PDA

View Full Version : Receptors and Ligands: Why Drugs Work



jubei33
16th December 10, 09:27 AM
The next time you have a headache and you crack open that bottle of old fashioned aspirin (etc), stop to appreciate the miracle that you hold in your hands. We have come a long way from the trial and error approach of ancient times: "Hey Grok, you feel all right? Hurrrrrrrrk!" Clearly, licking toads can only bring us so far. Today we have deduced not only the shape of medicinal compounds, but also many of their complex of interactions in the body. This stands true for not only medicine, but also of poisons, as their functionalities are often similar as well. Though far from completely understood, in the backbone of these processes lies a governing theory that has allowed us to develop increasingly safer and more effective drugs for the treatment of disease. The question stands: how does this work--What fundamental principles govern this science?

Part I: Factors affecting drug-receptor binding

Receptors are often first thought of in esoteric terms. The idea of a discrete place of binding where a certain shape will ideally fit (like a lock fits a key) and effect some kind of action in the body is a simple and often used image in text books. In reality, the process is more complex as individual characteristics, like ionic charge, stereoisomerism, hydrogen bonding and even genetic nuance play a greater role in drug binding. Clearly, this allows the possibility of many things having the ability to bind to a receptor, yet we know from experience that only a few things can and even fewer activate the receptor itself. The idea can be reconsidered with the concept of induced fit (http://www.encyclopedia.com/doc/1O7-inducedfittheory.html), where a nearly ideal compound will induce shape changes in a protein receptor, bind and activate (or inhibit) some process in a cell. This idea is thought to be partially responsible for the ligand specificity in receptor binding. Furthermore, a receptor is not a singular entity or single group of things. Many things can be considered receptors, like cell membrane proteins, intracellular regulatory proteins, structural proteins or extracellular enzymes, to name a few. The interplay of chemical characteristics and their effect on the biological strata can be harnessed in the form of a drug to control specific cellular activities and create effective therapies for disease.

Most beneficial drugs bind to receptors with hydrogen bonds (http://en.wikipedia.org/wiki/Hydrogen_bonding) or weak ionic bonds. Because these bonds are usually of sufficiently low energy to break, they ensure not only that ligands can be removed under biological conditions. Nearly as important, these bonds also ensure that a compound has the specificity to bind at the receptor as well. Many kinds of functional groups are capable of hydrogen bonding and enzymes use these groups to their advantage by positioning the compound in question snugly in the binding site. Think of this like a plug and outlet: Three prong plugs fit three prong outlets the best and two prong plugs may fit as well, but the funky Lithuanian four prong plug won't fit at all. The closer a ligand's hydrogen binding sites are to matching (right position, right angle, optimum distance, etc) the enzyme's 'outlet', the stronger the binding interaction will be and the more likely the compound will activate the receptor. This kind of system prevents faulty signaling by requiring a certain level of specificity and precision in binding at the receptor. Simple +/- ionic interaction alone cannot ensure that a receptor won't be activated by anything and everything that comes its way. With hydrogen bonding, the structure and position of groups becomes more important for functional interaction, thus adding another dimension of complexity to the system and providing the necessary precision for a functional system.

In contrast, covalent bonds (http://en.wikipedia.org/wiki/Covalent_bond) are stronger and require a higher amount of energy to break. This is harder to achieve in cellular conditions, making ligands that bind this way harder to remove. Covalent bonds are often, though not always, the result toxic interactions. For example, many mutagens bind to DNA in this manner, causing all sorts of mischief, like breaks in the helix, point mutations and chromosomal rearrangements. In the cases of insecticides like parathion (http://en.wikipedia.org/wiki/Parathion), or certain military grade poisons like VX (http://en.wikipedia.org/wiki/VX_%28nerve_agent%29) and soman, they are irreversible inhibitors of an enzyme called acetylcholinesterase (http://en.wikipedia.org/wiki/Acetylcholinesterase), which is responsible for the reduction of acetylcholine (a neurotransmitter) in nerve cells.⁹ These chemicals covalently bind to the enzyme, blocking its action and allowing excess acetylcholine to build up in nerve cells. This causes continual nerve stimulation in affected cells, especially in those controlling respiratory function, which causes bronchioconstriction, convulsions and/or death. In such a critical system, time is of the essence and since the body cannot remove the chemicals from acetylcholinesterase, the cells are left with only one option: to reproduce the enzyme itself. Unfortunately, this is a feat that cannot be produced under the time constraints as protein manufacture is measured in terms of hours. An example of a positive kind of covalent bonding comes from a class of drugs called NSAIDs (http://en.wikipedia.org/wiki/NSAIDs). Aspirin is a prime example of this, whose mode of action is to non-selectively inhibit cyclo-oxygenase (http://en.wikipedia.org/wiki/Cyclooxygenase) 1 and 2 (cox-1 and 2), enzymes that cause inflammation.¹⁰ Covalent bonding to this enzyme inhibits its activity, resulting in the reduced inflammation these drugs are known for.
http://i131.photobucket.com/albums/p297/jubei33/parathion.png

