UMLS:C0040822 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ethanol is metabolized in the brain by catalase/H2O2 to yield acetaldehyde and by an ethanol-inducible form of cytochrome P450 (P450 IIE1) in a reaction that yields oxygen radicals. Within the cytoplasm of serotonergic axon terminals these metabolic pathways together provide conditions for the endogenous synthesis of 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline (1), by reaction of acetaldehyde with unbound 5-hydroxytryptamine (5-HT), and for the oxygen radical-mediated oxidation of this alkaloid. The major initial product of the hydroxyl radical (HO.)-mediated oxidation of 1 in the presence of free glutathione (GSH), a constituent of nerve terminals and axons, is 8-S-glutathionyl-1-methyl-1,2,3,4-tetrahydro-beta-carboline-5,6-dione (6). When administered into the brains of mice, 6 is a potent toxin (LD50 = 2.9 microg) and evokes episodes of hyperactivity and tremor. Compound 6 binds at the GABA(B) receptor and evokes elevated release and turnover of several neurotransmitters. Furthermore, the GABA(B) receptor antagonist phaclofen attenuates the behavioral response caused by intracerebral administration of 6. These observations suggest that 6 might be an inverse agonist at the GABA(B) receptor site. Accordingly, it is speculated that ethanol drinking might potentiate formation of 6 that contributes to elevated release of several neurotransmitters including dopamine (DA) and endogenous opioids in regions of the brain innervated by serotonergic axon terminals. Subsequent interactions of DA and opioids with their receptors might be related to the initial development of dependence on ethanol. Redox cycling of 6 (and of several putative secondary metabolites) in the presence of intraneuronal antioxidants and molecular oxygen to produce elevated fluxes of cytotoxic reduced oxygen species might contribute to the degeneration of serotonergic pathways. Low levels of 5-HT in certain brain regions of the rat predisposes these animals to drink or augments drinking. Accordingly, 6, formed as a result of ethanol metabolism in the cytoplasm of certain serotonergic axon terminals, might contribute to the initial development of dependence on ethanol, by mediating DA and opioid release, and long-term preference and addiction to the fluid as a result of the progressive degeneration of these neurons.
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PMID:Putative oxidative metabolites of 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline of potential relevance to the addictive and neurodegenerative consequences of ethanol abuse. 916 Jul 98

The present study reports on a 17-year-old male who ingested approximately 70 ml trichloroethene (TRI) in a suicide attempt. The patient developed fever, tremor, general motor restlessness, and sinus tachycardia and lost consciousness 5 h after poisoning. After 5 days of intubation under narcosis with forced hyperventilation and diuresis he regained consciousness. During this period blood and urine were collected and TRI and its metabolites were quantified. The highest concentration of TRI in blood was detected 13 h after ingestion. Trichloroethanol and trichloroacetic acid, metabolites of the cytochrome P450-mediated pathway, and N-acetyl-S-(1, 2-dichlorovinyl)-l-cysteine and N-acetyl-S-(2, 2-dichlorovinyl)-l-cysteine from the glutathione-dependent pathway of TRI were quantified in urine samples. Besides these known metabolites in humans, chloroacetic acid and dichloroacetic acid were identified for the first time in urine of a human exposed to TRI. Although the patient exhibited normal levels of glucose and total protein in urine, excretion of alpha1- and beta2-microglobulin as well as beta-NAG was significantly increased. In addition to these typical markers of selective tubule damage, analysis of the urinary protein pattern by SDS-PAGE revealed increased excretion of several low-molecular-mass proteins between 10,000 and 50,000 Da, clearly indicating tubular damage. Based on the elucidated glutathione-dependent mechanism for the nephrotoxicity of TRI, activation of the formed S-conjugates by beta-lyases to reactive intermediates may account for the observed renal effects after a single, high dose of TRI.
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PMID:Acute intoxication with trichloroethene: clinical symptoms, toxicokinetics, metabolism, and development of biochemical parameters for renal damage. 952 Mar 51

