Thymus, T cells and Immunity

Lymph System 101

During open heart surgery, the surgeon cuts through the breast bone to expose the heart.  The thymus gland is completely removed.  Having had open heart surgery, I was concerned about the loss of my thymus because it is part of our immune system.  Lymphocytes (white blood cells) are transformed into T cells in the thymus. T-cells or T-lymphocytes  mature in the thymus and these help fight off infections, viruses, bacteria, fungi and general inflammation.

The thymus plays a vital role in the lymphatic system and endocrine system.  Thymosin is a hormone produced by the thymus that promotes the development of T cells from stem cells. I was glad to know that T cell production in the thymus is active mostly in adolescence and slows down as we age.  In our later years, T cells are maintained outside the central lymphoid organs.  New B cells, produced from bone marrow, continue to nurture our immune system.

Lymph Nodes

Once T cells have fully matured in the thymus, they migrate to the lymph nodes - groups of immune system cells throughout the body, where they aid the immune system in fighting disease.

Healthy gut flora will help keep your lymph fluids clean and healthy.  It’s that simple.  Before I had my health crisis and began to study nutrition, I had a wound that drained small calcifications.  The old term for this was “blood sand.”  It is the calcification that can occur when you do not have the proper ratio of calcium, magnesium, vitamin D and K2.

I learned about lymph first hand and I remember how that drainage smelled.  It had a chemical smell that reminded me of overheated plastic.  It was thick and dirty looking.  As I began to regain my health, the lymph ran clear as water and I instinctively knew I was on the right track.

Blood Cancer

Lymphoma is the most common blood cancer. The two main forms of lymphoma are Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). Cancerous lymphocytes can travel to many parts of the body, including the lymph nodes, spleen, bone marrow, blood, or other organs, and form a mass called a tumor. The body has two main types of lymphocytes that can develop into lymphomas: B-lymphocytes (B-cells) and T-lymphocytes (T-cells).

Adult T-cell leukemia/lymphoma (ATLL) is a rare and often grows fast. T-cell lymphoma can be found in the blood (leukemia), lymph nodes (lymphoma), skin, or multiple areas of the body. ATLL has been linked to infection by the human T-cell lymphotropic virus type 1 (HTLV-1).

With so much pollution in our day to day environment, it should be no wonder that these diseases are on the rise.

Keep your lymph system clean

Eat healthy foods. 

Exercise regularly

Drink plenty of clean water

Get some quality down time.  Meditate, do yoga or tai chi.  Relieve as much stress as possible in your life.

Do a liver cleanse.  Eat little or no processed sugars.  The liver works hard to process these.

Detox Your Liver With These 19 Super Foods

http://www.healthy-holistic-living.com/19-super-foods-naturally-cleanse-liver.html#

1. Beets and Carrots: Carrots are rich in Glutathione, a protein that helps detoxify the liver. Both are extremely high in plant-flavonoids and beta-carotene. Eating beats and carrots can help stimulate and improve overall liver function. (Source) (Related CE Article: The Mother of All Antioxidants)

2. Tomatoes: They have abundant amounts of Glutathione (see article above) which again, are a great detoxifier for the liver. As a side effect Lycopene in tomatoes will protect against breast, skin and lung cancer. (Source)

3.  Grapefruit: Another source of the liver cleansing glutathione. It’s also high in vitamin C and antioxidants, this boosts the production of the liver detoxification enzymes and increases the natural cleansing process of the liver.

4.  Spinach: Raw Spinach is a major source of glutathione that triggers toxin cleansing enzymes of the liver.

5.  Citrus Fruits: Lemons and Lime contain very high amounts of vitamin C, which helps stimulate the liver and aids the synthesizing of toxic materials into substances that can be absorbed by water.

6.  Cabbage:  The isothiocyanates (ITCs) made from cabbage’s glucosinolates provides liver detoxifying enzymes that help flush out toxins. (Source) (Source)

7. Turmeric: Turmeric is the liver’s favorite spice and helps boost liver detox. It does this by assisting enzymes that actively flush out dietary carcinogens. (Source)

8.  Walnuts: Walnuts are a good source of glutathione, omega-3 fatty acids and amino acid arginine, which support the normal liver cleansing actions, especially in detoxifying ammonia.

