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Biomedical subjects

D M Treiman

Publications and source records attributed to D M Treiman.

At least 19 recordsLinked to original sources
PubMed1992

Valproic acid treatment of experimental status epilepticus.

The efficacy of valproic acid (VPA) in control of generalized convulsive status epilepticus was tested in a rat model. Rats with cortical cobalt lesions were injected with homocysteine thiolactone to induce secondarily generalized tonic-clonic seizures (GTCS). The median effective dose (ED50) for control of GTCS was 211.9 mg/kg (270 micrograms/ml in serum 30 min post dose) when treatment was given intraperitoneally after the second GTCS. VPA entered both serum and brain very rapidly after injection, with little change in concentration from 5 to 30 min post dose. In earlier experiments with phenytoin, phenobarbital, diazepam and lorazepam in this model, we found that the serum concentrations produced by the ED50s versus GTCS were very similar to those which have been reported to be effective in treating human status epilepticus. If this same relationship holds true for VPA, we would predict that a serum concentration of around 270 micrograms/ml VPA would be required for control of generalized convulsive status epilepticus in human patients. The safety of this high a concentration of VPA has not been tested.

Animals↗
PubMed1991

Motor and electroencephalographic response of refractory experimental status epilepticus in rats to treatment with MK-801, diazepam, or MK-801 plus diazepam.

Pharmacologic control of refractory status epilepticus has been little-studied in experimental models. In this experiment, rats in status epilepticus induced by lithium and pilocarpine were treated with MK-801 alone, diazepam alone or MK-801 plus diazepam, with treatment begun at a time when this model of status is refractory to anticonvulsant drugs. EEG samples were digitized before and for two hours after treatment, and the digitized samples subjected to computerized frequency analysis. MK-801 plus diazepam halted all manifestations of status epilepticus. Although neither MK-801 alone nor diazepam alone stopped the ongoing electrographic status epilepticus, both drugs diminished motor seizures and total EEG power. MK-801 treatment prevented the progression of changes in EEG pattern which normally occurs in this model of status epilepticus, while diazepam did not. MK-801, with and without diazepam, allowed the rats to survive the episode of status epilepticus, but rats treated with MK-801 alone required several days to recover completely, while the MK-801 plus diazepam rats appeared normal the next day. MK-801 may be a useful agent for treatment of human refractory status epilepticus, because of its neuroprotective action as well as its ability to potentiate GABAergic drugs.

Animals↗
PubMed1991

Design of an individualized fixed-dose clinical trial to test the antiepileptic efficacy of a plasma flunarizine concentration.

Flunarizine (FLN) is a potential antiepileptic drug whose pharmacokinetic properties include a long half-life (2-7 weeks) and high interpatient variability in volume of distribution and clearance. The National Institutes of Health (NIH) is sponsoring a randomized, double-masked, multicenter, parallel-group, placebo-controlled clinical trial to demonstrate the antiepileptic activity of FLN. The design is based on the premise that plasma concentrations are more strongly related to drug response than are doses. For each patient, an estimate of the concentration-time curve following a single dose of FLN is used to determine a loading dose and maintenance dosage targeted at a specified plasma FLN concentration. After an inpatient, drug-loading period, the fixed maintenance dosage (of FLN or placebo) is prescribed for the entire 24-week outpatient treatment period unless a change is required for medical reasons. If the target concentration is well chosen and approximately achieved, this design has several potential advantages: (a) A fixed-dose design is simpler and less subject to bias than a design involving dosage adjustments; (b) the drug-loading period reduces from several weeks or months to 1 week the time required to achieve the target plasma FLN concentration; (c) compared with a design in which each patient receives the same dose, the decreased variability in FLN concentrations should result in fewer patients receiving subtherapeutic doses and fewer patients requiring dose reductions, as well as increased power to detect treatment effects in a population where such effects are generally small.

Data Interpretation, Statistical↗
PubMed1991

Multicenter long-term safety and efficacy study of vigabatrin for refractory complex partial seizures: an update.

