Pemetrexed (Alimta) - Let's see how you do without a ready supply of nucelotides, stupid cancer cells

• cancer (well, more like anticancer) drug developed especially for the treatment of malignant pleural mesothelioma (MPM), although it also can be used against a number of other cancers including non-small cell lung, colorectal, and breast
• mesothelioma is a generally incurable variety of cancer that develops in one's mesothelium, a thin layer of flattened cells (they look kinda like scrambled eggs) that line several of the cavities found inside your trunk (chest + abdomen)
• the pleural cavity is a fluid-filled space separating your lungs from the rest of your body
• mesothelioma is nearly always caused by exposure to asbestos, a group of minerals that have been used to insulate, strengthen, and fireproof darn near well everything until recently
  
• folate antimetabolite (antifolate) drug, which means that it resembles folic acid and is empowered with the ability to muck up the production of purines and pyrimidines, which are essential components of nucleic acids (made from folic acid), thus disrupting the growth of cells, particularly rapidly dividing cells like cancer cells
• patients receiving pemetrexed have their diet supplemented with folic acid to enable their normal cells to better resist the effects of the drug (cancer cells are often less able to take up the folic acid)
• usually administered in combination with cisplatin, a platinum-based anticancer drug that has a different way of killing cancer cells, allowing for maximum neoplastic destruction
  
• caffeine has been shown, in the lab, to sensitize cancer cells to the effects of pemetrexed, potentially making it a useful adjuvant
• there are dual diagnosis treatment centers all over the country helping those who suffer from drug and alcohol addiction, so if you know someone that may be in need of drug treatment, contact a drug treatment center for help
  

- Martin M. Clinical experience with pemetrexed in breast cancer. Semin Oncol. 2006 Feb;33(1 Suppl 2):S15-8. Review.
- Min SH, Goldman ID, Zhao R. Caffeine markedly sensitizes human mesothelioma cell lines to pemetrexed. Cancer Chemother Pharmacol. 2007 Jun 27; [Epub ahead of print]
- http://en.wikipedia.org/wiki/Pemetrexed

Email Question: How permeable is your skin to chemicals?

New segment time! Also widely known as Chris has had a busy week but still wants to keep up appearances on his blog so that people don't think he's quitting or anything. Once in a while, I get drug and/or poison-related questions emailed to me. I usually try and respond to the best of my abilities, which for the most part consists of referring to my textbooks and pulling stuff out of my butt. Here is a question email I received a while back:

My mom and I have been having kind of a dispute about the permeability of chemicals to your skin. She believes that your skin breathes and that's why you can't cover it, as brought fourth [sic] in the James Bond movie. She takes it one step further to say that things like lotions
can be absorbed by your skin and have adverse health affects similar to eating the lotion. I disagree, the skin outright has no structure or role in breathing. I understand that some things can be absorbed by the skin, like the chemicals in nicotine and pregnancy patches, I've also read that in the 70's that there was a scare of people putting LSD on doorknobs because it can be absorbed through the skin.

So my question is, what really defines permeability to the skin, and what are or is a common carrier for dermal-permeable chemicals?

- Dave


Hey Dave,

Okay, so first off, the skin has no role in breathing. I'm assuming we're defining breathing as gas exchange between air and blood, which is an exclusive function of the lungs.

Covering your skin in an impermeable substance like gold would cause you to lose the ability to sweat AND you would no longer be able to effectively lose heat through your skin. Consequently, you would be unable to effectively regulate your body temperature, and so would overheat and potentially die as a result.

One of the primary purposes of the skin is to provide a barrier to block the entry of virtually all substances into your body. However, said barrier is not entirely effective, such that most chemicals will be able to pass through the skin, albeit usually at levels insufficient to cause any effect, into the bloodstream. This process is comparable to eating the chemical and it being absorbed in your intestine into your bloodstream.

