Raloxifene may infrequently cause serious blood clots to form in the legs, lungs, or eyes. Other reactions experienced include leg swelling/pain, trouble breathing, chest pain, and vision changes. Black box warnings were added to the label of raloxifene in 2007 warning of increased risk of death due to stroke for postmenopausal women with documented coronary heart disease or at increased risk for major coronary events, as well as increased risk for deep vein thrombosis and pulmonary embolism. The risk of venous thromboembolism with raloxifene is increased by several-fold in postmenopausal women (RR = 3.1). Raloxifene has a lower risk of thromboembolism than tamoxifen. In the MORE trial, raloxifene caused a 40% decrease in risk of cardiovascular events in women who were at increased risk for coronary artery disease, although there was no decrease in cardiovascular events for the group as a whole.A report in September 2009 from Health and Human Services Agency for Healthcare Research and Quality suggests that tamoxifen and raloxifene used to treat breast cancer, significantly reduce invasive breast cancer in midlife and older women, but also increase the risk of adverse side effects.A recent human case report in July 2016 suggests that raloxifene may in fact, at some point, also stimulate breast cancer growth leading to a reduction of advanced breast cancer disease upon the withdrawal of the drug.Unlike other SERMs, such as tamoxifen, raloxifene has no risk of uterine hyperplasia or endometrial cancer (RR = 0.8).Raloxifene does not increase the incidence of breast pain or tenderness in postmenopausal women.
Methoxsalen, sold under the brand name Oxsoralen among others, is a medication used to treat psoriasis, eczema, vitiligo, and some cutaneous lymphomas in conjunction with exposing the skin to ultraviolet (UVA) light from lamps or sunlight. Methoxsalen modifies the way skin cells receive the UVA radiation, allegedly clearing up the disease. Levels of individual patient PUVA exposure were originally determined using the Fitzpatrick scale. The scale was developed after patients demonstrated symptoms of phototoxicity after oral ingestion of methoxsalen followed by PUVA therapy. Chemically, methoxsalen belongs to a class of organic natural molecules known as furanocoumarins. They consist of coumarin annulated with furan. It can also be injected and used topically. Natural sources
In 1947, methoxsalen was isolated (under the name "ammoidin") from the plant Ammi majus, bishops weed.In 1970, Nielsen extracted 8-methoxypsoralen from four species of the genus Heracleum in the carrot family Apiaceae, including Heracleum mantegazzianum and Heracleum sphondylium. An additional 32 species of the genus Heracleum were found to contain 5-methoxypsoralen (bergapten) or other furanocoumarins. Biosynthesis
The biosynthetic pathway is a combination of the shikimate pathway, which produces umbelliferone, and the mevalonate pathway. Synthesis of umbelliferone
Umbelliferone is a phenylpropanoid and as such is synthesized from L-phenylalanine, which in turn is produced via the shikimate pathway. Phenylalanine is lysated into cinnamic acid, followed by hydroxylation by cinnamate 4-hydroxylase to yield 4-coumaric acid. The 4-coumaric acid is again hydroxylated by cinnamate/coumarate 2-hydroxylase to yield 2,4-dihydroxy-cinnamic acid (umbellic acid) followed by a bond rotation of the unsaturated bond adjacent to the carboxylic acid group.