The pathophysiology of sudden unexpected death in epilepsy (SUDEP) is uncertain, with ictal or peri-ictal cardiorespiratory compromise appearing probable. Risk factors for SUDEP include multiple antiepileptic drugs (AED), poor compliance, and abrupt AED withdrawal. The spectral analysis of the beat-to-beat heart rate variability (HRV) displays two main components: low frequency (LF), representing sympathetic and parasympathetic influence and high frequency (HF), representing parasympathetic influence. The LF/HF ratio is commonly regarded as an indicator of sympathovagal balance.
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Comparison of the costs of treatment of CBZ induced SJS/TEN and costs of HLA-B*1502 screening test. Results When persons having the HLA-B*1502 allele receive CBZ, the chance of developing SJS/TEN is as high as 88.1 %, while persons without the HLA-B*1502 allele do not develop SJS/TEN. Therefore, a model was calculated to compare the cost of treatment between HLA-B*1502 testing before giving CBZ and if the patients were not tested for HLAB*1502. It was found that screening 100 patients before giving CBZ would save an amount of 98,549.94 baht per 100 cases of CBZ-prescribed patients.
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Geochemical and microbiological techniques were used to assess water-quality impacts from the land application of treated municipal wastewater in the karstic Wakulla Springs basin in northern Florida. Nitrate-N concentrations have increased from about 0.2 to as high as 1.1 mg/L (milligrams per liter) during the past 30 years in Wakulla Springs, a regional discharge point for groundwater (mean flow about 11.3 m(3)/s) from the Upper Floridan aquifer (UFA). A major source of nitrate to the UFA is the approximately 64 million L/d (liters per day) of treated municipal wastewater applied at a 774 ha (hectare) sprayfield farming operation. About 260 chemical and microbiological indicators were analyzed in water samples from the sprayfield effluent reservoir, wells upgradient from the sprayfield, and from 21 downgradient wells and springs to assess the movement of contaminants into the UFA. Concentrations of nitrate-N, boron, chloride, were elevated in water samples from the sprayfield effluent reservoir and in monitoring wells at the sprayfield boundary. Mixing of sprayfield effluent water was indicated by a systematic decrease in concentrations of these constituents with distance downgradient from the sprayfield, with about a 10-fold dilution at Wakulla Springs, about 15 km (kilometers) downgradient from the sprayfield. Groundwater with elevated chloride and boron concentrations in wells downgradient from the sprayfield and in Wakulla Springs had similar nitrate isotopic signatures, whereas the nitrate isotopic composition of water from other sites was consistent with inorganic fertilizers or denitrification. The sprayfield operation was highly effective in removing most studied organic wastewater and pharmaceutical compounds and microbial indicators. Carbamazepine (an anti-convulsant drug) was the only pharmaceutical compound detected in groundwater from two sprayfield monitoring wells (1-2 ppt). One other detection of carbamazepine was found in a distant well water sample where enteroviruses also were detected, indicating a likely influence from a nearby septic tank.
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The aim of this paper is to describe a case of musical hallucinations with temporal lobe abnormalities responding to carbamazepine treatment.
Prescription and nonprescription drugs have been detected in rivers and streams in Europe and the United States. Sewage treatment plants (STPs) are an important source of these contaminants, but few data exist on the spatial distribution of drugs in surface waters near STPs. Samples of surface water were collected in the summer and fall of 2000 at open-water sites in the lower Great Lakes (Lake Ontario and Lake Erie), at sites near the two STPs for the city of Windsor (ON, Canada), and at sites in Hamilton Harbour (ON, Canada), an embayment of western Lake Ontario that receives discharges from several STPs. In a follow-up study in the summer of 2002, samples of surface water and final effluent from adjacent STPs were collected from sites in Hamilton Harbour and Windsor. In addition, surface water and STP effluent samples were collected in Peterborough (ON, Canada). All samples of surface water and STP effluents were analyzed for selected acidic and neutral drugs. In the survey of Hamilton Harbour and Windsor conducted in 2000, acidic drugs and the antiepileptic drug carbamazepine were detected at ng/L concentrations at sites that were up to 500 m away from the STP, but the hydrological conditions of the receiving waters strongly influenced the spatial distribution of these compounds. Drugs were not detected at open-water locations in western Lake Erie or in the Niagara River near the municipality of Niagara-on-the-Lake (ON, Canada). However, clofibric acid, ketoprofen, fenoprofen, and carbamazepine were detected in samples collected in the summer of 2000 at sites in Lake Ontario and at a site in the Niagara River (Fort Erie, ON, Canada) that were relatively remote from STP discharges. Follow-up studies in the summer of 2002 indicated that concentrations of acidic and neutral drugs in surface waters near the point of sewage discharge into the Little River (ON, Canada) STP were approximately equal to the concentrations in the final effluent from the STP. Caffeine and cotinine, a metabolite of nicotine, were generally present in STP effluents and surface waters contaminated by drugs. The antidepressant fluoxetine and the antibiotic trimethoprom were also detected in most STP effluents and some surface water samples. For the first time, the lipid regulating drug atorvastatin was detected in samples of STP effluent and surface water.
