Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Some patients fail to respond to antiepileptic drugs (AEDs) or their response varies over time. Unexpected fluctuations in AED concentrations can cause loss of seizure control or side effects. Recent advances in AED clinical pharmacology have characterized a number of factors that alter AED concentrations. Storage of carbamazepine (CBZ) and phenytoin (PHT) formulations in hot, humid conditions alters the dosage form and reduces bioavailability up to 50%. Diurnal changes in gastrointestinal physiology affect disintegration of valproate (VPA) enteric-coated tablets, reducing nighttime drug concentrations 30 to 40% compared with daytime values. Drug-drug interactions or pathophysiologic conditions (e.g., hypoalbuminemia) may displace AEDs from protein-binding sites reducing total but not unbound drug concentrations decrease. VPA not only displaces PHT from protein-binding sites but inhibits its metabolism, causing a decrease in total concentration and an increase in the unbound concentration, occasionally necessitating a reduction in PHT dosage. Alterations in drug metabolism can cause fluctuations in the concentrations of AEDs and active metabolites. Enzyme inhibitors such as cimetidine or VPA can increase concentrations of both CBZ and CBZ epoxide (CBZE). Enzyme inducers such as ethanol, PHT, CBZ, and phenobarbital accelerate the metabolism of other AEDs. Some forms of physiologic stress increase binding to alpha 1-acid glycoprotein (AAG), which is stimulated within hours of a myocardial infarction or major surgery. Total CBZ and CBZE, both of which bind to AAG, increase over the same period. Stress may also activate hepatic drug metabolism. Unbound PHT clearance increases 7 to 21 days following head trauma, necessitating larger maintenance doses. Age greater than 65 years is associated with decreases in protein binding and drug clearance and longer elimination half-lives. In elderly patients, AED dosage may need to be reduced and the dosing interval extended. Knowledge of these factors permits prospective assessment of risk and the design of treatment plans that minimize fluctuations in response.
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PMID:Pharmacokinetic pitfalls of present antiepileptic medications. 174 71

1. Twenty-one epileptic patients completed a double-blind, double-dummy, random order, crossover comparison of conventional carbamazepine (CBZ, Tegretol, Ciba-Geigy) with a new controlled-release formulation (CBZ-CR, Tegretol Retard). All participants were stabilised on maximally tolerated doses of CBZ as monotherapy (one twice daily, twelve three times daily, eight four times daily). Each preparation was taken with a matched placebo of the other for 4 weeks. 2. Peak serum CBZ concentrations (mean +/- s.e. mean) were lower (CBZ 11.4 +/- 0.4 mg l-1; CBZ-CR 10.4 +/- 0.5 mg l-1; P less than 0.01) and times to peak longer (CBZ 3.6 +/- 0.5 h, CBZ-CR 5.2 +/- 0.7 h, P less than 0.01) during CBZ-CR treatment. Mean CBZ concentrations, however, were also slightly reduced with the new formulation (CBZ 9.9 +/- 0.3 mg l-1; CBZ-CR 9.1 +/- 0.5 mg l-1, P less than 0.05) and this was associated with greater seizure frequency (CBZ 2.8 +/- 1.2, CBZ-CR 3.8 +/- 0.9; P less than 0.05) during the CBZ-CR treatment phase. 3. Diurnal fluctuations (CBZ 41 +/- 3%, CBZ-CR 28 +/- 2%, P less than 0.01) and variations (CBZ 53 +/- 5%, CBZ-CR 33 +/- 3%; P less than 0.01) in serum CBZ concentration were substantially less with CBZ-CR and were similar to those calculated during a 6 or 8 hourly dosage interval with conventional CBZ (fluctuation 33 +/- 3%, variation 42 +/- 5%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Monotherapy with conventional and controlled-release carbamazepine: a double-blind, double-dummy comparison in epileptic patients. 188 46

The VPA total level (T value), the free level (F value), and the free fraction (FF) were measured in 74 epileptic children under valproic acid (VPA) monotherapy. The relationship between the T value, blood collection time, therapy duration, serum free fatty acid, clinical features, F value and FF were then studied. Blood was taken either before the morning (pre-breakfast) administration of medicine (Cmin), 2-3 hours after the post-breakfast administration (Cmax), or both. The subjects were divided into one Cmin. and one Cmax. group. The results of serum VPA measurement revealed that T values in the Cmin. group ranged from 23.0 micrograms/ml to 113.0 micrograms/ml (average: 50.0 +/- 16.2 micrograms/ml), F values from 2.0 micrograms/ml to 16.0 micrograms/ml (6.0 +/- 2.7 micrograms/ml) and FF from 5.9% to 21.7% (11.8 +/- 3.8%). In the Cmax. group, T values ranged from 41.0 micrograms/ml to 163.0 micrograms/ml (80.5 +/- 24.3 micrograms/ml), F values from 3.7 micrograms/ml to 22.8 micrograms/ml (10.0 +/- 4.2 micrograms/ml) and FF from 7.1% to 22.2% (12.2 +/- 3.3%). There was no difference in FF between the two groups. In both groups, T and F values significantly and positively correlated and FF was not affected by age or VPA therapy duration. However, FF varied in the early stage of medication. In individual cases with no seizures and receiving constant doses, the longer the period of medication, the greater the decrease in FF. Although free fatty acid was concurrently measured in some cases, it did not correlate with the F value or the FF. In 45 cases, changes in the FF were followed in both groups on the same day, but no general tendencies were noted. Diurnal fluctuation was studied in 4 cases. Significance of the clinical features was evaluated. The subjects were then classified by seizure type for group comparison and no differences in the FF among the different types were observed. During the follow-up period, 5 cases had seizures, but when their serum levels were compared with those of members of both groups, the T values did not differ. The F values and the FF in the 5 cases were below the mean values of the two groups. These findings suggest that when factors affecting VPA protein binding are expected to be present or when seizures cannot be controlled despite a sufficient T value in the blood, the F value measurement is of particular importance.
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PMID:[A clinicopharmacological study of serum sodium valproate free level in children with epilepsy]. 228 44

