Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Presystemic elimination of levodopa (20 mg kg-1) has been studied in 5- to 104-week-old male Wistar rats. The gastrointestinal and hepatic contribution to the overall first-pass effect was estimated separately after the drug had been administered intravenously, orally and intraportally. The contribution of the gut to the overall first-pass effect of this drug was greater than that of the liver in any age-group of the rats. Both the overall and intestinal first-pass effects of levodopa were greatest in 11-week-old rats and relatively small in both young (between weeks 5 and 7) and aged (between weeks 52 and 104) rats. In contrast, the hepatic first-pass effect did not show any significant age-dependent change. Age-related change in the jejunal blood flow could not explain the unique age-dependence in the intestinal first-pass metabolism of levodopa. However, the present age-dependence in the oral systemic availability of this drug between adult (11 weeks) and aged (52 to 104 weeks) rats was found to be similar to the tendency that has been reported between normal adult subjects and aged patients with Parkinson's disease.
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PMID:Effect of age on gastrointestinal and hepatic first-pass effects of levodopa in rats. 288 98

Clinical studies suggest that gut disorders are common in Parkinson's disease, but the morphological basis is unknown. Depletion of dopamine-containing neurons in the central nervous system is a basic defect in Parkinson's disease. We compared colonic tissue from 11 patients with advanced Parkinson's disease, 17 with adenocarcinoma (normal tissue was studied), and five who underwent colectomy for severe constipation. Immunohistochemistry was used to stain myenteric and submucosal neurons for dopamine, tyrosine hydroxylase, and vasoactive intestinal polypeptide (VIP). Each class of neurons was quantified as a percentage of the total neuronal population stained for the marker protein gene product 9.5. Nine of the 11 Parkinson's disease patients had substantially fewer dopaminergic myenteric neurons than the other subjects (mean 0.4 [SE 0.2] vs 6.9 [2.3] in controls and 5.7 [2.0] in constipated subjects). There was very little difference between the groups in numbers of tyrosine-hydroxylase and VIP neurons. Two Parkinson's disease patients had similar distributions of all types of neurons, including dopaminergic myenteric neurons, to the controls. High-performance liquid chromatography showed lower levels of dopamine in the muscularis externa (but not mucosa) in four Parkinson's disease patients than in four controls (7.3 [5.1] vs 24.2 [4.6] nmol per g protein), but levels of dopamine metabolites were similar in the two groups. The identification of this defect of dopaminergic neurons in the enteric nervous system in Parkinson's disease may lead to better treatment of colorectal dysfunction in this disease.
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PMID:Dopaminergic defect of enteric nervous system in Parkinson's disease patients with chronic constipation. 756 69

GI motility changes little--if at all--with age in healthy patients. However, a variety of diseases, including diabetes and Parkinson's disease, may cause autonomic neuropathy that is manifest as a motility disorder in the GI tract. Autonomic neuropathy can cause dysmotility in the esophagus, stomach, and gut. Symptoms are often nonspecific, including difficulty in swallowing, nausea, vomiting, heartburn, indigestion, diarrhea, and constipation. Nonpharmacologic treatment includes management of underlying diseases, avoidance of anticholinergic medications, and dietary changes. Agents with prokinetic action are the therapy of choice when drug treatment is indicated.
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PMID:GI motility disorders: diagnostic workup and use of prokinetic therapy. 790 Nov 29

Patients with Parkinson's disease generally have a smooth clinical response from levodopa therapy for the first 3 to 5 years. Motor fluctuations later become noticeable and may ultimately give way to unpredictable responses to treatment. Mechanisms responsible for motor fluctuations are not fully understood, but can be separated into three groups: (1) central pharmacokinetics, or delivery of dopamine from the presynaptic to the postsynaptic receptor; (2) peripheral pharmacokinetics, or delivery of levodopa from an exogenous source to the brain; and (3) pharmacodynamics, or alterations in the interactions between dopamine and the striatal receptor. Changes in central pharmacokinetics caused by diminished presynaptic dopamine storage capacity probably account for early end-of-dose "wearing-off." As patients lose further storage capacity, peripheral levodopa pharmacokinetics may play an important role in the fluctuation response from erratic gastric emptying or variables that change gut-to-blood and blood-brain barrier transport. Finally, erratic motor responses (eg, the "on-off" phenomenon) in advanced Parkinson's disease may be caused in part by alterations at the striatal dopamine receptor.
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PMID:Basic mechanisms of motor fluctuations. 804 56

