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.
Reconstruction is usually very challenging and should be delayed until full recovery (usually about one year following initial intervention). Prognosis
Noma is associated with a very high morbidity, and a mortality rate of approximately 90 percent. Epidemiology
The disease affects mainly children in the poorest countries of Africa, Asia and South America. Most people who acquire this disease are between the ages of two and six years old. The World Health Organization estimates that 500,000 people are affected, and that 140,000 new cases are reported each year. History
Known in antiquity to such physicians as Hippocrates and Galen, noma was once reported around the world, including Europe and the United States. With improvements in hygiene and nutrition, noma has disappeared from industrialized countries since the 20th century, except during World War II when it was endemic to Auschwitz and Belsen concentration camps. The disease and treatments were studied by Berthold Epstein, a Czech physician and forced-labor prisoner who had recommended the study under Josef Mengeles direction. Society and culture
Children and other noma survivors in Africa are helped by a few international charitable organizations, such as Facing Africa, a UK registered charity that helps affected Ethiopian, and Swiss charity Winds of Hope. There is one dedicated noma hospital in Nigeria, the Noma Children Hospital Sokoto, staffed by resident and visiting medical teams supported by Médecins Sans Frontières.