Pharmaceutical Industry

How to stop viral vampires: virus life cycle and antiviral 101

Cyto Citadel 2

This is some of the research that contributed to the recently released Darwin’s Paradox: An international science mysteryhttp://amzn.to/2k8qJgi. Anti-virals are way more complicated that I first imagined.

The Battle for Cyto Citadel – A Primer in Antiviral Warfare

This is the story of viral vampires and their clone armies attacking the friendly territory defended by cyto citadels. Viruses, not quite alive, walking dead, attack cells, armored castles (Cyto Cidadel), defended by vaccines and drugs. Some are defeated.

Skirmish 1 – VACCINATION

All around the Cyto Citadel are roaming squads of deadly B-cell skirmishers and T-cell marauders searching for viral vampires. These forces are very effective and win most of their battles leaving vanquished vampires in their wake.

Unfortunately, they only attack vampires they have seen before. Any new viral vampires get by them unnoticed as if they were wearing invisibility cloaks.

Vaccines introduce B-cells and T-cells to recognized vampires of the viral armies, such as measles, mumps, rubella, polio, and hepatitis. Captain Cytoplasm uses as many vaccines as possible, but still many viral vampires get pass this defense, especially influenza viruses which constantly mutate into unrecognizable forms.

Skirmish 2 – ATTACHMENT

When the invisibility-cloaked vampires approach the Cyto Citadel, their first objective is to attach to the citadel walls to stage their break in. Medical sentries can stop some viral attacks before they attach to the wall.

Docosanol dragoons prevent herpes simplex viral vampires from attaching to the citadel walls. Unfortunately, if these loyal dragoons do not recognize the viral vampires, the invaders slip by undeterred.

Skirmish 3 – ENDOCYTOSIS

With the vampires at the wall, they need to worm their way through. The Cyto Citadel has strong walls to thwart this intrusion.

For example, even the dreaded HIV horde, causers of the AIDS scourge, can not penetrate the citadel without the help of CCR5 crackers or CXCR4 crashers. Blockers can be brought against CCR5 and CXCR4 to isolate the HIV horde outside the Citadel where they can do no damage.

Skirmish 4 – UNCOATING

Once inside, all is not lost. First of all the viral vampires come heavily armored for the battle to breach the citadel walls. Before they can do their real damage, they need to remove this armor. This is called uncoating.

Two antiviral armies, the amantadine arsenal, and the rimantadine rangers, prevent influenza vampires from releasing acid to dissolve their armor. Without this acid, they are stuck inside their own armor and helpless to do any damage.

Skirmish 5 – MUTAGENESIS

Once uncoated, the viral vampires break into the citadel storeroom to steal parts to build a vampire clone army. This is the last thing the citadel defenders want: a viral vampire clone army!

The citadel storerooms are infiltrated by ribavirin robots that fool the vampires to accepting mutating parts. When the vampires build clones from mutating parts, errors pile up and the clones die from error catastrophe. Too many errors equal dead clones.

Skirmish 6 – SYNTHESIS

Another attack on the synthesis of the viral clone army is to supply the vampires with the wrong parts. Reverse Transcriptase quartermasters delivering the wrong parts from inventory can foil the cloning efforts of some of the HIV horde, and the Hepatitis B horde also. The parts look right, but when used, the result is defective.

Skirmish 7 – REPLICATION

If a few clones get this far, all is not lost. Building a clone is a slow process. Unfortunately, once they are operational, they can replicate themselves. From a few clones, they can grow a full clone army.

Patrol of protease (pronounced PRO-TEA-AZE) inhibitors can stop the replication. Unfortunately, like all the fighters in the Cyto Citadel, patrols are very specific about who they will attack. Smart citadel defenders recruit as many different protease inhibitor patrols as possible.

If the HIV horde invades, the saquinavir, ritonavir, indinavirnelfinavir, and amprenavir patrols are recommended. For the hepatitis C horde, different patrols are needed: boceprevir and telaprevir.

The last defense: Skirmish 8 – EXOCYTOSIS

If the clone army is successfully put together, the Cyto Citadel is lost, but a lost battle is not a lost war. As a last ditch effort, oseltamivir (aka Tamaflu) can prevent the clone army from breaching the walls from the inside. With the clone army trapped in this citadel, other Citadels can be safe.

Good News and Bad News

The good news is that there are many ways the Cyto Citadel defenders can stop the viral vampires and their clone armies.

The bad news is that all the defenders are all very specific, and each different vampire attack must be met with the correct response. Unfortunately, some vampires mutate rapidly, so there is an arms race to keep finding new defenders. Even worse, for some viral attacks, there are no known defenders.