The permeability of the skin to a chemical is dependent on the lipid solubility of the chemical, that is, how readily it will dissolve into fat relative to into water. Chemicals that prefer to dissolve into fat will be absorbed to a greater extent via the skin. Chemicals that are not very lipid soluble can be suspended in an oily vehicle to enhance their ability to enter the body through the skin. Even so, giving a drug via the skin (percutaneously) is generally not considered an efficient method for getting the drug into the bloodstream, except in the case of patches for nicotine, sex hormones, scopolamine (for motion sickness), and nitroglycerin (for angina). All of these drugs are highly lipid soluble.

LSD is incredibly potent, so it only takes a really tiny amount for you to start tripping out. Thus, even though it is poorly absorbed through the skin, it can still cause effects that way.

Hope this all made some sense. Thanks for reading the blog!

Chris

Synephrine (oxedrine, Sympatol) - How oranges might help you lose weight

• so synephrine actually comes in three slightly different flavours: ortho, meta, and para
• these differ structurally in the position of the side chain on the benzene ring
  
• when people (including this blogger) talk about synephrine, they are usually referring to the para isomer (p-synephrine)
• meta-synephrine is better known as phenylephrine or neosynephrine, a decongestant that is currently making a comeback thanks to restrictions on the sale of pseudoephedrine, another decongestant, since it can be used to make sweet, sweet crystal meth
• has been used as a drug since 1927, usually formulated as eye drops for the treatment of glaucoma, but has also been employed to treat circulatory failure, asthma, and nasal congestion
• pharmacologically speaking, it's a sympathetic alpha-adrenergic agonist with some beta2-adenergic activity, which essentially means that it causes blood vessels to constrict (thus increasing blood pressure, reducing blood flow to the extremities, etc.) and is able to widen the airways (thus helping to relieve asthma)
• produced by several species of Citrus (it's an actual genus) plants, including Citrus aurantium (bitter/sour/Seville orange)
  
• C. aurantium is used primarily as a dietary supplement intended to promote weight loss
• is also produced in small amounts by the human body, where it may function as a neurotransmitter
• theorized to produce weight loss by: (a) increasing the number of calories you burn while you laze about the house (i.e. your resting energy expenditure), and (b) reducing your food intake (possibly by decreasing the rate at which food passes throughout your stomach and intestines, making you feel full for a longer period of time)
• similar in structure and action to ephedrine, a CNS stimulant that has been used to promote weight loss, although such use is currently banned by the FDA
  
• unsurprisingly, synephrine can be found in some diet pills, even though it has not yet been shown conclusively that it makes people less fat
• C. aurantium fruit extracts containing synephrine have been shown to reduce food intake, and ultimately body weight, in rodents
• eating a bunch of oranges might help you lose weight, but it will probably be due to all that wonderful diarrhea all that fresh fruit will cause and not due to the effects of synephrine
  
• larger and better studies are still required to assess the efficacy and safety of synephrine in humans
• if you are unsure of medical terminology, you should consult a medical dictionary, available for free online
  
• the Internet also can be used to find a doctor, locate a medical library, or select the right acne treatment for you
  

- Haaz S et al. Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: an update. Obes Rev. 2006 Feb;7(1):79-88. Review.
- http://www.itmonline.org/arts/syneph.htm

