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PubMed1981

[Therapeutic implications of the biochemical features about depressive illness (author's transl)].

The biochemical features of depressions able to guide the prescription of antidepressants are seen through a review of the literature. The papers were mainly focused on the peripheral catabolites of brain monoamines. Depressions characterized by low levels of 5 HIAA in the C.S.F. would predict a better efficacy of the antidepressants acting on the re-uptake of serotonin. The dosage of urinary MHPG seems to be a valuable index for the choice of the drug. Subjects with low levels response better to IMI, DE-IMI and NT, and those with normal levels to AMI. COMT activity and platelet MAO activity are may be a valuable index for the predictivity of the therapeutic results. Finally, the dexamethasone suppression test can be useful in order to guide the length of the treatment.

Antidepressive Agents↗
PubMed1981

Neurochemical studies of an analgesic, 1,3-diphenyl-5-(2-dimethylaminopropionamide)-pyrazole [difenamizole].

For the purpose of clarifying the action mechanism of the analgesic agent, difenamizole (DFZ), chemically known as 1,3-diphenyl-5-(2-dimethylaminopropionamide)-pyrazole, the following properties were investigated: 1) monoamine metabolizing enzymes, 2) biosynthesis of dopamine (DA), 3) binding of DA on the synaptic membrane of mice, 4) uptake of catecholamine (CA) by synaptosome in discrete brain areas and 5) DA release from the striatal slices of mice. Pertinent results obtained are delineated below: 1) DFZ at 10(-4) M inhibited the monoamine oxidase (MAO) activity to some extent although it had no activity on catechol-O-methyltransferase (COMT) at 10(-6) -10(-4) M. 2) DFZ significantly enhanced the DA accumulating activity of pargyline in the striatum. 3) DFZ inhibited the binding of 3H-DA to synaptic membrane by 25% at 10(-4) M in the striatum. 4) DFZ inhibited the DA uptake by 50% at 10(-4) M though the activity was somewhat weaker than imipramine or cocaine on the striatum. 5) DFZ inhibited the DA release due to high K+ concentration in striatal slices at 10(-4) -5x10(-4) M. From the above data, it was concluded that DFZ may exert its analgesic effect by inhibiting the release of DA and preventing the binding of DA with the receptors.

Adenosine Triphosphatases↗
PubMed1983

Norepinephrine uptake in arteries of spontaneously hypertensive rats.

The aim of our study was to investigate the activity of sympathetic nerves in arteries as a possible factor in the development of hypertension. In this paper, we report our results on the uptake of norepinephrine by the arteries of spontaneously hypertensive rats (SHR). Tail arteries of 7--9 week-old SHR and of normotensive controls (WKY) were incubated with [3H]norepinephrine for various periods of time. The 3H content in vessels of SHR and WKY was identical after 5 min but significantly higher in SHR after 15, 30, 60 and 90 min incubation. The rate of time-related uptake was greater in SHR as revealed by analysis of variance. The uptake of [3H]norepinephrine after 60 min was substantially less in vessels treated with cocaine in inhibit neuronal uptake or with desoxycorticosterone to inhibit extraneuronal uptake. After MAO activity was blocked with pargyline. 3H content remained higher in arteries of SHR than in those of WKY but after catechol-O-methyltransferase (COMT) was inhibited by U-0521, the difference was not significant. Our results demonstrate an alteration in the function of the sympathetic nerves in arteries as indicated by enhanced uptake of norepinephrine in the tail arteries of young SHR prior to the full development of hypertension.

Animals↗
PubMed1984

Assay of cerebral catecholamines, serotonin and their metabolites in experimental hemorrhagic shock in rats.

