Antiseizure properties

Sodium valproate, also used as the free acid, valproic acid, was found to have antiseizure properties when used as a solvent in the search for other drugs effective against seizures. It was marketed in France in 1969 but was not licensed in the USA until 1978. Valproic add is fully ionized at body pH, and for that reason the active form of the drug may be assumed to be the valproate ion regardless of whether valproic acid or a salt of the acid is administered. 

A large number of benzodiazepines have broad antiseizure properties, but only clonazepam (Klonopin) and clorazepate (Tranxene-SD, others) have been approved in the United States for the long-term treatment of certain types of seizures. Diazepam (Valium, Diastat, others) and lorazepam (Ativan) have well-defined roles in the management of status epilepticus. 

Most barbiturates have antiseizure properties. The discussion below is limited to the two barbiturates that exert maximal antiseizure action at doses below those required for hypnosis, a property that determines their clinical utility as antiseizure agents. The pharmacology of barbiturates is considered in Chapter 16. 

PHARMACOLOGICAL EFFECTS The antiseizure properties of valproic acid (DEPAKENE, others) were discovered serendipitously when it was employed as a vehicle for other compounds that were being screened for antiseizure activity. Its efficacy in animal models parallels its efficacy against absence as well as partial and generalized tonic-clonic seizures in humans. 

In animals, the profile of antiseizure properties for CBZ is similar to that of phenytoin. CBZ is effective in the maximal electroshock (MES) test (electrically induced seizure test) but is ineffective against pentylenetetrazole-induced seizures. It is not effective for absence or myoclonic seizures and, indeed, may exacerbate their onset (30,41). Like phenytoin, CBZ acts on voltage-dependent sodium channels to prevent the spread of seizures. CBZ depresses synaptic transmission in the reticular activating system, thalamus, and limbic structures. In a double-blind, crossover study in patients whose seizures were not controlled completely by combinations of AED, CBZ was equal in efficacy to phenobarbital and phenytoin in controlling seizure frequency, and side effects were minimal. 

The barbiturates are substituted pyrimidine derivatives with an ureide configuration (Fig. 20.4). They are lipophilic weak acids (pKa 7-8) that are weii distributed into brain (see Appendix A for the respective pKa values). Although many barbiturates dispiay sedative-hypnotic activity (see Chapter 19), oniy a few have antiseizure properties. Paradoxically, many barbiturates cause convulsions at larger doses. The barbiturates clinically useful as AEDs are phenobarbital, mephobarbital, and primidone (Fig. 20.8). In laboratory animals, phenobarbital is effective by several tests in nontoxic doses. It is active against electrically induced seizures (MES), and it elevates the threshold for pentylenetetrazole stimulation. The mechanism of antiseizure action for the barbiturates... 

Tribological investigations were carried out by means of a four-ball tester and a T-11 tester with a ball-on-disk friction pair. Antiseizure properties (scuffing load— A. seizure load—and limiting pressure of seizure—as well as motion resistance and wear at a constant load were determined using a four-ball tester. It has been found that ethoxylates used as additives significantly modify tribological properties. The measured A. Az> Poz values increase by as much as several times compared with water. The coefficient of friction and wear measured at a constant load decrease considerably to about half relative to water. 

The error in the complex quantity (p ) was determined by the total differential method, whereas the errors in individual quantities p and d are represented by standard deviation. A set of three quantities—scuffing load seizure load (PJ), and the limiting pressure of seizure (p )—characterizes the antiseizure properties of lubricating substances. 

Antiseizure properties were determined according to the methodology presented in the previous section. Changes in the friction force moment (Mj) as a function of increasing load (P) form the basis for the determination of individual quantities. As an example, this dependence for 0.5 wt% solutions of lauryl alcohols is shown in fig. 17.9. 

The individual curves represent 0.5 wt% solutions of alcohols of various oxyeth-ylation degrees. Studies were also carried out for water, which represents a reference system. The course of changes observed is relatively complicated, but it is possible to notice three intervals that differ in the rate of increase in the friction force moment. A slight increase can be observed at low loads, a moderate one at intermediate loads, and a rapid one ending with seizure at the friction force moment 10 N-m. Three quantities will be used to assess antiseizure properties scuffing load (P,), maximum seizure load (P ), and the limiting pressure of seizure (p. Seizure tests were carried out in the presence of oxyethylated lauryl alcohol solutions at concentrations of 0.1, 0.5, 1, 4, and 10 wt%, and for cetyl, oleyl, and stearyl alcohols at concentrations of 0.1,1, and 10 wt%. 

Antiseizure properties of oxyethylated alcohol solutions were described in terms of the values of Pj (figs. 17.10 and 17.11), (figs. 17.12 and 17.13), and p z (figs. 17.14 and 17.15). Surface-active agents were selected in a way that would make it possible to examine the effects of their structures on the tribological characteristics. It turns out that an increase in the hydrophilicity of the ethylene oxide chain (increase in m) causes an increase in antiseizure properties, whereas an increase in the hydrophobic-ity of the alkyl chain (increase in n) causes a reduction in these properties. The effect of the latter factor is weaker. The relations indicate that hydration of oxyethylates is the dominant process [62, 63]. The necessary condition for favorable antiseizure properties is the ability of the compound to undergo hydration and, thus, to maintain amphiphilic properties at higher temperatures. 

Summing up, all oxyethylated alcohols meet the criterion as additives that can significantly improve the antiseizure properties of water. Based on the results obtained, these properties can be associated with the structure of the compounds and depend on the changes in hydration together with temperature. 

Antiseizure properties were characterized by scuffing load (P,), seizure load (P x). and the limiting pressure of seizure (p. The tendency of changes in these three quantities as a function of alkyl and ethylene oxide chain lengths was analogous for most compounds. The measured values show a good correlation with the activity of the compounds that results from the alkyl chain length. Its increase caused a reduction in the amount of adsorbed additive and unfavorably affected the stability of the lubricant film. Contrary to all expectations, an increase in hydrophilicity of a... 

Interesting results were also obtained with regard to antiseizure properties of the compositions tested. None of the 1 wt% aqueous solutions caused seizure of friction pair elements in the load range of up to 8 kN. The lowest values of scuffing loads... 

In order to assess antiseizure properties, tests were performed at a linearly increasing load [130]. During the measuranents, the load increased from zero to 8000 N at a rate of409 N/s, and the rotational velocity was 500 rpm. After each test, wear was evaluated as an average of a wear-scar diameter measured in two directions parallel and perpendicular to the friction direction, d. Measurements of wear-scar profiles were also made in each case. 

Aqueous solutions (1%) of SML/ESMIS mixtures exhibited entirely different antiseizure properties than water. For SML/ESMIS mixtures, the obtained dependences of friction torque on time (a change in time is equivalent to increasing load) had a similar course. No sudden increase in friction torque was observed within the first seconds of the test. This shows that a relatively stable adsorbed film that effectively reduced the motion resistance was produced on the mating elements. Scuffing load was estimated from the dependences obtained (fig. 18.26). The results obtained are presented in fig. 18.27. The highest values were found for 1% aqueous solutions of mixtures with the 5 5, 3 7, and 1 9 ratios. These equaled, respectively, 2500 N, 2350 N, and 2300 N. Lower P values were obtained for the other compositions. For a solution containing the 7 3 SML/ESMIS mixture, the P, value was 2000 N, while for the ESMIS solution (0 10) the value was 1900 N. 

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