Tiagabine exerts its antiepileptic drug (AED) activity by selectively inhibiting the uptake of gamma-aminobutyric acid (GABA) onto the transporter molecules, and thus, increasing extracellular concentrations of GABA in the brain. The absorption and elimination of tiagabine follow linear pharmacokinetics. Tiagabine is metabolized by hepatic cytochrome P450 enzymes and enzyme-inducing AEDs increase tiagabine clearance by 50-65%. Tiagabine has shown no clinically important interactions with other drugs, including oral contraceptives. In the perforant pathway stimulation model of status epilepticus, tiagabine reduced the seizure number and severity, and also prevented the loss of pyramidal cells in the hippocampus as well as alleviated impairment of the spatial memory impairment associated with hippocampal damage. Tiagabine has both antiepileptogenic and anticonvulsant effects in the kindling model of epilepsy. Based on the data from the short- and long-term add-on studies, tiagabine is effective adjunctive therapy for all partial seizure types in adolescents and adults. Conversion to tiagabine monotherapy has been also possible in substantial amount of patients with partial seizures in three trials. Tiagabine is generally well-tolerated. The most common adverse events in controlled studies involve the central nervous system; for example, dizziness, asthenia, nervousness, tremor, depressed mood and emotional lability. Special safety analyses with formal neuropsychological testing suggest that tiagabine does not adversely affect cognition or mood. Tiagabine represents an important new therapeutic option for patients with treatment-refractory partial seizures. The role of tiagabine in the management of partial epilepsy of patients with intellectual disability is especially emphasized since tiagabine has a low side-effect profile in the cognitive area.
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PMID:Tiagabine: a new therapeutic option for people with intellectual disability and partial epilepsy. 1003 Apr 35

A meta-analysis of 20 short term comparative studies of 5 selective serotonin reuptake inhibitors (SSRIs; citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) has shown no difference in efficacy between individual compounds but a slower onset of action of fluoxetine. There were suggestions that fluoxetine caused more agitation, weight loss and dermatological reactions than the other SSRIs. More patients discontinued fluvoxamine and fewer patients stopped sertraline because of adverse effects than their comparator SSRIs. The most common adverse reactions to the SSRIs were gastrointestinal (especially nausea) and neuropsychiatric (particularly headache and tremor). Data from the Committee on Safety of Medicines showed more reports of suspected reactions (including discontinuation reactions) to paroxetine, and of gastrointestinal reactions to fluvoxamine and paroxetine, than the other SSRIs during their first 2 years of marketing. Prescription-event monitoring revealed a higher incidence of adverse events related to fluvoxamine than its comparators. There were higher incidences of gastrointestinal symptoms, malaise, sedation and tremor during treatment with fluvoxamine and of sedation, tremor, sweating, sexual dysfunction and discontinuation reactions with paroxetine. Fluoxetine was not associated with a higher incidence of suicidal, aggressive and related events than the other SSRIs. Patients have survived large overdoses of each of the compounds, but concern has been expressed over 6 fatalities following overdoses of citalopram. Drug interactions mediated by cytochrome P450 enzymes are theoretically less likely to occur during treatment with citalopram and sertraline, but there is a sparsity of clinical data to support this. Methodological difficulties and price changes do not allow choice for recommendations on the choice of SSRI based on pharmacoeconomic data. Taking into account the strengths and weaknesses of the methods used to compare drugs, guidelines to the selection of individual SSRIs in clinical practice are proposed. Citalopram should be avoided in patients likely to take overdoses. Fluoxetine may not be the drug of first choice for patients in whom a rapid antidepressant effect is important or for those who are agitated, but it may have advantages over other SSRIs in patients who are poorly compliant with treatment and those who have previously had troublesome discontinuation symptoms. Fluvoxamine, and possibly paroxetine, should not be used as first choice in patients especially prone to SSRI-related adverse reactions, while paroxetine should be avoided if previous discontinuation of treatment was troublesome. When in doubt about the risks of drug interactions, citalopram or sertraline should be considered given the lower theoretical risk of interactions.
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PMID:Systematic review and guide to selection of selective serotonin reuptake inhibitors. 1065 95

