digoxin and Parkinson-Disease

The isoprenoid pathway produces four key metabolites important in cellular function--digoxin (endogenous membrane Na(+)-K+ ATPase inhibitor), dolichol (important in N-glycosylation of proteins), ubiquinone (free-radical scavenger), and cholesterol (component of cellular membranes). This study assessed the changes in the isoprenoid pathway and the consequences of its dysfunction in Parkinson's disease (PD). There was an elevation in plasma HMG CoA reductase activity, serum digoxin and dolichol levels, and a reduction in serum magnesium, RBC membrane Na(+)-K+ ATPase activity, and serum ubiquinone levels. Serum tryptophan, serotonin, strychnine, nicotine, and quinolinic acid were elevated, while tyrosine, morphine, dopamine, and noradrenaline were decreased. The total serum glycosaminoglycans (GAG) and glycosaminoglycan fractions (except chondroitin sulphates and hyaluronic acid), the activity of GAG degrading enzymes, carbohydrate residues of serum glycoproteins, the activity of glycohydrolase-beta galactosidase, and serum glycolipids were elevated. HDL cholesterol was reduced and free fatty acids increased. The RBC membrane glycosaminoglycans, hexose and fucose residues of glycoproteins and cholesterol were reduced, while phospholipid was increased. The activity of all serum free-radical scavenging enzymes, concentration of glutathione, alpha tocopherol, iron binding capacity, and ceruloplasmin decreased significantly in PD, while the concentration of serum lipid peroxidation products and nitric oxide increased. A dysfunctional isoprenoid pathway and related cascade are important in the pathogenesis of Parkinson's disease. A hypothalamic digoxin mediated model for Parkinson's disease is also postulated.

Topics: Aged; Digoxin; Dolichols; Enzyme Inhibitors; Erythrocytes; Female; Glycoconjugates; Glycosaminoglycans; Humans; Hydroxymethylglutaryl CoA Reductases; Hypothalamus; Male; Membrane Proteins; Middle Aged; Models, Biological; Neurons; Parkinson Disease; Polyisoprenyl Phosphates; Sodium-Potassium-Exchanging ATPase; Tryptophan; Tyrosine; Ubiquinone

The aim of this single-blind study was to assess the effect of ropinirole, a novel treatment for Parkinson's disease, on the steady-state pharmacokinetics and safety of digoxin in 10 patients with Parkinson's disease.. There were three parts to the study: digoxin once daily plus placebo three times daily for 1 week; digoxin once daily plus ropinirole three times daily for 6 weeks; and digoxin once daily plus placebo three times daily for 1 week. Serial blood samples were collected over 24 h at the end of each part of the study for pharmacokinetic assessment. Pre-dose blood samples were collected on specific days throughout the study to assess the attainment of steady-state plasma levels of digoxin. The primary endpoints were AUC(0, tau) and Cmax for digoxin.. There was a mean decrease of 10% in digoxin AUC (0, tau) (90% CI: 0.79, 1.01) and a 25% decrease in digoxin Cmax (90% CI: 0.58, 0.97) when ropinirole was co-administered, compared with digoxin alone Cmin plasma values for digoxin, however, were fairly constant throughout the study (point estimates 0.99, 95% CI: 0.85, 1.15). Changes in trough levels of digoxin are believed to be the most reliable way of assessing steady-state concentrations of digoxin, and therefore the clinical significance of an interaction. Changes in Cmax are too readily influenced by other factors.. These results therefore indicate that on pharmacokinetic grounds no dose adjustment is necessary for digoxin co-administered with ropinirole.

Topics: Aged; Anti-Arrhythmia Agents; Antiparkinson Agents; Digoxin; Drug Administration Schedule; Drug Interactions; Humans; Indoles; Parkinson Disease; Placebos; Single-Blind Method

Syncope due to orthostatic hypotension (OH) refers to loss of consciousness caused by hypotension induced by the upright position; it is an important risk factor for fall-related physical injuries, especially in the elderly adults. We evaluated the prevalence of OH syncope and the clinical characteristics of patients older than 65 years with syncope due to OH in the Evaluation of Guidelines in Syncope Study 2 group population.. Two hundred fifty nine patients older than 65 years consecutively admitted to the emergency department because of loss of consciousness in a period of a month were submitted to a standardized protocol approved by the European Task Force for the diagnosis of syncope; all the patients were studied by a trained physician who interacted with a central supervisor as the management of syncope was concerned, using a decision-making software.. Prevalence of OH syncope was 12.4%. Patients with OH syncope were more likely to be affected by Parkinson's disease and by other neurological diseases. ST changes and longer values of QTc were found in OH syncope group, and they took a greater number of diuretics, nitrates, and digoxin. In multivariate analysis, Parkinson's disease (p = .001) and use of nitrates (p = .001) and diuretics (p = .020) were independently related to OH syncope.. In patients older than 65 years, Parkinson's disease and neurological comorbidity are strictly related to OH syncope. Moreover, this study suggests the independent link between OH syncope and the use of vasoactive drugs, identifying the majority of cases as adverse drug reaction, a preventable risk factor for syncope and falls in the older population.

