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PubMed1999

Management of Parkinson's disease a review of current and new therapies.

The management of Parkinson's disease has undergone recent changes with the advent of new therapies, both pharmacotherapy and surgery. Available interventions are discussed. Levodopa remains the mainstay of therapy. New drugs include the dopamine agonists and COMT inhibitors. New dopamine agonists which may have a levodopa "sparing effect;" it has been suggested that some of the drugs should be considered as first line treatments for newly diagnosed Parkinson's disease patients. We review roles of these drugs. The concept of neuroprotection in neurodegenerative disorders such as Parkinson's disease became popular in the mid 1980s and it is hoped that eventually therapy will be directed at slowing progression of the disease. A great deal more work needs to be done before a suitable agent is identified as being neuroprotective. Potential neuroprotective agents are reviewed. Surgical therapies for Parkinson's disease consisting of various forms of lesion surgery as well as stimulation procedures are reviewed. Complications of drug therapy include motor problems such as motor response fluctuations, as well as psychiatric complications including levodopa-induced psychosis. Atypical neuroleptic agents and ECT for psychiatric syndromes associated with Parkinson's disease are discussed. Algorithms for the management of early disease as well as the management of psychosis in Parkinson's disease are included. Treatment options for advanced disease are tabulated.

Antiparkinson Agents↗
PubMedDate not supplied

[Motor complications of treatment with levodopa in Parkinson's disease].

INTRODUCTION: Motor complications of treatment with levodopa affect more than 50% of patients after several years' treatment. This has a marked effect on patients with Parkinson's disease since these side effects are undesirable, affect the natural course of the disorder and complicate treatment. DEVELOPMENT: In this review we describe the main epidemiological, physiopathological and therapeutic aspects of the motor complications of levodopa. According to most epidemiological studies, starting treatment at an early age and more severe degree of the disorder are the main risk factors. The physiopathology of motor complications is varied. It has been thought to be due to loss of the buffer effect of the brain on plasma levels of levodopa, alterations in the functional state of the postsynaptic receptors and chronic intermittent use of levodopa. Management includes division and/or reduction of the dose of levodopa, use of slow-release preparations and association of dopaminergic agonists with COMT inhibitors which are the latest drugs to be tried. Various surgical possibilities in specialist centres may also be considered for serious cases of motor complications which do not respond to medical treatment. CONCLUSIONS: Recent advances in understanding the physiopathology and in the medical and surgical treatment permit improved control of the motor complications of chronic treatment with levodopa.

Aged↗
PubMedDate not supplied

[Entacapone: is it useful as complimentary treatment with levodopa?].

Entacapone (Comtan) is a potent, selective inhibitor of peripheral catechol-O-methyltransferase (COMT) with therapeutic potential as an adjuvant to levodopa therapy in patients with Parkinson's disease. Entacapone decreases peripheral conversion of levodopa to 3-O-methyldopa increasing central extracellular levodopa and consequently striatal dopamine concentrations. At doses of 200 mg 2 to 10 times daily coadministered with levodopa/carbidopa or levodopa/benserazide entacapone may increase the duration of clinical response both after the first single dose and after repeated dosing in patients with end-of-dose fluctuations. At this dosage, it has a time to peak-plasma concentration of 1.2 hours and an elimination half life of 3.4 hours. In two multicentric, long-term (approximately 6 month), randomized and placebo-controlled studies, the duration of 'on' time was increased and the duration of 'off time' was decreased in patients who received adjunctive entacapone therapy. Moreover, patients randomized to entacapone reduced their levodopa requirements. In these and other phase III studies, entacapone was generally well tolerated, with few reported adverse events, mainly dyskinesias and gastrointestinal disorders. The dyskinesias were generally well controlled by decreasing the mean daily levodopa dose. Entacapone appears as a clinically significant and beneficial adjunct to levodopa therapy in Parkinson's disease patients with end-of-dose fluctuations.