Stereoisomerism (http://en.wikipedia.org/wiki/Stereoisomerism) is a concept central to the organic chemistry portion of pharmacology, such that greater than half of the drugs we use today are stereoisomers, or more specifically what is known as chiral molecules. Chirality (http://en.wikipedia.org/wiki/Chirality_%28chemistry%29) is a concept often seen in carbon atoms. Carbon can bind a total of four times and when the situation occurs that all four groups attached are different the order in which they are arranged becomes important. Though similar, identical in structural formula, the order of the groups can affect the shape of the molecule in question and consequently its binding affinity to a particular receptor. The idea of left/right handedness was developed to describe this concept, with one group either on the left side or right side of a molecule. To visualize this idea, think of the receptor as a slab of clay with an imprint that matches our chiral molecule. Though very close in shape, both may be close enough to fit, but only one will fit perfectly and this one will have the most activity at our makeshift receptor.
http://i131.photobucket.com/albums/p297/jubei33/stereoisomers.png
insert clay image here

http://i131.photobucket.com/albums/p297/jubei33/carvedilolgif.gif Chirality as it concerns drugs is intimately important, as oftentimes only one enantiomer will be active at a given receptor. Take for example, the (S)(-) isomer of carvedilol is 100 times as effective at binding to its receptor (α and β adrenoceptors (http://en.wikipedia.org/wiki/Adrenergic_receptor)) than its brother the (R)(+) isomer¹. A hundred fold difference in binding specificity has important consequences for us, considering that most of our drugs are still chiral mixtures. "Most studies of drug effectiveness have been carried out with chiral mixtures of drugs, with in many cases only one being the active ingredient." Thus, "many patients are receiving drug doses of which 50% or more is less active, inactive, or actively toxic."² Currently, a lot of research is being put forward to develop stereo-specific methods of manufacture, which guarantee the more active component is being used in the drug. This could mean not only a reduction of side effects, but also smaller dose schedules for inherently toxic drugs, like cancer chemotherapies for instance.

Genetic nuances also affect drug binding, with individual differences causing reduced or more effective drug binding to a particular receptor. For example, slow acetylators (http://www.genetichealth.com/Resources_Personalized_Medicine.shtml)are people with a genetic polymorphism that causes them to produce less of a specific enzyme than the normal phenotype. This causes a hazard when they take certain drugs, like isoniazid, that utilize that enzyme for metabolism. The reverse is also possible as well, where a person might be gifted with the ability to metabolize a certain drug faster than others. Another relevant example: the enzyme aldehyde dehydrogenase is charged with the removal of a critical byproduct of ethanol metabolism: acetaldehyde. Aldehydes (http://en.wikipedia.org/wiki/Aldehyde) are generally considered systemic poisons³ and ethanol's byproduct is no exception as it is widely considered responsible for many of the bad effects of a hangover. Changes to the enzyme are common in Asian populations, particularly the Japanese, and cause "slow acetaldehyde removal, low alcohol tolerance perhaps which leads to a lower frequency of alcoholism."⁴ This is similar to the effects of drugs used to mitigate alcoholism, specifically the drug disulfiram, that cause vomiting and severe hangovers with even a small amount of alcohol. The drunken, red faced Japanese businessman can surely appreciate this the morning after.

Part II: Some receptors and how they work

Until recently, the actual shape of most receptors was unknown, but with the opening of the genetic age and mainstay use of sequencing techniques, whole families of receptors, their shapes and functions have been identified. Both human and animal examples serve as the basis for a growing collection of receptors, many of which showing a common evolutionary lineage with portions of the receptors being conserved throughout many species.⁵ These similarities are often close enough to allow the testing of drugs on non-human subjects first. The rainbow of receptors is usually classified by their mechanism of action. Some are ion channels, some work by controlling translation in the cell, others work by sending other messengers to command proteins where action can be taken. Still others, such as the so called orphan receptors (http://en.wikipedia.org/wiki/Orphan_receptor), have no known ligands and drugs affecting them have yet to be studied. The wide variety of receptors enables the cell to gain knowledge of and react to its environment in a reasonable amount of time. These receptors and their corresponding transduction pathways can be utilized in new drugs or exploited by toxins.

