Theories for the dissociation include differences between AAS in terms of their intracellular metabolism, functional selectivity (differential recruitment of coactivators), and non-genomic mechanisms (i.e., signaling through non-AR membrane androgen receptors, or mARs). Support for the latter two theories is limited and more hypothetical, but there is a good deal of support for the intracellular metabolism theory.The measurement of the dissociation between anabolic and androgenic effects among AAS is based largely on a simple but outdated and unsophisticated model using rat tissue bioassays. It has been referred to as the "myotrophic–androgenic index". In this model, myotrophic or anabolic activity is measured by change in the weight of the rat bulbocavernosus/levator ani muscle, and androgenic activity is measured by change in the weight of the rat ventral prostate (or, alternatively, the rat seminal vesicles), in response to exposure to the AAS. The measurements are then compared to form a ratio. Intracellular metabolism
Testosterone is metabolized in various tissues by 5α-reductase into DHT, which is 3- to 10-fold more potent as an AR agonist, and by aromatase into estradiol, which is an estrogen and lacks significant AR affinity. In addition, DHT is metabolized by 3α-hydroxysteroid dehydrogenase (3α-HSD) and 3β-hydroxysteroid dehydrogenase (3β-HSD) into 3α-androstanediol and 3β-androstanediol, respectively, which are metabolites with little or no AR affinity. 5α-reductase is widely distributed throughout the body, and is concentrated to various extents in skin (particularly the scalp, face, and genital areas), prostate, seminal vesicles, liver, and the brain. In contrast, expression of 5α-reductase in skeletal muscle is undetectable.
Adverse effects
There is a high risk of bleeding and some people have had hypersensitivity reactions to defibrotide.Common adverse effects, occurring in between 1 and 10% of people, included impaired blood clotting, vomiting, low blood pressure, bleeding in the brain, eyes, lungs, stomach or intestines, in the urine, and at catheterization sites.Other side effects have included diarrhea, nosebleeds, sepsis, graft vs host disease, and pneumonia.Pregnant women should not take defibrotide and women should not become pregnant while taking it; it has not been tested in pregnant women but at normal doses it caused hemolytic abortion in rats. Pharmacology
Defibrotides mechanism of action is poorly understood. In vitro studies have shown that it protects the endothelium lining blood vessels from damage by fludarabine, a chemotherapy drug, and from a few other insults like serum starvation. It also appears to increase t-PA function and decrease plasminogen activator inhibitor-1 activity. Chemistry
Defibrotide is a mixture of single-stranded oligonucleotides. The chemical name is polydeoxyribonucleotide, sodium salt. It is purified from the intestinal mucosa of pigs. History
The efficacy of defibrotide was investigated in 528 participants treated in three studies: two prospective clinical trials and an expanded access study. The participants enrolled in all three studies had a diagnosis of hepatic VOD with liver or kidney abnormalities after hematopoietic stem cell transplantation (HSCT). The studies measured the percentage of participants who were still alive 100 days after HSCT (overall survival). In the three studies, 38 to 45 percent of participants treated with defibrotide were alive 100 days after HSCT.