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PubMed1988

Isocratic liquid chromatographic determination of theophylline, acetaminophen, chloramphenicol, caffeine, anticonvulsants, and barbiturates in serum.

An isocratic reverse-phase high-performance liquid chromatographic system is described for resolving theophylline, acetaminophen, caffeine, chloramphenicol, ethosuximide, primidone, phenobarbital, phenytoin, and carbamazepine within 7 min. A procedure for routinely measuring these drugs in serum is validated and has been extended to include the quantification of N-desmethylmethsuximide, barbital, amobarbital, secobarbital, pentobarbital, mephobarbital, and thiopental. A 250 x 4.6 mm column packed with trimethylsilyl (C-1)-coated 5-microns particles is used. The mobile phase is phosphate buffer (10 mmol/L, pH 6.3):methanol:acetonitrile, 65:17.5:17.5. A common solvent extraction procedure is used for all of these drugs. The extractant is chloroform:isopropanol (95:5), containing three internal standards: 3-isobutyl-l-methylxanthine (IMX), tolybarb, and methsuximide. Theophylline, acetaminophen, caffeine, and chloramphenicol are quantified at 273 nm with IMX as the internal standard. With two exceptions, the rest of the drugs are quantified at 204 nm using tolybarb as the internal standard; ethosuximide is quantified at 204 nm using methsuximide as the internal standard, and thiopental is quantified at 285 nm using IMX as the internal standard.

Acetaminophen↗

PubMed1987

Protection against hypoxia-induced lethality in mice: a comparison of the effects of hypothermia and drugs.

The role of hypothermia in the antihypoxic effects of drugs was examined in the present experiments. The effects of environmentally induced hypothermia and drugs were tested by exposing mice to 100% nitrogen gas for 80 sec and counting the number of survivors. In a series of 68 vehicle control groups, the mean of mice surviving the test was 8.6% (SEM = 1.4). Hypothermia induced by lowering the ambient temperature or by isolating mice for a brief period increased the number surviving hypoxia, and the per cent of animals surviving was linearly related to body temperature. When the effects of drugs were compared to that of hypothermia, several drugs were found which protected mice from hypoxia to a greater extent than hypothermia alone. Active substances included the anticonvulsant drugs phenobarbital, phenytoin, carbamazepine and diazepam, but not primidone. Physostigmine and the muscarinic agonist oxotremorine also caused significant protection, while the effects of nicotine could be completely accounted for by hypothermia. Arecoline had a biphasic, time-dependent effect that may be explained by a combination of muscarinic and nicotinic actions. The effects of the muscarinic agonists are centrally mediated, since they could be blocked by low doses of scopolamine HCl, but not by the quaternary analog scopolamine methyl nitrate. Furthermore, the antihypoxic effect of physostigmine was not mimicked by the peripherally acting acetylcholinesterase inhibitor, neostigmine. These results suggest that some drugs do have protective effects against hypoxia which are independent of drug-induced hypothermia and that these effects may be mediated through the CNS.

Animals↗

PubMed1987

Phenytoin-induced hypersensitivity reactions.

A case of phenytoin-induced hepatitis with mononucleosis is reported, and syndromes associated with phenytoin hypersensitivity reactions are discussed. A 23-year-old black woman with a two-month history of seizure disorder was admitted to a hospital with nausea, vomiting, fever, lymphadenopathy, diffuse maculopapular rash, left-upper-quadrant tenderness, and hepatomegaly. She was receiving phenytoin sodium 300 mg/day; carbamazepine 200 mg four times daily had been discontinued four days before admission because of leukopenia. Phenytoin was discontinued after admission; however, phenytoin 1 g i.v. was given for a tonic-clonic seizure two days after admission, after which swelling of the face and legs and pruritus developed. Over the next few days, signs and symptoms of hepatotoxicity progressed, and she became comatose. Seizures were treated with diazepam. She began to recover after 10 days of supportive therapy and was discharged several weeks later on primidone therapy. Serious phenytoin hypersensitivity reactions may appear as dermatologic, lymphoid, or hepatic syndromes. Fever, rash, and lymphadenopathy often accompany hepatic injury. Encephalopathy and death may occur. Proposed mechanisms for phenytoin hypersensitivity include antigen-antibody reactions, alteration of lymphocyte function, and an enzyme abnormality causing the production of toxic metabolites. Treatment is supportive; phenobarbital and carbamazepine may be used with caution as alternate anticonvulsant therapy. The possibility of phenytoin hypersensitivity reactions should be considered when patients receiving phenytoin have unusual symptoms, particularly fever, rash, and lymphadenopathy.

Adult↗

PubMed1985

Rapid measurement of free anticonvulsant drugs by direct liquid chromatography of serum ultrafiltrates.