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Drug-resistance epilepsy (DRE) is attributed to the brain P-glycoprotein (P-gp) overexpression. We previously reported that nuclear factor-kappa B (NF-κB) played a critical role in regulating P-gp expression at the brain of the acute seizure rats. This study was extended further to investigate the interaction effect of NF-κB and pregnane X receptor (PXR) on P-gp expression at the brain of chronic epileptic rats treated with carbamazepine (CBZ). The chronic epileptic models were induced by the micro-injection of kainic acid (KA) into rats' hippocampus. Subsequently, the successful models were treated with different intervention agents of CBZ; PMA(a non-specific PXR activity inhibitor) or PDTC(a specific NF-κB activity inhibitor) respectively. The expression levels of P-gp and its encoded gene mdr1a/b were significantly up-regulated on the brain of KA-induced chronic epilepsy rats or the epilepsy rats treated with CBZ for 1 week, meanwhile with a high expression of PXR. The treatment of PMA dramatically reduced both PXR and P-gp expressions at the protein and mRNA levels in the chronic epilepsy brain. By compared to the epilepsy model group, the P-gp expression was not markedly attenuated by the inhibition of NF-κB activity with PDTC treatment, nevertheless with a decrease of NF-κB expression in this intervention group. Higher levels of proinflammatory cytokines(IL-1β, IL-6, TNF-α) were found both in the brain tissue and the serum in the epilepsy rats of each group. There was a declined trend of the pro-inflammatory cytokines expression of the PDTC treatment group but with no statistical significance. This study demonstrates for the first time that P-gp up-regulation is due to increase PXR expression in the chronic phase of epilepsy, differently from that NF-κB signaling may induce the P-gp expression in the acute seizure phase. Our results offer insights into the mechanism underlying the development of DRE using or not using CBZ treatment.
Betasorb hemoperfusion shows a potent adsorptive capacity concerning therapeutic drugs (except aminoglycosides) and could be of major value in the treatment of intoxications. On the other hand, drug monitoring and possible adjustments are necessary during Betasorb hemoperfusion to maintain the therapeutic ranges of the drugs in blood.
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Our data suggest that epilepsy may represent an initial symptom of MS and a single clinical manifestation of a relapse, and further support the assumption of the existing correlation between the presence of cortical-subcortical lesions and epileptic seizures or epilepsy in patients with MS.