Rats were subjected to standard conditions of hemorrhagic shock. Animals were sacrificed 5 minutes and two hours after reinjection of blood which had effused into a syringe. The extent of shock was determined by measuring the acid base balance of the serum. Cerebral concentrations of NE, DA, DOPAC, HVA, 5-HT and 5-HIAA were measured and compared to controls. There was a significant decrease of the NE concentration and a highly significant increase of that of DA. Although the DOPAC concentration varied to a slight extent, that of HVA was significantly depressed 5 min after reinjection and exceeded initial values two hours later. It is consistent to interpret these results as a synaptic quiescence of DA utilization, which is no longer methylated by COMT. After two hours, however, extraneuronal DA metabolism was greatly increased, as indicated by the decreased DA concentration and the considerable increase of HVA levels. 5-HT turnover seemed to follow the same temporal variations, decreasing in the acute phase and then increasing during the recovery phase.

Animals↗
PubMed1982

In vitro effect of haloperidol, chlorpromazine, imipramine and lithium on the erythrocyte catechol-O-methyltransferase.

Haloperidol, chlorpromazine, imipramine and lithium in concentrations similar to the average therapeutic plasma levels did not exert any in vitro inhibition on the erythrocyte catechol-O-methyltransferase (COMT). The inhibitory effects of haloperidol, chlorpromazine and imipramine were noted first at concentrations 1000-10 000 times their respective average therapeutic plasma levels. Unlike the former three psychotropic drugs, lithium exerted an in vitro inhibition already at a concentration 40 times the average therapeutic plasma level and that in a competitive way. The inhibitory effect of lithium could be neutralized by increasing the magnesium concentration, likewise in a competitive way.

Catechol O-Methyltransferase↗
PubMed1995

[Is adrenaline in a 2% lidocaine solution after enoral injection hemodynamically effective?].

Adrenaline in local anesthetic solutions is thought to be the causative factor of acute exacerbations of preexisting cardiac diseases during dental anesthesia. This assumption presupposes the systemic effectiveness of adrenaline when coinjected with a local anesthetic drug. To test the above assumption, cardiovascular effects (PS, PD, dP/dTmax LVEP, CO, HR, EGG) and arterial drug concentrations were measured before and after injection of 1.0 ml/kg b.w. of a 0.9% NaCl, 1:300,000/1:100,000 adrenaline-HCl or 2% lidocaine-HCl alone and in combination into the mucobuccal fold of adrenalectomized rats. The transient increase in the cardiovascular parameters by adrenaline was abolished by lidocaine coinjection. The cardiodepressant effect of plain lidocaine was only reversed by the higher adrenaline dose, which however induced a small fall in PD, R and PM. Lidocaine increased the bioavailability of adrenaline from the intraoral depot. Inhibition of COMT activity by lidocaine may contribute to this effect. These findings demonstrate no cardiac response to adrenaline, up to 1:100,000 in a 2% lidocaine solution. In agreement with clinical findings the 1:100,000 adrenaline containing solution can be safely used in compromised cardiovascular patients. However, an interaction between a vasoactive comedication and lidocaine/adrenaline on the vascular system has to be taken into consideration.

Adrenalectomy↗
PubMed1994

[The effect of droxidopa on the monoamine metabolsim in the human brain].

Droxidopa (L-threo-3,4-dihydroxyphenylserine) is an artificial amino acid, which is used to supplement noradrenaline (NA) in neurodegenerative disorders. Droxidopa is decarboxylated into NA by aromatic L-amino acid decarboxylase in the brain, but its effects on other monoamine neurotransmitters, such as dopamine (DA) and serotonin (5-HT) have not been systematically examined. The monoamine metabolism has been suggested to interact with each other in the brain, and by analysis of the cerebrospinal fluid, L-DOPA, a precursor amino acid used for supplement of DA, was found to inhibit serotonin synthesis in the brain. To examine the effects of droxidopa on the monoamine metabolism, the intraventricular fluid of the patients administered with droxidopa and L-DOPA was analyzed. The levels of monoamines, their precursor amino acids, and their metabolites were compared between the patients administered with L-DOPA. In the patients administered by droxidopa and L-DOPA, droxidopa was shown to increase the concentrations of monoamines (NA, DA and 5-HT), but the difference was not statistically significant by comparison with those treated by L-DOPA alone. The metbolites of DA and 5-HT by monoamine oxidase, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) were also found to increase by droxidopa administration. On the other hand, the metabolites of NA and DA by catechol-O-methyltransferase (COMT), normetanephrine (NMN) and 3-methoxytyramine (3-MT), decreased in the patients treated with droxidopa and L-DOPA compared with the patients administered with L-DOPA alone and control patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

The effect of prolonged vasopressin administration on the level and metabolism of catecholamines in the rat brain and kidneys.