In this simultaneous assay of unbound phenobarbital, phenytoin, primidone, and carbamazepine, serum ultrafiltrate is prepared by centrifugation in disposable filter units (Centrifree Micropartition System, Amicon Corp.) and injected directly onto a reversed-phase liquid-chromatography column. Drugs in the effluent are detected by absorbance at 210 nm. The measured concentrations were not critically dependent on the exact conditions of ultrafiltration (rotor angle, speed or time of centrifugation, amount of sample filtered). Pooled serum containing all four drugs gave reproducible results in repeated analyses during several days. For comparison we assayed 113 clinical specimens for one or more of these drugs by this method, and for the total (bound plus unbound) concentration of each drug by immunoassay. For each drug there was a nearly linear relationship between the two types of measurements, except for six specimens that had unusually high fractions of unbound drug. This assay appears highly suitable for routine determination of the free, biologically active fraction of anticonvulsant drugs, possibly as an alternative to measurements of total drug concentrations.

Anticonvulsants↗

PubMed1979

[Bone diseases due to long-term administration of anticonvulsants during the age of growth].

On the basis of literature and 2 own observations a survey is given concerning the modern knowledge of bone changes as concomitant effect by long-term treatment with anticonvulsive drugs (diphenyl hydantoin and primidon) at the age of growth (osteopathia antiepileptica). The discussion of arising actual questions is demonstrated on instructive cases with consequences important for practice.

Adolescent↗

PubMed1985

Drug therapy for seizures.

Phenytoin, valproic acid, carbamazepine, phenobarbital, primidone, and ethosuximide are important in anticonvulsant therapy. Each drug's structure determines its properties and its activity against particular seizure types. Single-drug therapy is generally preferable to multiple-drug therapy. Absorption, half-life, metabolism, and other pharmacokinetic characteristics are important considerations in the selection of an anticonvulsant drug.

Anticonvulsants↗

PubMed1979

The 1978 College of American Pathologists Therapeutic Drug Monitoring Interlaboratory Survey Program.

In 1978 the College of American Pathologists introduced a Therapeutic Drug Monitoring Interlaborabory Survey Program. Each participant recieved six vials of lyophilized human serum on two occasions, approximately 13 weeks apart. The specimens contained various combinations of 12 drugs in subtherapeutic, therapeutic, and toxic concentrations. The drugs included in the specimens were phenytoin, phenobarbital, primidone, ethosuximide, carbamazepine, digoxin, procainamide, N-acetylprocainamide, quinidine, theophylline, lithium, and gentamicin. The weighed-in quantity of each drug was used as the target value for that drug. The specimens were analyzed by a variety of analytic methods. Statistics were calculated for all results regardless of the analytic method used and for each individual method. This report presents the data from the Program.

Anticonvulsants↗

PubMed1980

[Interrelations between serum folic acid and hematologic changes in psychiatric patients].

Changes in the blood picture as well as in the content of folic acid and iron in the serum were investigated in 223 patients treated in a psychiatric clinic because of psychoses and dementia. Psychopharmaka of the phenobarbiturate type, dihydrophenytoine as well as primidone were administered in 29 cases. As anaemia could be identified in 32 patients; 3 of them turned out to be a hyperchronic anaemia, 25 a normochromic anaemia and 4 a hypochromic type one. In 78.1% of the anaemic patients there was a lowered folic acid level. All four cases with hypochromic anaemia showed a lowered serum level. A hypersegmentation of neutrophilic granulocytes could be identified in 48 patients (28.4%), with a lowered folic acid content in the serum being present in all cases. A lowered folic acid content in the serum could be found in 76.2% of the patients. All patients treated with psychopharmaka showed a subnormal folic acid content. On the other hand, a lowered iron content in the serum could only be identified in 8.1% of the cases. The final evaluation of all findings gathered results in the recommendation to attach greater importance to a direct determination of folic acid concentration in the serum in those cases of disease particularly exposed.

Adolescent↗

PubMed1977

Anticonvulsivant-induced depression of clotting factors in children.

A few neonates born to mothers receiving anticonvulsant drugs during pregnancy have shown defects in vitamin K dependent clotting factors with or without clinical bleeding. Experimentally, phenytoin (diphenyl hydantoin, DPH) has induced clotting defects in cats and inhibited production of clotting factors in rat liver slices. Phenobarbital has produced similar but milder defects. Anticonvulsants have been observed to produce clotting defects in 9 children, 2 weeks to 8 years in age. Elevated levels of phenytoin or other anticonvulsants, or a combination of anticonvulsants were measured in the children. Six patients were on drug combination including two or more of the following: phenytoin, phenobarbital, primidone, carbamazepine, diazepam, ethosuximide. Clotting defects included: elevated prothrombin time, elevated partial thromboplastin time, diminished factors V, VII or X. All children had neurologic symptoms of anticonvulsant toxicity, but the only hematologic problems were oozing from venipuncture sites and increased bruising in 3. All patients were on normal diets and had normal liver function tests. By lowering the level of anticonvulsants, clotting factors returned toward normal. Elevated levels of anticonvulsants can potentially produce clotting defects in neonates and young children.