Theophylline toxicity has been recognized since its introduction into clinical medicine. Clarithromycin is a new oral macrolide antibiotic with excellent antibacterial activity and rare adverse effect. Patients with upper respiratory infection are often treated with theophylline and clarithromycin concurrently. We report a case of acute renal failure due to acute rhabdomyolysis caused by the interaction of theophylline and clarithromycin. A 72-year-old man visited our hospital because of coughing and a sore throat continuing for 1 week. He was diagnosed as having the common cold with a bronchial asthmatic symptom and was prescribed 200 mg/day of sustained-release theophylline for the treatment of asthma for 7 days. One week later, he visited our hospital again. Radiographic study of the chest revealed mild interstitial pneumonia and 200 mg/day of sustained-release theophylline and 400 mg/day of clarithromycin were administrated concomitantly. Five days after the second visit, the patient was admitted to our hospital because of generalized twitching, muscular weakness, high fever and serious general condition. He experienced generalized muscular twitching and tremor. Blood urea nitrogen was 106.1 mg/dl, serum creatinine was 7.4 mg/dl, serum creatinine kinase (CK) was 36,000 IU/l (normal 15-130 IU/l), CK isozyme revealed the following ratio: BB 0%, MB 1% and MM 99%. He was diagnosed as having acute renal failure with rhabdomyolysis caused by the interaction of theophylline and clarithromycin. Hemodialysis therapy was started. After 5 weeks, his serum creatinine was markedly decreased. It is well-known that clarithromycin enhances the serum concentration of theophylline by inhibition of the cytochrome P450-dependent pathway in hepatocytes. Theophylline toxicity may be enhanced when clarithromycin is administrated concomitantly, especially to elderly patients with dehydration.
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PMID:[A case of acute renal failure with rhabdomyolysis caused by the interaction of theophylline and clarithromycin]. 1044 97

Conditions for the optimal expression of the human CYP1B1 hemoprotein in Escherichia coli have been investigated. CYP1B1 cDNA was prepared from a retinal cDNA template and used to generate cDNA fragments with modified 5'-sequences reported to allow enhanced expression in E. coli DH5alpha. Plasmids were constructed, using the pCWori+ expression vector and were used to examine necessity for thiamine, delta-aminolevulinic acid (ALA), and IPTG. The optimal shaking speed in an orbital incubator was 150 rpm at 30 degrees C. Higher speeds resulted in increased cell death and lower speeds resulted in lower expression of cytochrome P450. IPTG was necessary for this expression system, which makes use of the lac repressor, but levels above 0.5 mM were without additional benefit. We were able to show thiamine to be unnecessary in this expression system, although included by others expressing CYP1B1. ALA has been reported to enhance expression of several different forms of cytochrome P450. We examined the dependence of CYP1B1 expression on ALA. The expression proved to be highly dependent upon this heme precursor, with levels of CYP1B1 increasing approximately 20-fold, to 920 nmol/l in the presence of up to 2.5 mM ALA. The question of whether heme synthesis and apoprotein synthesis were coupled was then investigated. It could be shown that although heme synthesis was not limiting (CYP101 holoenzyme expression in the absence of ALA was four times higher than the ALA-supported CYP1B1 holoenzyme expression), it was necessary for optimal expression of CYP1B1. CYP1B1 protein synthesis appears to be coupled to heme precursor availability, as seen by SDS-PAGE, because in the absence of heme precursor apocytochrome P450 1B1 does not accumulate.
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PMID:Enhanced expression of CYP1B1 in Escherichia coli. 1078 90