Dopamine (DA) and noradrenaline (NA) levels and activities of the enzymes metabolizing catecholamines were determined in the rat brain and kidneys during prolonged (4 weeks) administration of lysine vasopressin (LVP) and 2 weeks after its withdrawal. DA level was elevated during the whole period of experiment. NA level increased mainly after LVP withdrawal. Dopa-decarboxylase activity was elevated in all the experimental animals. Tyrosine and dopamine-beta-hydroxylase activities increased at the final period of LVP administration and after its withdrawal. Activities of MAO and COMT were markedly increased only after 3 weeks of LVP administration.

Animals↗
PubMed1993

Synthesis and in vitro dopaminergic activity of (2-aminoethyl)-1-hydroxy-2-pyridone type dopamine analogs.

Two isoteric/isoelectronic dopamine analogs based of (2'-aminoethyl)-1-hydroxy-2-pyridone without having the COMT vulnerable m-hydroxy group were synthesized via ten synthetic steps. Their dopaminergic activities were evaluated by measuring the inhibitory effects of prolactin secretion from the anterior pituitary in rats. The compounds 1 and 2 caused a reduction of prolactin secretion at the 10(-6) M concentration. Semiempirical MO calculations (at the AM-1 level) were performed on 1 and 2 in order to understand the structural and electronic features as compared to dopamine.

Animals↗
PubMed1977

[Abnormal movements of patients with Parkinsonism treated with L-dopa and anomalies of dopamine metabolism].

The authors describe the results of biochemical analysis carried out on 28 patients with Parkinson's disease who had been treated by L-dopa. Twenty of them showed either no abnormal movements at all or very few, eight others had considerable dyskinesia. Biochemical analysis of the urinary degradation products of L-Dopa revealed the existence of a swing in the degradation of dopamine towards 4-O-methylate derivatives in dyskinetic patients (significant difference at .01). The results confirm those obtained in their initial analysis carried out in 1973. The authors express the view that abnormal movements while under L-Dopa treatment are dependent on two factors: one, the hypersensitivity of dopaminergic reception, the other, the greater or lesser preponderance of the COMT isozyme giving rise to 4-O-methylates;

Dopamine↗
PubMedDate not supplied

[The role of enzymatic systems in pathophysiology and pharmacotherapy of Parkinson's disease].

In the metabolism of one of the main CNS neurotransmitters dopamine very important roles are played by four enzymes: two synthetizing dopamine: TH and DDC, and two enzymes breaking down dopamine: MAO-B and COMT. In a short review the author discusses disturbances of these enzymatic systems in parkinsonism and therapeutic possibilities of using drugs stimulating or inhibiting the activity of these systems.

Brain↗
PubMed1995

[Clinical aspects and conservative therapy of Parkinson disease].

Parkinson's disease is essentially motor. The core symptoms comprise akinesia, rigidity and tremor. Concomitantly, signs of autonomic, cognitive and affective disturbances may be found. The disease progresses slowly and, without treatment, ultimately results in disability and loss of independence. The symptoms can be controlled for a long time by pharmacotherapy. Dopaminergic drugs such as L-DOPA, dopaminreceptor agonists, and MAO-B- and COMT-blockers can essentially improve most of the symptoms. The tremor may be alleviated by central anticholinergic drugs. With time, however, unwanted side effects such as "end of dose akinesia", "on-off phenomena", hyperkinesis and exogenous psychosis come into play. Therefore, pharmacological treatment becomes very complex in the late stages of the disease and the unwanted side effects can no longer be sufficiently controlled. It is not clear whether conservative approaches will be ever able to cope with these problems. This explains the search for novel treatment strategies, e.g. neurotransplantation, stereotaxic lesion of the subthalamic nucleus or stimulation techniques.