Anticonvulsants↗

PubMed1978

Quantitation of anticonvulsant drugs in serum by gas-chromatography on the stationary phase SP-2510.

A new column packing, SP-2510 DA (Supelco, Inc., Bellefonte, Pa. 16823), is an excellent stationary phase for the determination of a wide variety of anticonvulsant drugs by gas--liquid chromatography without derivatization. However, when uncomplicated extraction procedures are used, serum cholesterol interferes with the determination of primidone. By the simple expedient of adding a short "pre-column" containing another phase (SP-2250 DA) the problem is overcome.

Anticonvulsants↗

PubMed1983

Automated fluorometer/photometer system for homogeneous immunoassays.

A fully automated bench-top clinical analyzer (OPTIMATE TM; Ames/Gilford) performs homogeneous fluorescent immunoassays, colorimetric immunoassays, and determinations of routine blood analytes; drugs, enzymes, metabolites, specific proteins, and hormones in serum. Unique features include a combination fluorescence/absorbance aspirating thermocuvette, a photon-counting fluorometer/photometer, a multi-reagent distribution valve to dispense as many as three reagents plus buffer, and a user-replaceable programmable memory cartridge for software updates. We have evaluated the performance of OPTIMATE substrate-labeled fluorescent immunoassays for gentamicin, tobramycin, amikacin, theophylline, phenytoin, phenobarbital, primidone, carbamazepine, and quinidine with this automated system. A sample throughput of 92 samples per hour is achieved by reading fixed-point fluorescence results every 39 s after an initial 4-min reaction period. Precision studies indicate typical CVs of less than or equal to 6% for mid-range controls. Standard curves can be reused for as long as two weeks before recalibration. With clinical samples, results by the OPTIMATE procedure correlated well (r greater than or equal to 0.97) with those by a reference method.

Autoanalysis↗

PubMedDate not supplied

[Epilepsy and pregnancy (review of the literature)].

The relationship between pregnancy and epilepsy has often been object of particular attention and care by many epileptologists. The aim of this survey of the literature is to give an up-to-date and comprehensive review of this relation and to focalize the many related problems which still are unsolved. The following principal chapters are discussed: 1) the influence of pregnancy on epilepsy; 2) the influence of epilepsy on pregnancy and delivery; 3) the influence of epilepsy on newborns; 4) the teratogenic effects of antiepileptic medication. Many conflicting data make it very difficult to summarize the results, however it is clear that the effect of pregnancy on seizure frequency may be quite variable. Seizures, in fact, during pregnancy may be increased, decreased or remain unchanged. The most conflicting data are those related to the effects of epilepsy on pregnancy and delivery, while concordant opinions indicate an increased perinatal mortality and morbidity in offsprings of epileptic women. Special attention has to be payed to the offsprings of epileptic mothers. The presence of congenital abnormalities in fact, is about 2 times higher for newborns of mothers with epilepsy than for offsprings of mothers without the disease. Another important problem is related to the presumed teratogenicity of antiepileptic drugs. It has not yet been demonstrated that antiepileptic compounds have a teratogenic effect on offsprings. However it has been shown that this assumption is often associated to a higher presence of congenital malformations. The majority of malformations (facial clefts and heart defects) occur in association with the use of trimethadione, phenobarbital, primidone and acetazolamide, whereas they are much less frequent in association with phenytoin, carbamazepine, valproate.

Abnormalities, Drug-Induced↗

PubMed1984

[Simultaneous high performance liquid chromatographic determination of 8 anti-epileptics and sedatives in plasma. Use of a radial compression column system].

The authors describe a method of assaying anti-epileptic and sedative drugs by high performance liquid chromatography. This method allows for simultaneous separation and quantification of these drugs (Ethosuximide, Primidone, Phenobarbital, Beclamide, Prominal, Diphenylhydantoin, Glutethimide, Carbamazepine) in a relatively short analysis time, by means of a system of radial compression of the column. The serum is acidified and extracted by ethyl acetate. After evaporation, the residue is taken up in the mobile phase. The various drugs are eluted in a 10 micron Rad-Pak C 18 column with a mobile phase consisting of a mixture of methanol and water with a flow rate of 4 ml/min. The chromatograph is read at 200 nm and the separation is effective in about 16 minutes. The yield is between 75 and 100 per cent and the repeatability of the method is good (C. V. less than 9 per cent). The originality of the method resides in the assay of drugs such as beclamide, methylphenobarbital and glutethimide at the same time as the major anti-epileptics.