The "wearing-off" phenomenon is a clinically recognized adverse effect of long-term L-DOPA therapy in Parkinson's disease. Several causes of this phenomenon have been proposed, but no direct evidence has yet been obtained. The present study was therefore conducted to investigate the effects of long-term L-DOPA administration on the dopamine system. We examined in rats the time course of the levels of L-DOPA and its metabolites in the serum and striatum, the activities of tyrosine hydroxylase and catechol O-methyltransferase, and the D1 and D2 dopamine receptor bindings in the striatum until 12 h after the final dose on the 28th day of repeated oral L-DOPA administration, and compared the results with those after a single L-DOPA administration. The results revealed that long-term L-DOPA administration induced (1) acceleration of DOPA absorption at the gut and the blood-brain barrier, (2) reduction of dopamine retention in the striatum, and (3) loss of "supersensitive response" of dopamine receptors. "Supersensitive response" induced by single L-DOPA administration was preceded by the increase of D1 messenger RNA. We suggest that these changes after long-term L-DOPA administration are causes of the "wearing-off" phenomenon in Parkinson's disease.
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PMID:Repeated L-dopa administration reduces the ability of dopamine storage and abolishes the supersensitivity of dopamine receptors in the striatum of intact rat. 838 61

The artificial sweetener aspartame (NutraSweet) is hydrolyzed in the gut as phenylalanine (PA), a large neutral amino acid (LNAA). LNAAs compete with levodopa for uptake into the brain. To determine the effect of aspartame on levodopa-treated Parkinson's disease (PD) patients, we studied 18 PD patients with protein-sensitive motor fluctuations by administering in a double-blind and single-crossover design, on alternate days, aspartame (600 or 1,200 mg) and placebo. Every hour, we performed a motor examination and drew blood to estimate plasma LNAA, PA, and levodopa levels. Six-hundred mg of aspartame had no effect on plasma PA or motor status. Although 1,200 mg of aspartame significantly increased plasma PA, motor performance did not deteriorate. Aspartame consumption in amounts well in excess of what would be consumed by heavy users of aspartame-sweetened products has no adverse effect on PD patients.
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PMID:Aspartame use in Parkinson's disease. 845 Oct 9

Selegiline is a selective, irreversible inhibitor of MAO-B, used in the treatment of Parkinson's disease, either alone or as an adjunct to L-DOPA. The sole recommended dosing regimen is 5 mg given in the morning and at noon with breakfast and lunch. A pulsatile oral dosage form was developed to mimic the conventional tablet release from two oral administrations separated by 4 h, to permit once-daily dosing and increase compliance. The pharmacokinetics of the pulsatile delivery system was studied in six healthy male volunteers. The plasma concentration-time profile from the pulsatile system of selegiline and metabolites is dissimilar to that obtained from the 5 mg bid administration of the conventional tablet and cannot be considered to be bioequivalent. The initial pulse of the delivery system is rapidly absorbed but to a lesser extent than the conventional regimen; the second pulse exhibits absorption which is delayed and prolonged. The decrease in the selegiline concentration may be due to the less absorptive surface of the lower GI tract which is available to the second pulse. Another reason could be the disparity between the in vitro and in vivo release profiles from the second pulse. Compartmental analysis indicates that the ratio of formation-absorption rate constant for the selegiline to N-desmethylselegiline pathway decreases from 1.57 +/- 1.04 for the first pulse to 0.61 +/- 0.54 for the second pulse of the pulsatile delivery system, suggesting that the upper portion of the GI tract has a greater capacity to convert selegiline to N-desmethylselegiline than the lower GI tract. The lack of in vivo and in vitro correlation is most likely due to site specific absorption/metabolism. Regimen has been previously shown to be a significant factor in estimating the extent of selegiline and metabolite exposure following oral administration. The inequivalence of dosing regimens of the same total daily dose may ultimately be linked to the saturability of gut wall metabolism. This phenomenon may preclude the development of novel delivery systems designed to mimic the recommended dosing regimen of the conventional Eldepryl tablet.
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PMID:Pharmacokinetic evaluation of a selegiline pulsatile oral delivery system. 937 24

The gastrointestinal tract, and especially the esophagus, is frequently involved in neurological diseases; however, objective studies of gut motor function are few. We carried out an esophageal manometric study in 18 patients with various stages of Parkinson's disease (4 stage I, 4 stage II, 7 stage III, and 3 stage IV) to evaluate the function of the viscus in this disease. Clinical assessment showed that 61% complained of esophageal symptoms such as dysphagia, acid regurgitation, pyrosis, and noncardiac chest pain. Manometric abnormalities were documented also in 61% patients, and were represented by repetitive contractions, simultaneous contractions, reduced LES pressure, and high-amplitude contractions. However, only 33.3% of patients had both symptoms and manometric abnormalities. We conclude that esophageal motor abnormalities are frequent in Parkinson's disease, and may appear at an early stage of the disease.
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PMID:Esophageal manometric abnormalities in Parkinson's disease. 939 Dec 27

Abnormal postprandial cardiovascular responses such as postprandial hypotension (PPH) occur in primary autonomic failure and contribute significantly to morbidity. The extent and frequency of PPH and its relationship to the parkinsonian state in idiopathic Parkinson's disease (IPD) is unknown. By studying 20 patients with IPD (without autonomic failure) and 16 age-matched controls after both groups ingested a standard isocaloric balanced liquid meal, we have shown that supine PPH complicates IPD and is related to marked worsening of the parkinsonian state as measured by a cumulative score of tremor, rigidity, bradykinesia, posture, and gait. Furthermore, significant postural hypotension is unmasked that results in postural intolerance due to presyncopal symptoms. Our study indicates that, in patients with IPD, ingestion of a meal may lead to abnormal postprandial cardiovascular responses and aggravation of the parkinsonian stage. The underlying mechanisms are unclear, although vasodilatory gut peptides released in response to food ingestion may be contributory.
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PMID:Postprandial hypotension and parkinsonian state in Parkinson's disease. 939 10

