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[Direct and indirect parameters of free thyroxine. I. Method, quality control and in vitro experiments on storage of samples and effect of drugs].

The clinical applicability of direct FT4 determinations by the radioimmunoassays ImmoPhase, GammaCoat, Liquisol, Amerlex and LisoPhase is tested in comparison to the FT4 index and the T4/TBG ratio. Part I of this study deals with technical aspects concerning quality control as well as with in-vitro experiments concerning storage of samples and interference of drugs. The precision of FT4-RIAs is satisfactory; inter-assay coefficients of variation are generally lower than 10% for medium hormone concentrations. Because of a change of the standard curve calibration by the manufacturer of the Liquisol kit, the inter-assay variability (17%) of this assay is unacceptably high. The comparison of working ranges shows that the sensitivity of all FT4 assays is sufficient. However, the upper limits of working ranges of the Liquisol and LisoPhase kits are too low. Storing the samples in form of serum yields lower values for any FT4 parameter than storing as whole blood. This unexpected observation is true for room temperature as well as for refrigeration at 4 degrees C. To be sure, the values of indirect FT4 parameters from serum and whole blood coincide somewhat better especially when the samples are stored in the refrigerator. Repeated thawing and refreezing does not influence the results of FT4-RIAs significantly. In vitro testing of drug interferences by addition of therapeutic doses of primidone, phenobarbital, phenytoin and acetylsalicylic acid yields significant effects only for the last quoted pharmaceutical. While the FT4 levels of the Liquisol and LisoPhase assays rise with the acetylsalicylic acid dose according to expectations, the values of the Amerlex and GammaCoat assays decrease. With regard to handling of the tests, there are no special technical problems for all FT4-RIAs tested.

Aspirin↗

[Anticonvulsive combined therapy (author's transl)].

19 patients were treated with valproic acid (VPR) in combination with classical anticonvulsants (phenytoin, phenobarbitone, primidone, carbamazepine). Patients with a mean serum concentration of 340 micron moles/l showed a marked improvement as to the frequency of seizures or were even completely free from seizures, provided that the other anticonvulsants were also given in the therapeutic range. Cases showing only a slight reduction in seizure frequency or no improvement had a mean serum level of 229 micron moles/l. This investigation shows that in severe cases of epilepsy treated by combined therapy all given anticonvulsants must reach therapeutic levels to achieve effective control of seizures in most patients.

Anticonvulsants↗

[Autoallergic drug exanthemas].

A short discussion of known facts on iatrogenic autoallergic dermatoses of the pemphigus and lupus erythematosus type followed by the clinical, histological and immunological data of a subepidermal autoallergic bullous dermatosis in two children after anticonvulsive treatment with primidon.

Autoimmune Diseases↗

Treatment of tinnitus with tocainide hydrochloride.

Intravenous (IV) injection of lidocaine was used in patients with tinnitus for combined treatment with oral anticonvulsants carbamazepine (Tegretol) and primidone (Mysoline). In most cases, the high complication rate with these drugs precluded their long-term use. Tocainide hydrochloride (HCl), a primary amine analog of lidocaine, can be taken orally and was evaluated for the use in the treatment of tinnitus. A double-blind study in which one group received 200 mg tocainide HCl four times a day and one group received a placebo revealed no significant differences in tinnitus relief between the two groups. A single-blind study in which 600 mg tocainide HCl four times a day was administered showed 80% to 98% tinnitus relief in five of the six patients who tolerated the drug. Tocainide HCl treatment of tinnitus is promising.

Adult↗

The medical treatment of tinnitus.

Currently there are three methods of treating patients with intractable tinnitus, a physical one using masking (Vernon, 1977), a psychosomatic method using biofeedback (House et al., 1977), and a chemical treatment using intravenous lidocaine and the oral anticonvulsants--carbamazepine, primidone and lidocaine amine. The latter seems to be the most promising, being easier to use, less time-consuming, more accurate to assess, and relying less on the patient's active participation and intelligence. The only disadvantages of the chemical method are the serious side-effects of the drugs in use. This can be managed by careful administration of these drugs and monitoring of the patient. In the future, new anticonvulsants with fewer side-effects will certainly be produced. It may be that chemical treatment can be combined with the masking and/or the biofeedback methods with a synergistic result. Another possible use of carbamazepine is in the treatment of palatal myoclonus and other similar disorders. Further clinical studies are needed to corroborate this application of the treatment.