Antiparkinson Agents↗
PubMed1976

Regional changes in [3H]-noradrenaline uptake, catecholamines and catecholamine synthetic and catabolic enzymes in rat brain following neonatal 6-hydroxydopamine treatment.

6-Hydroxydopamine (6-OH-DA) treatment of rats at birth (with the analyses conducted in the adult stage) produced marked regional variations in changes in endogenous noradrenaline (NA) and [3H]NA uptake in the CNS. The most pronounced reductions were seen in the cerebral cortex, hippocampus and the spinal cord. Moderate changes or none at all were seen in the hypothalamus, septum and thalamus. Marked increases in endogenous NA and [3H]NA uptake were seen in the mesencephalon and the pons-medulla oblongata. There was in general a close correlation between the changes in endogenous NA and [3H]NA uptake. The results from the cerebellum varied, depending on the developmental stage at which the 6-OH-DA treatment was performed. 6-OH-DA treatment up to three days after birth generally led to a marked increase in both endogenous NA and [3H]NA uptake, while continuing the treatment caused a marked reduction of both parameters. The 6-OH-DA treatment caused no changes in endogenous dopamine (DA) in all regions analysed. Enzyme activity assays showed that DA-beta-hydroxylase (DBH) and tyrosine hydroxylase (TH) were greatly reduced in the cerebral cortex, while the activity of both enzymes was almost double in the pons-medulla. No changes in the activity of phenylethanol-amine N-methyltransferase (PNMT), DOPA decarboxylase, COMT and MAO were seen after 6-OH-DA at birth. Measurements of choline acetyltransferase activity displayed only minute changes. The present results strongly support the view that 6-OH-DA treatment in the neonate stage produces a very selective action on NA neurones belonging to the locus coeruleus system from a structural standpoint, leaving DA- and PNMT-containing neurones unaffected. [3H]NA uptake in whole CNS was almost unchanged, despite the marked regional variations. The results have been interpreted as being due to a 'pruning effect', where the permanent NA denervation in distant nerve terminal projections (e.g. cerebral cortex) leads to a compensatory sprouting and increased outgrowth of NA terminal projections in areas close to the perikarya (e.g. pons-medulla). Furthermore, the results support the view that the growing locus coeruleus neurones are strictly programmed to produce a certain quantity of nerve terminal volume and arborization during the postnatal development.

Age Factors↗
PubMed1996

[Recent progress in development of psychotropic drugs (3)--Antiparkinsonian agents applied in the treatment of Parkinson's disease or are under investigation for patients or model animals].

Tremor, akinesia, rigidity and postual instability are key signs of Parkinson's disease. The most important one is akinesia, which includes decreased spontaneous locomotor activity, slowness of movement, awkwardness and freezing. On the other hand, an electrical focal lesion in the brain, neurotoxin to dopaminergic neurons such as 6-hydroxydopamine (6-OHDA) or I-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), cholinomimetic tremorogenic agents such as oxotremorine or tremorine, monoamine depleting agents such as reserpine or tetrabenazine, or dopamine receptor antagonists such as haloperidol are applied to render animal parkinsonism. The estimation of locomotor activity can be done accurately in animal models. Tremor can be studied using the animals treated by cerebral focal lesion, neurotoxins or cholinomimetics. Skillfulness is hard to estimate in animals, however, it can be done in primates. Freezing appeared in patients with levodopa treatment over a long period. This is a specific motor sign in Parkinson's disease, and cannot be observed in animals. Supplementing dopamine by levodopa administration, retarding the metabolism of levodopa or dopamine by dopa decarboxylase inhibitor (DCI), monoamine oxidase inhibitor type B (MAO-B) inhibitor or catechol-O-methyltransferase (COMT) inhibitor, dopamine receptor agonists, anticholinergic agents, dopamine release enhancer/ uptake inhibitor, N-methyl-D-aspartate (NMDA) receptor antagonists, adenosine receptor antagonists, neurotrophic factors, GM1-ganglioside and nicotinic receptor agonists have been applied in the treatment of Parkinson's disease or are under investigation for patients. Agents to facilitate nerve growth or to inhibit the degeneration of nerves will be developed in the future.