We have come to understand apoptosis as not merely a single form of cell death, but as a fundamental theme in cell biology that has far-reaching implications in the fields of physiology and pathology. At the present time, however, the mechanism of apoptosis is not clearly understood, as research into apoptosis is still at the initial stages. Nevertheless, the links between apoptosis and a variety of pathological conditions are gradually becoming clearer. In this article, we will provide a simple explanation of apoptosis and its mechanism as a novel concept of cell death and discuss the way in which apoptosis has been linked to a variety of pathological conditions. WHAT IS APOPTOSIS?: In normal tissue, cells that are no longer needed are rapidly eliminated without affecting the overall function of the tissue. In this process cells undergo an active and spontaneous suicide called programmed cell death. In fact, the majority of physiological cell deaths take the form of apoptosis. The word apoptosis is used, in contrast to necrosis, to describe the situation in which a cell actively pursues a course toward death upon receiving certain stimuli [1]. The morphological changes of apoptosis found in most cell types first involve contraction in cell volume and condensation of the nucleus. When this happens the intracellular organelles such as the mitochondria retain their normal morphology. As apoptosis proceeds, blebbing of the plasma membrane occurs, and the nucleus becomes fragmented. Finally, the cell itself fragments to form apoptotic bodies that are engulfed by nearby phagocytes. With respect to biochemical changes, it is known that the chromosomes become fragmented into nucleosome units, and DNA forms characteristic ladder patterns when subjected to agarose gel electrophoresis. MECHANISM OF APOPTOSIS: It has been reported that apoptosis is induced in various cells by many kinds of irritations, but the precise mechanism is still unclear. Cell injuries that induce apoptosis include those that cause DNA damage such as radiation and anticancer drugs, those that are mediated by the TNF receptor and Fas receptor (the so-called "death signal receptors"), and the deprivation of cytokines that supply survival signals such as IL-3 and erythropoietin. The tumor suppressor gene p53 plays a very important role in apoptosis induced by damage to DNA. This has been demonstrated by studying resistance to apoptosis of cells derived from p53 knockout mice [2]. Other than the irritations that induce apoptosis, molecules that have been strongly implicated as major players in the drama of apoptosis include the Bcl-2 family proteins and the IL-1 converting enzyme (ICE) and its homolog proteases (caspase family). Both groups of proteins show homology with proteins that affect cell death in nematodes. It is believed that molecules that contribute to cell death have been well conserved in multicellular organisms all the way from the relatively primitive nematodes to mammals including humans. It was discovered that Bcl-2 suppressed apoptosis induced in IL-3 dependent cells by deprivation of IL-3 [3]. It has since become the gene around which apoptosis research revolves. Recently, it has become clear that cell death involving the Bcl-2 protein is under the control of similar proteins from the same family [4]. It is interesting that the phenomenon of cell death may be regulated by the balance of the molecules involved in it. APOPTOSIS ABNORMALITIES AND DISEASE: Physiological cell death plays a major role in the growth and permanent maintenance of the human body [5]. In the process of forming the nervous system, neurons that do not form proper connections die. Physiological cell death also accompanies the removal of virus-infected cells by cytotoxic T cells, the elimination of autoreactive immune cells, the formation of the gut, the reconstitution of cartilage and bone, etc. When physiological cell death that normally should occur is inhibited, inappropriate physiological cell death may occur that is harmful to the body and forms the basis of disease. For example, in patients with neural degenerative disorders such as Alzheimer's disease and Parkinson's disease, we can find premature cell death in a particular subset of neurons. The death of T cells in AIDS patients is also a form of physiological cell death. Inhibition of cell death in the immune system enables the survival of autoreactive B cells and T cells, and is therefore a cause of autoimmune disorders. Apoptosis has been particularly linked to cancer. Normal cells are programmed for death if they are subjected to many types of non-physiological stress such as anticancer drugs or radiation, if they become isolated from surrounding cells and are unable to receive their tissue-specific survival signals [6], or if oncogenes are expressed haphazardly [7]. On the other hand, it is believed that the ability to survive is enhanced in transformed cancer cells because they are more resistant to apoptosis, they exhibit resistance to anticancer drugs, they are no longer dependent on survival signals, and they can metastasize. Therefore, the cancer progresses as the cancer cells maintain the proliferative superiority they acquire from their oncogenes. In other words, when cancer cells become resistant to apoptosis, they become resistant to treatment, metastasize, and proliferate destructively. The concept that the malignancy of cancer is due to its resistance to apoptosis is a relatively new one and is worthy of further study.
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PMID:Physician Education: Apoptosis. 1038 21


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