http://i131.photobucket.com/albums/p297/jubei33/achnicotinicreceptor.pngThe nicotinic acetylcholine (http://en.wikipedia.org/wiki/Nicotinic_acetylcholine_receptor) receptor is an ion channel that is involved heavily with neuronal regulation. The natural ligands of it are all famous neurotransmitters like serotonin, glutamate and acetylcholine. The receptor is made of 5 sections of polypeptides arranged into the shape of a tube that penetrates both sides of the cell membrane. When a drug binds, the receptor's shape changes to allow a pore to open and this allows sodium ions to flow inside the cell for a very brief period of time. The sodium influx creates a flow of charge scientifically called a depolarization, or colloquially known as a "nerve impulse". These receptors are important to processes like learning and memory. It is interesting to note that many natural poisons, like spider or snake venoms have chemicals that bond permanently to these receptors leaving them open. This allows for a long term stimulation similar in some ways to the effects of organophosphate poisoning mentioned before.

Steroids are lipophilic (http://en.wikipedia.org/wiki/Lipophilicity) molecules that are able to penetrate the cell wall. This is the reason why steroidal creams for rashes and bug bites can be applied directly to the skin. Rather than utilize a membrane bound receptor for their actions, they usually bind intracellularly to receptors that activate the machinery that produces changes in gene expression and protein manufacture. Glucocorticoid (http://en.wikipedia.org/wiki/Glucocorticoid) steroids, for example, bind to a special protein called HSP-90 in the cell nucleus that transcribes genes. HSP-90 (http://en.wikipedia.org/wiki/Hsp90) is initially coiled to prevent its activity, but when activated by a steroid the receptor's transcription portion unfolds like a spring into its active shape. Once there it transcribes sections of DNA from target genes to manufacture these new proteins. Glucocorticoids have effects on and influence the function of most cells in the body. An important example of this is fat maintenance and metabolism as: "Glucocorticoids increase serum glucose levels and thus stimulate insulin release and inhibit the uptake of glucose by muscle cells. The increased insulin secretion stimulates lipogenesis...leading to a net increase in fat deposition combined with increased release of fatty acids and glycerol into circulation."⁶

Another classic example is that of the seven-transmembrane receptor (7TM) (http://en.wikipedia.org/wiki/Seven-transmembrane_protein) or "serpentine" receptor, so-called because it winds like a snake through the cell membrane 7 times. There are many in this family and they have a long list of functions as they are found in almost every tissue in the body. Generally, these use G-proteins (http://en.wikipedia.org/wiki/G-protein) to transfer and magnify chemical signals inside the cell by initiating a signaling cascade. This class of proteins are attached to the end of the receptor inside the cell. When a ligand binds to the receptor, the shape changes to allow the G-protein piece to leave the receptor. The piece is free to activate another protein that typically releases a second messenger. G-proteins use a system of "second messengers," which relay a chemical signal to another protein in a chain, like a chemical relay until the message reaches a command position and action is taken. In the specific case of adenylate cyclase (http://en.wikipedia.org/wiki/Adenylate_cyclase), G-protein binding activates it to produce its second messenger: cyclic adenosine monophosphate (cAMP) (http://en.wikipedia.org/wiki/CAMP-dependent_pathway). Depending on the pathway and the cell, increased cAMP concentration can activate ion channels, release glucose stored in liver cells, cause cell proliferation and/or activate protein kinase-A (http://en.wikipedia.org/wiki/Protein_kinase_A), a critical messenger protein involved with enzyme activation and transcription.
http://i131.photobucket.com/albums/p297/jubei33/receptorslist.png
Major types of receptors. 1,4 and 5 were discussed. Can you guess which are which?

Since these receptors are ubiquitous throughout the body, the list of endogenous ligands for these receptors is far too long to mention here. One of the most famous is certainly epinephrine (aka: adrenaline) involved in the famous 'fight or flight' response. When something scary is seen or felt, nerves from the brain send signals to the adrenal medulla and in response it releases epinephrine into the blood stream. Binding at receptors in various locations causes the heart to rate to increase and beat more forcefully, liver cells to release their store of glucose, blood flow to decrease in skin, but increase in skeletal muscles and the constriction of bronchioles among other things.⁷ All of these things prepare the body to react in emergency situations and are chemically mediated through the action of these receptors. On the subject of toxicity, toxins produced by Vibrio cholerae (http://en.wikipedia.org/wiki/Vibrio_cholerae) bind covalently to this kind of receptor in intestinal cells causing continual production of cAMP.⁸ This causes the release of ions and water into the intestines and is responsible for the characteristic raging, non-stop diarrhea ("rice-like stools") symptom of the infection.

