SORIVUDINE (BV-araU) is an Anti-Herpes Virus Drugs, which was Withdrawn in 1995. Aantiviral action of BV-araU against VZV (varicella-zoster virus) and herpes simplex virus type 1 (HSV-1) is based on the inhibition of DNA synthesis in herpesvirus-infected cells.

Tolfenamic acid is a selective COX-2 inhibitor, which was marketed in Europe for the treatment of acute migraine disorders. Tolfenamic acid is currently unavailable for human use, however, it may be prescribed for veterinary purposes.

Gabexate is a synthetic protease inhibitor, was shown to be effective in treating patients with sepsis-associated disseminated intravascular coagulation in which tumor necrosis factor-alpha (TNF-alpha) plays a critical role. Gabexate mesylate is a drug marketed only in Italy and Japan and it is considered an essential drug in the treatment of acute pancreatitis. Gabexate is marketed under the brand name REMINARON among others in Japan. It relieves inflammatory symptoms in the pancreas by inhibiting various enzymes. It also improves organ disorders and bleeding tendency caused by blood clots in blood vessels by inhibiting blood coagulation. It is usually used to treat acute pancreatitis with deviation of proteolytic enzymes (such as trypsin, kallikrein and plasmin), acute exacerbation of chronic recurrent pancreatitis, acute pancreatitis after surgery and disseminated intravascular coagulation.

Carbetocin is a synthetic analogue of human peptide hormone, oxytocin. Like oxytocin, it stimulate oxytocin receptors and is used to facilitate childbirth. The drug is being marketed in Europe under the name Pabal for the prevention of uterine atony following delivery of the infant by Caesarean section. If untreated by carbetocin, uterine atony may lead to postpartum haemorrhage.

Vapreotide (Sanvar) is cyclic octapeptide analog of somatostatin with higher metabolic stability than the parent hormone and developed by Debiopharm Group for the treatment of esophageal variceal bleeding in patients with cirrhotic liver disease and AIDS-related diarrhea. Somatostatin inhibits the secretion of vasodilatory peptides from the gastrointestinal tract, including glucagon, which has been shown to contribute to the maintenance of portal hypertension. While natural somatostatin has a very short half-life (3 min), the elimination half-life of vapreotide is reported to be approximately 10 times longer than that of its parent compound. Pharmacodynamic studies of healthy volunteers demonstrated suppression of gastric acid secretion and inhibition of the secretion of pancreatic enzyme, which is similar to somatostatin. Vapreotide has demonstrated efficacy in the early management of acute variceal hemorrhage but only based on combined primary endpoints of hemostasis and survival after 5 days. In addition, vapreotide’s efficacy is limited to only one major study performed in Europe and not yet in the United States. Although it did not show a significant reduction in mortality, vapreotide’s observed the effect on hemostasis, as well as its favorable safety profile. Adverse effects that occurred in the vapreotide trials were generally mild and primarily included gastrointestinal symptoms and alterations of the gastrointestinal hormonal system. Vapreotide not recommended for approval by an FDA Advisory Panel due to Insufficient evidence that the drug provided a benefit in the treatment for acute esophageal variceal bleeding.

Aplidin (plitidepsin) is an investigative anticancer agent under development by PharmaMar, a pharmaceutical company that commercializes anticancer drugs of marine origin. Aplidin is isolated from the sea squirt (Aplidium albicans) and has shown anti-myeloma activity even in myelomas resistant to other agents. The drug has received orphan drug designation in the U.S., the European Union, and Switzerland. The target of plitidepsin is the eEF1A2 protein. The bonding of plitidepsin to this protein blocks its pro-oncogenic property and impedes the transportation of the misfolded proteins, which are toxic to the tumor, to the proteasome for their destruction. It also inhibits the activation of the aggresome by eEF1A2 and the destruction of the aggresome in the lysosome. This provokes anexcess of misfolded proteins, this causing cell death through apoptosis. Recently, a Phase III randomized trial in patients with relapsed/refractory multiple myeloma reported outcomes for plitidepsin plus dexamethasone compared with dexamethasone. Median progression-free survival was 3.8 months in the plitidepsin arm and 1.9 months in the dexamethasone arm. However, on 14 December 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of the marketing authorisation for the medicinal product Aplidin, intended for the treatment of multiple myeloma. At the time of the initial review, the CHMP was concerned that the data from the main study showed only a modest increase of around one month in the time patients given Aplidin lived without their disease getting worse, compared with those treated with dexamethasone alone. In addition, improvement in overall survival (how long patients lived overall) was not sufficiently demonstrated. Regarding safety, severe side effects were reported more frequently with the combination of Aplidin and dexamethasone than with dexamethasone alone. Based on the above, the CHMP was of the opinion that the benefits of Aplidin did not outweigh its risks and recommended that it be refused marketing authorisation.After re-examination, the Committee remained of the same opinion. The CHMP therefore confirmed its recommendation that the marketing authorisation be refused.