Rasburicase (Elitek, Fasturtec) - 'Cause curing cancer can cause catastrophe

• recombinant form of urate oxidase (uricase), a peroxisomal enzyme that catalyzes the transformation of uric acid, a waste product of nucleic acid (purine) catabolism, into a more water soluble molecule called allantoin, thus facilitating the removal of uric acid by the kidneys
• this enzyme is found throughout the five kingdoms, including in most animals, but the gene that encodes it in humans is no longer functional (likely due to a sudden significant mutational event)
• used to treat hyperuricemia (abnormally high levels of uric acid in the blood), which can lead to kidney damage
• gout (a variety of arthritis) is the result of low-level, long term hyperuricemia
• hyperuricemia is usually due to either reduced removal of uric acid by the kidneys or increased production of uric acid due to things like a deficiency in HGPRT (Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome), eating too much purine-rich foods (meats, alcohol, legumes), and tumour lysis syndrome (TLS)
• TLS refers to a bunch of metabolic problems that can occur when chemotherapy successfully kills a bunch of cancer cells
• usually associated with hematologic cancers like lymphomas and leukemias
• cells tend to concentrate certain ions within their cytoplasm, so when a whole whack of them are killed en masse, these ions are released into the blood, causing things like hyperkalemia and hyperphosphatemia (leading to hypocalcemia)
• the degradation of all of the nucleic acid released from the destroyed cancer cells can lead to a rapid and impressively huge rise in uric acid, capable of precipitating acute renal failure
• since rasburicase is produced using non-human cells, the immune system can mount an allergic reaction against it, and the development of antibodies that bind it all up can lead to a reduction in efficacy
• if you have medical questions, there are a variety of Internet resources such as library or medical reference sites available for free
• the Internet also can be used to find a doctor or select the right acne treatment for you
  

- Cammalleri L, Malaguarnera M. Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and in gout. Int J Med Sci. 2007 Mar 2;4(2):83-93. Review.
- Wu XW, Lee CC, Muzny DM, Caskey CT. Urate oxidase: primary structure and evolutionary implications. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9412-6. [link]

Shiga Toxin - Two words: bloody diarrhea

Today's post is compliments of Toaster, who knows a whole lot about bacterial toxins. Check out his website, Mad Scientist, Jr.

Background:
Bad-ass hexameric molecule produced by some strains of your friendly neighborhood bacteria, most notably Shigella dysenteriae (named after Kiyoshi Shiga, who discovered them in 1898: "Hmm...I wonder what this bloody diarrhea looks like under my microscope?") and Escherichia coli.

Structure:
Once again, hexameric (although this a picture of SLT-1, which warrants a discussion on nomenclature)

Nomenclature:
This terminological mess once confused me, I hope this will make it clearer for you. True Shiga toxin is made by S. dysenteriae, although several strains of E. Coli (collectively termed STEC, which includes EHEC, the stuff that was on spinach recently) also make very closely
related toxins. Shiga-like toxin 1 is made by STECs and differs from S. dysenteriae by only 1 amino acid, while Shiga-like toxin 2, also made by STECs, has ~60% sequence homology with Shiga-like toxin 1. However, most microbiologists refer to Shiga toxins interchangeably,
and may call any of the above Shiga toxins (abb. Stx), verotoxins, or verocytotoxins, leading to a lot of people being very often confused and frustrated, which I think that microbiologists secretly enjoy.

Back to Structure:
So, Shiga toxins are hexameric, with 6 distinct subunits: 5 B subunits and 1 A subunit per molecule. The whole thing is shaped like a big hook (A subunit) with a fan at one end (the B subunits).

Genetics:
From what I understand, Shiga toxin generally isn't encoded in the genome of E. Coli strains that produce it (I don't know about Shigella strains), but is instead encoded in the genome of a bacteriophage that infects most of the bacteria in a population of STECs. So when the
bacteriophage is induced from its happy little quiet lysogenic phase to the lytic phase it fills the bacteria up with Shiga toxins until the bacteria bursts like a sticky balloon of kidney death.

Pathophysiology:
Shiga toxin will mess you up. Seriously. Like, no joke. The LD50 for Shiga-like toxin 2, calculated upwards from animal studies, for a 60kg person would be approximately 3 milligrams. Luckily, true Shiga toxin and Shiga-like toxin 1 are about 400 times less toxic.

In any event, playing pretend is a good way to learn. So let's say you eat some undercooked beef that's been contaminated with poop. The STECs manage to colonize your digestive system and start sticking to your intestinal epithelia. At this point, bloody diarrhea begins. But
as the bacteria pop and release Shiga toxin everywhere, some of it is going to wind up in your bloodstream. And, like anything that gets into your bloodstream, it winds up pretty much everywhere in your body. But Shiga toxin affects mostly renal tissue, hepatic tissue, endothelial cells, and the central nervous system, where it can wreak cellular havoc.

