Puerarin - Good for hangovers, good for hearts

Kudzu (Pueraria lobata) is a fast-growing and incredibly resilient invasive climbing vine that was introduced to North America from its native habitat in East Asia. This plant is an intense sonofabitch, being capable of growing at a rate of up to 30 centimetres (inches) per day. It has been known to smother forests with its growth, and is taking over the American south as we speak. The purple flowers of the plant are used to make a scrumptious jelly, and the leaves and roots can be eaten.

Kudzu produces a number of isoflavones, organic compounds with rings and stuff that are typically strong antioxidants (may reduce tissue damage by free radicals, which are produced as a part of normal metabolic activity) and capable of mimicking the effects of estrogen in mammals (phytoestrogens).

Puerarin is the most concentrated isoflavone found in kudzu. This makes it the major active ingredient in Ge-gen, a traditional Chinese medicine made from kudzu root. Ge-gen is used traditionally to treat fever, pain, diabetes, measles, diarrhea, and cardiovascular diseases including coronary artery disease, arrhythmia and hypertension. It also has been employed as a means of relieving drunkenness and hangover after a long night on the town.

Interestingly, puerarin is capable of selectively suppressing alcohol intake in animal models of excessive drinking (rats and monkeys), suggesting that it may have application as a drug therapy for alcoholism (anticraving agent). It is thought to reduce alcohol absorption by inhibiting the movement of alcohol across gut membranes, thus reducing blood alcohol levels.

- Rezvani AH, Overstreet DH, Perfumi M, Massi M. Plant derivatives in the treatment of alcohol dependency. Pharmacol Biochem Behav. 2003 Jun;75(3):593-606.
- Zhang SY, Chen G, Wei PF, Huang XS, Dai Y, Shen YJ, Chen SL, Sun-Chi CA, Xu HX. The effect of puerarin on serum nitric oxide concentration and myocardial eNOS expression in rats with myocardial infarction. J Asian Nat Prod Res. 2008 Apr;10(4):323-8.

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

Heads up: Sweet Onion A.V. Club drug article

Dig this fine article on fictional drugs.

Caffeine - Drink coffee to breathe easier

Caffeine is a methylxanthine stimulant found in coffee that makes morning lectures somewhat more tolerable. Methylxanthines are methylated derivatives of xanthine. Animals produce xanthine as an intermediate in the breakdown of purines (e.g. guanine or adenine, the purine bases found in DNA and RNA) to uric acid, the stuff that causes gout and is excreted in urine. Other methylxanthines include theophylline (found in tea) and theobromine (found in cocoa, and thus in chocolate).

At the biochemical level, caffeine inhibits an enzyme called phosphodiesterase (the same target of Viagra!) and blocks the action of adenosine. These actions wake you up (and produce nervousness and insomnia at high doses), get your heart pumping (increase heart rate and increase the force of heart contraction), cause vasodilatation (except in the brain), and make you have to pee (by increasing how much urine your kidney makes).

Caffeine is used to diagnose people who have a genetic predisposition to malignant hyperthermia, a condition invoked by general anaesthesia that causes your muscles to intensely contract, producing tonnes of heat such that you run an exceptionally high fever and the enzymes in your body begin to stop working and you die very quickly. Incidentally, this terrifying condition is also a side effect of ecstasy (MDMA) use and can be treated with a drug called dantrolene.

Back in the day, caffeine was used to treat asthma, since it causes bronchodilation (relaxes the smooth muscle of the airways, causing them to expand) and so can help to reverse the constriction that occurs during an asthma attack.

- Kalant H, Grant D, and Mitchell J. Principles of Medical Pharmacology 7th ed. Toronto: Saunders Canada, 2006.

Drugs, drugs, everywhere: Throat lozenges edition

Hey everyone. My wonderful and ever patient girlfriend is fighting a nasty cold right now, and has taken to using throat lozenges made by Strepsils to make her sore throat less sore. I got my hands on the lozenge box and discovered that they contain not one, but two active ingredients. Hokey doodle! Each lozenge of Strepsils extra Black Cherry contains 2.4 mg of hexylresorcinol and 4 mg of menthol.

Menthol is a cyclic terpene alcohol that makes plants belonging to the genera Mentha (the mints) smell and taste the wonderful way that they do. It is able to produce a cooling sensation by stimulating a receptor found in skin and mucous membranes called TRPM8 that usually responds to cool temperatures (i.e. 8-28 degrees Celsius). At concentrations of 1% of less, menthol depresses skin sensory receptors, resulting a local anaesthetic effect. At concentrations between 1.25 and 16%, it actually stimulates sensory receptors, countering the effects of any irritants. In either case, topical pain relief (including relief from a sore throat) is achieved. At concentrations above 30%, menthol actually can induce cold pain. Menthol also somehow kills bacteria and fungi, making it a reasonably good antiseptic.

Hexylresorcinol (also called 4-hexylresorcinol) has a long history of use as a drug and ingredient in cosmetics. It works as an antiseptic, and can therefore be found in soaps, skin cleaners, and throat lozenges. Back in the day, before the development of more selective agents, hexylresorcinol was widely used as an antihelmintic. Meaning you could potentially use throat lozenges to get rid of parasitic worms if they were growing inside of you. Awesome. Hexylresorcinol can also be used to prevent shrimp black spot (melanosis), an unappealing surface discoloration of shrimp caused by the enzymatic production of pigmented compounds, as well as the browning and decay of fresh-cut mangoes and apples. It accomplishes these tasks by inhibiting enzymes called polyphenol oxidases.

Strepsils is probably named for Streptococcus, a genus of bacteria that includes a number of species capable of causing sore throats. They've been making it since 1958, so I guess it must do something. That said, if you've got friggin' Strep throat, you want prescription antibiotics and not some OTC throat lozenges. Trust me on this one.

Incidentally, the fine folks at Wikipedia have informed me that cough drops are not the same things as throat lozenges. You see, cough drops are designed to reduce coughing, while throat lozenges are designed to sooth a sore throat.

- Frankos VH, Schmitt DF, Haws LC, McEvily AJ, Iyengar R, Miller SA, Munro IC, Clydesdale FM, Forbes AL, Sauer RM. Generally recognized as safe (GRAS) evaluation of 4-hexylresorcinol for use as a processing aid for prevention of melanosis in shrimp. Regul Toxicol Pharmacol. 1991 Oct;14(2):202-12.
- Patel T, Ishiuji Y, Yosipovitch G. Menthol: a refreshing look at this ancient compound. J Am Acad Dermatol. 2007 Nov;57(5):873-8. Epub 2007 May 10. Review.