The investigational anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA) was developed by the Auckland Cancer Society Research Centre (ACSRC). It has recently completed Phase I trials in New Zealand and UK under the direction of the Cancer Research Campaign's Phase I/II Clinical Trials Committee. As a biological response modifier, pharmacological and toxicological properties of DMXAA are remarkably different from most conventional chemotherapeutic agents. Induction of cytokines (particularly tumour necrosis factor (TNF-alpha), serotonin and nitric oxide (NO)), anti-vascular and anti-angiogenic effects are considered to be major mechanisms of action based on in vitro and animal studies. In cancer patients of Phase I study, DMXAA also exhibited various biological effects, including induction of TNF-alpha, serotonin and NO, which are consistent with those effects observed in in vitro and animal studies. Preclinical studies indicated that DMXAA had more potent anti-tumour activity compared to flavone-8-acetic acid (FAA). In contrast to FAA that did not show anti-tumour activity in cancer patients, DMXAA (22 mg/kg by intravenous infusion over 20 min) resulted in partial response in one patient with metastatic cervical squamous carcinoma in a Phase I study where 65 cancer patients were enrolled in New Zealand. The maximum tolerated dose (MTD) in mouse, rabbit, rat and human was 30, 99, 330, and 99 mg/kg respectively. The dose-limiting toxicity of DMXAA in cancer patients included acute reversible tremor, cognitive impairment, visual disturbance, dyspnoea and anxiety. The plasma protein binding and distribution into blood cells of DMXAA are dependent on species and drug concentration. DMXAA is extensively metabolised, mainly by glucuronidation of its acetic acid side chain and 6-methylhydroxylation, giving rise to DMXAA acyl glucuronide (DMXAA-G), and 6-hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA), which are excreted into bile and urine. DMXAA-G has been shown to be chemically reactive, undergoing hydrolysis, intramolecular migration and covalent binding. Studies have indicated that DMXAA glucuronidation is catalysed by uridine diphosphate glucuronosyltransferases (UGT1A9 and UGT2B7), and 6-methylhydroxylation by cytochrome P450 (CYP1A2). Non-linear plasma pharmacokinetics of DMXAA has been observed in animals and patients, presumably due to saturation of the elimination process and plasma protein binding. Species differences in DMXAA plasma pharmacokinetics have been observed, with the rabbit having the greatest plasma clearance, followed by the human, rat and mouse. In vivo disposition studies in these species did not provide an explanation for the differences in MTD. Co-administration of DMXAA with other drugs has been shown to result in enhanced anti-tumour activity and alterations in pharmacokinetics, as reported for the combination of DMXAA with melphalan, thalidomide, cyproheptadine, and the bioreductive agent tirapazamine, in mouse models. Species-dependent DMXAA-thalidomide pharmacokinetic interactions have been observed. Co-administration of thalidomide significantly increased the plasma area of the plasma concentration-time curve (AUC) of DMXAA in mice, but had no effect on DMXAA's pharmacokinetics in the rat. It appears that the pharmacological and toxicological properties of DMXAA as a new biological response modifier are unlikely to be predicted based on preclinical studies. Similar to many biological response modifiers, DMXAA alone did not show striking anti-tumour activity in patients. However, preclinical studies of DMXAA-drug combinations indicate that DMXAA may have a potential role in cancer treatment when co-administered with other drugs. Further studies are required to explore the molecular targets of DMXAA and mechanisms for the interactions with other drugs co-administered during combination treatment, which may allow for the optimisation of DMXAA-based chemotherapy.
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PMID:5,6-dimethylxanthenone-4-acetic acid (DMXAA): a new biological response modifier for cancer therapy. 1220 91