We followed 66 patients with refractory complex partial seizures and a favorable initial response to vigabatrin for 5 to 72 (median, 43) months. Thirty-seven patients discontinued vigabatrin for the following reasons: benefit-to-risk evaluation, 8; seizure breakthrough, 6; adverse events, 6; seizure breakthrough and adverse events, 5; moved or lost, 4; no longer eligible for study, 2; non-drug-related death, 2; narcotic abuse, 1; and patient request, three. There were no clinically significant abnormalities in laboratory studies including SMA 12, complete blood count, ECG, EEG, and visual evoked response testing, and no toxicity other than reversible, dose-dependent side effects. Based on this and other long-term data, clinical trials of vigabatrin have resumed in the United States and Canada.

Aminocaproates↗
PubMed1991

Psychobiology of ictal aggression.

1. Aggression in animals has been classified into a number of stereotyped behavioral responses on the basis of the psychosocial environment in which it occurs. Many such responses can be either replicated or blocked by stimulation or ablation of selected sites in the brain, especially in the hypothalamus or amygdala. Stimulation of the amygdala or the hypothalamus in a limited number of humans has produced agitation, anger, or rage. Ablation of the amygdala has reduced aggression in violent patients. However, the ictal nature of episodic aggression in these patients has not been proven. 2. The diagnosis and classification of epileptic seizures is based on their characteristic clinical manifestations and electrical patterns. Independent objective markers of ictal events need to be identified. Epileptic seizures are characterized by stereotyped nondirected behavior, especially at onset. The more organized, directed, and modifiable by the environment the behavior is, the less likely it is epilepsy. 3. Ictal aggression can be classified into primary and secondary ictal aggression, resistive violence, and postictal psychosis. Few alleged cases of ictal violence or aggression fulfill criteria for ictal events; most which do are examples of resistive violence. 4. If animal models can be developed which exhibit spontaneous paroxysmal stereotypical aggression, they may be used to improve our understanding of the classification and pathophysiology of ictal aggression.

Aggression↗
PubMed1990

High-performance liquid chromatographic determination of selected amino acids in rat brain by precolumn derivatization with phenylisothiocyanate.

We describe here a simple, sensitive, selective and reproducible assay method for quantitative determination of aspartate, glutamate, serine, glutamine, glycine and gamma-aminobutyric acid in rat brain using reversed-phase high-performance liquid chromatography. The method is based upon formation of phenylthiocarbamyl derivatives of the amino acids. Good resolution of the six amino acids and the internal standard norvaline is achieved within 40 min. Other amino acids which have been reported to be present in rat brain do not interfere with the analysis. Standard curves for each of the amino acids exhibited good linearity (r greater than 0.9993) over the range 0.5-20 nmol. The coefficient of variation for the intra-day and inter-day determinations ranged from 0.4% at the highest to 11% at the lowest concentration limit. Storage of whole brains at -0 degrees C for up to 8 weeks did not affect mean concentrations of the six amino acids.

Amino Acids↗
PubMed1990

Analysis of lorazepam in rat brain using liquid/liquid and solid-phase extraction in combination with high performance liquid chromatography.

A method for the determination of lorazepam in rat brain is described using liquid/liquid and solid-phase extraction, followed by high performance liquid chromatography. After addition of chlordiazepoxide as the internal standard, 100 mg brain tissue was homogenized and incubated with alkaline protease. Lorazepam and chlordiazepoxide were extracted three times with toluene. After treatment through a C18-Bond Elut column, lorazepam and chlordiazepoxide were analyzed isocratically on a reversed-phase column with a mobile phase consisting of methanol +0.025 M sodium phosphate buffer (66:34, v/v). The eluted drugs were monitored by their absorption at 240 nm. The sensitivity limit of this method was 10 ng of lorazepam per 100 mg of brain tissue sample. The standard curve was linear over the range of 20 to 200 ng lorazepam. The coefficient of variation for day-to-day precision established by 21 replicate analyses was 4.5 to 13.6%.

Animals↗
PubMed1990

Brain amino acid concentration changes during status epilepticus induced by lithium and pilocarpine.

Amino acid concentrations were measured in specific structures from the brains of rats decapitated before and during the course of status epilepticus induced by lithium and pilocarpine, with the stages of status defined by the electroencephalographic (EEG) pattern displayed. Early status was marked by discrete seizures on EEG, mid status by continuous spiking, and late status by periodic epileptiform discharges. Aspartate levels were lower than control levels in most regions prior to the onset of status. The decline continued and reached statistical significance in different regions at times from early to late status. Glutamate concentrations were typically higher than control just prior to status onset and then decreased in a manner similar to aspartate, but with less percentage change. gamma-Aminobutyric acid increased during status, with the earliest statistically significant differences observed in mid status. These changes were observed in most forebrain structures studied, but the largest percentage changes in excitatory amino acid concentration were found in substantia nigra, where they fell to less than half of control.

