Anticonvulsant effects

Long-acting barbiturates used as sedative-hypnotics and also for their anticonvulsant effects include phenobarbital (Luminal) and mephobarbital (Mebaral). 

Newer drugs ME (and 2) too slow to explain initial anticonvulsant effect. Increasing use in ME, PM, GM (5-15)... 

Additional in vivo studies on the biological activity of proanthocyani-dins investigating a series of behavioral activities (motihty, body weight gain, body temperature, motoric coordination, anticonvulsant effects and central analgesic activities) showed no or only moderate pharmacological effects [53]. On the other hand, dietary supplementation with cocoa pro-cyanidin supplements can dose-dependently prevent the development of hyperglycemia in diabetic obese mice [54]. 

Male Dublin-ICR white mice were administered pentylenetetrazol (dissolved in normal saline) by tail vein infusion. This slow intravenous infusion of PTZ to mice provided three consistent and easily measured endpoints for assessing anticonvulsant effects ... 

The profiles of anticonvulsant effects for phenobarbital, pheny-toin, and trimethadione were also determined in the PTZ model. 

We have evaluated the dose-related effects of PCP, ketamine, and selected anticonvulsant drugs on seizure activity in the hippocampal model of kindled seizures. The hippocampal model is particularly well suited for the study of the anticonvulsant effects of drugs because of the slow rate of acquisition of the fully kindled seizure. Electrical stimulation of the dorsal hippocampus initially evokes a stereotyped sequence of behavior, accompanied by a characteristic EEG pattern. Repeated electrical stimulation eventually results in generalized kindled seizures. This allows the testing of drugs on the unkindled hippocampal seizure (afterdischarge) to be compared to effects on the fully kindled seizure in the same rats. 

The results demonstrate anticonvulsant properties of PCP and ketamine in two quite different seizure models. On the one hand, ketamine was effective in antagonizing several components of PTZ activity. Others have previously reported anti-PTZ effects of ketamine. However, the present results demonstrate that the anticonvulsant effects of ketamine against PTZ seizures closely resembled the effects of phenobarbital in that both compounds delayed clonic convulsions and prevented tonic extension. Moreover, a low dose of ketamine, which alone showed no anticonvulsant effect or overt behavioral changes, potentiated the anti-PTZ effects of phenobarbita 1. These findings suggest that ketamine possesses selective anticonvulsant properties. The anticonvulsant mechanism of action for phenobarbital is not known. However, the similarities between ketamine and phenobarbital, and the interaction between the two compounds, suggest a common mechanism or site of acti on. 

On the other hand, the results using the hippocampal seizure model revealed an interesting profile of anticonvulsant effects for PCP and ketamine, compared to several classical anticonvulsant compounds. When tested against the unkindled hippocampal seizure, the effects of behaviorally equivalent doses of PCP and ketamine were remarkably similar, but differed substantially from the effects of the anticonvulsant drugs. The compression of the entire EEG seizure episode to a shorter duration was unique to PCP and ketamine, and suggests an anticonvulsant effect. Conversely, the small prolongation of the initial AD episode, and the decreased duration of the postictal depression, could be reflective of pro-convulsive influences. There were, however, no other indications of enhanced seizure activity, such as the appearance of motor convulsions or spread of seizure activity to the cerebral cortex. 

The pro- and anticonvulsant effects of the phencyclinoids were studied by assessing their ability to increase or decrease the intensity of electrically-induced convulsions. A 32 mA, 0.2-second stimulus was delivered via corneal electrodes with a constant-current electroshock apparatus. The shock parameters were chosen to produce a convulsion intensity of "3" on a five-point rating scale as follows 0 = stunned only, 1 = facial and vibrissae tremor, 2 = clonic forepaw treading, 3 = tonic forelimb extension, 4 = tonic forelimb and hindlimb extension, and 5 = death. Thus, both increases and decreases in the convulsion intensity subsequent to drug administration could be observed. 

Hayes, B.A., and Balster, R.L. Anticonvulsant effects of phencyclidine- 1ike drugs in mice. Fed Proc 44 724, 1985. 

PCP, like barbiturates, also has anticonvulsant effects in various animal models (Chen et al. 1959 Geller et al. 1981 Hayes and Balster 1985). Certain convulsants, such as strychnine, are not antagonized, and PCP has some specificity for tonic rather than clonic convulsions. 

Cannabinoids appear to have a very complex interaction with seizure activity, exerting both anticonvulsant and proconvulsant effects. Anecdotal testimonies abound (Grinspoon and Bakalar, 1993), but there has been very little controlled human research. In single-case studies both use and withdrawal of marijuana have been linked to the resumption of seizures (Keeler and Reifler, 1967 Consroe et al., 1975). In a randomised placebo-controlled blind study, patients who responded poorly to standard treatments experienced improved seizure control in response to cannabidiol administration. Cannabidiol does not interact with cannabinoid receptors, and animal studies indicate that it has different anticonvulsant effects to other cannabinoids (Cunha et al., 1980). As such it may prove to have useful therapeutic properties. 