Part III: signal cascades: signals from the background noise

To be continued...

jubei33
16th December 10, 09:30 AM
just in case:

READ THESE BOOKS:
A. Johnson, George; Raven, Peter. Biology 6th ed.
B. Katzung, Bertram G. BASIC & CLINICAL PHARMACOLOGY - 10th Ed. (2007)
C. Strohl, William A. Lippincott's Illustrated Reviews Microbiology 1st Ed. (2007)
D. Manahan, Stanley E. Toxicological chemistry and biochemistry 3rd. Ed. (2002)
E. Krauss, Gerhard. Biochemistry of Signal transduction and Regulation 3rd Ed.(2003)
F. Kubinyi, Hugo. Pharmacokinetic optimization in drug research: Hydrogen Bonding: The Last Mystery in Drug Design?
G. Hodgson, Ernest. A Textbook of Modern Toxicology 3rd Ed. (2004)
H. Solomons, Graham T.W. Solomon's organic chemistry 6th Revised Ed. (1998)
I. Smith, Michael B., March, Jerry. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Sixth Ed. (2001)


References:

1. "Carvedilol, a drug that interacts with adrenoceptors, has a single chiral center and thus two enantiomers. One of these enantiomers, the (S)(-) isomer, is a potent b-receptor blocker. The (R)(+) isomer is 100-fold weaker at the b receptor. However, the isomers are approximately equipotent as a-receptor blockers. Ketamine is an intravenous anesthetic. The (+) enantiomer is a more potent anesthetic and is less toxic than the (-) enantiomer. Finally, because enzymes are usually stereoselective, one drug enantiomer is often more susceptible than the other to drug-metabolizing enzymes. As a result, the duration of action of one enantiomer may be quite different from that of the other." (from B. introduction )
2. "Unfortunately, most studies of clinical efficacy and drug elimination in humans have been carried out with racemic mixtures of drugs rather than with the separate enantiomers. At present, only about 45% of the chiral drugs used clinically are marketed as the active isomer¾the rest are available only as racemic mixtures. As a result, many patients are receiving drug doses of which 50% or more is less active, inactive, or actively toxic. However, there is increasing interest at both the scientific and the regulatory levels in making more chiral drugs available as their active enantiomers." (from B. introduction)
3. "Aldehydes are lipid soluble and relatively toxic, whereas carboxylic acids are more water soluble and undergo phase II reactions leading to their elimination." (from D. p164) "Alkylaldehydes are associated with mutagenesis and genotoxicity." (From D. p192)
4. "The deficiency is manifested by slow acetaldehyde removal, low alcohol tolerance perhaps which leads to a lower frequency of alcoholism.[5][2] These symptoms are the same as those observed in people who drink while being treated by the drug disulfiram, which is why it is used to treat alcoholism. The patients show higher blood levels of acetaldehyde, and become violently ill upon consumption of even small amounts of alcohol.[2] Several drugs (e.g., metronidazole) cause a similar reaction known as "disulfiram-like reaction." <http://en.wikipedia.org/wiki/Aldehyde_dehydrogenase> (in pathology section. )
5. "Most transmembrane signaling is accomplished by a small number of different molecular mechanisms. Each type of mechanism has been adapted, through the evolution of distinctive protein families, to transduce many different signals. These protein families include receptors on the cell surface and within the cell, as well as enzymes and other components that generate, amplify, coordinate, and terminate postreceptor signaling by chemical second messengers in the cytoplasm. " (from B. receptors)
6. "Glucocorticoids increase serum glucose levels and thus stimulate insulin release and inhibit the uptake of glucose by muscle cells, while they stimulate hormone-sensitive lipase and thus lipolysis. The increased insulin secretion stimulates lipogenesis and to a lesser degree inhibits lipolysis, leading to a net increase in fat deposition combined with increased release of fatty acids and glycerol into the circulation...The net results of these actions are most apparent in the fasting state, when the supply of glucose from gluconeogenesis, the release of amino acids from muscle catabolism, the inhibition of peripheral glucose uptake, and the stimulation of lipolysis all contribute to maintenance of an adequate glucose supply to the brain." (from B. corticosteroids)
7. "When the sympathetic division becomes activated, epinephrine is released into the blood as a hormonal secretion, and norepinephrine is released at the synapses of the postganglionic neurons. Epinephrine and norepinephrine act to prepare the body for fight or flight. The heart beats faster and stronger, blood glucose concentration increases, blood flow is diverted to the muscles and heart, and the bronchioles Dilate." (from A. pg1100)
8. "Cholera toxin is a multimeric protein composed of an A and a B subunit. The B subunit (consisting of five identical monomers) binds to the GM1 ganglioside receptor of cells lining the intestine. The A subunit has two components: A2, which facilitates penetration of the cell membrane, and A1, an ADP-ribosyl transferase that ADP-ribosylates the membrane-bound Gs protein. The Gs protein activates adenylate cyclase, which produces elevated levels of intracellular cAMP. This in turn causes an outflowing of ions and water to the lumen of the intestine. " (from C. p185)
9. "Parathion, an early insecticide, works by inhibiting acetylcholine esterase by binding covalently to the binding site. Though the insecticide itself is an inhibitor, the more active metabolite is formed by bond cleavage at the phosphate group. This releases an ion with a very strong affinity for the enzyme's functional group." (from D. pg393)
10. "The anti-inflammatory activity of the NSAIDs is mediated chiefly through inhibition of biosynthesis of prostaglandins...Aspirin irreversibly acetylates and blocks platelet cyclooxygenase, while most non-COX-selective NSAIDs are reversible inhibitors." (from B. NSAIDs section)

