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)

Apomorphine (APO) is considered to be a classical mixed type dopamine D(1) and D(2) receptor agonist. It has been used in the therapy of Parkinson's disease and, more recently, for the treatment of erectile dysfunction. Like other catechols (e.g. dopamine), APO easily autoxidizes, producing quinone and semiquinone derivatives that may lead to the formation of reactive oxygen species and induce neurotoxicity. We assayed mutagenicity, antimutagenicity, and cytotoxicity of these compounds by means of the Salmonella/microsome assay, WP2 Mutoxitest and sensitivity assay in Saccharomyces cerevisiae yeast strains lacking antioxidant defenses. In the absence of S9 mix both compounds Apomorphine and its oxidation derivative, 8-oxo-apomorphine-semiquinone (8-OASQ), both at doses ranging from 20 to 80 microg per plate, induced frameshift mutations in TA98 and TA97 S. typhimurium strains, with 8-OASQ being up to two times more mutagenic. However, for strains which detect oxidative mutagens, 8-OASQ acted as a mutagen while APO was an antimutagen, inhibiting H(2)O(2) and t-BOOH-induced mutagenicity in TA102 S. typhimurium and WP2-derived E. coli strains. The S9 mix inhibited all mutagenic effects, probably either by conjugation of APO and 8-OASQ to proteins or by quenching reactive oxygen species. In sensitivity assays with S. cerevisiae, APO was only clearly cytotoxic to some strains at higher doses (200 and 400 microg/ml), whereas 8-OASQ dose-dependently sensitized all the strains, mainly the mutants lacking catalase (deltactt1), superoxide dismutase (deltasod1) and Yap1 transcription factor (deltayap1), suggesting that 8-OASQ cytotoxicity towards S. cerevisiae results from its pro-oxidant properties. APO also tended to protect S. cerevisiae strains against oxidative damage induced by high concentrations of H(2)O(2) and t-BOOH, while 8-OASQ enhanced pro-oxidant effects and induced adaptation responses to these agents. These results suggest that the 8-OASQ oxidation product of APO might induce cytotoxic and genotoxic effects.
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PMID:Differential mutagenic, antimutagenic and cytotoxic responses induced by apomorphine and its oxidation product, 8-oxo-apomorphine-semiquinone, in bacteria and yeast. 1294 12

A questionnaire investigating bladder problems, symptoms of autonomic dysfunction, social handicap and depression was mailed to a sample of patients with Parkinson's disease (PD) and to elderly control subjects without PD. The patients reported two-fold greater risk of bladder problems and four-fold risk of autonomic problems compared to the controls. Erectile dysfunction was nearly twice as frequent in patients compared to controls. Depressive symptoms in the PD group were predictive of bladder problems and autonomic impairment and also poorer social functioning and dependency in activities of daily living. No associations between bladder and autonomic dysfunction, age, or severity/duration of PD were found. This investigation shows that the risk of bladder, autonomic and erectile dysfunction is significantly greater in patients with PD compared to a control group.
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PMID:The risk of bladder and autonomic dysfunction in a community cohort of Parkinson's disease patients and normal controls. 1464 95

1. The relative roles of various members of the human sulfotransferase (SULT) enzyme family in the metabolism of apomorphine, a dopamine receptor antagonist used in the treatment of Parkinson's disease and, more recently, erectile dysfunction, were examined. In humans, sulfation is the major route of metabolism of this drug. 2. Using recombinant SULTs expressed in Escherichia coli, R(--)-apomorphine sulfation was studied using the universal barium precipitation assay in the presence of [35S] 3'-phosphoadenosine 5'-phosphosulfate and SULTs 1A1, 1A2, 1A3, 1B1, 1C2, 1E1 and 2A1. It was shown that SULTs 1A1, 1A2, 1A3 and 1E1 all sulfated apomorphine to varying extents. Low activity with SULT1B1 was only seen at the highest concentration (100 microM) and no activity with SULT1C2 or SULT2A1 was observed. 3. Kinetic analysis using purified recombinant SULTs showed that 1A1, 1A3 and 1E1 all had similar Vmax/Km values, although SULT1E1 had a slightly lower Km at around 1 microM compared with approximately 4 microM for the other SULTs. 4. By correlating apomorphine sulfation (at 10 microM) in a bank of 28 liver cytosols with SULT activity towards 10 microM 4-nitrophenol (SULT1A1) and 0.2 microM 17beta-oestradiol (SULT1E1), a strong correlation with SULT1A1 activity was clearly demonstrated, suggesting this enzyme was primarily responsible for hepatic apomorphine sulfation. 5. These findings were confirmed using immuno-inhibition experiments with antibodies against SULT1A and SULT1E1, which showed preferential inhibition of apomorphine sulfation in human liver cytosol by anti-SULT1A. 6. The results strongly implicate SULT1A1 as the major enzyme responsible for hepatic apomorphine metabolism. As SULT1A1 is subject to a common functional polymorphism, sulfation phenotype may be an important determinant of susceptibility to side-effects of apomorphine and/or efficacy of treatment.
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PMID:Sulfation of apomorphine by human sulfotransferases: evidence of a major role for the polymorphic phenol sulfotransferase, SULT1A1. 1466 Jan 77

