The new antiepileptic drugs: pharmacological and clinical aspects

In recent years several new drugs (oxcarbazepine, lamotrigine, topiramate, gabapentin, zonisamide, tiagabine, fosphenytoin, vigabatrin and felbamate) have been added to the therapeutic armamentarium against epilepsy. Some of these represent structural modifications of pre-existing compounds, others were developed with the specific objective of modifying neurotransmitter function, and many more were found to be clinically useful even though their mode of action is unclear or differs from that originally planned. The pharmacokinetics of these drugs differ widely from one agent to another. Some (gabapentin and vigabatrin) are eliminated unchanged in urine and have little or no interaction potential; others (tiagabine, lamotrigine, topiramate, oxcarbazepine, zonisamide, felbamate) are subject to induction of metabolism by concomitant anticonvulsants; lamotrigine is vulnerable to metabolic inhibition by valproate, and felbamate is a powerful enzyme inhibitor in addition to being an inducer of the metabolism of carbamazepine and steroid oral contraceptives. All new antiepileptic drugs have been found to be effective in improving seizure control in patients with partial and secondarily generalized seizures. However, lamotrigine, topiramate, zonisamide and felbamate appear to have broader efficacy against both partial and many generalized seizure types, while vigabatrin is also valuable in the management of infantile spasms. In monotherapy studies, new drugs have not been found to be more efficacious than older agents, but some may offer limited advantages in terms of improved tolerability. On the other hand, serious toxicity restricts considerably the use of vigabatrin and felbamate. Overall, new drugs represent valuable tools in the fight against epilepsy, but because of limited experience and cost considerations their first-line use cannot be recommended in most situations.     

The endocannabinoid signaling system: pharmacological and therapeutic aspects

Since the discovery of anandamide in 1992, our knowledge of the endocannabinoid system and its physiological effects has increased greatly, not the least as a result of the availability of compounds affecting endocannabinoid function. In the present review, the pharmacology of the endocannabinoid system is discussed. At present, there are no compounds selectively inhibiting the synthesis of anandamide, and the mechanisms by which anandamide release and reuptake are blocked are a matter for current debate. In contrast, selective agonists and inverse agonists at the CB1 and CB2 receptors have been well characterised, as have inhibitors of the metabolism of anandamide by fatty acid amide hydrolase. Accumulating evidence has suggested that such compounds may be useful for the treatment of a number of disorders. With respect to the treatment of pain, topical CB1 agonists and CB2 agonists may prove therapeutically useful, and there is evidence that the non-steroidal inflammatory agent indomethacin produces effects secondary to activation of the endocannabinoid system. Modulation of the endocannabionid system may also produce neuroprotective effects, although present data would suggest that the observed effects are highly dependent upon the nature of the neurotoxic insult.     

Antiplatelet drugs: clinical pharmacology and therapeutic use.

Because platelets are so important in thrombus formation, drugs which inhibit platelet function (the 'antiplatelet drugs') have considerable potential as antithrombotic agents. Among the antiplatelet drugs, only aspirin, sulphinpyrazone, dipyridamole, hydroxychloroquine, and clofibrate have had wide clinical trial. Their effects on platelet metabolism differ. Aspirin prevents platelet prostaglandin synthesis by acetylating and irreversibly inactivating platelet prostaglandin synthetase, while sulphinpyrazone is a reversible inhibitor of the same enzyme. Both aspirin and sulphinpyrazone impair the platelet release reaction and reduce platelet aggregation, but neither prevents platelet adhesion to the subendothelium or to foreign surfaces. On the other hand, dipyridamole reduces platelet adhesion as well as aggregation, probably by inhibiting phosphodiesterase and so raising platelet cyclic AMP levels. The effects of hydroxychloroquine and clofibrate have been less well defined. As the antiplatelet drugs form a diverse group of substances with differing effects on platelet function, it is hardly surprising that every potential clinical application of each antiplatelet drug or drug combination has had to be tested separately, and that these drugs have not proved to be equally effective. One or more antiplatelet drugs have now been evaluated in each of the following situations.     

Liver disease in drug addicts: clinical course-toxicological and clinical pharmacological aspects.

Drug addicts admitted to the hospital had acute hepatitis in 44%, chronic hepatitis in 34%, toxic liver injury in 16%. About 50% of the patients with acute hepatitis were HAA positive. Patients with intravenous drug abuse acquired acute hepatitis after a mean period of 1.8 years. Acute hepatitis in drug addicts shows a prolonged course in the majority of the cases. Biochemically increases in serum bilirubin and transaminase levels are less pronounced as compared to non-addicted persons. 30-35% of the patients develop chronic hepatitis. Speed abuse promotes the tendency to cholestasis in acute episodes of liver disease. A toxic effect of the drug preparations upon the liver cells is assumed. Chronic hepatitis in drug addicts mainly develops from earlier acute hepatitis with prolonged course. In our material, the percentage of chronic hepatitis at present is 47.5%. Besides toxic effects, also repeated infections have to be discussed with regard the etiology and pathogenesis of the disease.     

Antianxiety drugs: clinical pharmacology and therapeutic use.

It is difficult to choose among the many drugs advocated for treating anxiety symptoms. The barbiturates were the most commonly used antianxiety agents until recently but are being superseded by the benzodiazepines. The latter are more effective than the barbiturates as shown in comparative clinical trials, they are safer in overdosage (deliberate or accidental), and they are somewhat less likely to induce dependence. The barbiturates have the additional drawback of interfering with the action of other drugs by inducing liver microsomal (oxidising) drug metabolising enzymes. The major tranquilisers (neuroleptics or antipsychotics) are often of value in low dosage in patients with a previous history of dependence on alcohol, the barbiturates or the benzodiazepines. Tricyclic antidepressants are the treatment of choice in anxious and depressed patients and monoamine oxidase inhibitors may be helpful in phobic patients. The beta-adrenoreceptor blocking agents such as propranolol often ameliorate somatic symptoms such as palpitations and tremor. In the treatment of anxious patients it is important to remove causes for anxiety and to limit any course of drug treatment to a finite period. Both dosage level and dosage interval should be flexible. Benzodiazepines remain the drug treatment of choice.     

Melatoninergic receptor agonists and antagonists: pharmacological aspects and therapeutic perspective

Melatonin, or N-acetyl 5-methoxytryptamine, a neurohormone produced in the pineal gland during periods of darkness, plays a key role in the regulation of circadian and seasonal biological rhythms. In mammals, specific MT1 and MT2 receptors are located in the central nervous system, mainly in suprachiasmatic nuclei, and also in a number of peripheral sites. Besides its chronobiotic action on light-dependant functions, such as sleep/waking alternance or seasonal depression, melatonin exerts modulatory effects on immune, endocrine and metabolic functions. However, its short half-life and extensive metabolism lead to a poor bioavailability. This prompted to search for metabolically stable analogs displaying new and innovative properties. The S 20098 compound, a melatoninergic agonist, has proven potent antidepressive and anxiolytic actions. The S 20928 compound, a melatonin antagonist, was shown to enhance basal metabolism and reduce weight gain. Thus, both of these melatonin derivatives open perspectives for the development of innovative therapeutic agents in the fields of depression and obesity.