Non-Scientists Guide to PharmacoGenomics

Pharmacogenomics

What is Pharmacogenomics?

The world of medicine is constantly changing, and new drugs are being approved in record numbers. The FDA approved a total of 59 new drugs in 2018. This may not seem like a high number but the last year that the FDA approved over 50 drugs in one year was 1996, making this the highest in at least 25 years. What is more astounding than the number of drugs approved however, is the type of drugs. More and more of the drugs being approved are drugs for personalized medicine, or what is known as pharmacogenomics.

Pharmacogenomics is the study of how a person’s genes affect their response to drugs. This new and emerging science is an area that pharmacists can make a huge role in a patient’s healthcare. This article hopes to explore pharmacogenomics in a little more detail, that way no matter who you are you can understand how pharmacogenomics affects you.

History:

Pharmacogenomics was first identified in 510 BC by Pythagoras. The same guy who was responsible for creating the pythagorean theorem we all blocked from memory as soon as we learned it as teenagers.. He did not call it pharmacogenomics at the time of course. He simply noticed that when some people ate fava beans they had a severe, potentially fatal, reaction, while others did not. It wasn’t until the 1950s that modern science identified this reaction as due to a G6PD deficiency.

After Pythagoras, in 1866, Mendel established the rules of heredity by using pea plants to test for genes. Known as the father of genetics he was able to coin the idea of dominant and recessive traits in plants by creating punnett squares. These squares were another of the many items we forgot during our schooling. While these squares may bring back memories of being back in a classroom for some, they also show just how simple pharmacogenomics can be. These basic principles are still used today. So if you could grasp the concepts behind these squares in school than you can understand pharmacogenomics now.

After Mendel created the idea of genetics, it took several trials and many years until Vogel coined the term pharmacogenetics in 1957. Since this time the expansion of this scientific field has grown exponentially. We have identified the structure of DNA, and know that it is made up of different bases. These bases are largely the same, however variation in the genome is seen every 500-1,000 bases, thus accounting for the difference between humans. These differences can come in many different forms, but the most well studied are known as SNPs or single nucleotide polymorphisms.

These SNPs are a large part of why a drug that works for one person may not work for someone else. In 2000 we were able to complete a map of the human genome sequence variation identifying 1.42 million SNPs. The information we learned from this was invaluable. Now that we know what the differences between the genes are, we can compare those to responses to medications and thus form the basis of pharmacogenomics. Because of this, the first pharmacogenomics test was approved by the FDA in 2005. This tested for variations in two alleles, CYP2D6 and CYP2C19.

Currently:

To date we have multiple pharmacogenetic tests available that test over 50 genes for potential interactions. According to the FDA, currently there are 214 drugs that have proven, documented drug-gene interactions. When a drug has such a strong drug-gene interaction that it must be included in the package labeling, that means there is a plethora of peer reviewed, researched, and published information out there proving the drug-gene interaction. The majority of this research is only 10 years old.

Some medications can only be prescribed after pharmacogenomic testing has been done. For example, abacavir is used to treat HIV patients, and can only be prescribed after testing for the HLA-B biomarker. If a patient is positive for HLA-B*5701 allele, they could have a potentially fatal hypersensitivity reaction.

Some medications may need to have their doses adjusted based on the results of pharmacogenetic testing. For example Warfarin has drug-gene interactions with both CYP2C9 and VKORC1. The package insert uses a chart that shows how both these genes can cause alterations in the starting dose.

So What Is Next?

This field is so new, and the amount of information we are learning every day is astounding. If you want to keep up with this field I highly recommend checking out the FDA’s website on pharmacogenomics. They are a great resource on this emerging field.

Your physician or your pharmacist should know if you are taking a medication that would require pharmacogenomic testing. However, if you are interested in having yourself tested than simply schedule an appointment with your healthcare provider. These tests are not cheap, however they are becoming so prevalent that they are getting cheaper very quickly. It is also important to consider the privacy of your pharmacogenomic information. Popular home testing kits have had data breaches in the past. So by going through your healthcare provider your information will be more protected than if you did it at home, as it would be part of your protected health information.

Our team member Catlina will be presenting a poster about her research on Pharmacogenomics at the College of Psychiatric and Neurologic Pharmacists Annual Meeting next month! If you have any questions about pharmacogenomics you can always use our contact us page to reach out.

Be on the lookout for more information about this emerging field by signing up for our email list at the bottom of this page!

