The diagnosis is made upon the history of absence seizures during early childhood without other seizure types and the observation of 3 Hz generalized spike waves paroxysmal discharges on the EEG. In children with CAE without atypical features electroclinical features, no neuroimaging is needed. Management
There are three antiepileptic drugs that have been used for the first-line treatment for CAE; these are ethosuximide (ETX), valproic acid (VPA), and lamotrigine (LTG). ETX is an effective first-line treatment for seizures only by blocking the low-threshold calcium currents produced by T-type calcium channels in the thalamus. The peak level occurs after 3–5 hours of intake; steady levels of the drug in the blood are achieved after 7–10 days of the same daily dose. The usual dosage is 20–30 mg/kg/day divided into two doses. Common side effects include gastrointestinal disturbances such as hiccups, vomiting, abdominal discomfort, and diarrheic and exceptionally. The other symptoms, like fatigue, insomnia, dizziness and ataxia. Valproate (VPA) has also been proven effective monotherapy in CAE although ETX is usually preferred as it has a lower impact on attention according to the Childhood Epilepsy study. There are several mechanisms related to VPA’s antiepileptic action, including raising the level of gamma-aminobutyric acid (GABA), calcium-dependent potassium activating, and blocking of voltage-sensitive sodium channels, but there is no specific evidence for the mechanism by which VPA controls absence seizures.
Cobicistat is a potent inhibitor of cytochrome P450 3A enzymes, including the important CYP3A4 subtype. It also inhibits intestinal transport proteins, increasing the overall absorption of several HIV medications, including atazanavir, darunavir, and tenofovir alafenamide. Chemistry
Cobicistat is a drug analogue of ritonavir, in which the valine moiety is exchanged for a 2-morpholinoethyl group, and the backbone hydroxyl group is removed. These changes effectively eliminate the anti-HIV activity of ritonavir while preserving its inhibitory effects on the CYP3A isozyme family of proteins. Cobicistat is therefore able to increase plasma concentration of other coadministered anti-HIV drugs without the risk of causing cobicistat-resistant mutations in the HIV virus. Synthesis
Cobicistat may be synthesized from any number of commercially available starting materials. The synthesis shown below utilizes L-methionine and bromoacetic acid as starting materials. Discovery and development
Cobicistat was developed through structure-activity relationship studies using ritonavir and desoxyritonavir as lead compounds. These studies were conducted by scientists at Gilead Sciences, and successfully optimized ritonavir into a potent CYP3A inhibitor lacking anti-HIV activity. Cobicistat shows potent, selective inhibition of the CYP3A isozyme family (IC50 0.15 μM) compared to some CYP1A and CYP2C isozymes. As cobicistat was discovered using structure-activity relationship studies, its CYP3A binding is still poorly understood; however, research on the protein-ligand interactions between CYP3A4 and ritonavir analogues demonstrates that CYP 3A4 residues Ile369, Ala370, Met371, as well as Arg105 and Ser119, play an important role in ritonavir analogue inhibition of CYP3A4. References
External links
"Cobicistat". Drug Information Portal. U.S. National Library of Medicine.