It's best understood how Shiga toxin affects renal tissue, which is to say, it targets distal tubules and the glomerular thingies because these tissues express an abnormally large amount of globotriaosylceramide, a lipid also known as Gb3, which Shiga toxin binds to very strongly. This is highly unusual because lipids don't normally function as receptors. No one knows why this is or why it happens here. Nonetheless, it is the B subunits of the Shiga toxin that bind Gb3
(interestingly, Stx-B subunits have been found to be very potent adjuvants) and somehow (once again, no one knows) get the Shiga toxin into the cell, where the A subunit dissociates from the B subunits and binds to one of the subunits of the ribosomes, essentially shutting all protein synthesis down, which is very, very bad for your cells.

It has been hypothesized, but not conclusively determined, that Shiga toxin plays a role in the development of HUS. HUS is not good. It stands for hemolytic uremic syndrome and involves your red blood cells being transformed from their normal fat happy selves into ragged hunks
of cellular detritus. This condition is associated with infection with STECs (e.g., H7:O157) and usually only happens in those who are very young, old, or immunocompromised.

Then come the complications of Stx interaction with LPS, but that is an entirely different post.

- Palermo M et al. Pretreatment of mice with lipopolysaccharide (LPS) or IL-1beta exerts dose-dependent opposite effects on Shiga toxin-2 lethality. Clin Exp Immunol. 2000 Jan;119(1):77-83.
- Warnier M et al. Trafficking of Shiga toxin/Shiga-like toxin-1 in human glomerular microvascular endothelial cells and human mesangial cells. Kidney Int. 2006 Dec;70(12):2085-91. Epub 2006 Oct 25.

Reader experiences: Demerol horror story

Hey folks. Here's a story:

My experience with Demerol

When I was 14 years old, it was determined that I required a spinal fusion to correct a congenital birth defect with one of my vertebrae. (Congentical kyphosis, for those interested.) The operation itself went ok, with the possible exception that the instrumentation failed near the end of the surgery and they had to extend the fusion down one slot, resulting in only 2 vertebrae left to do my bending for me for the rest of my life. (The Xrays now, 20 years later, are not pretty. Not pretty at all.)

In any case, after the surgery, Demerol was selected as the pain killer of choice. After administration, about 10 minutes later, I basically had a low-grade heart attack. I had heart fibrillation, and they called in a heart specialist who managed to keep me alive for the short term, while I was off day-tripping some near-death light-at-the-end experience.

They determined that I had an extremely adverse reaction to the Demerol. As a result, they decided to eliminate all pain killers from my system for 48 hours, and then start me on straight morphine (mmmmm...smack...), since almost no one rejects the GOOD stuff. Now, my spine had been flayed open literally, metal clamps screwed down all over the place, and bone scraped from my hip to cover the instrumentation and start my body completing the fusion by itself. And staples to close it all up. With no pain killers.

48 hours.

My parents learned every single bad word I ever knew, and some I even made up. The ICU was in a children's hospital, and for some weird reason they had these recessed little panels right above each bed, with Biblical scenes of smurfs in them. (Seriously. I checked later. This is not the lack-of-smack talking.) I talked to Papa Smurf as he loaded the smurfs 2-by-2 on to the Ark. I warned him about flood plains, levees, and the force of water and riptides. I urged him to get a move-on or everyone was gonna' die. The nurses and my family had no idea what I was talking about. They assumed I had lost my mind.

I only remember a few things, one of which was this: I remember waking up, feeling like I had been in that bed for days and days and days. I looked over and a nurse was there, next to my bed. I asked her what day it was. She asked me what day I thought it was. (Grrrrrr...) The operation was on Sunday, so I thought I'd be conservative and say "Tuesday" even though it had to be Thursday at the earliest. She got this very sad look on her face and said "No, I'm sorry, it's been three minutes since the last time you woke up and asked me that very same question."