Antiparkinson Agents↗
PubMed1999

Patient with a 22q11.2 deletion with no overlap of the minimal DiGeorge syndrome critical region (MDGCR).

The apparent lack of genotype/phenotype correlation in patients with the DiGeorge anomaly and velocardiofacial syndrome (DGA/VCFS; the "22q11 deletion syndrome") indicates a complex genetic condition. Most cases, whatever the phenotype, have a 1.5-3 Mb chromosomal deletion that includes the minimal DiGeorge critical region (MDGCR). Another potential critical region on 22q11 has been suggested based on two patients with distal deletions outside the MDGCR. We report on a patient with a VCFS phenotype who has a deletion, mapped by short tandem repeat polymorphic loci and fluorescence in situ hybridization analysis, distal to and not overlapping the MDGCR. This patient is deleted for several genes, including the T-box 1 gene (TBX1; a transcription regulator expressed early in embryogenesis) and catechol-O-methyltransferase (COMT; involved in neurotransmitter metabolism). We discuss the role these two genes may play in the clinical phenotype of the patient.

Adult↗
PubMed1975

Activity of catecholamines inactivating enzymes in heart muscle during anoxic cardioplegia in cardiosurgical patients.

On the model of anoxic cardioplegia in cardiosurgical patients the influence of anoxia on the activity of monoamine oxidase (MAO) and catechol-O-methyltransferase (COMPT) in right auricular tissue was studied. It was found out that the activity of COMT does not change during anoxia, the activity of MAO considerably increases. With regard to catecholamines stimulating effect upon cardiac metabolism as well as to their calorigenic and oxygen wasting effect the raise of MAO activity may be regarded as favourable phenomenon, because the hastened degradation of released catecholamines at least to a certain degree diminishes the disproportion between oxygen supply and actual oxygen need of the heart and by means of that mitigates the anoxic damage of myocardium.

Cardiac Output, Low↗
PubMed1999

Dopamine in the developing kidney.

The adult kidney has a high rate of dopamine (DA) production, metabolism, and signalling. The non-neuronal DA system in the adult kidney is of utmost importance for the regulation of salt metabolism. DA may also act as a transcription factor and may be of importance for tissue differentiation. In the central nervous system, D1 receptors require the dopamine- and cAMP-regulated phosphoprotein with a molecular weight of 32,000 Dalton (DARPP-32) to mediate their actions. The renal D1 mediates DARPP-32 activation via a cascade involving cAMP and PKA, and protein kinase C (PKC) activation via phospholipase C. Active DARPP-32 has a specific inhibitory effect on protein phosphatase 1 (PP1), leaving, e.g. Na+,K+-ATPase in a phosphorylated, inactive, state. Thus, dopamine acts as a natriuretic hormone in the mature kidney. Here, we discuss the age-dependent distribution and some functional aspects of several parts of the renal dopamine system (dopamine, AADC, COMT, D1 receptor, and DARPP-32) during renal morphogenesis.

Animals↗
PubMed1999

A systematic review of genetic polymorphisms and breast cancer risk.

Studies investigating the relationship between common genetic variants and cancer risk are being reported with rapidly increasing frequency. We have identified 46 published case-control studies that have examined the effect of common alleles of 18 different genes on breast cancer risk. Of these, 12 report statistically significant associations, none of which were reported by more than one study. However, many of the studies were small: 10 of the 46 had 80% power or greater to detect a rare allele homozygote relative risk <2.5. We therefore combined the results of individual studies to obtain more precise estimates of risk. Statistically significant differences in genotype frequencies were found in three case-control comparisons of unselected cases. These were for CYP19 (TTTA)n polymorphism [(TTTA)10 carrier odds ratio (OR) = 2.33; P = 0.002], the GSTP1 Ile105Val polymorphism (Val carrier OR = 1.60; P = 0.02), and the TP53 Arg72Pro polymorphism (Pro carrier OR = 1.27; P = 0.03). In addition, the GSTM1 gene deletion was found to be significantly associated with postmenopausal breast cancer (null homozygote OR = 1.33; P = 0.04). There was also some evidence that homozygotes for the PR PROGINS allele are protected against breast cancer, although this result was of borderline statistical significance. For polymorphisms in BRCA1, COMT, CYP17, CYP1A1, NAT1, and NAT2, the best estimate of risk either from the individual studies or the meta-analyses was sufficiently precise to exclude a relative risk of 1.5 or greater. For the polymorphisms in EDH17B2, ER, CYP2D6, CYP2E1, GSTT1, HSP70, and TNFalpha, the risk estimates, although nonsignificant, were insufficiently precise to exclude a moderate risk (>1.5). Precise estimation of the risks associated with these and other as yet untested genes, as well as investigation of more complex risks arising from gene-gene and gene-environment interactions, will require much larger studies.