Map credit: Dyson Logos rpgcharacters.wordpress.com.

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Taxol – A Natural Cure for Cancer?

Taxol

In this post we explore the cost to develop a natural product cure.

The National Cancer Institute’s web site declares, Paclitaxel, the most well-known natural-source cancer drug in the United States, is derived from the bark of the Pacific yew tree. Paclitaxel is the generic name for Taxol, and an illuminating case in the development of natural medicines.

Flash back to the 1950s, a period of postwar optimism and prosperity. Science is making significant strides. Penicillin, accidentally discovered in mold, proved to be a potent antibiotic during World War II. During the same period, the scourge of World War I, mustard gas, was shown to be an effective chemotherapeutic agent (the first) against lymphoma. Medicine was transitioning mainly diagnoses to actual cures.

A key catalyst in the development Taxol was Mary Lasker, founder of the Lasker Foundation.  Through the American Cancer Society, she campaigned successfully to significantly increase the funding the the National Cancer Institute (NCI).

Hoping to build on the success of natural sources (Penicillin) and chemotherapy (mustard gas), the NCI contracted with the US Department of Agriculture (USDA) to collect samples.  In 1962 they found what became Taxol.

Discovery of Taxol

Discovery of Taxol plaque: Near this location on August 21, 1962, Arthur Barclay and a team of botanists from the U.S. Department of Agriculture collected bark of the Pacific yew, Taxus brevifolla Nutt. Drs. Monroe Wall and Mansukh, of Research Triangle Institute, North Carolina, under contract to the U.S. National Cancer Institute, isolated Taxol from that sample.

So, just to summarize, TEN YEARS into the search, this important medication was discovered in the bark of the Pacific yew. 10 years.

Actually not much happened in 1962. Yews were already well known to be poisonous. People in Europe had been using this poison for over 2,000 years very effectively. Researchers tended to avoid yew poisons because the conventional wisdom was they these poisons had no specificity-they killed everything.

Monroe Wall and Mansukh Wani at the Research Triangle Institute in North Carolina accepted the challenge and by 1971 they isolated Taxol from the yew bark. Progress was slow because a 1/2 gram of Taxol required 12 kilograms of bark or 6 trees.

Interest waned another 5 years until Susan Horowitz and coworkers at Albert Einstein College of Medicine in New York City discovered the Taxol mechanism of action was unique and seemed to be effective against several cancers in animal models.

Let’s summarized again. Another 14 year of basic science before real interest is generated.  Studies in human cancer patients were begun at Johns Hopkins University in Baltimore and had some success.

In July 1977 Matthew Suffness of the NCI placed an order with the USDA for 7,000 pounds of bark, which meant killing about 1,500 trees. The environmentalists got involved, but research continued even though more and more trees were being harvested.

1024px-Taxol(Paclitaxel)3D

In 1984, NCI began Phase I (safety) clinical trials. There were many other hurdles, but perhaps the major one was cleared when a team of Florida State University Taxol researchers led by Bob Holton synthesized the drug on Dec. 9, 1993-no more killing trees.

This was not a moment too soon, as the FDA had approved Taxol a year earlier. Taxol sales peaked at $1.6 billion in 2000.

Final summary: natural product from the Pacific yew in 1962 became an important anti-cancer treatment in 1993, over 30 years later, 30 years of biology, chemistry, experiments, and trials. No other industry invests so much money over such a long period as the pharmaceutical industry. Compare this to the investors in Google who saw tremendous returns on their investments when Google went public in less than ten years. Most high-tech investors expect their returns much sooner than 10 years even. Other industries have similar or even shorter time horizons.

Pharmaceutical companies are the heroes of capitalism.

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One pill makes you smaller… #SFRTG #IARTG #Kindle

GAA2

One pill makes you larger, and one pill makes you small
And the ones that mother gives you, don’t do anything at all

Grace Slick of the Jefferson Airplane

This is some of the research that contributed to the recently released Darwin’s Paradox: An international science mysteryhttp://amzn.to/2k8qJgi. “Doctor” Brian is in Mozambique and has been given pills to test for activity against a new disease. This raises all of the ethical issues associated with off-label drug use.

Grace Slick might have been singing about prescription drugs [I was there and I’m not talking]. If so, those pills would have been used off label. Off label is when a legal drug is used for something other than its FDA-approved indication. For example, drugs approved for bipolar disease or schizophrenia are often prescribed for depression, and blood thinners are prescribed for hypertensive and coronary heart disease.

This is legal. The FDA does not regulate the practice of the medicine, only the drug companies. For example, over three-quarters of children discharged from a hospital receive at least one off-label prescription.