This pain would never, ever, ever, ever, ever end.

But, of course, it did, and they gave me morphine, and everything was coolio after that.

Not the best way to discover that Demerol will kill you...

- Trey

Sanguinarine - How toothpaste can cause cancer and mustard can cause swollen limbs

• quaternary benzophenanthridine glycoside alkaloid synthesized by plants belonging to the Papaveraceae, Fumariaceae, and Rutaceae families
• quaternary compounds possess a permanent positive charge, making them exceedingly lousy at passing through fatty things like cell membranes
• specific plants include Sanguinaria canadensis (Bloodroot), Chelidonium majus (Greater celandine), and Argemone mexicana (Mexican prickly poppy)
• the seeds of Argemone mexicana look very much like mustard seeds, which can (and has) lead to the adulteration of foods cooked using mustard oil with sanguinarine
• people consuming said foods this thing called epidemic dropsy, which features such exciting symptoms as your limbs swelling up (extremity swelling with pitting edema), anemia, heart failure, renal failure, and glaucoma
• found in some mouthwashes and toothpastes since it kills bacteria (helping to reduce dental caries) and has antiinflammatory effects (apparently helping to reduce gingivitis)
• Viadent, a toothpaste/mouthwash brand that contains sanguinarine, has been linked to oral leukoplakia
• has been shown to induce apoptosis in certain cancer cell lines, possibly related to its ability to inhibit the activation of nuclear transcription factor NF-kB (which is involved in regulating cell growth and apoptosis and stuff) or promote the production of reactive oxygen species and/or mitochondrial membrane depolarization
• it's worth considering the purchase of drugs online, since it's easy and inexpensive, and there is lots of information available to inform you
• whether it's diet drugs or cheap Viagra, which happens to have more uses than you might think, they can be found on the Internet
  

- Allen CL, Loudon J, Mascarenhas AK. Sanguinaria-related leukoplakia: epidemiologic and clinicopathologic features of a recently described entity. Gen Dent. 2001 Nov-Dec;49(6):608-14.
- Chang MC et al. Induction of necrosis and apoptosis to KB cancer cells by sanguinarine is associated with reactive oxygen species production and mitochondrial membrane depolarization. Toxicol Appl Pharmacol. 2007 Jan 15;218(2):143-51. Epub 2006 Nov 1.

Reader experiences: More readers respond

I am pleased to announce that my mouth no longer contains any wisdom teeth. I also just misspelled wisdom as widoom three times in a row, so the codeine is definitely working it's wonders on my brain. I better stop typing while I'm ahead, so here are a couple of stories that people have sent in for you to read. Thank you, people! Check out the first installment. Here we go:

Steve wrote in to say, "I think it's fair to say that they're [SSRIs] the best thing that's ever happened to me." Well, I've got to share the love for my antidepressant of choice, venlafaxine (a. k. a. Effexor), which is actually an SNRI (it affects norepinephrine as well as serotonin). Before, I was chronically depressed, rock-bottom self-esteem, apathetic, anxious, the whole shebang. Now -- well, I feel like things are going to turn out all right. Ordinary, everyday
hopefulness. Gooooo drugs!

- ap

P. S. Ironically, one of Effexor's most dangerous side effects is suicidal ideation -- which is why it's most definitely NOT recommended for kids and teens.

---

Your blog is sweet! Ok well I've had the privilege to experience a multitude of drug experiences but here's one from last night which involved our friend DXM (dextromethorphan HCL).

Ok so I was experiencing these very nasty coughing fits and decided it was worth it to bicycle in the rain to the grocery store before it closed to get some syrup. Being an impoverished university student I opted for the generic brand which contained 15 DXM/5mL plus some disgusting cherry flavors (read the labels kiddies, brand names are for suckers).