Alleles↗
PubMedDate not supplied

[Inhibition of the COMPT with entacapone in the treatment of motor fluctuations in Parkinson disease].

Motor fluctuations are a common problem in the long-term treatment of Parkinson's disease (PD). Entacapone (Comtan) is a potent, peripherally acting, reversible and selective inhibitor of catechol-O-methyltransferase (COMT). Used as an adjuvant to levodopa therapy, entacapone slows the elimination of levodopa by decreasing peripheral conversion to 3-O-methyldopa, increasing central extracellular levodopa and striatal dopamine concentrations. Coadministered with levodopa/carbidopa or levodopa/benserazide, at doses of 200 mg 2 to 10 times daily in patients with end-of-dose fluctuations, entacapone may increase the duration of clinical response, both after the first single dose and after repeated dosing. At this dosage, it has a time to peak plasma concentration of 1.2 h and an elimination half life of 3.4 h. In two multicentric, long-term (24 weeks), parallel, randomized and placebo-controlled studies, entacapone increased the duration of 'on' time (by approximately 1 hour daily) and decreased the duration of 'off' time with a concomitant reduction in the mean daily levodopa dose. In these and other phase III studies, entacapone was generally well tolerated, with most adverse effects being dyskinesias and gastrointestinal disorders. Increased dyskinesia were generally controlled by reducing levodopa doses. Entacapone appears to be a useful adjunct in extending the benefit of each levodopa dose in PD patients with end-of-dose fluctuations.

Aged↗
PubMed1999

Study of DT-diaphorase in pigment-producing cells.

DT-diaphorase is an FAD-containing enzyme capable of a two-electron reduction of ortho- and paraquinones. Nicotinamide coenzymes (NADH + H+ and NADPH + H+) serve as hydrogen sources in these reactions. The role of DT-diaphorase has been thoroughly investigated in situations when the enzyme is able to reduce exogenous and endogenous quinones, hence protecting the cells against these reactive intermediates. The enzyme has also been studied in connection with its ability to activate some quinoid cytostatics. It is surprising that DT-diaphorase has never been investigated in pigment-producing cells that are known to generate considerable amounts of ortho-quinones. Using a spectrophotometric method we could readily measure the activity of DT-diaphorase in epidermis and various cultured pigment cells. The melanocytes isolated from dark skin showed generally higher DT-diaphorase activity than those from fair skin samples. Also, darkly pigmented congenital naevus cells exhibited higher activity of this enzyme. The most striking was the high DT-diaphorase activity in melanoma cell cultures. In these cells DT-diaphorase activity could be induced by incubation of the cells with 4-hydroxyanisole. A similar effect was seen when a catechol-O-methyltransferase (COMT) inhibitor (3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione (OR-462) was utilised. The induction was inhibited by cyclohexidine.

Anisoles↗
PubMedDate not supplied

Interactions between neomycin and cerebral dopaminergic and serotoninergic transmission in rats.