Neildo
16th December 10, 11:59 AM
i read most of that and the only thing i'm confused about is why you're doing all this work for us plebs. are you publishing this elsewhere, and if not why not?

Dr. Socially Liberal Fiscally Conservative Vermin
16th December 10, 01:00 PM
Looks like an assignment to me

jubei33
16th December 10, 04:54 PM
practice, I suppose. Someone asked a question I could answer in depth, so I took it as a challenge.

and I'm out of school at the moment and I'm working back to that mindset.

PLus, I like the format as a teaching platform. Part of what I do here, aside from the straight up informative thread, is tell stories. The mad scientist gag, I thought it was a good way to encourage people to read more on the subjects I presented. I had quite a few people seriously worried about hives of diarrhea bees in their neighborhoods. The game was kind of about blending truth and reality to a degree, I was encouraging you to find out where I exaggerated, not with the science portions, but with its limits and accomplishments. This kind of turned it into a scifi treasure hunt in way.

As for the article, it was easy to understand, clear?

I wish I could get some one to fix those pics ***ADMIN cough***!

I've never really considered science writing. Maybe I should start? Anyone know anything about it?


Looks like an assignment to me
You want home work!? OK:

What are the other two receptors in the 'receptor list picture' that i didn't mention. Tell us how they work and one or two drugs that affect them and for what reason.

Neildo
16th December 10, 06:52 PM
that read like an article out of a scientific magazine. could have used a touch of proof-reading, but not for accuracy just for printings sake.

Kiko
16th December 10, 08:02 PM
I tried to read it, but it gave me a headache...

*ducks*

I WISH I could absorb that stuff... honest.

jnp
16th December 10, 10:23 PM
I love jubei33 and his scientific threads.

AAAAAA
17th December 10, 04:35 AM
I've never really considered science writing. Maybe I should start? Anyone know anything about it?


You mean science divulgation or academic articles?
If you're talking about the former, I loved Asimov's "Short history of biology" and "Understanding physics" as a youngster, I think it doesn't get much better than that in being accessible though rigorous. That might be a good style guide.

Dr. Socially Liberal Fiscally Conservative Vermin
17th December 10, 05:34 AM
You want home work!? OK:

What are the other two receptors in the 'receptor list picture' that i didn't mention. Tell us how they work and one or two drugs that affect them and for what reason.

Ok I'll have a go,

1) Was the lipophilic, sneaks it way though the membrane kinda thing.
2) Enzyme linked receptor
3) Trick question as this is also an enzyme linked receptor!
4) Ion channel
5) G-protien activated receptor

Enzyme linked receptors are activated by extracellular ligand binding with whatever proper shaped molecule floats by, which causes the transmembrane protien to deform causing an intracellular cascade.

As to what drugs affect them err dunno at a guess BOOOOOOOOOOOOZE

jubei33
17th December 10, 06:54 AM
Ok I'll have a go,

1) Was the lipophilic, sneaks it way though the membrane kinda thing.
2) Enzyme linked receptor
3) Trick question as this is also an enzyme linked receptor!
4) Ion channel
5) G-protien activated receptor

Enzyme linked receptors are activated by extracellular ligand binding which causes the transmembrane protien to deform causing an intracellular cascade.