9.   Avocados: The nutrient-dense superfood, avocado helps the body produce glutathione

10. Apples: They are high in pectin and other chemicals essential to cleanse and release toxins from the digestive tract. Apples make it easier for the liver to handle the toxic load during the cleansing process.

11. Brussels sprouts: Brussels sprouts are high in sulfur and antioxidant glucosinolate, which forces the liver to release enzymes that block damage from environmental or dietary toxins.

12. Garlic: Garlic is loaded with sulfur that activates liver enzymes that help your body flush out toxins. Garlic also holds high amounts of allicin and selenium, two natural compounds that aid in liver cleansing.

13. Dandelion: Dandelion root tea assists the liver in breaking down fats, producing amino acids and generally ridding it of toxins.  There are other good natural supplements you can use, such as milk thistle.

14. Leafy Green Vegetables: Green Veggies are extremely high in plant chlorophyll’s that absorb environmental toxins, increase bile production, neutralize heavy metals, chemicals and pesticides, which lowers the burden on the liver.

15. Cruciferous Vegetables: Eating broccoli and cauliflower will increase production of enzymes glucosinolate in your system that help flush out carcinogens and other toxins.

16. Asparagus: Asparagus is a great diuretic helping in the cleansing process and sharing the detox load of the liver and kidneys.

17. Green Tea: Green tea is full of plant antioxidants known as catechins, a compound known to assist liver function.  Fresh lemon juice added in your tea is also good.

18. Olive Oil: Cold-pressed organic oils such as olive, hemp and flax-seed are great support for the liver, providing the body with a liquid base that can suck up harmful toxins in the body.  Don’t forget the coconut oil.

19. Alternative Grains: Gluten rich grains such as wheat, flour, or other whole grains increase the load on the liver’s detox function and enzyme production. Switch to alternative grains like quinoa, millet and buckwheat.

References and further reading

http://www.fgf.uk.com/content/lymphaticsystem

Lymph capillaries are bigger than blood capillaries and remove unwanted fat, waste, toxins, poisons, excess water and proteins.  Laying directly underneath the skin and covering your whole body they mingle between all the spaces between your cells.  Dirty lymph fluid when collected travels along the lymphatic system then back into the blood and through the heart.

http://articles.mercola.com/sites/articles/archive/2014/02/24/dry-skin-brushing.aspx

Stimulate Your Lymphatic System

In your body, your lymphatic system is the system responsible for eliminating cellular waste products. Hundreds of miles of lymphatic tubules allow waste to be collected from your tissues and transported to your blood for elimination, a process referred to as lymphatic drainage.  When your lymphatic system is not working properly, waste and toxins can build up and make you sick. Lymphatic congestion is a major factor leading to inflammation and disease. By stimulating your lymphatic system and helping it release toxins, dry skin brushing is a powerful detoxification aid. When you dry brush your skin, it increases circulation to your skin, which encourages the elimination of metabolic waste.

Immunobiology: The Immune System in Health and Disease. 5th edition.

http://www.ncbi.nlm.nih.gov/books/NBK27123/

Thymosin beta-4 and cardiac repair  http://www.ncbi.nlm.nih.gov/pubmed/20536454

Flawed and Biased Research

The Drug$ Must be Approved before they can be Marketed

Big Pharma wants to get new medicines on the market as quickly as possible.  Time equals money and the less time spent in pre-approval clinical trials, the better.  They are not above “loading the deck” to suit their agenda. 

Simply put, financial deals influence NIH judgments about grants, research priorities and the interpretation of research results.  Some NIH scientists make hundreds of thousands of dollars in consulting fees and more in stock options.  This is on top of a nice six figure salary.  NIH does not require most senior scientists to file public disclosures of their outside income.  The pay scales were arranged to keep highly paid scientists in a lower salary range category on paper so they would not have to disclose conflicts of interest. Researchers with industry connections will more likely favor company products.  That is the way of the world.

Spin Doctoring

Industry funded research clearly trumps studies funded by nonprofit organizations.  Bias is built into placebo controlled clinical trials.  These studies, in reality, conclude that a new product is better than nothing!  A better test would be to find out if a new product is better than what is already on the market.  In many cases, it is not.