Adult↗

On-line liquid-chromatographic analysis for drugs in serum with the Technicon "FAST-LC" system: performance data for theophylline and for four commonly used anticonvulsants and their metabolites.

We describe a new instrument for use in assay of therpeutic drugs in serum by "high-performance" liquid chromatography, the "FAST-LC" system (Technicon). Serum samples are aspirated directly into the unit, extracted with solvent, and the evaporated and redissolved extract is injected onto a chromatographic column. We illustrate the performance of the system by assays in serum for theophylline and four anticonvulsants (primidone, phenobarbital, phenytoin, and carbamazepine) plus two of their active metabolites (phenylethylmalonamide and carbamazepine epoxide). For theophylline, final chromatograms are monitored at 270 nm, at analysis rates of 10/h. Concentration and absorbance are linearly related from 0 to 130 mg of theophylline per liter. For the anticonvulsants, chromatograms are monitored at 200 nm, at analysis rates of 7.5/h. The six individual determinations are each linear beyond the therapeutic range. For both drug panels, day-to-day CV's were 4 to 6%. Results correlate well with those by enzyme immunoassay. A total sample volume of 150 microL is required.

Anticonvulsants↗

Essential tremor: an overview.

Essential tremor (ET) is typically 4 to 12 Hz frequency, absent at rest, maximal during maintenance of a posture, attenuated during movement and often accentuated at the termination of movement. Prevalence in Americans is 300 to 415 per 100,000 population, and it is frequently disabling. There is controversy about the central or peripheral origin of ET. There is no specific diagnostic test for ET; the diagnosis is made clinically. Ethanol is the most effective suppressor of ET. Treatment is with beta-adrenergic blockers, primidone, and benzodiazepines. The first systematic description of essential tremor (ET) was 100 years ago by Dana in 1887, who regarded the disorder as a hereditary tremor that was a form of "motor neurosis." Most subsequent contributions to the English literature consisted predominantly of case reports until Critchley's exhaustive survey of the subject in 1949. The disorder has been variously termed essential, benign essential, hereditary, familial, idiopathic, juvenile, presenile or senile tremor.

Adrenergic beta-Antagonists↗

Micro-scale anticonvulsant assay with use of nitrogen/phosphorus detector and on-column methylation compared with a macro-scale procedure involving flame-ionization detection.

We report a modified micro-scale gas-chromatographic procedure for determining phenobarbital, primidone, and diphenylhydantoin in serum with use of a nitrogen/phosphorus detector. Serum, 20 mul, is extracted into chloroform, the solvent is evaporated, and the residue dissolved in dilute (32 mmol/liter) trimethylanillinium hydroxide, which yields the methyl-derivatives of the drugs upon on-column injection. Within-run precision (CV) for the three drugs was 1.0, 2.1, and 1.4+, respectively, at concentrations of 19.2, 13.2, and 18.9 mg/liter; run-to-run precision at these concentrations was 4.4, 3.8, and 2.8%. Comparison of the 20-mul micro-scale procedure (y) with our conventional, flame-ionization macro-scale procedure (x), in which on-column methylation is used and which requires 1 ml of serum, gave the following respective results: y = 1.01 X -- 0.16 mg/liter, r = 0.992, y = 1.02 X + 0.29 mg/liter, r = 0.973; and y = 0.96x + 0.04 mg/liter, r = 0.996.

Anticonvulsants↗

Comparison of six procedures for the simultaneous determination of antiepileptic drugs.