As to what drugs affect them err dunno at a guess BOOOOOOOOOOOOZE

all correct. 1 is indeed steroid receptor. anOther ligand binding this way is thyroxine, the metabolism regulating hormone of that thing in your neck, that causes goiters if you don't get enough iodine (know what I mean? :) ) these can be cytoplasmic or nuclear, which usually are involved with transcription and gene regulation. 2 is meant to be a general enzyme linked receptor. 3 is a tyrosine kinase linked receptor of similar action. These are usually bound by growth factors like epidermal growth factor and platelet derived growth factor. Some cancer cells usually produce their own growth factors in later stages of tumorigenesis. Some newer drugs are designed to block these receptors from being stimulated (gefetnib) or monoclonal antibodies which bind and block the receptros (cetuximab).


You mean science divulgation or academic articles?
I'd like to do option A, but in the very near future I'll have to be doing B as well.

thanks for your votes of confidence

jubei33
19th December 10, 11:05 PM
I tried to read it, but it gave me a headache...

*ducks*

I WISH I could absorb that stuff... honest.

I've thought a lot about what you said. I think that there are different ways to go about learning science. A lot of people go on and on about things like being a kinesthetic learner and the different approaches to learning, or what not. I would say go with what works. If you have to make a game of it: fine play cards or memory; if you have to sing it: make mnemonics and sing them on the #2 bus; if you like jokes: make light of H. influenzae (preferably not in front of people with meningitis). What ever works is all good.

For me it was kind of like learning a new language when I started. Chemistry, let alone 'science' itself, is a massive subject. Any one subject has subsections and specializations, each with its own jargon and concepts that need to be understood and applied. Considering this, there is always going to be this little hill, that any neophyte will have to climb before a general understanding can be achieved. I liken this to learning a new language. The first couple of weeks or months, a person has no idea how to say much and their vocabulary is very limited conversationally, confidence is low. But after practice, a little immersion in the material and the top of that little hill gets closer and closer and confidence grows. Pretty soon a person can use the language to function in society and do everyday things. From their perch atop this hill, they can see a much larger mountain in the background, one that represents fluency.

With subjects in science the concepts are the important part, so just understanding the point and the action of what's going on is good. Even if you take only small pieces from an article, it's beneficial and it builds a larger fluency in the 'language of science'. Also, keep in mind that personal interest plays a big role as well. You might not even like chemistry or physics or whatever. I'm the same way with physics and the search for the illustrious Higgs boson. I don't know enough about that subject to really comment on it other than: "Hey, that's great," and I have little understanding of physics outside of a chemical context or the intro cousrework.

Nasreal
23rd January 11, 01:04 AM
A professor of mine brought up an interesting idea that I'm going to interject here with, though it's perhaps a tad more philosophical than physical.

To Paraphrase: It is interesting that for a lot of drugs, we know what they do, and we know that it helps, but what is really interesting is just because a drug treats for an illness, doesn't mean it necessarily addresses the cause of that illness. For a logical analogy he said, "I see you sitting and looking gloomy and very depressed, and I give you a big sac of money( maybe saying that you found out you won 100 million in the lotto would be more...topical?), and that causes you to become very happy." Now does that mean that the reason(root cause) of your unhappiness was a lack of money? No. At least that is not necessarily the case. You have, at least apparently in the case of this simple analogy, fixed the problem. It could be that you only helped by accident, not because the person was depressed by their lack of money, they very well could have been depressed by say a recent break-up, etc.

Take that for what you will.

Dr. Socially Liberal Fiscally Conservative Vermin
23rd January 11, 11:55 AM
Its a common argument. When I worked in mental health we used to call the drug therapies "Band aids for broken bones".

Nasreal
23rd January 11, 12:11 PM
Its a common argument. When I worked in mental health we used to call the drug therapies "Band aids for broken bones".

Lol good analogy

jubei33
23rd January 11, 04:15 PM
A professor of mine brought up an interesting idea that I'm going to interject here with, though it's perhaps a tad more philosophical than physical.

To Paraphrase: It is interesting that for a lot of drugs, we know what they do, and we know that it helps, but what is really interesting is just because a drug treats for an illness, doesn't mean it necessarily addresses the cause of that illness. For a logical analogy he said, "I see you sitting and looking gloomy and very depressed, and I give you a big sac of money( maybe saying that you found out you won 100 million in the lotto would be more...topical?), and that causes you to become very happy." Now does that mean that the reason(root cause) of your unhappiness was a lack of money? No. At least that is not necessarily the case. You have, at least apparently in the case of this simple analogy, fixed the problem. It could be that you only helped by accident, not because the person was depressed by their lack of money, they very well could have been depressed by say a recent break-up, etc.