The aim of this work was to investigate the effects of neomycin on monoamine contents of rat striatal tissue. The analysis was performed by HPLC with electrochemical detection. Rats were injected with neomycin (2 mg/kg; i.p.) and killed at different times over 24 h. The striatal homogenate was injected in a reversed-phase HPLC. Results showed a significant increase in dopamine tissue level (+35 per cent; 4 h after neomycin injection) and a decrease (-36 per cent) in the level of its metabolites. Striatal serotonin level showed a rapid and significant (p < 0.001) increase, +130 per cent, 2 h after neomycin injection. DOPAC/DA and 5HIAA/5HT ratios were reduced by 34 per cent and 46 per cent respectively. These results indicate an inhibitory effect of neomycin on striatal dopaminergic and serotoninergic systems. Several mechanisms could be involved in these effects of neomycin in the biosynthesis process through stimulation of tyrosine hydroxylase and tryptophane hydroxylase and/or MAO and COMT activities. The blockage of calcium channels was also suggested.

Animals↗
PubMedDate not supplied

Importance of treatment of depression in assuring the most efficacious management of Parkinson's disease.

Parkinson's disease (PD) is characterized by pathological changes which include degeneration of dopaminergic neurons in the substantia nigra pars compacta coupled with intracytoplasmic inclusions known as Lewy bodies. Neurodegeneration and Lewy bodies can also be found in the locus coeruleus, nucleus basalis, hypothalamus, cerebral cortex, cranial nerve motor nuclei, and central and peripheral components of the autonomic nervous system. PD progression is associated with the development of dementia, autonomic dysfunction, and postural instability, which do not respond well to conventional therapy. Therapeutic efforts aimed at preventing or at least delaying PD progression by reducing the overload of iron and generation of ROS, correcting the zinc deficiency may be of great benefit. Current pharmacotherapy of PD, in addition to symptomatic L-dopa treatment, includes the neuroprotective strategies with dopamine agonists, monoamine oxidase-B inhibitors (MAO-B), glutamate antagonists, catechol O-methyltransferase (COMT) inhibitors and other antioxidants or free radical scavengers. Depression, anxiety disorder and stress are all associated with PD and it is therefore necessary to include treatment regimens for these ailments in addition to the traditional pharmacotherapy for the symptoms of PD, as well as the neuroprotective measures noted above, in order to ensure the greatest possible benefit to PD patients.

Depression↗
PubMedDate not supplied

In vitro PET evaluations in lung cancer cell lines.

UNLABELLED: One purpose of the study was to explore the PET tracer 11C-L-DOPA for the discrimination between small-cell lung cancer (SCLC) and non small-cell lung cancer (NSCLC). A further aim was to explore the potential antitumoral effects of 6-diazo-5-oxy-L-norleucine (DON) and the use of a PET proliferation marker for the evaluation. MATERIALS AND METHODS: Four lung cancer and one endocrine tumour cell line (BON) were cultured as monolayer. The uptake of 5-[76Br]-bromo-2-fluoro-deoxyuridine (76Br-BFU), [11C]-L-DOPA (11C-DOPA) and [18F]-fluorodeoxyglucose (18FDG) were evaluated. The effects of specific enzyme inhibitors affecting the DOPA metabolism were explored. The effect of DON on proliferation and uptake of 76Br-BFU were assessed. RESULTS: All cell types showed a measurable uptake of 11C-DORA, with slightly lower values in lung cancer. There were no clear differences between SCLC and NSCLC. The addition of COMT inhibitor induced a significantly increased uptake of the tracer in BON cells, but not in lung cancer cells. DON significantly reduced the proliferation in all cell lines. The 76Br-BFU uptake was reduced markedly in all cell lines during DOn treatment. CONCLUSION: 11C-DOPA failed to distinguish between SCLC and NSCLC. DON showed strong antiproliferative effects which might motivate renewed interest in this drug for clinical cancer treatment. PET with 76Br-BFU might be used for treatment evaluation.

Antibiotics, Antineoplastic↗
PubMed2000

[A prospect of treatment for Parkinson's disease in the 21st century].

