantly depressed the thyroidal response. Inhibition of colloid droplet formation induced by alpha-MT was not altered by the administration of DL-dihydroxyphenylserine (DL-DOPS). On the other hand, treatment of the alpha-MT-treated rats with L-DOPA to normalize dopamine synthesis resulted in a dramatic recovery from the inhibition. Blockade of serotonin biosynthesis with p-chlorophenylalanine (p-CPA) failed to produce a significant inhibition of colloid droplet formation. However, 5-hydroxytryptophan (5-HTP) markedly inhibited the thyroidal response to cold. Brocresine phosphate (BP) was another inhibitor of the thyroidal endocytotic response to exposure to cold. Oxotremorine also markedly depressed the thyroidal response to cold. Since these drugs did not interfere with pituitary thyroid responsiveness to exogenous thyrotropin-releasing hormone (TRH), it seems that the throidal endocytotic response to exposure to cold as a reflection of TSH secretion was directly influenced by alterations of brain biogenic amine concentrations or turnover rates.

5-Hydroxytryptophan↗
PubMed2003

Norepinephrine precursor therapy in neurogenic orthostatic hypotension.

BACKGROUND: In patients with neurogenic orthostatic hypotension (NOH), the availability of the sympathetic neurotransmitter norepinephrine (NE) in the synaptic cleft is insufficient to maintain blood pressure while in the standing posture. METHODS AND RESULTS: We determined the effect of oral administration of the synthetic amino acid L-threo-3,4-dihydroxyphenylserine (L-DOPS), which is decarboxylated to NE by the enzyme L-aromatic amino acid decarboxylase (L-AADC) in neural and nonneural tissue, on blood pressure and orthostatic tolerance in 19 patients with severe NOH (8 with pure autonomic failure and 11 with multiple-system atrophy). A single-blind dose-titration study determined the most appropriate dose for each patient. Patients were then enrolled in a double-blind, placebo-controlled, crossover trial. L-DOPS significantly raised mean blood pressure both supine (from 101+/-4 to 141+/-5 mm Hg) and standing (from 60+/-4 to 100+/-6 mm Hg) for several hours and improved orthostatic tolerance in all patients. After L-DOPS, blood pressure increases were closely associated with increases in plasma NE levels. Oral administration of carbidopa, which inhibits L-AADC outside the blood-brain barrier, blunted both the increase in plasma NE and the pressor response to L-DOPS in all patients CONCLUSIONS: Acute administration of L-DOPS increases blood pressure and improves orthostatic tolerance in patients with NOH. The pressor effect results from conversion of L-DOPS to NE outside the central nervous system.

Administration, Oral↗
PubMed1991

Dopamine beta-hydroxylase deficiency. A genetic disorder of cardiovascular regulation.

Dopamine beta-hydroxylase (DBH) deficiency is a genetic disorder in which affected patients cannot synthesize norepinephrine, epinephrine, and octopamine in either the central nervous system or the peripheral autonomic neurons. Dopamine acts as a false neurotransmitter in their noradrenergic neurons. Neonates with DBH deficiency have had episodic hypothermia, hypoglycemia, and hypotension, but survivors sometimes cope relatively well until late childhood when overwhelming orthostatic hypotension profoundly limits their activities. The hypotension may be so severe that clonic seizures supervene. Most currently recognized patients are young or middle-aged adults. The diagnosis is established by the observation of severe orthostatic hypotension in a patient whose plasma norepinephrine/dopamine ratio is much less than one.

Adult↗
PubMed1994

The protective effect of L-threo-3,4-dihydroxyphenylserine on ischemic hippocampal neuronal death in gerbils.