Thirty-five years since its introduction into clinical use, valproate (valproic acid) has become the most widely prescribed antiepileptic drug (AED) worldwide. Its pharmacological effects involve a variety of mechanisms, including increased gamma-aminobutyric acid (GABA)-ergic transmission, reduced release and/or effects of excitatory amino acids, blockade of voltage-gated sodium channels and modulation of dopaminergic and serotoninergic transmission. Valproate is available in different dosage forms for parenteral and oral use. All available oral formulations are almost completely bioavailable, but they differ in dissolution characteristics and absorption rates. In particular, sustained-release formulations are available that minimise fluctuations in serum drug concentrations during a dosing interval and can therefore be given once or twice daily. Valproic acid is about 90% bound to plasma proteins, and the degree of binding decreases with increasing drug concentration within the clinically occurring range. Valproic acid is extensively metabolised by microsomal glucuronide conjugation, mitochondrial beta-oxidation and cytochrome P450-dependent omega-, (omega-1)- and (omega-2)-oxidation. The elimination half-life is in the order of 9 to 18 hours, but shorter values (5 to 12 hours) are observed in patients comedicated with enzyme-inducing agents such as phenytoin, carbamazepine and barbiturates. Valproate itself is devoid of enzyme-inducing properties, but it has the potential of inhibiting drug metabolism and can increase by this mechanism the plasma concentrations of certain coadministered drugs, including phenobarbital (phenobarbitone), lamotrigine and zidovudine. Valproate is a broad spectrum AED, being effective against all seizure types. In patients with newly diagnosed partial seizures (with or without secondary generalisation) and/or primarily generalised tonic-clonic seizures, the efficacy of valproate is comparable to that of phenytoin, carbamazepine and phenobarbital, although in most comparative trials the tolerability of phenobarbital was inferior to that of the other drugs. Valproate is generally regarded as a first-choice agent for most forms of idiopathic and symptomatic generalised epilepsies. Many of these syndromes are associated with multiple seizure types, including tonic-clonic, myoclonic and absence seizures, and prescription of a broad-spectrum drug such as valproate has clear advantages in this situation. A number of reports have also suggested that intravenous valproate could be of value in the treatment of convulsive and nonconvulsive status epilepticus, but further studies are required to establish in more detail the role of the drug in this indication. The most commonly reported adverse effects of valproate include gastrointestinal disturbances, tremor and bodyweight gain. Other notable adverse effects include encephalopathy symptoms (at times associated with hyperammonaemia), platelet disorders, pancreatitis, liver toxicity (with an overall incidence of 1 in 20,000, but a frequency as high as 1 in 600 or 1 in 800 in high-risk groups such as infants below 2 years of age receiving anticonvulsant polytherapy) and teratogenicity, including a 1 to 3% risk of neural tube defects. Some studies have also suggested that menstrual disorders and certain clinical, ultrasound or endocrine manifestations of reproductive system disorders, including polycystic ovary syndrome, may be more common in women treated with valproate than in those treated with other AEDs. However, the precise relevance of the latter findings remains to be evaluated in large, prospective, randomised studies.
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PMID:Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. 1226 62

A 52 year old woman on buspirone was prescribed paroxetine for depressive symptoms. She also got papaverine. Within a month she experienced high fever, shivering, tremor, hyper-reflexia, tachycardia (120 bpm), and tracheal cramps, symptoms of the serotonin syndrome. Since both paroxetine and buspirone have serotonergic effects it is probable that the symptoms were caused by the drug combination. She also had ecchymoses on her thighs, probably due to serotonergic effects. The symptoms rapidly decreased after withdrawing paroxetine. Paroxetine, papaverine, and possibly also buspirone interact with cytochrome P450 CYP2D6. They can probably inhibit the metabolism of each other. We recommend observance of serotonergic syndrome symptoms and restricted combination of serotoninergic drugs.
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PMID:[Combination of serotonergic agents resulted in severe adverse effects]. 1518 39

Numerous studies indicate that opioid tolerance involves a disruption in Ca2+ homeostasis. In vivo studies have indicated the involvement of dihydropyridine-sensitive (L-type) voltage-gated channels in morphine abuse. In this study, the effect of multiple administration of the dihydropyridine calcium channel blocker nifedipine (5 mg/kg/twice daily), given in combination with morphine, on the signs of morphine withdrawal and some biochemical parameters were assessed. Multiple morphine administration in increasing doses (from 5 to 40 mg/kg for 7 days) and consequent withdrawal after 18 h, induced writhing, squealing, diarrhea, teeth chattering, eyelid ptosis and wet-dog type shaking. Coadministration of nifedipine prevented the squealing, diarrhea and teeth chattering. On a biochemical level, the activity of brain nitric oxide synthase (NOS) and the quantity of cytochrome P450 in rat brain and liver were measured. Nifedipine treatment decreased the brain nNOS activity, induced by multiple administration of morphine. The quantity of liver cytochrome P450, after multiple coadministration of morphine and nifedipine, was also increased. The quantity of brain cytochrome P450 was not significantly changed by morphine and nifedipine alone or in combination. The results of our study suggest that nifedipine influences the effects of morphine both at a pharmacokinetic and a pharmacodynamic level.
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PMID:Effects of nifedipine on behavioral and biochemical parameters in rats after multiple morphine administration. 1560 24

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