Another way to rig the results is to use young subjects in trials even though the drugs will be used in older people.  Younger people generally experience fewer side effects and so the drugs look safer in trials than they would in actual practice.

Another trick is to compare the new drug with an old drug given at too low a dose.  This trick is used with many NSAIDS and even statins.  These trials may also administer the old drug incorrectly.

Trials can be too brief to be meaningful.  Long term use would tell a more accurate story but big pharma doesn’t want to uncover those kinds of facts.  Furthermore, a drug can actually do a person good for a short time but long-term use could be harmful.

It is not uncommon to present only part of the data – the data that makes the drug look good – while ignoring the rest.   

Pharmica did this with Celebrex.  The rigged trials concluded that Celebrex caused fewer side effects than two older arthritis drugs.  All this research was published along with a favorable editorial in JAMA. (The Journal of American Medical Association)  The published article was based on the first six months of a year long trial.  After the entire trial was analyzed, it was clear that there was no advantage to Celebrex.   

It is easy to suppress negative results in privately run trials but can also be done at academic centers.  Companies contract with researchers for large investments of money and they expect favorable results.  Some researchers blow the whistle on unethical sponsors but many just go along.  Over the years, corporate contracts give companies the ultimate control over such research.

How it Works: If at first you don't succeed.....

Though the original clinical trials on Remune (an HIV/AIDS drug) proved that the vaccine was worthless, Big Pharma plans to test it again on children!

https://clinicaltrials.gov/ct2/show/NCT02291809

Remune Studies Dropped - 2001

http://www.natap.org/2001/jul/remune070901.htm

Effectiveness of Remune – University of California

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC96084/

Churdboonchart et al. paint an impressive picture of the effects of Remune on CD4 cell count in HIV-infected subjects. However, as individuals who were closely involved in the study, we believe that the paper presents a misleading account of the study results and a distorted view of the beneficial effects of Remune in this population.

In 1996, Immune Response Corporation contracted with Dr. James O.Kahn – University of California at San Francisco and Dr. Stephen W. Lagakos of the Harvard School of Public Health to conduct a multicenter trial of its drug Remune.  The drug was supposed to slow the progression of AIDS by boosting the immune system.  The company was seeking FDA approval to market the drug as a vaccine.  The trial was carried out on 2500 HIV-infected patients at 77 medical centers.  After three years, it was clear that Remune was not effective.  Immune Response Corporation objected to these negative results and wanted to manipulate the information to support their drug approval.  The researchers refused and stated that the company’s analysis was not in accord with scientific standards.

How many times is this scenario repeated during the course of obtaining approval for drugs that may or may not work?  For drugs that have more harmful side effects than health benefits?   You cannot watch American TV without seeing at least one drug commercial in 30 minutes or less.  The possible side effects are plainly given to the viewer and anyone with just a bit of common sense would conclude they’d rather be sick than risk those side effects!   It has become a joke but it is not funny.  The public is so bombarded with this type of information that  they become immune to it and no longer take it seriously.  The result?  They buy the drugs anyway.

Corporate Disclosure

WA drug company is required to submit results from every one of the clinical trials it has sponsored when it applies to the FDA for approval of a new drug.  IT IS NOT REQUIRED TO PUBLISH THEM.

The FDA approves drugs on the basis of minimal evidence.  They require that the drug work better than a placebo in two clinical trials.  If it doesn’t work better in other trials – those are simply suppressed and ignored.

Drug companies will publish only positive results and the FDA has no control over such selective publishing.

For example, in the case of SSRI drugs – Zoloft, Paxil, Prozac and Celexa et al, the clinical trials lasted just six weeks.  It turns out that placebos were 80% effective as the drugs. (IMO, maybe more so!)

There are a number of pdf papers at this site for more information.

Exposing the Dangers of Antidepressants Despite Cover-ups

SOP – Business as Usual

Even if Big Pharma was to stumble upon the miracle drug of the century, how would we ever know?  They have little, if any, credibility and are like the boy who cried “wolf” too often.  They are unethical and use every trick in the book, every legal loophole and every manipulation they can think of to push their drugs onto trusting doctors and patients.  Buyer Beware!!!!

