Nitric oxide, prostaglandins, and other vasoactive substances have been hypothesized as powerful mediators of splanchnic vasodilation in cirrhosis. The consequence of this phenomenon is a decrease in the "effective" volume of blood sensed by the juxtaglomerular apparatus, leading to the secretion of renin and the activation of the renin–angiotensin system, which results in the vasoconstriction of vessels systemically and in the kidney specifically. However, the effect of this is insufficient to counteract the mediators of vasodilation in the splanchnic circulation, leading to persistent "underfilling" of the kidney circulation and worsening kidney vasoconstriction, leading to kidney failure.Studies to quantify this theory have shown that there is an overall decreased systemic vascular resistance in hepatorenal syndrome, but that the measured femoral and kidney fractions of cardiac output are respectively increased and reduced, suggesting that splanchnic vasodilation is implicated in the kidney failure. Many vasoactive chemicals have been hypothesized as being involved in mediating the systemic hemodynamic changes, including atrial natriuretic factor, prostacyclin, thromboxane A2, and endotoxin. In addition to this, it has been observed that the administration of medications to counteract splanchnic vasodilation (such as ornipressin, terlipressin, and octreotide) leads to improvement in glomerular filtration rate (which is a quantitative measure of kidney function) in patients with hepatorenal syndrome, providing further evidence that splanchnic vasodilation is a key feature of its pathogenesis.
History in multiple sclerosis
In the mid-1990s, Beutler, in collaboration with Jack Sipe, a neurologist at Scripps Institute, ran several clinical trials exploring the utility of cladribine in multiple sclerosis, based on the drugs immunosuppressive effects. Sipes insight into multiple sclerosis, and Beutlers interest in multiple sclerosis due to his sister having the disease, initiated a very productive collaboration. Ortho-Clinical, a subsidiary of Johnson & Johnson, filed a new drug application for cladribine for multiple sclerosis in 1997 but withdrew it in the late 1990s after discussion with the FDA proved that more clinical data would be needed.Ivax acquired the rights for oral administration of cladribine to treat multiple sclerosis from Scripps in 2000, and partnered with Serono in 2002. Ivax was acquired by Teva in 2006, and Merck KGaA acquired control of Seronos drug business in 2006.An oral formulation of the drug with cyclodextrin was developed: 16  by Ivax and Serono, and then Merck KGaA conducted clinical trials. Merck KGaA submitted an application to the European Medicines Agency in 2009, which was rejected in 2010, and an appeal was denied in 2011.: 4–5   Likewise Merck KGaAs new drug application with the FDA rejected in 2011.The ratio of benefit to harm was not clear to regulators, and further studies were requested to address concerns related to severe lymphopenia and cancer cases observed during pivotal trials. : 54–55  Clinical studies of multiple sclerosis were still ongoing at the time of the rejections, and Merck KGaA committed to completing them.