Sexual dysfunction is common in Parkinson's disease (PD). We investigated the premorbid and present sexual functioning of 75 people with PD (32 women and 43 men). Women reported difficulties with arousal (87.5%), with reaching orgasm (75.0%), with low sexual desire (46.9%), and wih sexual dissatisfaction (37.5%). Men reported erectile dysfunction (68.4%), sexual dissatisfaction (65.1%), premature ejaculation (40.6%), and difficulties reaching orgasm (39.5%). Premorbid sexual dysfunction may contribute to cessation of sexual activity during the course of the disease (among 23.3% men and 21.9% women). Associated illnesses, use of medications, and advanced stage of PD contributed to sexual dysfunction.
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PMID:Sexual dysfunction in Parkinson's disease. 1474 99

GPI-1485 is a neuroimmunophilin ligand that binds to FK-506-binding proteins and is under development by Guilford for the potential treatment of erectile dysfunction following nerve injury during prostate resection and Parkinson's disease. In August 2002, phase II clinical trials investigating GPI-1485 for Parkinson's disease commenced, and in November 2003, further phase II trials commenced for post-prostatectomy erectile dysfunction.
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PMID:GPI-1485 (Guilford). 1498 83

Neuroimmunophilin ligands (NILs) are drugs derived from the immunosuppressant FK506 (tacrolimus) that have been shown to have variable efficacy in reversing neuronal degeneration and preventing cell death. In a wide range of animal models mimicking Parkinson's disease, dementia and even surgical nerve damage they induce re-sprouting, are neurotrophic or prevent nerve damage. The neurotrophic mechanism of action of these compounds is not known and may be dependent on the type of damage and genetic variability at the species or cellular level. Some evidence suggests that NILs may act through a family of proteins called FK506 binding proteins, some of which may regulate steroid hormone receptors. Other evidence suggests that NILs may protect neurons by upregulating the antioxidant glutathione and stimulating nerve regrowth by inducing the production of neurotrophic factors. Initial clinical trials have had mixed success. In one, patients with moderately severe Parkinson's disease showed no overall improvement in fine motor skills following 6 months of treatment by the neuroimmunophilin GPI 1485. But these patients did exhibit decreased loss of dopaminergic nerve terminals with a low dose of GPI 1485 and in fact some increase in dopaminergic terminals within 6 months of the higher dose of GPI 1485 drug treatment. As a result, a second phase II clinical trial using a patient population with less severe degeneration has been initiated concurrent with an investigation of GPI 1485 and other neuroprotective therapies funded by the National Institute of Neurological Disorders and Stroke. Another clinical trial ongoing at this time is exploring the use of a neuroimmunophilin ligand to prevent nerve degeneration and erectile dysfunction resulting from prostatectomy. In summary, neuroimmunophilins show promise to reverse some forms of neurodegeneration but exact factors that predict outcome have not been identified.
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PMID:Neuroimmunophilins: a novel drug therapy for the reversal of neurodegenerative disease? 1545 Mar 48

Frequency and clinical importance of autonomic failure in idiopathic Parkinson's disease (PD) are discussed controversially. 141 patients with PD and 50 healthy age-matched control subjects were interviewed for symptoms of autonomic failure and their influence on daily life using a questionnaire. In PD patients, the prevalence of orthostatic dizziness, bladder dysfunction, erectile dysfunction and hyperhidrosis was significantly higher compared with controls. About 50% of PD patients rated the impact of the symptoms of autonomic failure on their daily lives as "a lot" or "very much" due to orthostatic dizziness, bladder dysfunction and constipation, which were more statistically significant than in age-matched controls. Prevalence and number of autonomic symptoms were not correlated with duration and severity of PD. In 32% of patients, impaired cardiovascular regulation was found by standardized cardiovascular function tests. If testing showed abnormal findings, orthostatic dizziness, bladder dysfunction, constipation and erectile dysfunction were significantly more frequent than in patients with normal regulation, but the impact on daily life due to these symptoms differed significantly only for bladder dysfunction between groups. It is concluded that autonomic failure is a clinically relevant, pervasive problem in PD and compromise patients' daily life activities in all stages of the disease. This underlines the necessity to adequately search for and treat these non-dopaminergic symptoms during the whole course of the disease.
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PMID:Symptoms of autonomic failure in Parkinson's disease: prevalence and impact on daily life. 1583 63