BACKGROUND AND PURPOSE: L-Threo-3,4-dihydroxyphenylserine (DOPS) is reported to increase the nerve growth factor (NGF) synthesis in cultured mouse L-M fibroblast and astroglial cells, and this effect is not blocked by treatment with decarboxylase inhibitor. NGF is suggested to play an important role in neuronal survival and regeneration under pathological conditions. We evaluated the possible protective effect of DOPS against hippocampal CA1 cell death after transient forebrain ischemia in gerbils. METHODS: Male mongolian gerbils were treated with DOPS (30, 100, or 300 mg/kg IP) plus benserazide (10 mg/kg IP) (n = 28) or vehicle (n = 7) before 3.5 minutes of forebrain ischemia. For histopathologic study, the animals were decapitated 7 days after recirculation, and neuronal density of the hippocampal CA1 area was counted after cresyl violet staining. For immunohistochemical study, another group of gerbils (n = 34) was recovered for 1, 3, and 8 hours and 1, 2, and 7 days, when they were decapitated. The brain sections were stained against NGF, NGF receptor, and HSP70 using the avidin-biotin-peroxidase method. RESULTS: Preservation of the hippocampal CA1 cells was found in the brains treated with 300 mg/kg DOPS plus benserazide (neuronal density, 125 +/- 24 cells per millimeter) compared with the vehicle-treated ones (49 +/- 11 cells per millimeter) (P < .01). The immunoreactive NGF was greatly reduced from 3 hours after recirculation in the vehicle group, but it was much less reduced in the 300-mg/kg-DOPS-plus-benserazide group as compared with the vehicle group. The immunoreactivity for NGF receptor was gradually induced from 1 hour after recirculation with the peak at 1 day in the vehicle group, but it was only slightly induced at 8 hours in the 300-mg/kg-DOPS-plus-benserazide group. HSP70 immunoreactivity was also induced from 3 hours with the peak at 1 day in the vehicle group. However, in the 300-mg/kg-DOPS-plus-benserazide group, the induction of HSP70 was found from 8 hours and was much less intensive. CONCLUSIONS: Treatment with DOPS is protective to the ischemic hippocampal CA1 cells, and the NGF-receptor system may play a role in this protective effect of DOPS.

Animals↗
PubMed1981

Alteration of lidocaine- or procaine-induced convulsions by manipulation of brain amines.

Lidocaine and procaine seizure thresholds were studied. The i.p. median convulsant dose (CD50) of lidocaine and procaine with saline pre-treatment was 95 and 240 mg/kg, respectively. Dopamine depletion by pre-treatment with d1-alpha-methyl-p-tyrosine plus dihydroxyphenylserine resulted in a significant drop of CD50 to 69 and 175 mg/kg for lidocaine and procaine, respectively. Serotonin depletion by pre-treatment with p-chlorophenylalanine resulted in a significant drop of CD50 to 68 mg/kg for lidocaine, but no significant change for procaine.

Animals↗
PubMed2000

A pilot study of the effect of L-threodops on rehabilitation outcome of stroke patients.

We investigated whether L-threodops (L-DOPS), a norepinephrine precursor, improves rehabilitation outcome in patients with initial hemiparetic supratentorial ischemic stroke (2 months post stroke). Five patients who agreed to be treated with L-DOPS received 45-minute physical therapy (PT) and occupational therapy (OT) for 2 months, 3 days a week, with an oral dose of 200 mg L-DOPS 2 hours before each session, followed by PT and OT without L-DOPS for 2 months (DOPS group). Eight patients who disagreed received PT and OT for 4 months (control). Each group demonstrated comparable age, sex, complications, Mini-Mental State Examination, and the baseline Functional Independence Measure (FIM, DOPS/control = 36/42), Fugl-Meyer (F-M) motor scale (30/27), and ambulation endurance (10/9 meters). DOPS group had significantly greater gain than control (p < 0.05, Mann-Whitney U test) in FIM score at 4 (51/45) and 6 months (57/49), ambulation at 4 (66/16) and 6 months (82/24), and F-M score at 4 months (40/29). There were no side effects that required discontinuation of the drug. These results suggest that L-DOPS treatment paired with PT and OT may be effective in improving functional outcome in stroke.

Activities of Daily Living↗
PubMed1976

Neurotransmitter regulation of growth hormone and ACTH in the rhesus monkey: effects of biogenic amines.

In an attempt to clarify the role of central neurotransmitters in GH and ACTH regulation, chair-adapted unanesthetized adult male rhesus monkeys and chronic indwelling intratrial cannulae were given 30 min infusions of various agonists known to affect central amines, and plasma samples were withdrawn for GH and cortisol determinations. Infusion of acid-saline vehicle alone had no significant effect on plasma GH or cortisol (P less than 0.05). L-Dihydroxyphenylalanine (L-Dopa) (4.5 and 45 mg/kg), but not apomorphine (7 mug/kg), a specific dopaminergic agonist, produced significant elevations of GH. Both noradrenergic (clonidine HCl, 1.5, 15, and 150 mug/kg, and D,L-threodihydroxyphenylserine (D,L-threodops) 90 mg/kg) and serotoninergic (5-hydroxy-L-tryptophan (5-HTP), 45 mg/kg) agonists induced significant GH responses. These findings suggest that GH is regulated in the rhesus monkey by noradrenergic and serotoninergic neurons, whereas participation of dopaminergic neurons has not been established. Significant cortisol responses were only observed following infusion of 5HTP (45 mg/kg). Dopaminergic and noradrenergic agonists not only failed to alter resting cortisol levels but also did not affect the cortisol response to 5-HTP. In the rhesus monkey serotoninergic mechanisms appear to be responsible for the regulation of resting cortisol levels. A catecholamine inhibitory mechanism was not demonstrated in this species.