Amino Acids↗
PubMed1990

Efficacy of ACC-9653 (a phenytoin prodrug) in experimental status epilepticus in the rat.

Status epilepticus was induced by injection of homocysteine thiolactone to rats with epileptogenic cortical cobalt lesions. Either standard phenytoin or ACC-9653 (a phenytoin prodrug) was injected after the second generalized tonic-clonic seizure. Rats treated with ACC-9653 had significantly poorer treatment outcomes than rats treated with standard phenytoin, although no differences were found in the concentration of phenytoin in plasma or brain 65 min after injection.

Animals↗
PubMed1990

Lorazepam treatment of experimental status epilepticus in the rat: relevance to clinical practice.

We studied the efficacy, pharmacokinetics, and brain entry of lorazepam in the treatment of status epilepticus (SE) using a rat model of secondarily generalized convulsive SE. Lorazepam entered the bloodstream rapidly following intraperitoneal injection. Brain concentrations peaked 10 minutes after peak serum levels were achieved. Lorazepam remained in brain longer than in serum, leading to increasing brain: serum ratios over time once peak serum levels had been reached. Free lorazepam was 9.1% of the total concentration in serum, a fraction similar to that which has been reported for humans. The median effective dose for control of generalized tonic-clonic seizures in this model was 0.94 mg/kg, which would produce a serum concentration of 196 ng/ml. Rats in SE had higher serum lorazepam concentrations than controls given the same doses, but lower brain: serum ratios, perhaps due to lactic acidosis during SE. Our data confirmed clinical reports of lorazepam's effectiveness as a treatment for SE and suggest that a target serum concentration of 200 ng/ml should be effective in most cases and provide seizure protection for 24 hours following treatment.

Animals↗
PubMed1990

The role of benzodiazepines in the management of status epilepticus.

Benzodiazepines are the most potent drugs used in the management of status epilepticus (SE). A number of presynaptic, postsynaptic, and nonsynaptic actions of benzodiazepines have been described. However, only the benzodiazepines' enhancement of gamma-aminobutyric acid (GABA)ergic inhibition and their reduction of repetitive firing occur at concentrations of unbound drug comparable to those that block absence seizures or stop clinical SE in patients. Thus, it is likely that these actions contribute to antiepileptic and anti-SE efficacy of the benzodiazepines. A predictable sequence of progressive electroencephalographic (EEG) changes during the course of generalized convulsive SE, both in humans and in experimental models, has been recently described. The homology of the sequence of EEG patterns in patients and in experimental models supports the concept that animal models should be useful in evaluating the treatment of clinical SE, and benzodiazepines are effective in stopping SE in a number of animal models. Late SE in animals, however, as in humans, is less responsive to treatment than is early SE. Forty-seven clinical studies in which clonazepam, diazepam, or lorazepam was used in the treatment of SE have been reported. Overall, lasting control of SE was achieved in 79% of the 1,346 patients in these noncontrolled studies. However, no data yet exist to differentiate the efficacy of 1 of the benzodiazepines from that of the others. Therefore, the choice of benzodiazepine is best determined by availability and by pharmacokinetic differences. Because of a much smaller volume of distribution of unbound drug, lorazepam appears to have a significantly longer effective duration of action against SE than does diazepam, which is rapidly redistributed to lipid stores in the body after intravenous administration. For this reason, we now use lorazepam in the initial treatment of patients with generalized convulsive SE.

Action Potentials↗
PubMed1989

A multicentre study of vigabatrin for drug-resistant epilepsy.

1. Vigabatrin (GVG) was given in a single-blind fashion to 89 patients with complex partial seizures (CPS) refractory to conventional drugs. 2. The median number of CPS per month decreased from 11.0 to 5.0 after addition of GVG, and 51% of patients had a 50% or greater decrease in CPS frequency (P less than 0.001). 3. Side effects (principally drowsiness, ataxia, headache) occurred mainly during the initiation of therapy and decreased during therapy. After 12 weeks on GVG side effects significantly interfered with functioning in only 13% of patients, and the efficacy: toxicity ratio warranted continued administration in 74% of patients. 4. Co-administration of GVG resulted in a mean decrease of 20% in phenytoin serum concentration (P less than 0.001). 5. Sixty-six patients having a favourable response to GVG during the single-blind study have been followed for 6-54 (median 33) months on GVG. Only 17 patients have dropped out of long-term follow-up due to break through seizures and/or side effects. No serious systemic or neurological toxicity has been detected.

