Saturday, May 8, 2010

How Much Antifreeze Does a Parkinson's Patient Swallow?

What the Heck Is in My PD Medication and Why?

A serious issue for people with Parkinson's disease is those times when medication wears off before the next dose is due.
Remembering to take the first dose in the morning but sometimes forgetting the next  one can be a problem as well.
That's why there are pills specially designed to address and correct/remove those problems. We know them as timed release, controlled release (CR), sustained release (SR), extended release or long acting ER, XR, or XL), slow-release, and continuous-release (CR or Contin). 

We know we can't chew them. But else do we know about how they work? What makes it possible for this timed-release to occur after the pill is swallowed?  Is it safe?  

And when we looked at the ingredients of these shinny pills. Sometimes there is polyethylene glycol (PEG) or ethylene oxide which we know is a precursor to ethylene glycol ... antifreeze...or we see propylene glycol and butylated hydroxytoluene. We learned that part of the latter is a solvent. What's the story here? Why is this stuff in a pill which is supposed to help?  How is it used?

We know that when treating certain medical conditions it can be helpful to have a medication which can be released slowly and steadily throughout the day in order to maintain a constant blood serum level of the medication. Controlled release drugs have an advantage of being somewhat cost-saving and many may actually release a safer level of the medication. Most do this fairly well; a few have unresolved issues.

The mechanism of burst-release still needs refining because on occasion more medication is released than designed. New technologies are developing which will use not polymers but possibly recently developed polypeptide agents possibly utilizing RNA and/or siRNA (small interfering RNA). Not yet, but perhaps within a few years. In London at the end of the month there will be a specific presentation for "Controlled release in chronic diseases" at a controlled release event.  And we would expect these pills to be safer as well as having a higher efficacy rate.

The mechanism is that either the drug matrix dissolves slowly and steadily or that the drug is released cyclically over a long period. The formulations may vary from chitin to acrylic to polymer based tablets with a porous membrane on one side with different processes occurring once in the body. The bursts seem to occur in the CRs but perhaps steadier control will be possible in the future.

But what about that other stuff?

According to what we've read, polyethylene glycol (PEG) - as used in medications - has a low toxicity "When attached to various protein medications, polyethylene glycol allows a slowed clearance of the carried protein from the blood. This makes for a longer acting medicinal effect and reduces toxicity, and it allows longer dosing intervals." This would explain why it is in the Extended or Controlled Release pills. Is it totally safe? Apparently for now it will have to be safe enough. Even taking several pills of this type a day should not become an issue unless there is a intestinal blockage.

The differences between PEGs are molecular weight.  What about polyethylene oxides (PEO)? We know that PEs are carcinogenic at certain ppms. But we are not chemists and that is an area for the experts to discuss.

These chemicals are sometimes used in laxatives and calcium channel blockers. The calcium channel blockers have a semi-permeable membrane which surrounds the actual drug. The core itself is bi-layered with the active layer of the medication and an inert layer, known as the "push" layer of an osmotic. And this is where we find the PEO polymer. The push layer will swell and force the active drug out of the membrane through a pre-drilled laser opening on the active layer side of the membrane. This creates a fairly steady release of the active chemicals into the gastrointestinal tract.

What happens to the inert but actively working push layer when emptied of the active drug?  It's already in the intestinal tract and so is simply taken out with the trash.

In laxatives, osmotics create excess water in the intestine to loosen stool buildups. Taken with an electrolyte solution osmotic laxatives are often used prior to bowel surgery. Some of these contain polyethylene glycol and are intended for short term use only.  Some Parkinson's patients take Polyethylene Glycol 3350, an osmotic laxative, in the form of MiraLax or Macrogol for constipation as a last resort because nothing else works for them.  The caveat is that too much or too often can result in diarrhea. Side effects include nausea, gas and bloating.

There is no question that it is not a good idea to take any medication with polyethylene glycol if you are allergic to it as it can cause rash, swollen tongue, hives and other typical unpleasant allergy reactions.