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Primary wake disorders encompass various conditions of excessive daytime sleepiness and/or increased nighttime sleep, of unknown origin beginning most often in adolescence and of chronic or recurrent natural history. The best known of these conditions is narcolepsy associating two major clinical features, irresistible episodes of sleep, sleep onset REM periods and an almost constant association with HLA DR2-DQ1. The prevalence of the condition is close to the one of multiple sclerosis but positive diagnosis requires most often over 10 years to be made. The treatment of excessive daytime sleepiness has recently benefited from a new non-amphetamine awakening compound, modafinil, active in 60 to 70 p. 100 of the cases. The treatment of cataplexy still relies on antidepressants, tricyclics or selective serotonin reuptake blockers. Major advances in pathophysiology and pathogeny have been obtained through a natural model of the disease, canine narcolepsy. Pharmacological studies point to the importance of alpha-1 b adrenergic mechanisms in cataplexy, while dopaminergic systems seem more involved in excessive daytime sleepiness. As concerns genetics, the HLA DQB1*0602 gene predisposes to narcolepsy. In the canine model it is mirrored by an autosomal recessive gene showing a strong homology with the human immunoglobulin gene mu-switch. Familial studies have shown that besides typical phenotypes, attenuated forms of the condition characterized by isolated recurrent daytime naps and/or lapses into sleep do exist. In addition one or several other genes may be involved. Narcolepsy is multifactorial, including one or several genes as well as environmental factors. Idiopathic hypersomnia is noted for very long night sleep, difficulty waking up and more or less constant excessive daytime sleepiness. In contrast with narcolepsy sleep in not refreshing. There is no polysomnographic or immunogenetic special feature. Idiopathic hypersomnia is 10 times less frequent than narcolepsy. It is often overdiagnosed due to insufficient knowledge of other causes of excessive daytime sleepiness such as the upper airway resistance syndrome. Modafinil is also of great value in the treatment of idiopathic hypersomnia. In the absence of an animal model, pathophysiology and pathogeny are still poorly understood. Even rarer is the Kleine-Levin syndrome which is easily distinguishable through its recurrent character and its tendency to progressively disappear. It mainly occurs in early adolescent males. Its main features are episodes of sleep of a week duration recurring at a several months' interval along with disturbances of alimentary and sexual behavior. There is no satisfactory treatment of hypersomniac episodes. On the other hand a prophylactic treatment with carbamazepine or lithium may be active. Pathophysiology remains unsettled in spite of some evidence of a hypothalamic functional disturbance.
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Analytical method was developed which allowed for the detection of four beta blockers (acebutolol, atenolol, metoprolol and sotalol), an antiepileptic drug (carbamazepine) and three fluoroquinolone antibiotics (ciprofloxacin, ofloxacin and norfloxacin) with a single pre-treatment and chromatographic method. The method included an isolation and concentration procedure using solid phase extraction, a separation step using high performance liquid chromatography and a detection procedure applying triple quadrupole mass spectrometry, which was working in the multiple reaction monitoring mode. The method was validated for ground, surface and sewage influent and effluent waters. Due to ion suppression in the electrospray source, the signals monitored for the analytes were less intense in sewage waters compared to ground and surface waters. The limits of quantification were as low as 1 ng L(-1) in ground water and 3.5 ng L(-1) in sewage influent. The method was successfully applied to the determination of the target compounds in raw and treated sewages of three treatment plants in Finland and in their recipient rivers. The results showed that many of the studied compounds pose a moderate to high persistency in sewage treatment as well as in the recipient rivers. The analytical protocol presented may be used for more in-depth studies on the occurrence and fate of these commonly used pharmaceuticals in the sewage treatment plants and in the aquatic environment.
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At present, data from trials do not confirm or refute an advantage for CR CBZ over IR CBZ for seizure frequency or adverse events in patients with newly diagnosed epilepsy.For trials involving epilepsy patients already prescribed IR CBZ, no conclusions can be drawn concerning the superiority of CR CBZ with respect to seizure frequency.There is a trend for CR CBZ to be associated with fewer adverse events when compared to IR CBZ. A change to CR CBZ may therefore be a worthwhile strategy in patients with acceptable seizure control on IR CBZ but experiencing unacceptable adverse events. The included trials were of small size, had poor methodological quality and possessed a high risk of bias, limiting the validity of this conclusion.Randomised controlled trials comparing CR CBZ to IR CBZ and using clinically relevant outcomes are required to inform the choice of CBZ preparation for patients with newly diagnosed epilepsy.
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A retrospective analysis of four cases of antiepileptic drug hypersensitive syndrome (AHS) were performed on the basis of clinical data, cutaneous adverse reactions to carbamazepine (CBZ) (n = 2) including Stevens-Johnson syndrome (SJS) (n = 1) and hypersensitivity syndrome (HSS) (n = 1); phenobarbital-induced HSS (n = 1) and oxcarbazepine (OXC)-induced HSS (n = 1). All patients received the examinations of polymerase chain reaction (PCR) with sequence specific primers to analyze HLA-B*1502. Two healthy subjects had no history of using antiepileptic drugs as the control.