Adult↗
PubMed1989

Pharmacokinetics and clinical use of benzodiazepines in the management of status epilepticus.

Benzodiazepines are potent and effective drugs for the management of acute seizures and status epilepticus. Lorazepam, diazepam, and clonazepam have been the most widely studied of the benzodiazepines in the treatment of status epilepticus. In 47 studies of these drugs involving 1,455 patients, lasting control of status epilepticus was achieved in 79% of the patients. None of these benzodiazepines is clearly superior to another for the effective control of status epilepticus. Differences in pharmacokinetic parameters, therefore, will influence the choice of drug. All three benzodiazepines are lipid-soluble and enter the brain within seconds to minutes after intravenous administration. Diazepam, however, is very lipid-soluble and highly protein-bound and thus has a very large volume of distribution of unbound drug. As a result, the effective duration of action of diazepam in status epilepticus is only 20 to 30 min, whereas that of lorazepam, which has a much smaller volume of distribution of unbound drug, is at least several hours after a single intravenous injection. This allows the orderly administration of an antiepileptic drug for long-term seizure control after status epilepticus has been controlled. For this reason, lorazepam is preferable for the initial management of status epilepticus. Continuous intravenous infusion of diazepam has been used successfully in the management of some patients with status epilepticus refractory to initial treatment.

Benzodiazepines↗
PubMed1989

gamma Vinyl GABA: current role in the management of drug-resistant epilepsy.

The goal of management in epilepsy is to make patients completely seizure-free without side effects. Currently, this goal can be achieved fully in only about one-half of the 50,000,000 people in the world with epilepsy. Epilepsy is not a benign condition. Uncontrolled epilepsy produces significant morbidity and mortality. Even infrequent seizures put a patient at risk of sudden death and compromise employability and other social functions. The potential risk of a new antiepileptic drug has to be weighted against the potential risk of continuing seizures and the potential for the new drug to control those seizures. Vigabatrin (gamma vinyl GABA, GVG) is one of the promising new antiepileptic drugs now under development. In four large clinical trials half of the patients in each trial had a greater than or equal to 50% reduction in seizure frequency when GVG was added to existing antiepileptic drug. This represents a significant response rate in add-on trials, which are a severe test of a new antiepileptic drug. Although microvacuoles have been seen in the white matter of the brains of rats and dogs treated with GVG, such pathological changes have not yet been observed in humans. Evoked potential studies have failed to reveal any evidence of microvacuolization in humans. Because of the potential efficacy of GVG in controlling previously therapeutic-resistant seizures and of the absence of evidence of significant toxicity in humans, carefully monitored clinical trials of GVG in therapy-resistant patients with epilepsy should continue.

Aminocaproates↗
PubMed1988

Response of status epilepticus induced by lithium and pilocarpine to treatment with diazepam.

Status epilepticus (SE) was induced in rats by administration of 3 mmol/kg lithium chloride followed 24 h later by injection of 25 mg/kg pilocarpine. Treatment with 20 mg/kg diazepam was initiated at the time each of four EEG patterns was seen: (i) discrete electrographic seizures; (ii) waxing and waning epileptiform activity; (iii) continuous, high-amplitude, rapid spiking; and (iv) periodic epileptiform discharges (PEDs) on a relatively flat background. Success of diazepam in stopping all seizure activity was predicted by the EEG pattern seen at the time of treatment. All rats treated while displaying discrete electrographic seizures had status stopped with diazepam, but only three of six with waxing and waning epileptiform activity and one of six each with continuous spiking and PEDs. Rats which continued to seize had a decrease in spike amplitude of 74.8 +/- 18.25% following diazepam injection. These data confirm the clinical impression that the longer the duration of status epilepticus, the more difficult it is to control and suggest that the EEG pattern at the time of treatment predicts the probability of success.

Analysis of Variance↗