During the last half of the 20th century, medical treatment for Parkinson's disease (PD) showed remarkable progresses, resulting in marked prolongation of life and self-dependency of patients. In Japan, peak of ages of PD patients visiting all medical institutions was between 75 and 84 years of age(1993), with which course of illness is predicted to exceed twenty years in a large number of patients. As exploration of neuroprotective therapies for PD has not been successful yet, continuous progress in neuronal cell death in the substantia nigra result in loss of efficacy of medication, motor fluctuations and CNS side effects such as dyskinesia and psychosis in the long course of dopaminergic supplementation therapies. Future development of medical therapies for PD is expected in different ways. First, elaboration in controlled-release of DCI/levodopa, utilization of dopamine(DA) receptor agonists with different profiles in affinity to DA receptor subtypes and half-time of blood concentration, and utilization of COMT inhibitors. Second, neuroprotection with MAO-B inbitators or DA receptor agonists. Neuroprotective function is expected in animal studies for these substances but clinical usefulness should be verified with randomised controlled trials. Third, treatment for extra-motor symptoms such as dementia, cognitive disorders, depression, autonomic disturbances such as orthortatic hypotension and bladder disturbances, which is essential for maintenance of quality of life of patients with long course of illness. Gene therapy, neuroprotection before development of symptoms in PD may be attained within the first few decades of the next century. In this respect, establishment of preclinical diagnosis with neuroimaging and sensitive motor and psychological tests is imperative.

Animals↗
PubMed2000

[Pharmacological modulation of dopaminergic transmission in the rat striatum in vivo].

Inhibition of catechol-0-methyltransferase (COMT) activity by Tolcapone was shown to result in increase of the striatal DA extracellular content in unrestrained rats pretreated with L-3,4-dihydroxyphenilalanine combined with Carbidopa, the decarboxylation inhibiting agent. Tolcapone enhanced the increase of the DA level in the rat striatal dialysates produced by treatment of these animals with specific DA re-uptake blocker GBR 12909. The latter elicits stereotype behaviour in rats that is substantially enhanced by tolcapone. The DA turnover rate in the striatum was decreased by the GBR 12909. The data obtained suggest that the DA transporter of neuronal membrane plays a major role in the neurochemical homeostasis at synaptic level.

Animals↗
PubMed2000

Complications and limitations of drug therapy for Parkinson's disease.

Levodopa is the most effective drug treatment for Parkinson's disease (PD). However, its chronic use is associated with dyskinesia, motor fluctuations, and hallucinations. There are various approaches to the management of levodopa complications. Motor fluctuations can be treated with a long-acting levodopa preparation, liquid levodopa, or the addition of dopamine agonists or catechol-O-methyl transferase (COMT) inhibitors. Drugs that may improve levodopa-induced psychiatric complications are olanzapine, clozapine, and ondansetron. A large proportion of patients with long-standing PD cannot be controlled adequately with the available pharmacologic tools and are candidates for surgery. Pallidotomy and deep brain stimulation (DBS) of the globus pallidum pars interna and the subthalamic nucleus are currently the preferred surgical approaches. Appropriate patient selection becomes a critical issue for achieving the best surgical results.

Humans↗
PubMedDate not supplied

[Parkinsonian syndromes in Medellin (Colombia)].