Physical organic causes are now thought to account for most cases of erectile dysfunction (ED), although there is often a psychogenic contribution to the condition. Atherosclerotic disease is estimated to account for 40% of ED in men over 50 years, and vascular disease, including diabetes, is a common cause of ED. ED may be considered an early marker for cardiovascular disease. Ageing is a strong risk factor, and both psychological conditions such as anxiety and depression and neurological conditions such as Parkinson's disease are also common risk factors. Pelvic surgery, with which there is a risk of nerve damage, may also result in ED. Other causes include endocrine disorders, and interactions from prescribed drugs such as antihypertensives, antidepressants, antipsychotics, hormone treatments, and histamine H2 antagonists such as cimetidine. Anatomical features and anatomical conditions such as Peyronie's disease are a less common cause of ED.
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PMID:The underlying pathophysiology and causes of erectile dysfunction. 1615 20

Female sexual dysfunction (FSD) is a multifactorial set of conditions associated with multiple anatomical, physiological, biological, medical and psychological factors that can have major impact on self-esteem, quality of life, mood and relationships. Studies indicate that FSD is commonly seen in women who report a low level of satisfaction with partner relationship and in women with male partners who have erectile dysfunction. This complexity of FSD is augmented by the presence of chronic disease. Negative sexual effects are widely reported in studies of women with chronic diseases (such as metabolic syndrome, diabetes mellitus, chronic kidney disease, cancer, spinal cord injury, lupus, rheumatic diseases, Parkinson's disease, fibromyalgia and chronic pain) as compared to a general healthy female population. Physical problems, emotional problems and partnership difficulties arising from disease-related stress contribute to less active and less enjoyable sex life. Chronic pain, fatigue, low self-esteem as well as use of medications might reduce sexual function. These effects of chronic diseases on female sexual function still remain largely unstudied. The study by Manor and Zohar published in this issue of Harefuah draws our attention to the sexual dysfunction of women with breast cancer and examines their needs for information regarding their sexual function. In the absence of definite treatment evidence, psychological counseling, improved vaginal lubrication, low dose of hormonal therapy can be used to relieve FSD. Physicians must consider integrating diagnosis of their female patients' sexual needs and dysfunction, especially women with chronic diseases. Patients' education and counseling may contribute to a better quality of life in spite of their chronic disease.
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PMID:[Female sexual function and chronic disease]. 1650 15

Sildenafil, a phosphodiesterase-5 inhibitor is widely used for the treatment of erectile dysfunction. Recently, the FDA approved the use of sildenafil in the therapeutic treatment of pulmonary arterial hypertension. Sildenafil crosses the blood-brain barrier and has been shown to enhance memory. Tremor, rigidity and akinesia are the most common symptoms seen in Parkinson's disease. Fatigue and sexual dysfunction are the other prominent features seen in Parkinson's disease. Interestingly, sildenafil is used therapeutically to treat sexual dysfunction in Parkinson's disease patients. Currently research on Parkinson's disease focuses on developing novel drug therapies for retarding the nigral dopaminergic neurodegeneration. Hence, we investigated the anti-fatigue and neuroprotective effects of sildenafil. In this study, the effect of sildenafil on fatigue was evaluated using forced swim test in mice. Sildenafil had no effect on fatigue as seen by the swim time. With regard to neuroprotective effects, we investigated the effects of sildenafil using two animal models of Parkinson's disease. In this study, 6-hydroxydopamine-lesioned (unilateral) rats and MPTP-treated mice were used as the animal models of Parkinson's disease. 6-Hydroxydopamine-lesioned rats were used to determine the effect of sildenafil on rotational behavior. Ipsilateral or contralateral rotational behavior can indicate the amphetamine-like activity or apomorphine-like activity of sildenafil. Sildenafil did not induce contralateral or ipsilateral rotations in 6-hydroxydopamine-lesioned rats. Sildenafil did not protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion in the striatum.
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PMID:Evaluation of neuroprotective and anti-fatigue effects of sildenafil. 1782 48


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