Further Research and Reading

NIH Conflicts of Interest Policies

http://grants.nih.gov/grants/policy/coi/

Reporting Allegations of Conflicts of Interest

http://oma.od.nih.gov/public/DPI/Pages/Allegations.aspx

Public Citizen: Conflict of Interest within NIH Study

The Pharmaceutical Drug Supply Chain 101

After the drugs are approved for market, they must be manufactured.

Drugs can be branded (patented), generic  (off patent) and biosimilars.  Generics can be a “brand name generic.”  

Pharmaceutical wholesalers buy and trade in the manufactured pharmaceuticals

They are distributed by the buyer/retailers – pharmacies, hospitals and third party payers (TPPs)

The Big Three

Pharmaceutical wholesalers act as middlemen for retail drugstores. They stock brand-name drugs, generics, over-the-counter drugs and sundry items to sell to retail, hospital and clinical pharmacies. Primary pharmaceutical wholesalers can buy directly from the manufacturer.  They can also buy from secondary wholesalers. The three biggest pharmaceutical wholesalers are Cardinal Health, Inc. (NYSE: CAH), McKesson Corporation (NYSE:MCK) and AmeriSourceBergen.Corporation (NYSE:ABC).  They  generate about 85% of all revenues from drug distribution in the United States. 

In addition to these three companies, there are a number of smaller nationwide wholesalers such as Morris & Dickson, H.D. Smith, Smith Drug, Curascript Specialty Distribution, NC Mutual Wholesale Drug, Rochester Drug Cooperative and Anda Distribution.  Regional and specialty wholesalers include Burlington Drug, Dakota Drug, FFF Enterprises, Florida Infusion, Harvard Drug Group, King Drug, Metro Medical, Seacoast and Value Drug.  There are thousands of much smaller companies that are licensed as wholesalers.  The Big Three often buy out smaller wholesalers.

Additional regional and specialty wholesalers include: Burlington Drug, Dakota Drug, FFF Enterprises, Florida Infusion, Harvard Drug Group, King Drug, Metro Medical, Miami-Luken, Seacoast, and Value Drug. There are also thousands of very small companies that are licensed as wholesalers. Over the past 10 years, the Big Three companies have acquired many regional and specialty wholesalers.

Full-line wholesalers purchase inventory and often sell a manufacturer’s complete pharmaceutical product line.  They sell mostly to pharmacies.  (Keep in mind that most pharmaceutical pills cost very little to make and the markup is very high.  That is why the pharmaceutical business is so lucrative.)  Specialty distributors sell specialty pharmaceuticals mostly to physician-owned and operated clinics. Hospitals and hospital owned outpatient clinics.  These are often intravenous  drugs that must be administered.

The top five dispensing retail pharmacies are CVS Caremark, Walgreens, Express Scripts, Rite Aid and Walmart.   They account for nearly 2/3 of U.S. prescription dispensing revenues.

Pricing Basics

The price at which brand manufacturers sell to wholesalers and chain warehouses is generally the Wholesale Acquisition Cost (WAC).  This is generally a published list price minus a small discount for prompt payment and other incentives. In turn, wholesalers sell branded small molecules to retail and mail order pharmacies a few percent above their WAC, and at a 15-20% or larger discount off what is known as the Average Wholesale Price (AWP).

Providers include retail and mail order pharmacies, various wholesalers, hospitals, and physician offices that administer medicines (typically by intravenous, infusion or injection). In comparison, payers include health care plans, pharmaceutical benefit managers (PBMs), most group purchasing organizations (GPOs) and employers which do not handle drugs directly.  These reimburse providers for purchases of their beneficiaries.

Types of Drugs

Brand manufacturers (the pharmaceutical company) of  patented, small molecule drugs (branded drugs) sell primarily to wholesalers and chain warehouses.  In theory, they have relatively limited direct sales to hospitals, retail, mail order pharmacies and physician offices.  However, as we learned in my last post, Big pharma does use indirect means to encourage sales to hospitals and physicians under the guise of educational seminars and meetings, through the media and literature and various other sales incentives.