Take that for what you will.

I would say it depends on the drug. For some, the problem we're having right now is that we aren't doing research to find out if they actually help in the long run or are better than older safer treatments already in use. A great example of this would have to be carotid stenting, which is where they insert a tube like device to force the carotid open. Sounds like a great idea in heart failure cases where the artery in question is nearly closed off with plaque and stuff, but evidence doesn't seem to be available that conclusively shows benefit. Likewise, warfarin, a blood thinning agent hasn't been shown to be more effective than regular old ibuprofen at the same task. Over prescription of antibiotic, especially in cases of sore throats, where the argument is "hey, you could get an acute case of rheumatic fever and die". Sore throats are usually caused by viruses and this kind of usage risks the negative consequences of the anitbiotics as well. It's not that rare to hear of someone who had a poor reaction to them.

Nasreal
23rd January 11, 11:00 PM
On the subject of drugs, nothing pisses me off worse than the anti-immunization crowd. It just makes me rage.

Dr. Socially Liberal Fiscally Conservative Vermin
24th January 11, 04:31 AM
Its still early days for stents. I have read a number of articles that have shown some great medium term results though, especially with coronary stents.

jubei33
24th January 11, 07:01 AM
Its still early days for stents. I have read a number of articles that have shown some great medium term results though, especially with coronary stents.

Yeah, its too early. It was just an example of a place that requires more research and efficacy testing. I feel that this kind of research is going to be critical to reduce costs and rebuild a trust in medicine that I feel has been eroding for the last few decades. I feel that this kind of research should be required before drugs (etc) are released into the public sphere to, at the very least, give people an awareness of the risks of use and give them the chance to make decisions based on the best of the information available.

In the case of the opposite, people tend to have hard feelings when things don't go as well as they could, especially if something important was left out of the previous conversation. For instance: "The artery-opening stent can temporarily alleviate chest pain, but do not contribute to longevity. The vast majority of heart attacks do not originate with obstructions that narrow arteries." Consider if there was a older, safer, better studied alternative on the table and a person was sold on the newer one, because it was new. This is a conflict that erodes public confidence, one that is becoming more and more of a problem. These kind of problems are going to define health care in the US and elsewhere real soon.


On the subject of drugs, nothing pisses me off worse than the anti-immunization crowd. It just makes me rage.

Yeah, I feel you, but the majority of those guys are just scared parents trying to do what they think is best for their kids. Very few of them are the "AIDS was manufactured at Ft. Dietrick" kind of dudes. Even fewer of these guys are willing to argue a point and weigh evidence. These guys have invested so much in their ideas that to revise even a small point might require a total revision of the "manifesto", a life change in some cases.

Nasreal
24th January 11, 11:09 AM
Yeah, I feel you, but the majority of those guys are just scared parents trying to do what they think is best for their kids. Very few of them are the "AIDS was manufactured at Ft. Dietrick" kind of dudes. Even fewer of these guys are willing to argue a point and weigh evidence. These guys have invested so much in their ideas that to revise even a small point might require a total revision of the "manifesto", a life change in some cases. most definitely my problem is not with their intentions, which are perfectly good. My problem is that like many others, they do not listen to the advice of experts, and instead listen to a celebrity who is a perfect stranger, and when presented with the fact that there is absolutely no evidence that vacines cause autism outside of the incredibly weak, "I vaccinated my child, and now they have autism" they do not change their tune.....

And regardless of their intention what they are actually doing is putting an innocent child at risk.

Dr. Socially Liberal Fiscally Conservative Vermin
24th January 11, 11:38 AM
You dont think that there are issues with multiple vaccines and immature immune systems?

Nasreal
24th January 11, 12:25 PM
You dont think that there are issues with multiple vaccines and immature immune systems?
I'm willing to hear what you have to say about it and incorporate it into my thinking, that's what I'm trying to get at. You're giving more credit to some than they probably deserve. As I said, my main issue is with the folks that are convinced that vaccinations cause autism. It is bull, people reading correlation to mean causation.

jubei33
25th January 11, 03:51 AM
This kind of reminds me of something that happened to me when I was working as a mass spectroscopy tech a while ago. My boss and I were talking about this city in <name redacted> that our company had done testing for. The city in question had been home to a decommissioned military base and the land had been reused as public lands. The city had rebuilt schools and other public buildings on top of the reclaimed land. Since then families living in those neighborhoods had been plagued with an insidiously high rate of leukemia and other rare cancers.