Animals↗
PubMed1996

[20 years of progress in dissecting mechanisms of oncogenesis. Relations between magic of science and requirements of medicine].

In the last twenty years, our understanding of carcinogenesis has evolved from a description of the natural history of cancer development, a conception inherited from Darwin, to the dissection of the underlying molecular mechanisms leading to phenotypic changes in cells, a neodarwinian interpretation. Most scientists agree that random germ cell mutations enhancing cell survival and reproduction capacities play a major role in the evolution of species and that carcinogenesis progresses from acquisition of genetic anomalies which alter the normal function of oncogens or antioncogens. Since the discovery of src, the first oncogen to be identified twenty years ago, and more recently the discovery of antioncogens such as p53, hopes and expectations have grown steadily, and passionately, often far beyond reason dietated by the real world of clinical medicine. Yet curiously, many clinicians hesitate to express one essential point: advances in science and technology, is not equivalent to advances in medicine. It is our responsibility to resist the illusion of progress, for this illusion turns out to have a negative impact in our patients. To paraphrase the French philosopher André Comte-Sponville, the power conferred by the exercise of medicine is not based solely on scientific knowledge, but also on human compassion.

Humans↗
PubMed1997

[Clinical characteristics and trends in research of Parkinson's disease and parkinsonism in Japan].

Parkinson's disease (PD) is one of the major neurological diseases affecting elderly subjects. Presumed prevalence of PD is 80-100 per 100 thousands and it is estimated that there are approximately 100 thousands patients in Japan. From a statistic on age distribution of patients visiting doctors, it is estimated that patients with ages at 75-79(639/100,000) and 80-84(632/100,000) are highest in number. Juvenile parkinsonism is a syndrome with parkinsonian motor symptoms and dystonia developing before and after ten years of age. Reports on this syndrome have been accumulated in Japan and gene abnormality in a enzyme relating to dopamine metabolism was discovered in the hereditary progressive dystonia with marked diurnal fluctuation (Segawa). Among symptomatic parkinsonism, cerebrovascular parkinsonism is mainly due to multiple infarction in the basal ganglia or Binswanger's disease in Japan, and both conditions develops parkinsonism, pseudobulbar palsy and dementia progressively. Diffuse Lewy body disease and a unique type of progressive supranuclear palsy presenting a disorder designated "pure akinesia" were studied mainly in Japan. In drug therapies of PD, it has been argued why the maintenance dose of levodopa or dopamine agonists was generally low in Japan. In addition to constitution and drug metabolism, attitude of Japanese people to worry side effects more than merit with beneficial effects by a drug may have inevitably lead to low maintenance dose. Development of new drugs have been undertaken in parallel with US and Europe. Talipexole hydrochloride has been on market in Japan recently, but MAO-B inhibitors and COMT inhibitors are in final stages to wait evaluations by the governmental committee.

Adolescent↗
PubMed1997

[PET study using 6-[18F]-fluorodopa in Parkinson's disease].

6-[18F]-fluorodopa (FDOPA) was developed as an analogue of L-DOPA across the blood-brain-barrier and to carry into nigrostriatal dopaminergic neurons. PET study using FDOPA revealed presynaptic dopaminergic function in the striatum of nigrostriatal system of the human brain and many studies have performed to clarify the pathogenesis of Parkinson's disease. FDOPA is also an efficient tracer to analyze pharmacokinetics of L-DOPA by measuring radioactivities of its metabolites in the peripheral blood by HPLC and to evaluate pharmacological effects on dopamine metabolism by pretreatment of dopa decarboxylase inhibitor or COMT inhibitor. PET study using FDOPA is useful not only to diagnose Parkinson's disease but also to differentiate from parkinsonism in combination with other radioactive ligands and with other neuroimaging methods such as MRI.

Animals↗