Further, the removal of benzodiazepine sensitivity in a selective a subunit in a mouse using the gene knockin technique has established that the al subunit plays a major role in the sedative and amnesiac effects of benzodiazepines, part of the anticonvulsant effect and little of the anxiolytic effect the latter effects are more importantly mediated by the a2 subunit [5, 6], The 0 subunit selectivity for the drugs loreclezole (an anxiolytic) and etomidate (an anesthetic) allowed determination that a single residue in the M2 domain could account for this selectivity (02 = 03 >01). When a mouse knockin selectively removed the etomidate sensitivity of the 02 subunit, the animals showed reduced sensitivity to sedative effects of etomidate but no reduction of the true anesthetic effects. In contrast, mutation of the 03 subunit to negate etomidate sensitivity of that subunit alone resulted in a mouse with no sensitivity to the anesthesia produced by etomidate. This proved that the GABA receptor is the target of at least this one anesthetic (etomidate) and, furthermore, that the specific locations in the brain of 03 subunits are important for anesthetic action, while the... 

Adenosine and inosine can be transported across cell membranes in either direction, facilitated by a membrane-associated nucleoside transport protein. Concentrative transporters have also been identified. Messenger RNA for a pyrimidine-selective Na+-nucleoside cotransporter (rCNTl) and a purine-selective Na+-nucleoside cotransporter (rCNT2) are found throughout the rat brain. Most degradation of adenosine is intracellular, as evidenced by the fact that inhibitors of adenosine transport, such as dipyridamole, increase interstitial levels of adenosine. Dipyridamole is used clinically to elevate adenosine in coronary arteries and produce coronary vasodilation. In high doses, dipyridamole can accentuate adenosine-receptor-mediated actions in the CNS, resulting in sedation and sleep, anticonvulsant effects, decreased locomotor activity and decreased neuronal activity. 

Zolpidem, chemically unrelated to benzodiazepines or barbiturates, acts selectively at the y-aminobutyric acidA (GABAA)-receptor and has minimal anxiolytic and no muscle relaxant or anticonvulsant effects. It is comparable in effectiveness to benzodiazepine hypnotics, and it has little effect on sleep stages. Its duration is approximately 6 to 8 hours, and it is metabolized to inactive metabolites. Common side effects are drowsiness, amnesia, dizziness, headache, and GI complaints. Rebound effects when discontinued and tolerance with prolonged use are minimal, but theoretical concerns about abuse exist. It appears to have minimal effects on next-day psychomotor performance. The usual dose is 10 mg (5 mg in the elderly or those with liver impairment), which can be increased up to 20 mg nightly. Cases of psychotic reactions and sleep-eating have been reported. 

Myhrer T, Skymoen LR, Aas P. Pharmacological agents, hippocampal EEG, and anticonvulsant effects on soman-induced seizures in rats. Neurotoxicol. 24 357-367,2003. 

The anticonvulsant effect, as well as the hypertensive activity of yohimbine have also been studied (343, 344). It has been shown that yohimbine produces significant increases in subjective anxiety, autonomic symptoms, and blood pressure (345). 

A few of the phenyl esters of nipecotic acid were also examined for their anticonvulsant effects and found to be active. The most stable ester was also the most active, but more labile esters were also effective. Because nipecotic acid itself was not used for comparison, no conclusion can be derived regarding the pharmacological value of such prodrugs. 

Antiseizure effects One study examined antiseizure effects of chrysin on chemically induced (pentylenetetrazol) seizures in mice (Medina et al. 1997). Peripheral (IP) administration produced inconsistent effects, but central (intracerebroventricular) injection (40 pg) had a significant anticonvulsant effect. Further, this effect was abolished by prior injection of the benzodiazepine antagonist, Ro 15-1788 (3 mg/kg IP). 

The synthesis of these compounds will be described in Section 3.1, Opioid analgesics. Besides opioids, benzodiazepines (diazepam, lorazepam, and midazolam), which have anxiolytic, sedative, and anticonvulsant effects, that cause amnesia and muscle relaxation, are frequently used to relieve patients anxiety during anesthesia. 

Kozan, R., Sefil, F., and Bagirici, R. (2008). Anticonvulsant effect of carnosine on penicillin-induced epileptiform activity in rats. Brain Res. (in press). 

The story of the discovery of pregabalin (2) began in 1991, when Silverman and Taylor published a paper on the anticonvulsant effect of 3-alkyl GABA analogs (Silverman et ah, 1991). Out of this collection of compounds, 3-isobutyl GABA stood out as the most active analog in the series, which protected mice from seizures induced by corneal electroshock. 

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