Naturally, the thought that this had a chemical precursor, something left over that they forgot to clean up, was quick to come up. The EPA and other government regulatory commissions were the first to arrive and start testing. When they found nothing, independent companies were called to check the results. After months of testing we found exactly jack squat. No unusually high concentrations of known carcinogens (like benzine), no pools of hexavalent chromium in the water table, no unreasonably high radon leaks in the area, nothing apparently out of the ordinary*. *[This is by no means an extensive list, by the way.]

I was convinced that there had to be something wrong with our methodology or equipment, something that we had over looked. There had to be something there causing this plague on these poor people. My boss and I discussed it and he agreed, but he told me this: "I believe you. I think there is something there as well, but it could be entirely possible that its something new--something we never knew to look for. It could be something from a natural source or produced on the base that leaked into the water or soil. Or, it might even be just the lucky confluence of mutations that led to a proclivity for cancer in these people, or even a mutation revealing a weakness for some chemical found normally in city air or water. The point is that we just don't know and without proper evidence to guess would leave people with the wrong impression, especially if we're wrong. Suppose we say there is something (without proof), people's property values would plunge, they would have a harder time getting insurance coverage in the future and business might pull out of the area, among other things. Our responsibility is to report what we find, even if its that we find nothing. Suspicions have to be set aside until we have proof."

This is kind of a similar situation here. If you base your case only on Wakefield's stuff, then there's going to be problems, but recently there have been rare cases (http://www.sociocide.com/forums/showthread.php?56822-Autism-1-Big-Pharma-0&highlight=) that have shown verifiable evidence of this argument. As I understand it the people in question had a genetic proclivity for autism to begin with and it was found that the vaccinations may have exacerbated the problem. This same argument can't be the cause in every case of autism, but for some perhaps. This is a complicated situation and isn't something that can be thrown out of hand based on dogma.

Wakefield is dirty. He falsified his data and most likely accepted bribes to do so. But, he might also really believe what he proposed. Consider that if we find real evidence later showing that what he said was true, it wouldn't be because the science backed him, it would be because of a shitty guess. This is a hell of a risk to take with other people's lives and livelihood. It in all likelihood set the argument back years by making it controversial and harder to publish. Now, any inquiry into it is met with knee-jerk skepticism, which hinders the real science behind it, as well as creating panic among families.

In the end, the city closed all of the public buildings in the area and bought back the properties of the families living on the probably contaminated lands. Most families and business in the area moved away and very few people still travel across the wrong side of the tracks. We still don't know the cause.

Dr. Socially Liberal Fiscally Conservative Vermin
25th January 11, 05:21 AM
I'm willing to hear what you have to say about it and incorporate it into my thinking, that's what I'm trying to get at. You're giving more credit to some than they probably deserve. As I said, my main issue is with the folks that are convinced that vaccinations cause autism. It is bull, people reading correlation to mean causation.

Yes I know people who get hysterical even at the mention of the word 'antibiotic' never mind 'immunisation'.

Although the most common argument I hear is from parents who support immunisation but think that multiple immunisation (MMR etc) run the risk of overloading their young child's immune system, by giving it too much to deal with at one time.

I admit I have no idea how true these assertions are.

resolve
7th February 11, 10:57 PM
Yes Jubei I have been reading through this on my own time and have been eating it up.

I particularly liked the explanation of why the visual graphs are presented as they are and how they represent certain aspects, in theory, of cell receptors and the chemical reactions. Thinking back on my biology classes and remembering how cell membranes react and also seeing all that lab work from Invitrogen where I used to work shipping and all of those Discovery channel and Nova shows on cells being worked with in the lab I'm starting to get a greater picture of how this all works out.

resolve
8th February 11, 12:51 AM
pxrO5-HPIAw

jubei33
8th February 11, 04:32 PM
Is this a serenade? are you serenading me for science?

I stopped at signal transduction, which is a massive and important part of this topic. I did it for a reason, though. Its just hard to write about it in a way that doesn't sound repetitive and boring, while maintaining clarity and accuracy. or at least I haven't developed a good way to do it....

anyhoo, reading into that would be a pretty good topic expander. there's a lot of new stuff were learning about it and its opening up new opportunities for better and better therapeutic methods. The cancer drug Imatinib is a good example of this.

Dr. Socially Liberal Fiscally Conservative Vermin
9th February 11, 05:52 AM
Maybe getting some work after me PhD into mechanotransduction, hope it comes off, I find the whole thing facinating.