Anticonvulsants, analysis

A complete dose-response analysis was generated for PCP for doses from 0.625 to 20 mg/kg IP (data not shown). PCP exhibited dose-related anticonvulsant action when day one minus day three differ ence scores were compared for all doses tested. When retested with saline only on day five, no reduction in convulsant sever it or super-sensitive response was observed (day one minus day five), indicating no carryover drug effect 48 hours after dosing. At behavioral ly equivalent doses, all compounds assayed were clearly anticonvulsant (table 3). TCP was most potent at the doses tested. PCA was the most efficacious, and reduced convulsant severity by 2.58 points. As with PCP, none of the other phencycli-noids had any carryover effects 48 hours after dosing (day one minus day five). 

I with seizures and require anticonvulsant therapy. Phenytoin is the most frequently used agent, with a loading dose of 15 mg/kg followed by 300 mg by mouth daily (titrated to therapeutic levels between 10 and 20 mcg/mL). Diazepam 5 mg intravenously may be used for rapid control of persistent seizures. Prophylactic anticonvulsants have been used frequently, but a recent meta-analysis did not support their use.23 Thus, because adverse effects and drug interactions are common, the routine use of prophylactic anticonvulsants is not recommended. 

From the examination of structure-activity relationships, it has been concluded that a phenyl moiety at C-6 as well as a 4-hydroxypiperidine side-chain attached to C-3 of the pyridazine system is essential for anticonvulsant activity in this class of compounds [184], Compounds (54) and (55) have been found to have similar anticonvulsant profiles in animals (mice, rats and baboons) [165, and literature cited therein] and to represent potent broad-spectrum antiepileptic drugs. Their potency with regard to antagonizing seizures (induced by electro-shock or various chemicals) has been compared with standard anticonvulsants like carbamazepine and phenobarbitone [185, 186], A quantitative electroencephalographic analysis of (55) has been published [187]. From in vitro studies it has been concluded that the anticonvulsant activities of these compounds are not mediated by an enhancement of GABAergic transmission or by an interaction with benzodiazepine receptor sites [ 165,186,187], On the other hand, in vivo experiments showed that (54), at anticonvulsant doses, increases the affinity of flunitrazepam for its central receptor site [ 186], Investigations of (54) and (55) in a behavioural test predictive of antianxiety activity revealed a marked difference in the pharmacological profiles of these structurally closely related compounds the dichloro compound SR 41378 (55) has also been found to possess anxiolytic (anticonflict) properties [165],... 

Turkanis SA, Smiley KA, Borys FIK, Olsen DM, Karler R. (1979). An electrophysiological analysis of the anticonvulsant action of cannabidiol on limbic seizures in conscious rats. Epilepsia. 20(4) 351-63. Tyrey L. (1984). Endocrine aspects of cannabinoid action in female subprimates search for sites of action. NIDA Res Monogr. 44 65-81. 

Shen, M., Letiran, A., Xiao, Y., Golbraikh, A., Kohn, H., Tropsha, A. Quantitative structure-activity relationship analysis of functionalized amino acid anticonvulsant agents using k nearest neighbor and simulated annealing PLS methods./. Med. Chem. 2002, 45, 2811-2823. 

The potential benefits of regulating therapy on a precise biochemical basis are obvious. However, lack of suitable chemical methods of analysis has, until comparatively recently, limited biochemical monitoring of anticonvulsant therapy to a few specialized centers. Methodological problems still exist but routine phenytoin determinations now lie within the scope of any moderately well equipped clinical biochemistry laboratory. 

RPC has found use in the analysis of barbiturates including the determination of drugs taken in an overdose (332). Thiopental was determined using a mobile phase comprised of methanol-0.1% sodium citrate buffer, pH 6.5 (45 55) (333). Hydantoins, along with other species which have anticonvulsant activity, have been determined with barbiturates. These include phenytoin in the presence of phenobarbital and primidone (334,335) and the related anticonvulsants ethosuximide and carbamazepine (336). 

Potassium bromide is used to make photographic plates and papers and in engraving. Other uses are as a brominating agent in organic synthesis and in the bromate-bromide mixture in titrimetric analysis. In medicine potassium bromide is a sedative and anticonvulsant. 

Neuroimaging techniques assessing cerebral blood flow (CBF] and cerebral metabolic rate provide powerful windows onto the effects of ECT. Nobler et al. [1994] assessed cortical CBE using the planar xenon-133 inhalation technique in 54 patients. The patients were studied just before and 50 minutes after the sixth ECT treatment. At this acute time point, unilateral ECT led to postictal reductions of CBF in the stimulated hemisphere, whereas bilateral ECT led to symmetric anterior frontal CBE reductions. Regardless of electrode placement and stimulus intensity, patients who went on to respond to a course of ECT manifested anterior frontal CBE reductions in this acute postictal period, whereas nonresponders failed to show CBF reductions. Such frontal CBF reductions may reflect functional neural inhibition and may index anticonvulsant properties of ECT. A predictive discriminant function analysis revealed that the CBF changes were sufficiently robust to correctly classify both responders (68% accuracy] and nonresponders (85% accuracy]. More powerful measures of CBF and/or cerebral metabolic rate, as can be obtained with positron-emission tomography, may provide even more sensitive markers of optimal ECT administration. 

Pippenger, C.E. and Gillen, H.W. Gas chromatographic analysis for anticonvulsant drugs in biologic fluids. Clin. Chem. 15 582-590, 1969. 

Comparative analysis of known sodium channel blockers has resulted in several somewhat distinct models [88-91]. These models suggest that local anesthetic and anticonvulsant sodium channel blockers share a pharmacophore consisting of a hydrophobic group (typically an aryl ring) separated by 5-6 A from a hydrogen bond acceptor-donor group. 

Nafimldone Is an anticonvulsant drug with an obvious two-group disconnection of this type, nafimldone retroaynthatie analysis... 

Ikawa K, Eshima N, Morikawa N, Kawashima H, Izumi T, Takeyama M. Influence of concomitant anticonvulsants on serum concentrations of clonazepam in epileptic subjects an age- and dose-effect linear regression model analysis. Pharm Pharmacol Commun 1999 5 307-10. 

Epilepsy and osteoporosis are very common and frequently overlap. Nevertheless, the prevalence of low bone density appears to be disproportionately higher in patients with epilepsy, and patients with epilepsy have an excessive risk of fractures. A meta-analysis of 94 cohort studies and 72 case-control studies has shown that anticonvulsant treatment is highly associated with fractures (relative risk over 2) (117). Other risk factors were low body weight, weight loss, physical inactivity, consumption of corticosteroids, primary hjrperparathjroidism, type 1 diabetes melhtus, anorexia nervosa, gastrectomy, pernicious anemia, and age over 70 years. 

In addition to an extensive summary provided previously on this moiety (8), Brouillette et al. (209) employed comparative molecular field analysis (CoMFA), a three-dimensional structure-activity technique, to provide a new potential anticonvulsant, 2-hydroxy-2-phe-nylnonanamide (40), whose Na-i-channel inhibition (IC50 = 9 fiM) compared favorably to 40 yM for phenytoin (1). This study suggested that the hydantoin ring system is not necessary in Na+channel binding. Research on water-soluble prodrugs of phenytoin has continued since the work by Stella, which led to the synthesis of fosphenytoin (Id) (8,209-215). A... 

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