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The present work describes the development and validation of a highly sensitive analytical method for the simultaneous determination of 68 compounds, including illicit drugs (opiates, opioids, cocaine compounds, amphetamines, and hallucinogens), psychiatric drugs (benzodiazepines, barbiturates, anesthetics, antiepileptics, antipsychotics, antidepressants, and sympathomimetics), and selected human metabolites in influent and effluent wastewater (IWW and EWW) by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The method involves a pre-concentration and cleanup step, carried out by solid-phase extraction (SPE) using the adsorbent Strata-XC, followed by the instrumental analysis performed by LC-MS/MS, using a Kinetex pentafluorophenyl (PFP) reversed-phase fused-core column and electrospray ionization (ESI) in both positive and negative modes. A systematic optimization of mobile phases was performed to cope with the wide range of physicochemical properties of the analytes. The PFP column was also compared with two reversed-phase columns: fused-core C18 and XB-C18 (with a cross-butyl C18 ligand). SPE optimization and critical aspects associated with the trace level determination of the target compounds (e.g., matrix effects) have been also considered and discussed. Fragmentation patterns for all the classes were proposed. The validated method provides absolute recoveries between 75 and 120% for most compounds in IWW and EWW. Low method limits of detection were achieved (between 0.04 and 10.0 ng/L for 87% of the compounds), allowing a reliable and accurate quantification of the analytes at trace level. The method was successfully applied to the analysis of these compounds in five wastewater treatment plants in Santorini, a touristic island of the Aegean Sea, Greece. Thirty-two out of 68 compounds were detected in all IWW samples in the range between 0.6 ng/L (for nordiazepam) and 6,822 ng/L (for carbamazepine) and 22 out of 68 in all EWW samples, with values between 0.4 ng/L (for 9-OH risperidone) and 2,200 ng/L (for carbamazepine). The novel methodology described herein maximizes the information on the environmental analysis of these substances and also provides a first profile of 68 drugs in a Greek touristic area.
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A total of 909 patients finished the follow-up observation. No significant difference was found in proportion of patients with > or = 50% reduction, > or = 75% reduction and 100% seizure reduction in the LTG and OXC groups between the first and the second six months. In the TPM group there was a statistical difference between the first and the second six months in proportion of patients with > or = 50% reduction (P = 0.002), > or = 75% reduction (P < 0.0001) and 100% seizure reduction (P = 0.009) in the monotherapy subgroup, and about > or = 75% reduction and 100% seizure reduction in the add-on therapy subgroup (P < 0.0001). The efficacy between the add-on and monotherapy subgroups showed a statistical difference. The safety of the three newer AEDs was good.
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The syndrome of inappropriate antidiuretic hormone secretion (SIADH) remains a challenging disorder to diagnose and treat. Three cases are presented to illustrate these challenges. The first two cases had drug-induced SIADH secondary to a selective serotonin reuptake inhibitor (for depression) or carbamazepine (for trigeminal neuralgia). The third case had SIADH possibly secondary to bronchiectasis. The lowest serum sodium concentrations ranged between 118 and 124 mmol/L in the three cases. Hyponatraemia was not acute and severe symptoms were absent. However, several mild neurological symptoms were present. In the first case, hyponatraemia likely contributed to a fall, which resulted in a fracture of the odontoid process of the axis. The other two cases also had gait disturbances, in addition to nausea, headache, impaired memory, difficulty concentrating and confusion. In at least two of the cases, the underlying cause of SIADH was impossible to reverse. Traditional treatment for SIADH with fluid restriction and demeclocycline failed, caused side effects or increased duration of hospital stay. These examples suggest a need for better treatment options. The introduction of the vasopressin-receptor antagonists for SIADH may be a welcome new therapy to overcome some of these challenges.
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Myoclonic status epilepticus (MSE) is rarely found in juvenile myoclonic epilepsy (JME) and its clinical features are not well described. We aimed to analyze MSE incidence, precipitating factors and clinical course by studying patients with JME from a large outpatient epilepsy clinic.
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Our results showed that the CYP2C19 and/or POR genotypes have an impact on the CLB and/or N-CLB clearance. These results suggest that determining the CYP2C19 and/or POR genotypes is helpful for obtaining appropriate serum CLB and N-CLB concentrations and preventing an overdose when starting CLB therapy.
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Genetic factors contribute to the high interindividual variability in response to antiepileptic drugs. However, most genetic markers identified to date have limited sensitivity and specificity, and the value of genetic testing in guiding antiepileptic drug (AED) therapy is limited. The best defined indication for testing relates to HLA-B*15:02 genotyping to identify those individuals of South Asian ethnicity who are at high risk for developing serious adverse cutaneous reactions to carbamazepine. The indication for HLA-A*31:01 testing to identify individuals at risk for skin reactions from carbamazepine, or for CYP2C9 genotyping to identify individuals at risk for serious skin reactions from phenytoin is less compelling. The use of genetic testing to guide epilepsy treatment is likely to increase in the future, as better understanding of the function of epilepsy genes will permit the application of precision medicine targeting the biological mechanisms responsible for epilepsy in the specific individual.
