Pharmacotherapy of epilepsy.

Epilepsy represents the most common serious neurologic complications affecting approximately 1% of the world's populations. Although standard therapy permits control of seizures in about 80% of affected individuals, millions of global population have uncontrolled epilepsy. In the United States alone, the uncontrolled epilepsy represents more than 500,000 people. In the past decade, we have witnessed an array of new generations of antiepileptic drugs (AEDs) with more favorable pharmacokinetics and pharmacodynamic parameters, providing wider option to neurologists/epileptologists for more clinically effective and safer treatment. This was in part due to our better understanding of neural and molecular mechanisms in recurrent seizures. The new generations of AEDs currently include tiagabine, vigabatrin, lamotrigine, zonisamide, felbamate, oxacarbazine, topiramate, and gabapentine. There will be newer generations of AEDs being developed by pharmaceutical companies in United States, Japan, and European countries and will enter into global market sometimes during this decade. Although more clinical trails concerning the existing new generations of AEDs are needed, the available data suggest that in principal, these agents offer advantageous in terms of seizure control, fewer side effects and drug-drug interactions compared to traditional agents phenytoin, carbamazepine, phenobarbital, and valproate. The new generations of AEDs are significantly more expensive than the traditional agents. The two most clinical concerns over the use of traditional AEDs include (i) deleterious adverse effects and (ii) drug interactions, however, these agents are widely used in the third world countries. A thorough understanding of clinical pharmacology of both traditional and new antiepileptic agents will enable clinicians to have better appreciation of their clinical use and the treatment outcome, especially when the traditional agents are pharmacoeconomically preferred. Clinical pharmacology of AEDs is a vast science in medicine consisted of two principal arms, (i) pharmacokinetics and (ii) pharmacodynamics. This article briefly describes the pros and cons of common AEDs in practice, with more emphasis on new AEDs.

Pyrrolo[2,3-d]pyrimidine nucleosides as inhibitors of human cytomegalovirus.

Seven arabinosyl, 2'-deoxyribosyl, and ribosyl pyrrolo[2,3-d]pyrimidines were evaluated in vitro for activity against human cytomegalovirus and for cytotoxicity in primary and established cell lines of human origin. The parent ribosyl analogs exhibited little antiviral selectivity owing to high cytotoxicity. In contrast, ara-tubercidin, ara-toyocamycin, ara-sangivamycin, and deoxysangivamycin exhibited selectivity between antiviral effect (measured by plaque or titer reduction or both) and cytotoxicity (measured microscopically and by incorporation of radioactive precursors into DNA, RNA, and protein). The selectivity (in vitro therapeutic indexes) for these four compounds ranged from 2 to 40. The two sangivamycin analogs were the most potent and selective. Ara-sangivamycin, for example, inhibited virus replication 10(5)-fold at a concentration (10 microM) which produced only partial inhibition of cell growth and labeled precursor incorporation. The four arabinosyl and deoxyribosyl nucleosides appeared to act by inhibition of viral DNA synthesis as quantitated by DNA-DNA dot blot hybridization. These four analogs also were tested for activity against two strains of type 1 herpes simplex virus by a plaque reduction assay. Unexpectedly, all compounds inhibited herpes simplex virus to a lesser extent than human cytomegalovirus.