Topics: Accidental Falls; Aged; Aged, 80 and over; Digoxin; Diuretics; Electrocardiography; Emergency Service, Hospital; Female; Humans; Hypotension, Orthostatic; Italy; Male; Nitrates; Parkinson Disease; Practice Guidelines as Topic; Prevalence; Prospective Studies; Risk Factors; Syncope, Vasovagal

Catabolism of tryptophan and tyrosine in relation to the isoprenoid pathway was studied in neurological and psychiatric disorders. The concentration of trytophan, quinolinic acid, kynurenic acid, serotonin and 5-hydroxyindoleacetic acid was found to be higher in the plasma of patients with all these disorders; while that of tyrosine, dopamine, epinephrine and norepinephrine was lower. There was increase in free fatty acids and decrease in albumin (factors modulating tryptophan transport) in the plasma of these patients. Concentration of digoxin, a modulator of amino acid transport, and the activity of HMG CoA reductase, which synthesizes digoxin, were higher in these patients; while RBC membrane Na+-K+ ATPase activity showed a decrease. Concentration of plasma ubiquinone (part of which is synthesised from tyrosine) and magnesium was also lower in these patients. No morphine could be detected in the plasma of these patients except in MS. On the other hand, strychnine and nicotine were detectable. These results indicate hypercatabolism of tryptophan and hypocatabolism of tyrosine in these disorders, which could be a consequence of the modulating effect of hypothalamic digoxin on amino acid transport.

Topics: Adult; Biogenic Monoamines; Brain Diseases; Brain Neoplasms; Digoxin; Epilepsy, Generalized; Erythrocytes; Fatty Acids, Nonesterified; Female; Glioma; Glycine Agents; Humans; Hydroxymethylglutaryl CoA Reductases; Kynurenic Acid; Magnesium; Male; Microvascular Angina; Middle Aged; Morphine; Narcotics; Nicotine; Nicotinic Agonists; Parkinson Disease; Quinolinic Acid; Schizophrenia; Serum Albumin; Sodium-Potassium-Exchanging ATPase; Strychnine; Tryptophan; Tyrosine; Ubiquinone

Two substances which are products of the isoprenoid pathway, can participate in lipid peroxidation. One is digoxin, which by inhibiting membrane Na(+)-K+ ATPase, causes increase in intracellular Ca2+ and depletion of intracellular Mg2+, both effects contributing to increase in lipid peroxidation. Ubiquinone, another products of the pathway is a powerful membrane antioxidant and its deficiency can also result in defective electron transport and generation of reactive oxygen species. In view of this and also in the light of some preliminary reports on alteration in lipid peroxidation in neuropsychiatric disorders, a study was undertaken on the following aspects in some of these disorders (primary generalised epilepsy, schizophrenia, multiple sclerosis, Parkinson's disease and CNS glioma)--1) concentration of digoxin, ubiquinone, activity of HMG CoA reductase and RBC membrane Na(+)-K+ ATPase 2) activity of enzymes involved in free radical scavenging 3) parameters of lipid peroxidation and 4) antioxidant status. The result obtained indicates an increase in the concentration of digoxin and activity of HMG CoA reductase, decrease in ubiquinone levels and in the activity of membrane Na(+)-K+ ATPase. There is increased lipid peroxidation as evidenced from the increase in the concentration of MDA, conjugated dienes, hydroperoxides and NO with decreased antioxidant protection as indicated by decrease in ubiquinone, vit E and reduced glutathione in schizophrenia, Parkinson's disease and CNS glioma. The activity of enzymes involved in free radical scavenging like SOD, catalase, glutathione peroxidase and glutathione reductase is decreased in the above diseases. However, there is no evidence of any increase in lipid peroxidation in epilepsy or MS. The role of increased operation of the isoprenoid pathway as evidenced by alteration in the concentration of digoxin and ubiquinone in the generation of free radicals and protection against them in these disorders is discussed.

Topics: Central Nervous System Neoplasms; Digoxin; Epilepsy, Generalized; Free Radicals; Glioma; Humans; Lipid Peroxidation; Multiple Sclerosis; Nervous System Diseases; Parkinson Disease; Schizophrenia; Ubiquinone

Topics: Adult; Aged; Antidepressive Agents; Antiemetics; Digoxin; Dihydroxyphenylalanine; Diuretics; Drug Antagonism; Drug Synergism; Female; Guanethidine; Humans; Hypertension; Hypnotics and Sedatives; Hypoglycemic Agents; Hypotension; Male; Middle Aged; Nausea; Parkinson Disease; Pyridoxine; Time Factors