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Thirty-five PB-treated patients (27.6%) experienced SHS. In these patients SHS developed during the first 7 months of therapy and regressed after PB discontinuation or, in 2 cases, after dosage reduction. None of the patients in the control group developed SHS.
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Trigeminal neuralgia is as a chronic, debilitating condition, which can have a major impact on quality of life. There are few reports of trigeminal neuralgia in oriental populations.
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A 4-year-old girl with intractable epilepsy due to left-side hemispheric cortical dysplasia underwent a hemispherotomy. She was seizure-free after the surgery. EEG showed persistent abundant epileptiform activity over the left (disconnected) hemisphere, including ictal patterns that neither generalised nor had clinical correlates. Antiepileptic medication was completely withdrawn four years following the surgery. One week after the withdrawal, she developed episodes of intense left-sided hemicranias (ipsilateral to the surgery) with vomiting and photophobia that did not resemble her habitual seizures and were unresponsive to non-steroidal anti-inflammatory drugs. Video-EEG showed association of the headache attacks with ictal patterns over the disconnected hemisphere. Brain MRI revealed increased signal changes in the left hemisphere. Attacks responded promptly to i.v. midazolam and carbamazepine at a low dose. Mechanisms underlying peri-ictal headache originating in the disconnected hemisphere are discussed. [Published with video sequences].
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OXC is safe and effective as adjunctive therapy in patients with uncontrolled partial seizures. OXC 600 mg/d was the minimum effective dosage; effectiveness of OXC increased with dose. The rapid and fixed titration to high doses was associated with an increased risk of adverse events, which could potentially be reduced by adjusting concomitant antiepileptic medication and by using a slower, flexible OXC titration schedule.
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This is a retrospective study spanning 20 years. It concerns the therapeutic drug monitoring of Phenobarbital (PB) of carbamazepine (CBZ) and valproic acid (VPA).
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Cytochrome P450 (P450) 3A4 is the most abundant human P450 and oxidizes a diversity of substrates, including various drugs, steroids, carcinogens, and macrolide natural products. In some reactions, positive cooperativity has been reported in microsomal studies. Flavonoids, e.g., 7,8-benzoflavone (alpha-naphthoflavone, alpha NF), have been shown to stimulate some reactions but not others. In systems containing purified recombinant bacterial P450 3A4, positive cooperativity was seen in oxidations of several substrates, including testosterone, 17 beta-estradiol, amitriptyline, and most notably aflatoxin (AF) B1. With these and other reactions, alpha NF typically reduced cooperativity (i.e., the n value in a Hill plot) while either stimulating or inhibiting reactions. With the substrate AFB1, alpha NF both stimulated 8,9-epoxidation and inhibited 3 alpha-hydroxylation. The same patterns were seen with AFB1 in a fused P450 3A4-NADPH-P450 reductase protein. alpha NF did not alter patterns of activity plotted as a function of NADPH-P450 reductase concentration in systems containing the individual proteins. The patterns of AFB1 oxidation to the two products were modified considerably in systems in which NADPH-P450 reductase was replaced with a flavodoxin or ferredoxin system, iodosylbenzene, or cumene hydroperoxide. AFB2, which differs from AFB1 only in the presence of a saturated 8,9-bond, was not oxidized by P450 3A4 but could inhibit AFB1 oxidation. These and other results are considered in the context of several possible models. The results support a model in which an allosteric site is involved, although the proximity of this putative site to the catalytic site cannot be ascertained as of yet. In order to explain the differential effects of alpha NF and reduction systems on the two oxidations of AFB1, a model is presented in which binding of substrate in a particular conformation can facilitate oxygen activation to enhance catalysis.
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Carbamazepine (CBZ), a frequently used anticonvulsant drug, is one of the most common causes of life-threatening cutaneous adverse drug reactions such as toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS). Recent studies have revealed a strong association between HLA-B*1502 and CBZ-induced TEN/SJS in the Taiwan Han Chinese population.