Do not confuse ethylene glycol (EG) with polyethylene glycol (PEG). They are not the same thing. Ethylene glycol is metabolized into oxalic acid, a poison that affects the brain, the heart and the kidneys. Ethylene glycol (EG) is toxic to people and to pets. Your car is happy with it because adding it to your radiator offers protection in cold weather. In your body it can kill. Polyethylene glycol makes your intestinal tract happier because it can get rid of toxins. In your body it has low toxicity.

Propylene glycol, an organic compound (a diol or double alcohol) is used as a humectant (moisture retentive) food additive E1520, as a moisturizer in medicines, toothpaste, mouthwash among others. While it does have similar properties to ethylene glycol and is used in antifreeze and de-icers; it is less toxic. And of course, toxicity would depend upon the percentage used in a product. It metabolizes to pyruvic acid, as part of the normal glucose metabolism process. Although long term toxicity is low to humans; it can be toxic to dogs and cats (although the effects are apparently different in cats). Do note that this type of alcohol is different than that which you have in a drink.

Who else has weighed in? From the CDC we learn that the FDA classifies polyethylene glycol as an additive that is "generally recognized as safe" for use in foods. In large quantities it will increase the acidity of the body. What is does not do is to form the harmful crystals which collect to the kidneys as ethylene glycol produces while it breaks down. Polyethylene glycol breaks down rapidly in the body.

Although most of the warnings we saw related to overdose of the medication itself and not the individual components, this does not mean there is not room for improvement.  As more is learned about our air, water and food, we think that more attention will be directed to medicines. It may happen very quietly within the pharmaceutical companies because of economic impact.  At the same time, the drugs taken for Parkinson's disease are immediately necessary in their available forms and changes co$t.

By the way, the chemicals are also found in most toothpastes. 

Note:  The title question is in part rhetorical, however, the answer would be based upon each individual's medicine cabinet. We looked at DynaCirc CR and Nimodipine labels for this article.

Additional Reading:
American Academy of Neurology, Quality Standards Subcommittee guidelines - published Neurology. 2010;74:924-931.
Long term efficacy study 2000 placebo/blind small doses of isosmotic PED electrolyte balanced solutions over 6 months was an effective constipation treatment; "appeared to be safe,tolerated and devoid of significant side effects" 
Butylated hydroxytoluene, a lipophillic (fat-soluble) organic compound that is primarily used as an antioxidant food additive as E321
Polymers in Controlled Drug Delivery by Lisa Brannon-Peppas  
The Use of Polyethylene Oxide Mixtures to Study Formulation Robustness in Hydrophillic Extended Release Matrix Tablets
Formulation of a Model Poorly Soluble Drug with Low Molecular Weight Grades of Polyethylene Oxide demonstrates Improved Aqueous Solubility


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  2. I find you comment interesting that polyethylene glycol and ethylene glycol are not the same thing; back in 2008 the FDA tested 8 lots of miralax and they found ethylene glycol in all 8 lots they tested. To save you some time, just read the paragraph above objectives;

    Additionally, here's a study that was not completed that has Carlo Dilorenzo's name attached to it. Mr.Dilorenzo happens to be the former president of NASPGHAN and in this study, they show peg 3350 contains ethylene and triethylene glycol;

    You're absolutely correct, ethylene glycol is metabolized into oxalic acid, enough acid and the patients is dealing with oxalates. Oxalates are known to cause inflammation and may be the root cause to neurodegenerative illnesses. Our son was diagnosed with epilepsy in May 2014, his last seizure was in May 2015. His first anti seizure medication was trilpetal(suspension) it contained peg 3350 and seemed to lower his seizure threshold. All of his seizures seemed to be cyclical which I now believe were caused by oxalates. Once we restored his glutathione levels and gave him colostrom along with a quality probiotic, not only did his seizures stop but his disposition returned to a much more "normal" state.

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