A comparison of six gas-chromatographic procedures for the simultaneous analysis of antiepileptic drugs was made. Methylation with 0.2M trimethylanilinium hydroxide was superior to other derivatizing procedures evaluated. The methylated derivatives of phenobarbital, carba-mazepine, primidone, and diphenyl-hydantoin were separated on the chromatogram, and the peaks were sharp and symmetrical. The four drugs gave linear curves to twice their toxic levels.

Anticonvulsants↗

[Immunomodulatory therapy of epilepsy with transfer factor].

Effect of immunotherapy with Transfer factor administered for a period of three months was studied in a group of ten epileptic patients, treated with carbamazepine or primidon previously and throughout the study. Out of eight patients, who finished the study we could notice significant reduction of epileptic discharges in eight patients. The results of this study prove that addition of immunomodulatory treatment to patients with intractable epilepsy could substantially improve the course of the disease in some patients. (Tab. 1, Fig. 5, Ref. 13.)

Adolescent↗

Standards of laboratory practice: antiepileptic drug monitoring. National Academy of Clinical Biochemistry.

Discussion and development of standards for appropriate monitoring led to the following key recommendations for ordering, sampling, and analyzing antiepileptic drugs: Monitoring should usually be done on trough specimens after steady-state has been reached and always with an appropriate medical indication; non-steady-state concentrations may be indicated in selected situations. Monitoring of free phenytoin and free valproic acid is indicated in specific situations and should be done in serum. The metabolite of primidone, phenobarbital, should be measured concurrently with parent drug, but the active metabolite of carbamazepine does not need to be monitored unless the patient is exhibiting an unusual toxic response that cannot be otherwise explained. Assays used for antiepileptic drug monitoring should display a long-term CV of <10% and preferably <5%. Subtherapeutic and supratherapeutic drug concentrations should be investigated on a regular basis as part of a quality assurance process.

Anticonvulsants↗

["Primary" orthostatic tremor. 10 clinical electrophysiologic observations].

Orthostatic tremor is an unusual kind of potentially disabiling tremor appearing immediately when standing. Clinical examination is normal in primary form except for wide base standing and unsteadiness which disappear when walking. Arm tremor resembling essential tremor is found present in one third of cases. Electrophysiological exploration is necessary for diagnosis and shows a regular rapid tremor (frequency around 16 Hz). We present 10 new cases, 3 men and 7 women, 37 to 74 years old. Unsteadiness when standing was the predominant complaint in 9 cases, the other first described pains in the lower limbs. All had visible or palpable tremor predominant in thighs. Four patients had postural arm tremor, one had neurogen syndrome in the lower limbs corresponding to toxic polyneuropathy which developed after tremor. Electromyographic study found high frequency (13-17.3 Hz) rhythmic discharge in weight-bearing muscles. Orthostatic tremor cannot be considered as a clinical variant of postural essential tremor. Its pathophysiology is unknown but the efficacy of clonazepam, primidone or barbiturates suggests the impairment of the gabaergic system.

Adult↗

Therapeutic drug monitoring: measurements of antiepileptic and barbiturate drug levels in blood by gas chromatography with nitrogen - selective detector.

The nitrogen-specific detector for gas chromatography consists of a non-volatile rubidium silicate bead, around which nitrogen-containing compounds are pyrolyzed. Speed, sensitivity, specificity, accuracy, small sample size and minumum sample handling are characteristics of the nitrogen detector that render it superior to conventional gas chromatographic detectors. The detector has been utilized to effect a simple and rapid quantitation of allobarbital, amobarbital, butabarbital, heptabarbital, pentabarbital, phenobarbital and secobarbital, plus the anticonvulsants diphenylhydantoin and primidone. Extraction of the drugs from acidified serum into organic solvent containing internal standard is followed by oncolumn methylation with methanolic trimethylphenyl ammonium hydroxide. The drugs, separated on a column of 3 percent OV-101 on Gas-Chrom Q, 100-120 mesh are readily quantitated by simple calculations based on peak-height ratios. Therapeutic drug monitoring is discussed in relation to recent concepts of drug-protein binding, drug-drug interactions, drug biotransformation and problems of multiple drug therapy.