What do you think about your doctor prescribing medications for you that have not been fully tested for safety or efficacy? What do you think about your doctor enrolling you, often without your knowledge, in an ad hoc science experiment?

Drugs are used off-label for many reasons. If a drug is generic, no one is motivated to spend the time and money to run the clinical trials required to get an indication approved, regardless of how safe and effective it is, or isn’t. Even if a drug is not generic, the approval process might not be deemed cost effective. Ironically, the larger the off-label market, the less a drug company would be motivated to fund a clinical trial. They (and the patients) are already benefiting from the sales, so why bother with the testing?

This is the conflict. If the doctors prescribe and the drug companies sell — all without clinical trials — who is protecting you? For example, estrogen medications were prescribed extensively to menopausal women to prevent coronary disease. It wasn’t until a government-sponsored trial found them to increase, not decrease, the risk of stroke and heart attack that this was curtailed.

You can think of each off-label prescription as a tiny clinical trial, without informed consent, without controls, without records, and without oversight. What do you think about being a test subject knowing that there is little chance that the result of your sacrifice and risk will add to scientific knowledge or benefit those who come after you?

Some might tell you the system is even more sinister. It turns out that drugs for rare diseases can be declared as orphan products. In this case the FDA streamlines (cuts corners) the approval process. This is good for those rare diseases, but once the drug is approved, it can be used off-label for whatever the doctors decide. This can be a cost-saving way for drug companies to get to market. For this reason, among others, drug companies are forbidden from promoting off-label uses. Regardless, drug companies have been penalized billions of dollars for violating the rules.

Who is protecting your well being? How can this system work at all?

This anxiety ignores one important fact of life. The fact of your unique DNA. People are different, and EVERY prescription (FDA approved or off label) is a science experiment. People respond individually to drugs. Side effects differ from patient to patient, ranging from benign headaches or muscle cramps to life-threatening reactions. Even popular over-the-counter (OTC) drugs like Tylenol(R) pose risks.

Doctors are the ones who read all that fine print and journals articles to be prepared and watchful for negative reactions from ALL prescriptions whether for FDA-approved or off-label.

In summary, around a billion off-label prescriptions are written each year with the overwhelming majority benefiting the patient. Like ALL medicine, there are benefits and risks, and doctors are the ones who balance them. Without doctors writing off-label prescriptions, millions would be suffering needlessly. It is the doctors who contribute the judgment that the bureaucracy can not.

So as Grace Slick recommended, “Go ask Alice,” especially if she is a doctor.

I am not an MD and am not giving medical advice.

For more information: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538391/

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Freedom and Drugs – A Tryptych

Freedom Sculpture

In front of GSK‘s building in Philadelphia is the dramatic Freedom Sculpture by Zenos Frudakis. A drug company, a city, and a sculpture. How do they fit together?

Let’s go chronologically.

In 1776, the Continental Congress approved the Declaration of Independence in Philadelphia which assured Philadelphia’s place in United States history books to be learned by all elementary school children. This document stated,

We hold these truths to be self-evident, that all men are created equal, that they are endowed by their Creator with certain unalienable Rights, that among these are Life, Liberty and the pursuit of Happiness,

but in 1776, the noble ideals only applied to some men, and certainly not slaves or women.

So this is the first lesson of this eclectic triptych: Equality, freedom, liberty, independence is a process, not an absolute.

In 1830, John K Smith opened a drug store in Philadelphia. While this may not be an event celebrated like Philadelphia’s Independence Hall and Liberty Bell, Glaxo Smith Klein (GSK) is now one of the five largest pharmaceutical companies in the world.

The pharmaceutical industry takes the biggest risks on the longest projects of any industry. Costs over one billion dollars, and 10-20 years time frames are typical, and after all of that, failures are common. All this risk and expense allows people to be healthy enough to be concerned about other issues.

So the second lesson of our triptych: The process for equality, freedom, liberty, independence starts after health, which demands risk and long-term investment.

In 2001, the Freedom Sculpture was unveiled in front of the GSK World Headquarters in Philadelphia. This evocative sculpture represents freedom (equality, liberty, independence) as a process and a struggle with a joyous result. However, a closer look at the sculpture reveals the many left behind and even lost – including a the work of a sculptor who died of AIDS, a disease GSK scientists have long made part of their mission.

The final section of this triptych on human rights summarizes the process started with the declaration, and supported by scientists at corporations like by GSK dedicated to improving public health, leading to freedom, but not yet reaching it for all.

Freedom and Drugs, partners in the struggle for human rights.

Bonus: More sculptures.

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