Generics and “branded” generics.  A prescription generic must contain the same active ingredients as the original patented formulation.  They may not be identical to the original drug, however. A branded generic is simply a drug that is bioequivalent to the original product, but is now marketed under another company's brand name

Biosimilars

These are distinct from the small molecule drugs.  They are larger and more complex molecules and are more costly and challenging to manufacture.  Their surfaces may fold in different ways and not block receptor sites as uniformly as synthesized small molecules. Prior to 2010 there was no procedure for generic entry of biologics.  The Patient Protection and Affordable Care Act established a license procedure for biosimilars.  Original biologics are granted 12 years of market exclusivity.

Wholesalers face different markets for branded and generic drugs. They can purchase branded drugs only from a single manufacturer, whereas they can purchase most generic drugs from many manufacturers. As a result, they can create price competition among the various generic manufacturers of a particular small molecule – that is, the expired patented drugs.

Large retail chains also buy directly from generic manufacturers and shop for the best prices.  Gross profit margins for both wholesalers and large retail chains are larger for generic than branded, patented small molecule drugs.

Many biologics are administered via injection or infusion by health care providers (i.e., physicians and nurses), rather than being patient self-administered oral tablets or capsules purchased from retail or mail order pharmacies. As a result, manufacturers of branded biologics sometimes sell directly to hospitals and physician offices rather than to the wholesalers to which the branded small molecule manufacturers usually sell.

Firms known as “specialty pharmaceuticals,” however, often provide wholesaler-type intermediary services between biologic manufacturers and providers. Biologic manufacturers generally sell products to the specialty pharmaceutical firms at a slightly discounted WAC, and often at slightly higher prices to the providers who are buying directly.

Intermediary Services

Over the years a variety of intermediary services for all drugs have increasingly been provided by pharmaceutical benefit managers (“PBMs”). Services provided by PBMs include contracting with manufacturers for third party payers (insurers, employers, governments aka TPPs).  They underwrite benefit plans, process claims, regulate formularies, operate mail order pharmacies, negotiate for rebates with manufacturers and so forth.  Obviously the PBMs are a big business and they are the administrative middleman for most consumer’s drugs.

Pharmacies can contract with TPPs.  Both TPPs and GPOs can negotiate a TPP/GPO price with wholesalers.  The chargeback is the difference between the manufacturer’s price charged to the wholesaler and the manufacturer’s contract price with the TPP/GPO.  Manufacturers under contract with TPPs provide financial incentives (rebates) for them to meet certain sales targets.  We already know that there is big money in pushing pills and it seems that everyone but the patient is handsomely rewarded along this drug chain.

Patients pay more than ever for health insurance, managed by third party payers, group purchasing organizations and pharmaceutical benefit managers.  Insurers may pay a copay or coinsurance rate – a fixed dollar amount or fixed percentage of the total cost for drugs that are purchased.  Formularies have been established.  These are lists of drugs covered by the third party payer.  Formularies can be open or closed.  Open formularies cover all drugs approved by the FDA.  Closed formularies cover a subset of FDA approved drugs and the insured must pay full pharmacy price for the drugs that are not covered.

The Red Book was one of several directory or catalog publications that provided guidelines for wholesale and retail prices of drugs.  Pharmacists used these as a reference.  The books listed a “manufacturer’s suggested retail price”.  “Trade list prices” were what the retail druggist paid for the drugs.  The pharmacy could calculate their profits based on this information.

Next, a competitive price catalog publication called the American Druggist Blue Book  began publishing a similar informational guide.  However, rather than calling them “trade list prices”, they were now called “average wholesale price” (AWP) or Direct Net Price.  They also added a “suggested wholesale price.”  The terms were misleading since the public was not receiving a wholesale price at all.

First DataBank (FDB) - the unit of Hearst Corporation publishing the Blue Book - decided to increase the AWP to WAC markup from 1.20 to 1.25 for over 400 hundred drugs in a secret agreement with drug wholesaler McKesson. Third party payers and groups representing the uninsured sued FDB and McKesson.   McKesson and First Databank were accused of engaging in a racketeering enterprise to fraudulently increase the published AWP of over four hundred branded drugs during 2001 – 2005.  According to the settlement provisions, the price of the drugs was lowered 4%.   However, small pharmacies were hurt by the loss of this profit margin.

