Drugs of the future: CBLB502

A chunk of Salmonella flagellum has been shown to protect mice and rhesus monkeys from the toxic effects of ionizing radiation. The drug binds to Toll-like receptor 5 (TLR5) and turns on the nuclear factor-κB signaling pathway, which leads to the induction of factors that protect cells (apoptosis inhibitors and reactive oxygen species scavengers) and promote tissue regeneration (cytokines). The activation of this pathway also results in the inhibition of the p53 tumour suppressor pathway, which is one of the means by which cancer cells are able to resist the effects of radiation. Incidentally, things like cytokines and amifostine are also radioprotective, but CBLB502 appears to be the best of 'em.

Flagellin, the principal protein component of bacterial flagella, is the only thing that we know of that binds to and activates TLR5. The drug was synthesized based on the structure of flagellin made by Salmonella enterica serovar Dublin, a human pathogen found in raw cow milk.

A single injection of CBLB502 was able to protect mice from the normally lethal whole-body gamma-radiation doses of 10 and 13 Gy, and increased their survival by almost a week after a dose of 17 Gy.

If this is legit, it could mean safer cancer radiotherapy and better protection in radiation emergencies.

Burdelya LG, Krivokrysenko VI, Tallant TC, Strom E, Gleiberman AS, Gupta D, Kurnasov OV, Fort FL, Osterman AL, Didonato JA, Feinstein E, Gudkov AV. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science. 2008 Apr 11;320(5873):226-30.


Lobeline - Cure for meth and heroin addiction?

Matthias de L'Obel (1538-1616) was a French physician and botanist. He devised and published a system of plant classification, and served as the personal physician to William the Silent and James I. The plant genus Lobelia is named for him.

A number of Lobelia species, including Lobelia inflata (Indian tobacco) and Lobelia tupa (Devil's tobacco), produce a piperidine alkaloid called lobeline. Lobeline is a nicotine-like stimulant, which explains why L. inflata is used by Native Americans and others in the know as a substitute for regular tobacco.

Lobeline, like nicotine, enjoys long walks, romantic candlelit dinners, and binding to nicotinic acetylcholine receptors in the brain. However, it is apparently less active than nicotine at these receptors and so can actually diminish the effects of the drug. This antagonism is the basis for the use of lobeline as a treatment to help people quit smoking, although its effectiveness is still very much up for debate.

Lobeline has been shown to decrease methamphetamine self-administration in rats, while not being self-administered itself. This suggests that it could be used as a treatment for meth addiction and is unlikely to be abused on its own (unlike nicotine). The decrease in meth self-administration is thought to be due the ability of lobeline to screw around with the storage and release of dopamine by acting on the protein transporters such as VMAT2 that responsible for these processes. Dopamine release in the corpus striatum (a part of the brain) is responsible for the rewarding and reinforcing effects of methamphetamine.

Lobeline has also been shown to be capable of blocking mu opioid receptors, which are what morphine binds to in order to produce its effects. So potentially it can do a world of good for both amphetamine and opioid addiction.

- Miller DK et al. Lobeline, a potential pharmacotherapy for drug addiction, binds to mu opioid receptors and diminishes the effects of opioid receptor agonists. Drug Alcohol Depend. 2007 Jul 10;89(2-3):282-91.
- Neugebauer NM, Harrod SB, Stairs DJ, Crooks PA, Dwoskin LP, Bardo MT. Lobelane decreases methamphetamine self-administration in rats. Eur J Pharmacol. 2007 Sep 24;571(1):33-8. Epub 2007 Jun 13.


Sildenafil (Viagra) - Get on up

Ah, sildenafil. What more is there to say? It has saved marriages. Broken up marriages. Provided fodder for terrible comedians. Made spam just that much more intolerable.
It works as follows. You swallow a pill, which breaks down in your stomach and intestine, releasing molecules of sildenafil that are absorbed into your bloodstream and transported throughout your body. When these molecules encounter an enzyme called PDE5, they inhibit its ability to break down a signal molecule called cGMP. If you're a dude, PDE5 is found in your corpus cavernosum, which is the spongy region of expandable erectile tissue found along the length of your willy. It's responsible for getting you up, so to speak. In the corpus cavernosum, cGMP controls blood flow. By inhibiting PDE5, sildenafil causes cGMP to accumulate, resulting in the expansion of penile blood vessels due to the relaxation of smooth muscle in vessel walls mediated by the accumulated cGMP. This leads to an increase in blood flow to the penis, resulting in a boner.

In individuals with normal erectile function, cGMP is increased by the release of nitric oxide (NO) from nerves in the corpus cavernosum when you get horny or during REM sleep. NO is a gas that can bind to and stimulate guanylate cyclase, an enzyme that produces cGMP.

Fun side effects of sildenafil include sneezing, priapism (perma-boner, one which stays up for longer than four hours), photophobia (you become very sensitive to light), and weird visual changes (blurring, everything develops a bluish tinge to it, loss of peripheral vision).

- Kalant H, Grant D, and Mitchell J. Principles of Medical Pharmacology 7th ed. Toronto: Saunders Canada, 2006.
- http://en.wikipedia.org/wiki/Sildenafil