5-Hydroxytryptophan↗
PubMed2005

L-DOPS therapy for refractory orthostatic hypotension in autoimmune autonomic neuropathy.

The authors report a 46-year-old woman with antibodies to the nicotinic acetylcholine receptor (NiAchR) of the autonomic ganglia. She presented with severe orthostatic intolerance refractory to treatment with midodrine, fludrocortisone, erythropoietin, vasopressin, salt, and fluid loading. Addition of L-threo-3,4-dihidroxyphenylserine (L-DOPS) substantially improved blood pressure and orthostatic tolerance. L-DOPS may benefit patients with severe orthostatic intolerance and be particularly effective in patients with ganglionic NiAchR antibodies.

Adrenergic Agonists↗
PubMed1981

Orthostatic hypotension in familial amyloid polyneuropathy: treatment with DL-threo-3,4-dihydroxyphenylserine.

We measured plasma norepinephrine levels in patients with familial amyloid polyneuropathy. Patients with orthostatic hypotension had low basal plasma norepinephrine levels, which did not increase after postural change. On the basis of biochemical findings that suggest depletion of peripheral norepinephrine, DL-threo-3,4-dihydroxyphenylserine, an immediate precursor of norepinephrine, was given orally. Six hundred mg of this drug induced substantial and sustained elevation of blood pressure for several hours, and plasma norepinephrine content increased. Daily administration for 4 weeks improved postural dizziness and syncope, and daily activity increased.

Adult↗
PubMed1984

Treatment of parkinsonism with L-threo-3,4-dihydroxyphenylserine: a pharmacokinetic study.

We have examined the kinetics of oral L-threo-3,4-dihydroxyphenylserine (DOPS) alone and combined with peripheral decarboxylase inhibitors in patients with Parkinson's disease and other degenerative diseases of the brain. Combined administration of L-threo-DOPS and carbidopa or benserazide produced higher plasma concentrations of L-threo-DOPS and suppressed the increase in plasma norepinephrine. This finding indicates some advantages of combined therapy with L-threo-DOPS and decarboxylase inhibitors. Measurable quantities of DL-threo-DOPS were found in the CSF during repeated administration, but there was no consistent change in norepinephrine concentration.

Adult↗
PubMed1988

Effect of L-threo-3,4-dihydroxyphenylserine on muscle sympathetic nerve activities in Shy-Drager syndrome.

We observed changes in postganglionic efferent discharges of muscle sympathetic nerve (muscle sympathetic activity, MSA) microneurographically before and after the oral administration of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS), a precursor of norepinephrine, in a patient with Shy-Drager syndrome and irregular fluctuations of blood pressure. Before drug administration, MSA was only rarely observed with the patient in the supine position. There was a slight increase in MSA during head-up tilting to 40 degrees, and orthostatic hypotension (OH) occurred just after the body was tilted head upward to 40 degrees. MSA became prominent 30 minutes after the oral administration of 200 mg of L-threo-DOPS while the patient was in a 40 degree head-up position, and the OH was improved. The MSA discharge rate decreased and OH reappeared 3 hours after oral administration, when the plasma concentration of norepinephrine was at its highest level. We suggest that the OH improved mainly because of the increase in MSA due to L-threo-DOPS, and that the drug may activate sympathetic outflow at a site proximal to the sympathetic ganglion.

Autonomic Nervous System Diseases↗
PubMed1996

The treatment of postprandial hypotension in autonomic failure with 3,4-DL-threo-dihydroxyphenylserine.

Postprandial hypotension occurs commonly in patients with autonomic failure and may be due to attenuation of the normal sympathetic nervous system activation in response to meal ingestion. In a randomized, double-blind, placebo-controlled study, we investigated the therapeutic effect of the norepinephrine precursor 3,4-DL-threo-dihydroxyphenylserine (DL-DOPS) on this condition. We measured blood pressure, heart rate, forearm vascular resistance, and plasma DL-DOPS and norepinephrine in 11 patients with autonomic failure. DL-DOPS attenuated the postprandial fall in blood pressure. This was associated with an increase in plasma norepinephrine and forearm vascular resistance. DL-DOPS therapy did not change the postprandial increase in heart rate. There was a trend toward increased supine hypertension associated with DL-DOPS treatment. This study shows that DL-DOPS is a promising treatment for postprandial hypotension and provides support for the hypothesis that postprandial hypotension is, at least in part, due to decreased activation of the sympathetic nervous system.