Diurnal secretion profile of melatonin was studied by measuring multiple serum melatonin levels in three photosensitive epileptic children (group P) and eleven epileptic children without photosensitivity (group E). In the group E patients a normal fluctuation pattern of serum melatonin levels was observed; low and stable during daytime and rapidly elevating and high in the night. Five out of eleven patients took midday naps, which did not cause any change of serum melatonin level, remaining at the low baseline level. In 2 out of 3 patients in group P, nocturnal peak levels were far lower than those in group E. The third case with severe photosensitive epilepsy was kept in a dark room with the aim of avoiding slightest light stimuli that may provoke seizures. During the period of the dark room therapy extending over 105 days, her circadian rhythm of sleep-wakefulness was prolonged from 24.00 hours to 24.27 hours. Nocturnal increment of melatonin was observed in this case. It was concluded that an endogenous circadian rhythm is operating in the melatonin secretion and that this mechanism is intact in epileptic children irrespective to the presence or absence of photosensitivity.
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PMID:[Diurnal secretion profile of melatonin in epileptic children with or without photosensitivity and an observation of altered circadian rhythm in a case of completely under dark living condition]. 839 28

Melatonin is effective for treating sleep-wake cycle disturbances and has been reported occasionally to decrease epileptic seizure frequency, with no long-term side effects. In this pilot study, the investigators examined the effect of melatonin on seizures, sleep quality, and behavior in 10 patients aged 9 to 32 years with intractable epilepsy. Patients were randomized to receive melatonin (10 mg daily at bedtime) followed by placebo or placebo followed by melatonin for 3 weeks each, with a 1-week washout period in between. Seizure frequency was monitored by daily diaries and actigraphy recordings; behavioral and sleep parameters were rated by caregivers. Diurnal seizures decreased significantly with melatonin compared with placebo (P = .034, Wilcoxon test). Maximal number of seizures, seizure duration, sleep efficiency or latency, and behavioral parameters remained unchanged. No major side effects or seizure aggravation were documented. It is concluded that melatonin could be effective and safe for decreasing daytime seizure frequency in patients with intractable epilepsy.
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PMID:Effect of melatonin on seizure frequency in intractable epilepsy: a pilot study. 2237 57

This study examined melatonin (MLT) system in children with epilepsy. Diurnal patterns of salivary MLT, urinary metabolite 6-sulphatoxymelatonin, core body temperature, pulse and blood pressure were measured in 51 children with epilepsy (6.6-17.9 years) and 29 comparison children (5.5-17.3 years). The children with epilepsy preserved MLT and other circadian rhythms. In nine children with epilepsy (17.6%), peak salivary MLT concentrations were very high. There were no associations between MLT secretion/excretion parameters (diurnal profile, peak nocturnal concentrations, area under the time curve, duration of elevated concentrations, acrophase) and seizure characteristics (time, type of seizures, antiepileptic medications). The study observations are important for understanding of the MLT system in epilepsy and for exploring the potential for seizure treatment with melatonin.
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PMID:Melatonin secretion in children with epilepsy. 2310 3

Diurnal frequent urination is a common condition in elementary school children who are especially at risk for associated somatic and behavioral problems. Levetiracetam (LEV) is a broad-spectrum antiepileptic drug that has been used in both partial and generalized seizures and less commonly adverse effects including psychiatric and behavioral problems. Diurnal frequent urination is not a well-known adverse effect of LEV. Here, we reported 2 pediatric cases with epilepsy that developed diurnal frequent urination after LEV administration. Case 1 was a 6-year-old male patient who presented urinary frequency and urgency in the daytime since the third day after LEV was given as adjunctive therapy. Symptoms increased accompanied by the raised dosage of LEV. Laboratory tests and auxiliary examinations did not found evidence of organic disease. Diurnal frequent urination due to LEV was suspected, and then the drug was discontinued. As expected, his frequency of urination returned to normal levels. Another 13-year-old female patient got similar clinical manifestations after oral LEV monotherapy and the symptoms became aggravated while in stress state. Since the most common causes of frequent micturition had been ruled out, the patient was considered to be diagnosed with LEV-associated psychogenic frequent urination. The dosage of LEV was reduced to one-third, and the frequency of urination was reduced by 60%. Both patients got the Naranjo score of 6, which indicated that LEV was a "probable" cause of diurnal frequent urination. Although a definite causal link between LEV and diurnal urinary frequency in the 2 cases remains to be established, we argue that diurnal frequent urination associated with LEV deserves clinician's attention.
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PMID:Levetiracetam: Probably Associated Diurnal Frequent Urination. 2693 51