The Prescription Drug Insurance Market

In the U.S. prescription drug insurance benefit services are typically purchased from a pharmacy benefits manager (PBM). The employer may offer medical insurance plans from multiple health insurers but require all of them to use one PBM. The PBM acts as the middleman between the employer and the health insurers and of course, will want to pay what is most economical to their bottom line.

The American PBM industry has become increasingly concentrated.  At the beginning of 2010 it was dominated by three large firms (Caremark/CVS; ExpressScripts; Medco) who had a combined market share of just under 50 percent. The three large PBMs have substantial bargaining power with manufacturers.  Obviously, they too, want to buy low and “sell” high.

WalMart Pharmacy

In September 2006 mass merchandiser giant retailer Wal-Mart announced it was offering a number of 30-day generic drugs for a price of $4 per prescription. About a year later Wal-Mart expanded the list of available generic drugs and simultaneously added a new 90-day prescription for a price of $9 per prescription, implying a dime per day cost of that prescription. A Wal-Mart spokesperson called this the “commoditization” of generic drugs, made possible in part by its buying directly from generic manufacturers and bypassing wholesalers.   

By doing this, they not only beat their competition but they increase customer traffic in their one-stop-shopping environment.  Within months, a number of other mass merchandisers and food stores, such as Target, Kroger, Safeway and Giant Food, followed Wal-Mart and began offering very low priced generics, aimed particularly at cash customers.

Other retail pharmacies responded and set up their own prescription savings clubs. In 2008, Wal-Mart entered into an agreement with the Illinois based Caterpillar.  WM would charge a zero copay for Caterpillar’s 70,000 beneficiaries on 2,500 generic drugs.  Caterpillar’s PBM agreed to reimburse Wal-Mart based on Wal-Mart’s actual invoice prices on drugs.  Caterpillar added Walgreens to its network in 2010.  Other pharmacies still have generic copayments where customers pay cash, then fill out forms for reimbursement.  Walmart streamlined the process, benefiting both the patient and their business.

Vulnerability of the Drug Supply Chain

American consumers have purchased counterfeit Adderall, Vicodin, Viagra, Xanax, flu medication and even cancer drugs that have made their way into the established pharmaceutical supply chain.  Online pharmacies that peddle drugs without a doctor’s visit are not included in these statistics – that is an entirely different subject.

Public outcry, brought together a large group of drug supply line stakeholders to try and find solutions to the problems of fake and adulterated drugs and theft of drug shipments along the supply chain.  The technology existed to effectively operate a federal electronic traceability system, but the FDA lacked the authority to implement the federal standards. The Drug Supply Chain Security Act (2013-2014 Congress) passed and is now in effect. 

Now the drug supply chain can implement nationwide standards. Numerous companies have sprung up to provide this “security.”  Tracking and tracing programs have been created and put into operation but are they unified?  How can they be when the state laws regarding interstate commerce vary so greatly? 

One state requires all medication to have a serial number and electronic records detailing every instance where the product changed hands.  Only half of the states have similar track and trace laws and their implementation and enforcement vary widely. Some states use paper – other computers.  Some start tracing and tracking with the primary distributor and others, the secondary wholesaler.  Compliance with the new systems will cost billions of dollars overall and be passed on to all those along the drug supply chain including the consumer.

The idea and the new law sound good on paper but for the unethical, laws are meant to be broken.  This is the bare bones framework of the drug supply chain.  I plan to add more pieces of the structure in future posts.

Reference and Further Reading

Average Wholesale Price Red Book

Caterpillar

Contract Pharma for pharmaceutical and biopharmaceutical contract services and outsourcing

Dangerous Doses Paper Trail.  Katerine Eban.  

Drug Supply Chain Security Act (2013-2014)

FDA Office of Criminal Investigations cases  

First Data Bank  

National Association of Boards of Pharmacists

Out of State Wholesale Drug Distributors

Pharmaceutical Distributors List  

Pharmaceutical Market Leaders 

Pricing and reimbursement in U.S. pharmaceuticalmarkets.  Faculty research working paper series.  Ernst R. Berndt. Joseph P. Newhouse. Working Paper 16297 MIT Sloan School of Management and NBER and Harvard School of Public Health. 

Secure the pharmaceutical supply chain from riskycounterfeiters.  Forbes. 2013

Wholesale Drug Licenses by State