Thursday, April 14, 2016

Tales from the pharmaceutical minor leagues

When a drug company first gets its hands on a potential new drug, it will usually assign it a code name. Later on, as the drug works its way through trials designed to make sure it does something useful (e.g. reduce blood pressure) without causing serious harm (e.g. liver failure), it's given a catchier moniker like fluoxetine or atorvastatin. If the trials are a success, and the government is happy with how they were carried out, the drug can be brought to market. Most drugs don't make it. A good number don't even get to the point of being tested in humans, and thus are stuck with their code names. Here are some of their stories.

RO 19-8022
This is a classic example of a promising new drug gone horribly wrong. RO 19-8022 was initially heralded as an innovative anti-anxiety drug with less side effects compared to benzos. Unfortunately, it failed the Ames test, a quick way of uncovering a carcinogen without having to expose an animal to it and wait to see what develops. The test is based on detecting the ability of a compound to cause mutations in a particular strain of bacteria. Interestingly, a positive result only occurred when the bacteria (and the drug) were exposed to light. The chemical structure of RO 19-8022 is such that it will absorb visible or UV light and use it to generate reactive oxygen species. These substances, being highly reactive, can damage DNA, leading to mutations and ultimately cancer. Although it failed to make it as a medicine, RO 19-8022 found a second life as a tool for helping scientists study DNA damage and repair.

Ames test results, left = negative, right = positive (Source)

BRL-37344 and CL-316243
These beauties turn on lipolysis (increase the breakdown of fat) in rats and dogs, meaning they likely caused drug companies to practically wet themselves when they first stumbled upon them. Diet drug = printing money. However, upon further investigation, it was determined the two compounds don't work the same way in humans as they do in most other mammals. Turns out our fat cells don't appreciably express the particular receptor (beta 3-adrenoceptor) via which these drugs act.

RO 15-4513
In 1985, researchers at Hoffmann-La Roche reported the discovery of a drug capable of reversing the behavioural effects of ethanol. In other words, it was able to stop mice from being buzzed. RO 15-4513 accomplishes this outcome by blocking the action of ethanol at GABA receptors in the brain. GABA is a neurotransmitter capable of making the brain less excitable, which you feel as being relaxed and less anxious. Amusingly, RO 15-4513 is really bad at its job. It can't reverse being straight up drunk, only being lightly toasted. It doesn't work for very long, so you have to be constantly giving it to people and then making sure they don't do anything stupid before it wears off. It can't be used to treat acute alcohol poisoning since it doesn't prevent the respiratory depression usually responsible for killing people who drink way too much. If all that wasn't it enough, it also appears to increase the risk of experiencing convulsions and doesn't help prevent alcohol-induced birth defects.

Ro 15-4513, the pint-killer

RU 486
Very rarely, a drug company code ends up sticking around even after it gains a supposedly catchier name and is permitted to be sold. RU 486, also known as mifepristone, was developed in France in the 1980s and is used (along with misoprostol or another drug capable of mimicking the action of prostaglandin) to terminate pregnancies. It accomplishes this by blocking receptors otherwise activated by the sex hormone progesterone, bringing about the breakdown of the endometrium (the lining of the uterus to which an embryo is usually attached). Due to its ability to block the effects of glucocorticoids and androgens in addition to progesterone, RU 486 has been used to treat Cushing syndrome and has been investigated as a treatment for cancers of the prostate and meninges (membranes surrounding the brain and spinal cord).


References

Bousquet-Mélou A, Galitzky J, Carpéné C, Lafontan M, Berlan M. 1994. beta-Adrenergic control of lipolysis in primate white fat cells: A comparative study with nonprimate mammals. American Journal of Physiology 267(1):R115-R123.

Jenck F, Moreau JL, Bonetti EP, Martin JR, Haefely WE. 1992. Ro 19-8022, a nonbenzodiazepine partial agonist at benzodiazepine receptors: Neuropharmacological profile of a potential anxiolytic. Journal of Pharmacology and Experimental Therapeutics 262(3):1121-1127.

Linden AM et al. 2011. Ro 15-4513 antagonizes alcohol-induced sedation in mice through αβγ2-type GABAA receptors. Frontiers in Neuroscience 5:3. [Full text]

Lister RG, Nutt DJ. 1987. Is Ro 15-4513 a specific alcohol antagonist? Trends in Neurosciences 10(6):223-225. [First page]

Taplin ME et al. 2008. A phase II study of mifepristone (RU-486) in castration-resistant prostate cancer, with a correlative assessment of androgen-related hormones. BJU International 101(9):1084-1089. [Full text]

Touat M, Lombardi G, Farina P, Kalamarides M, Sanson M. 2014. Successful treatment of multiple intracranial meningiomas with the antiprogesterone receptor agent mifepristone (RU486). Acta Neurochirurgica 156(10):1831-1835. [First two pages]

Will O et al. 1999. Oxidative DNA damage and mutations induced by a polar photosensitizer, Ro19-8022. Mutation Research 435(1):89-101.

Zimmerman EF, Scott WJ Jr, Collins MD. 1990. Ethanol-induced limb defects in mice: Effect of strain and Ro15-4513. Teratology 41(4):453-462.

No comments:

Post a Comment