Anticonvulsants↗

PubMed1984

[The epileptic mother and her child].

This study is a review of the literature on the influence of epilepsy and antiepileptic medication on the course of pregnancy and the foetus, as well as of the effect of pregnancy on the disease. Antiepileptic treatment is supposedly responsible for the increased rate of abnormal bleeding after delivery. Data on the perinatal mortality of epileptics are conflicting. The offspring of epileptic women are often smaller than normal neonates, indicating retarded growth, and the incidence of malformations is 1.25 times higher. Until now there has been no direct evidence of a teratogenic effect of the commonly used antiepileptic drugs, and the risk of malformations may possibly be correlated with the severity of the epilepsy. The effect of pregnancy on seizure frequency seems to be quite variable. Higher seizure frequency is seen during pregnancy, but this is not a universal phenomenon. The incidence of seizures in gestational epilepsy has no predictive value with respect to the course of later pregnancy. A positive correlation seems to exist between the development of eclampsia and later epilepsy, a family history of epilepsy and cerebral dysrhythmias. Status epilepticus is uncommon in pregnancy. The requirement of several antiepileptic drugs is increased during pregnancy. The metabolism of carbamazepine, primidone, and clorazepate is probably accelerated in the gestational period, but data on other antiepileptic drugs are inconclusive or lacking. The intestinal absorption of antiepileptic drugs may be impaired during pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Anticonvulsants↗

PubMed1984

Anticonvulsants in epileptic fowl.

The high seizure susceptibility in epileptic fowl is an autosomal recessive trait characterized in homozygotes by seizures that occur spontaneously and in response to photic stimulation or hyperthermia. Both of the latter stimuli can be used to evoke seizures in drug studies. Epileptic fowl have abnormal inter-ictal EEG activity. When exposed to photic stimulation spiking is apparent on the EEG at seizure onset. Phenobarbital, primidone, phenytoin, and valproic acid reduce seizure susceptibility at plasma concentrations approximating those used to control generalized and focal cortical tonic-clonic seizures in humans. Carbamazepine and the benzodiazepines also reduce seizure susceptibility. These data indicate that epileptic fowl provide a useful model for generalized and focal cortical tonic-clonic epilepsies. Ethosuximide was inactive in epileptic fowl. However, trimethadione had anticonvulsant activity indicating that this model is only relatively specific for the above seizure types. When seizures were evoked by hyperthermia phenobarbital but not phenytoin or valproate reduced seizure susceptibility. GABA (gamma-aminobutyric acid), AOAA (amino-oxyacetic acid) and THPO (4,5,6,7-tetrahydroisoxazolo[4,5-c] pyridin-3-ole, a glial specific inhibitor of GABA uptake) all have anticonvulsant activity against seizures evoked by photic stimulation in young chicks. These data indicate that this model may be particularly useful for studies of the anticonvulsant activity of compounds designed to enhance GABAergic transmission.

Animals↗

PubMed1983

[Alpha 1-acid glycoprotein and carbamazepine].

Levels of alpha 1-acid glycoprotein (alpha 1-AGP) were determined in 40 epileptic patients who had been also treated with carbamazepine (CBZ) and, in some patients, phenobarbital (PB) for at least 3 months. alpha 1-AGP levels were also determined in 28 controls. CBZ dit not alter blood levels of alpha 1-AGP while CBZ-PB decreased them. Such results are at variance with recent studies which suggested an increase of alpha 1-AGP in epileptic patients treated either with phenytoin or phenytoin + PB, or + CBZ, or + primidone.

Adult↗

PubMedDate not supplied

Torsade de pointes.

Prolonged QT or QU intervals can be caused by a variety of conditions which include drugs, electrolyte imbalance, and acquired and congenital diseases. This finding is associated with life-threatening ventricular arrhythmias that, at times, have unusual morphologies characteristically named "torsade de pointes." Treatment, when iatrogenic, is obvious--when due to acute acquired diseases, therapy is supportive until the acute phase passes. In congenital prolonged QT syndromes, primidone (Mysoline) recently has been found to be successful in long-term management.

Electrocardiography↗

PubMed1980

Measurement of sodium valproate in serum by direct-insertion chemical-ionization/mass spectrometry.

To quantitatively determine sodium valproate, we use a stable isotope-labeled internal standard and chemical-ionization/mass spectrometry, without prior chromatographic separation. The technique is rapid, simple, sensitive, and provides for the routine analysis of 100 microL of serum with good within-day and day-to-day precision. The technique also allows for the simultaneous determination of phenobarbital, mephobarbital, carbamazepine, primidone, and phenytoin.

Carbamazepine↗