S. Piredda

The Free Fraction of Valproic Acid in Tears, Saliva, and Cerebrospinal Fluid

Summary: Valproic acid (VPA) was determined by EMIT® assay in plasma, tears, saliva, and cerebrospinal fluid (CSF) of patients with epilepsy. Closer correlation was shown between tear/plasma and tear/CSF ratios than between saliva/plasma and saliva/CSF ratios. The VPA CSF/serum ratio was in good agreement with data in the literature. Salivary levels were extremely erratic, while those for tears were much more reliable. Determination of VPA in tears is therefore the best method of studying the VPA free fraction in those cases in which investigations of protein binding of the drug are necessary.

Ethosuximide in tears, saliva, and cerebrospinal fluid.

Ethosuximide (ESM) was determined by the EMIT technique in tears, saliva, cerebrospinal fluid (CSF), and plasma of epileptic subjects. CSF/ plasma, saliva/plasma and saliva/CSF ratios were in good agreement with gasliquid chromatography (GLC). The tears/plasma ratio was not significantly different from the saliva/plasma ratio, although the standard deviation was higher in the latter. These data indicate that ESM can be determined in a quantitatively similar manner in both saliva and tears by EMIT.

Diphenylhydantoin and primidone in tears.

Summary: Diphenylhydantoin (PHT) and primidone (PRM) were determined by the EMIT® technique in the plasma, tears, saliva, and CSF of epileptic patients. Results indicate for PHT that tear values are more strictly correlated than are the saliva values to plasma and CSF concentrations. As for PRM, the data obtained show great interindividual variability of concentration in the different body fluids–in agreement with the wide range of both protein binding and half‐life of this drug.

Carbamazepine‐10,11‐Epoxide Determined by EMIT Carbamazepine Reagent

Carbamazepine‐10,11‐epoxide (CBZ‐OX) was determined in physiological solutions by means of EMIT carbamazepine reagent. It was recognized as 12 to 20% of the total amount, the cross‐reaction being higher at lower CBZ‐OX concentrations. A correction for CBZ‐OX is necessary when one wants to correlate EMIT carbamazepine values with gas‐liquid chromatography values. However, this correction is relevant only for body fluids other than plasma, since the unbound fraction of CBZ‐OX would greatly influence the ultrafiltrate serum ratios.

The quantification of myotonia ☆: A problem in the evaluation of new antimyotonic drugs

The evaluation of an antimyotonic drug is often difficult since the severity of myotonia is itself hard to assess. The rise in arterial potassium level produced by the infusion of increasing concentrations of potassium chloride brought about reproducible changes in the excitability level of myotonic muscles proportional to the plasma potassium concentration. The excitability changes were assessed by three methods commonly used for evaluating antimyotonic drugs. The duration of the electromyographic relaxation time after maximal voluntary effort proved to be the only test which reliably assessed the variations of muscular excitability proportional to the increased plasma potassium. By contrast, the duration of percussion- or electrically-induced myotonic after-discharges was extremely variable and independent of plasma potassium.

Brain Uptake of Carbamazepine in the Cat

Summary: Carbamazepine (CBZ) was determined by EMIT® assay in plasma, cerebrospinal fluid (CSF), and brain samples of cats after administration of the drug (40 mg/kg, i.p.). Plasma and CSF levels increase in a parallel manner from time 0 to 90 min after completion of injection, indicating a passive transport from one body fluid to the other. Brain levels reach a steady state at 15 min, with no significant difference being found between the concentrations at 15, 30, 60, and 90 min postinjection; this indicates that substantial early binding occurs in the brain. Since peak CSF concentrations occur at 90 min, concomitant with those for plasma, while brain levels are already high at 15 min, it is likely that CBZ enters the two compartments by independent mechanisms.

Psychotic onset of multiple sclerosis

A case is reported of a woman in whom acute manic attacks were followed later in life by neurological signs of multiple sclerosis, thus suggesting a possible correlation between the two clinical entities.SommarioÈ descritto il caso di una donna in cui la sclerosi multipla fu preceduta da attacchi acuti di tipo psicotico (maniacale).

Correlations between cerebellar activity and chronic nontoxic administration of phenytoin in rats

Summary: The effect of long‐term nontoxic treatment with phenytoin on the cerebellar Purkinje cell activity as determined by simultaneous monitoring of plasma and cerebellar levels of the drug has been studied in rats for the first time. The electrophysiological observations allowed the analysis of the spontaneous firing rate of the Purkinje cells and of the cerebellar field potentials generated by electrical stimulation of the ipsilateral radial nerve. The responses of single Purkinje cells to radial nerve stimulation were studied by constructing poststimulus time histograms and cumulative frequency distributions. The chronic treatment with phenytoin, which did not induce motor impairment or cerebellar symptoms, modified the firing rate of the Purkinje cells and the two modalities of Purkinje cell activation. In fact, phenytoin decreased significantly the spontaneous activity of the Purkinje cells and modified the strength of the mossy and climbing afferents.

Cerebellar Impairment Following Acute Nontoxic Administration of Phenytoin in Rat

Summary: In awake paralyzed Wistar rats, the following effects of an acute nontoxic dose of phenytoin (PHT) on different parameters of cerebellar electrical activity were evaluated: spontaneous discharge rate of single Purkinje cells (P‐cells), field potentials, and responses of P‐cells generated by electrical stimulation of a forelimb nerve. Variations of the response of single neurons located in the inferior olive were also studied, in order to assess the effects of PHT on this precerebellar relay station. The drug was administered orally and plasma and cerebellar levels regularly estimated. The results indicate that an acute, nontoxic dose of PHT is associated with an increase of P‐cell firing rate. This finding is supported by the analysis of the frequency distribution of in‐terspike intervals, and by the field potentials, P‐cell, and olivary responses induced by stimulation of a radial nerve. In addition, it was observed that the increase in P‐cell firing was mainly depending upon a higher activity of the climbing fibers. The increase in the response of P‐cells and olivary cells was correlated with plasma and cerebellar drug levels. The conclusion was reached that PHT increases the cerebellar cortical activity through two mechanisms: (a) by acting directly on the cerebellar P‐cell; and (b) indirectly by acting on the origin of climbing fibers at the inferior olive nucleus.

Normal Brain Distribution of Carbamazepine in Cat Penicillin Focal Epilepsy

Summary: Carbamazepine (CBZ) brain distribution was studied in cats rendered epileptic by penicillin topically applied on neocortex. CBZ penetration into the focus did not differ significantly from penetration into the other areas of the brain, with the drug rapidly entering the cerebral tissue (peak at 30 min). As no difference was found between CBZ brain concentrations at 15 and 90 min, substantial early binding of the drug was confirmed in this experimental model of epilepsy. As CBZ was able to decrease rapidly the spike frequency of the penicillin focus, it may be speculated that it was also able to prevent the metabolic alterations associated with severe epileptogenesis that would have caused an impaired CBZ brain distribution.