INTRODUCTION: The definition of parkinsonian syndromes is based on clinical criteria. OBJECTIVE: To determine the frequency and management of parkinsonism, using criteria of inclusion and exclusion. PATIENTS AND METHODS: We selected 302 consecutive patients, 147 females and 155 males, with parkinsonism, age 66.8 (11.4) (range: 13-90), grades of education 7.5 (4.3) (range: 0-20). A structured and quantitative protocol was applied to the sample. RESULTS: The most frequent parkinsonian syndrome was the defined idiopathic Parkinson's disease with 132 participants (43.7%). Probably idiopathic Parkinson's disease was found in 60 cases (19.9%), and possible idiopathic Parkinson's disease in eight cases (2.6%); early onset Parkinson's disease in 10 cases (3.3%), juvenile Parkinson's disease in one case (0.3%), familial Parkinson's disease in five cases (1.7%); cortical Lewy body disease in 16 cases (5.4%), progressive supranuclear palsy in nine cases (3.3%), multiple systemic atrophy in eight cases (2.6%). Secondary Parkinson's disease was distributed as follow: vascular disease in 24 cases (8%), local lesion in 11 cases (3%), medications in 16 cases (5.3%), meningoencephalitis in one case (0.3%) and syphilis in one case (0.3%). Without medication was found 1.5% of sample, which was in Hoehn & Yarh's state I to II. In monotherapy was found 23.2%, with two medications 46.7%, with three 23.5% and with four drugs 5.1%. Levodopa was prescript to 70.9%, anticholinergic to 51.3%, MAO-B-I to 33.4%, amantadine to 33.1%, D2 stimulants to 18.5%, and COMT-I to 2.6%. CONCLUSION: Structured protocol for assessment of parkinsonian syndromes allows reliable diagnoses for clinical and epidemiological purposes.

Adolescent↗
PubMed2001

Current and emerging treatments in Parkinson's disease.

INTRODUCTION: Parkinson's disease is one of the commonest neurodegenerative diseases of the elderly. The discovery of dopamine deficiency from the degeneration of substantia nigra neurons revolutionised treatment in the early 70's. METHOD: This review is based on Medline search with Keywords (Parkinson's disease, treatment, therapy, surgery). RESULTS: Levodopa remains the gold standard of medications. New drugs include recently introduced dopamine agonists like ropinorole and pramipexole, and COMT inhibitors. The role of selegiline in neuroprotection remains controversial. Dopamine agonist monotherapy may delay the onset of motor fluctuations. Levodopa may be associated with the earlier onset of motor complications such as dyskinesias, and it may be preferable to delay its use in younger patients. In older patients, especially those with significant disability, levodopa use should not be delayed. Surgical therapies such as pallidotomy, bilateral subthalamic deep brain stimulation and foetal transplantation can be considered for those who fail medical therapy. Molecular science techniques including gene therapy, neurotrophic factors, stem cell technology form the next frontier of Parkinson's research. CONCLUSION: No new medication has proven more efficacious than levodopa. More controlled trials are required in Parkinson's surgery to reach definite conclusions about its effects and long-term results.

Age Factors↗
PubMed1979

Pharmacological studies on a new thymoleptic antidepressant, 1-[3-(dimethylamino)propyl]-5-methyl-3-phenyl-1H-indazole (FS-32).

Some pharmacological actions of 1-[3-(dimethylamino)propyl]-5-methyl-3-phenyl-1H-indazole (FS-32), a newly synthesized indazole derivative, were investigated in comparison with imipramine. FS-32 showed anti-reserpine activity in a dose-dependent manner, whereas imipramine exhibited a bell-shaped dose-response pattern. Catecholaminergic potentiation was demonstrated with FS-32. The results obtained from a norepinephrine potentiation test in vitro suggest that FS-32 may act in a manner qualitatively different from the tricyclic antidepressant. FS-32 produced a definite suppressive effect on isolation-induced fighting without affecting coordinated motor activity and on the duration of afterdischarge elicited by electrical stimulation to the amygdala or the hippocampus without producing a slow wave pattern in the EEG. Similar effects on fighting behavior and the afterdischarge were shown under imipramine with a slight motor incoordination and with a slow wave pattern, respectively. FS-32 produced practically no peripheral anti-cholinergic action, while it antagonized central cholinergic activity. FS-32 tended to produce an increase in chatecholamine content in the brain without MAO or COMT inhibitory activity. Norepinephrine uptake was inhibited by FS-32, but less than by imipramine. These pharmacological properties suggest a potential clinical utility of FS-32 as an antidepressant possessing thymoleptic activities.

Acetylcholine↗