I drank approx 80 mL (240 mg DXM, much more than the recommended dosage) and the bad news was that it did absolutely nothing for my cough. However, I was treated to a wonderful state of opiated-semi-psychedelic-drunkenness, which was further complemented with some high-quality cannabis. This state lasted many hours and when I went to bed I was treated with some groovy shapes and funky colors behind the eyes, and a feeling I was leaving my body. Super-fun! Just don't tell your friends or they'll think you're huffing gas on the side too!

- Luke

---

Since you ask, I am reminded of one time I was in the hospital for kidney stones, which ended up being one of the longest sedative drug-binges of my life. It began as what I hoped was a quick visit for some hydrocodone to dull the relentless visceral groin pain, but ended up in a 3 day hospital stay and a lithotripsy. What follows is the truly amazing list of substances I was on, and my personal opinion of them.

In the ER, while hoping for Vicodin, they instead gave me an NSAID; I think it was dolobid, but I can't remember. I mentioned getting stomach upset from ibuprofen, so they gave it to me IV. That worked pretty well for a while, but left me a tad too alert to be entertained by hospital TV.

Once admitted, I asked for some better pain killers, and they decided to give me Dilaudid (hydromorphone). I doubt they gave me more than 1mg, but even that, I realized almost immediately, was much too much. Pretty soon the side effects were competing with kidney stone pain to see which could make me more miserable. As the drug hit in a matter of seconds, I first felt a wave of euphoria, but this was quickly followed by uncomfortable flushing and profuse sweating, with severe nausea. I should have lain down and stopped moving, but I was stubborn and talking to a friend, and so soon found myself vomiting into a trashcan. It was at this point that I asked for something for the nausea.

They gave me Zofran (ondansetron), a rather expensive drug that can only be given every 8 hours, apparently. It worked pretty well - for about 4 hours. After that time, I was left to fend off the opiate nausea myself. It was around this time that I really wanted some cannabis. Make whatever dumb stoner jokes you want, but nothing that I've tried or heard of works as well, or faster, at treating nausea that cannabinoids. It's way cheaper than Zofran, too. Given my hospitalized state however, it was not to be.

After the Dilaudid fiasco, they switched me to a 1mg/hour self-administered morphine pump. This worked out alright, but not great. It didn't control the pain as well as dilaudid, and performed worse and worse over time, not surprisingly. The nausea left me feeling useless and immobile, but fortunately I never vomited again.

The next day, I had my lithotripsy, and being a neuroscience major, I couldn't resist talking to the anesthesiologist about his pharmacological arsenal. As it turns out, the list of drug's he'd use was quite impressive:

chloral hydrate - for initial sedation. I'm not convinced about this one; I thought he mentioned it, but I'm not sure.

midazolam (Versed) - benzodiazepine for initial sedation, as well as retrograde amnesia. It worked very well in its latter role.

fentanyl - opioid for pain. I imagine it served its purpose effectively.

sevoflurane - one of the newer halogenated ethers. Be grateful they're not still using halothane, like I do on my rats.

Some other muscle relaxants he didn't name. The urologist probably used some local anesthetics for the procedure as well. He may have mentioned nitrous oxide as well, but I can't remember.

Despite the high risk of such a cocktail, I made it through ok, although I can't remember anything after lying down on the operating table until I was rolling towards recovery. I woke confused, thinking I was a child again, being pushed in a shopping cart down a grocery
store aisle. Aren't hallucinations fun?

The real bummer was that I hadn't had a bowel movement in three days, due to opioids and Zofran. This problem plagued me for a couple days after coming home as well. Still, I much prefer my suffering to that experienced by people in the past who had to have kidney stones surgically removed with no anesthesia but strong liquor!

- Aaron

If a drug screen is required by your employer, it is important that you educate yourself with drug testing information. Tests are usually a urine or hair drug test, which are established methods. A number of resources on hair drug testing are available. If the stress isn't already doing it, weight loss drugs exist and can be readily obtained online.