Urinary excretion load tests have been used to determine dietary requirements. For adult men, as oral doses were increased from 0.5 mg to 1.1 mg, there was a modest linear increase in urinary riboflavin, reaching 100 micrograms for a subsequent 24-hour urine collection. Beyond a load dose of 1.1 mg, urinary excretion increased rapidly, so that with a dose of 2.5 mg, urinary output was 800 micrograms for a 24-hour urine collection. History
The name "riboflavin" comes from "ribose" (the sugar whose reduced form, ribitol, forms part of its structure) and "flavin", the ring-moiety which imparts the yellow color to the oxidized molecule (from Latin flavus, "yellow"). The reduced form, which occurs in metabolism along with the oxidized form, appears as orange-yellow needles or crystals. The earliest reported identification, predating any concept of vitamins as essential nutrients, was by Alexander Wynter Blyth. In 1897, Blyth isolated a water-soluble component of cows milk whey, which he named "lactochrome", that fluoresced yellow-green when exposed to light.In the early 1900s, several research laboratories were investigating constituents of foods, essential to maintain growth in rats. These constituents were initially divided into fat-soluble "vitamine" A and water-soluble "vitamine" B. (The "e" was dropped in 1920.) Vitamin B was further thought to have two components, a heat-labile substance called B1 and a heat-stable substance called B2. Vitamin B2 was tentatively identified to be the factor necessary for preventing pellagra, but that was later confirmed to be due to niacin (vitamin B3) deficiency.
Selexipag, sold under the brand name Uptravi, is a medication developed by Actelion for the treatment of pulmonary arterial hypertension (PAH). Selexipag and its active metabolite, ACT-333679 (or MRE-269, the free carboxylic acid), are agonists of the prostacyclin receptor, which leads to vasodilation in the pulmonary circulation. It is taken by mouth or administered intravenously. Contraindications
In Europe, use of selexipag together with strong inhibitors of the liver enzyme CYP2C8, such as gemfibrozil, is contraindicated because it increases concentrations of selexipag twofold, and its active metabolite 11-fold, potentially leading to more adverse effects. Adverse effects
The adverse effects of selexipag are similar to those of intravenous prostacyclins used for pulmonary arterial hypertension. Common side effects include headache and jaw pain. An increased risk for hyperthyroidism has also been noted in people taking selexipag. Pharmacology
Mechanism of action
Selexipag and its active metabolite ACT-333679 act on the prostacyclin receptor of lung tissue, with the latter being 37-fold more potent. They are selective for the prostacyclin receptor. Binding to this receptor leads to three major effects: increased vasodilation of the arteries, decreased cell proliferation and inhibition of platelet aggregation, all beneficial in the treatment of pulmonary arterial hypertension. Pharmacokinetics
Selexipag is quickly absorbed from the gut and hydrolyzed in the intestines and the liver to ACT-333679 by carboxylesterases. Absolute bioavailability is about 49%, most likely because of a high first-pass effect. Highest concentrations in the blood plasma are reached after one to three hours for selexipag and after three to four hours for the active metabolite.