Amobarbital↗

Comparative trial of valproate sodium and clonazepam in chronic epilepsy.

A crossover comparative study of valproate sodium and clonazepam in the treatment of 32 adult epileptic patients receiving multiple drug therapy is described. Serum concentrations of other anticonvulsant drugs were unchanged by the addition of clonazepam. However, patients receiving high doses of other anticonvulsant drugs had lower serum concentrations of clonazepam (p less than .01). With valproate sodium, phenobarbital concentrations increased (P less than .05) in patients receiving phenobarbital but not significantly in patients receiving primidone. Phenytoin concentrations were reduced (P less than .05) during treatment with valproate sodium. Both drugs significantly reduced the frequency of minor seizures, with valproate sodium having the greater effect. However, it is important to monitor serum concentrations of other anticonvulsant drugs during treatment with valproate sodium since changes in these may influence seizure control or cause side effects.

Adult↗

Drawing-induced seizures.

In a review of the literature on triggering mechanisms in reflex epilepsy, we found no reported instance of drawing as the provoking factor. Recently we studied the case of a 17-year-old man with myoclonic seizures. These seizures were most effectively triggered by drawing, although occasionally they occurred spontaneously and could also be evoked by other activities requiring concentration. The results of a neurological examination were normal, and family history was unremarkable. Treatment with primidone and methsuximide has been very effective.

Adolescent↗

Pure red cell aplasia as possible early manifestation of chronic myeloid leukemia.

Cytogenetic studies as well as erythroid and myeloid progenitor cell assays were performed in a 29-yr-old epileptic man with pure red cell aplasia (PRCA) who had been treated with primidone for several years. Despite clinical evidence of preleukemia, our studies indicated an underlying atypical Philadelphia chromosome-positive myeloproliferative disorder. These laboratory findings were confirmed by the subsequent development of chronic myeloid leukemia (CML) which terminated in a CALLA-positive lymphoblastic crisis 32 months later. The rare concurrent occurrence of PRCA and CML and the possible inducing role of the preceding antiepileptic treatment are discussed.

Adult↗

Inhibitory effects of anticonvulsant drugs on cyclic nucleotide accumulation in brain.

Veratridine causes deplorization of excitable cells and produces marked elevation of adenosine 3',5'-monophosphate (cyclic AMP) and guanosine 3',5'-monophosphate (cyclic GMP) levels in incubated slices of mouse cerebral cortex. Phenytoin, carbamazepine, phenobarbital, primidone, phensuximide, methsuximide, alpha-methyl-alpha-phenylsuccinimide, and high concentrations of clonazepam are anticonvulsant drugs that preferentially prevent maximal electroshock seizures (MES) and generalized tonic-clonic convulsions; all these agents inhibit veratridine-induced accumulation of both cyclic AMP and cyclic GMP. In contrast, ethosuximide, trimethadione, valproic acid, and low concentrations of clonazepam are anticonvulsant drugs that act predominantly against Metrazol and absence seizures; these agents are ineffective or inhibit accumulation of only cyclic GMP. The results suggest that inhibition of cyclic AMP and cyclic GMP accumulation in depolarized brain tissue is a molecular neuropharmacological action characteristic of anticonvulsant drugs that have direct effects on cellular membrane function and prevent MES. Anticonvulsant drugs that do not inhibit accumulation of both cyclic AMP and cyclic GMP in depolarized brain tissue preferentially prevent Metrazol and absence seizures and probably exert their effects by altering neurotransmission mechanisms.

Animals↗

Impaired biotin status in anticonvulsant therapy.

In 264 epileptics undergoing long-term therapy with anticonvulsants, significantly reduced plasma biotin levels were found compared with a normal control group: 74% of the epileptics had biotin levels of 250 ng/L or less. In patients undergoing single-drug therapy, the mean plasma biotin levels for those treated with sodium valproate were higher than for those treated with phenytoin, primidone, or carbamazepine. The observed reduction in biotin levels might be a factor influencing the efficacy of these three anticonvulsants.

Anticonvulsants↗