Adult↗
PubMed1999

The treatment of neurogenic orthostatic hypotension with 3,4-DL-threo-dihydroxyphenylserine: a randomized, placebo-controlled, crossover trial.

OBJECTIVE: To study the therapeutic effect and mechanism of action of 3,4-DL-threodihydroxyphenylserine (DL-DOPS) in neurogenic orthostatic hypotension. METHODS: The blood pressure (BP) response to an orthostatic challenge on DL-DOPS was compared with that of placebo in a randomized, double-blind, placebo-controlled, crossover trial in 10 patients. The mechanism of action of DOPS was studied by measuring forearm vascular resistance and changes in supine and upright plasma DL-DOPS and norepinephrine levels. The effect of DL-DOPS on the quality of life was determined by questionnaire. RESULTS: DL-DOPS increased the supine (p<0.001) and upright (p<0.05) systolic blood pressure (SBP) and diastolic blood pressure (DBP) (both p<0.01). The peak SBP on DL-DOPS in the supine position occurred 300 minutes after ingestion of the medication. The increase in BP was accompanied by an increase in plasma levels of norepinephrine and DL-DOPS in both the supine and upright positions after DL-DOPS ingestion (p<0.0001). There was a trend toward improvement in symptoms of orthostatic intolerance. CONCLUSION: DL-DOPS improved features of neurogenic orthostatic hypotension in patients with central and peripheral autonomic nervous system disease. There was an increase in plasma norepinephrine. No major side effects occurred.

Adult↗
PubMed1994

[Development of L-threo-DOPS, a norepinephrine precursor amino acid].

threo-Dihydroxyphenylserine (DOPS) is a synthetic amino acid which can be decarboxylated by L-aromatic amino acid decarboxylase to yield natural form of norepinephrine (l-NE), a principal neurotransmitter in both central and peripheral (sympathetic) nervous systems. Like L-Dopa as an agent for dopamine precursor therapy, DOPS was expected to have a potential as an agent for NE precursor therapy. Previous studies carried out by several groups in early 1970s, however, reached a negative conclusion that threo-DOPS was not an effective precursor of NE in the brain because of its low NE-increasing activity and weak pharmacological action. Since the latter half of 1970s, on the contrary, three Japanese research groups have successfully shown the possibility of DOPS as a useful NE-precursor. That is, Tanaka (Kobe Univ.) showed that L-threo-DOPS is the real l-NE precursor among four DOPS-enantiomers, and that it has several pharmacological activities such as a slow-onset and long-lasting pressor effect, an inhibitory effect on harmaline-induced tremor and so on. Hayashi and Suzuki (Osaka Univ.) found through the mobility study on familial amyloid polyneuropatchy (FAP) that the progress of the disease develops NE-deficiency (NE-D), that severe orthostatic hypotention in FAP might be due to NE-D, and that L-DOPS has favorable effects on this symptom. Narabayashi (Juntendo Univ.) found that NE-D develops in patients with advanced Parkinson's disease (PD), that a freezing phenomenon in these patients might be associated with NE-D, and that L-DOPS improves the phenomenon. Based on these findings, the development of L-DOPS for registration had been undertaken by Sumitomo Pharmaceuticals Co., and an approval was given to it in 1989 as an agent for the treatment orthostatic hypotention in FAP or Shy-Drager syndrome and freezing phenomenon in PD. Preclinical and clinical studies done in the R&D confirmed that L-DOPS markedly restored NE-D and improved related-syndrome in the NE-deficient animals/patients, and that its actions were slow-onset, long-lasting and gentle. The R & D of L-DOPS described in this paper includes studies on industrial production, efficacy pharmacology (mode of action), metabolism and clinical trial of this agent.

Amyloid Neuropathies↗
PubMed1992

Effect of L-threo-3, 4-dihydroxyphenylserine on orthostatic hypotension in a patient with spinal cord injury.

A 72-year-old female who underwent the extirpation of metastatic intraspinal tumor showed an extremely wide variation of blood pressure with recurrent episodes of syncope due to paroxysmal hypotension. Treatment of the patient with salt supplement and L-threo-3, 4-dihydroxyphenylserine, an exogenous precursor of norepinephrine, markedly improved the syncopal attack as well as the daily activity.

Adenocarcinoma↗