Resources/References:

1. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm592464.htm

2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014592/

3. https://www.fda.gov/drugs/scienceresearch/ucm572698.htm

4.https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020977s033s034,020978s036s037lbl.pdf

5. https://www.admerahealth.com/faq-items/physician-faq/

6.https://oneome.com/rightmed-comprehensive#genes

7. https://oneome.com/rightmed-comprehensive#genes

Patient Counseling That Patients Will Want

Patient Counseling

Have you ever woken up one morning and thought “I am going to give eight years of my life and potentially go into $300,000 of debt to count pills behind a counter and not talk to a single person all day?” No? Me neither. I think it’s safe to say that nobody has ever had this thought. And the reason for that is while pharmacy school provides a great training and a doctorate level education it also requires a high amount of communication. Pharmacists talk to technicians, physicians, nurses, store managers, and of course patients all day long. And while being a doctor of pharmacy means we have a high degree of knowledge about medications, it doesn’t mean we have great communication skills.

OBRA 90

Pharmacists started formally counseling their patients due to OBRA 90. This was a huge law passed in 1990 (passed in 1990… OBRA 90… noticing a theme?) that changed the profession of pharmacy forever. Obra 90, among many other things, was the first ever to mandate patient counseling. Now pharmacists have been practicing since way before 1990, and of course they had been counseling patients since before this time too. However, this law was enacted to help the federal government (and thus the American taxpayers) save money. Their theory was that if pharmacists did more counseling, there would be fewer adverse drug events and interactions, better care for the patients, and less healthcare spending. This is absolutely true. This study shows that when pharmacists provide structured counseling:

  • Confusion about when to take medications declined from 4% to 2.5%.
  • The average number of prescription drugs and the number of doses taken per day decreased.
  • Hospitalization frequency decreased from 39.8% to 31.3%.

Numbers like this show that counseling really can work. Yet another study showed that only 47.3% of pharmacists and 34.0% of patients were satisfied with the current medication counseling service. How many times have you gone to pick up a prescription, and the pharmacist didn’t even counsel you? How many times have you gone and picked up a prescription, the technician asks if you want to speak to the pharmacist, and you say no? You rush out of the pharmacy and don’t even look back. Or worse, the pharmacist comes over, counsels you, and you end up even more confused than when you started. I have heard over and over again from patients that counseling with a pharmacist can be a waste of time.

My theory is that it really isn’t a waste of time, if we are doing the right type of counseling. Our counseling sessions are so inadequate that they often go like this:

Pharmacist: “Hi Mr. Smith Are you picking up your medication today?”

Joe Smith: “Yes, it’s right there.”

Pharmacist: “Great! What did the doctor tell you about the medication?”

Joe Smith: “She told me it is for my high blood pressure.”

Pharmacist: “Yep, this is lisinopril, you take it once a day, and it helps with hypertension. You can take it with or without food. Do you have any questions about your medication?”

Joe Smith: “No, not really.”

Pharmacist: “Okay, here you go. Have a nice day.”

Joe Smith: “Thanks, you too.”

 

 

This may seem like a perfectly good counseling session, but in reality it is absolutely terrible. Let’s look at a proper counseling session using motivational interviewing:

Pharmacist: “Hi Mr. Smith, are you picking up your medication today?”

Joe Smith: “Yes it’s right there.”

Pharmacist: “Great! What did your doctor tell you about this medication?”

Joe Smith: “She told me it is for my high blood pressure.”

Pharmacist: “Yes it is for high blood pressure. This medication is called lisinopril. Have you taken it before?”

Joe Smith: “Yes, I’ve taken it for at least a decade now.”

Pharmacist: “That’s a long time. How have you been taking the medication?”

Joe Smith: “I take it once a day.”

Pharmacist: “That’s good, have you had any side effects?”

Joe Smith: “No, it works well for me.”

Pharmacist: “Good, what have your blood pressure readings been like?”

Joe Smith: “I don’t know. I don’t check them. My doctor does.”

Pharmacist: “When you are on this medication, it is very important to know what your blood pressure readings are. If you know your blood pressure, you can know if you are meeting your goal. What is your goal with taking this medication?”

Joe Smith: “Well my goal would be to not take the pill. I don’t like taking pills.”

Pharmacist: “That’s a great goal, and one that I think you can reach if you work hard. Definitely let your doctor know before you stop taking this medication, but there are non-pharmaceutical ways that we can use to decrease your blood pressure so hopefully you won’t have to take this medication long term.”

Joe Smith: “Non-pharmaceutical ways? Like aromatherapy? I don’t believe in that stuff”

Pharmacist: “No, like eating right and exercising. I know it seems silly, but it really can make a difference. If you want, we have a blood pressure machine right over there. I can show you how to take your blood pressure, and once we know what your numbers are, I can help you come up with some ways we can possibly reduce your blood pressure.”

Joe Smith: “Yeah I’ve heard all the speil before about eating healthy and losing weight. Every time I go to the doctor, she tells me I need to lose weight.”

Pharmacist: “What do you think is keeping you from losing the weight?”

Joe Smith: “I drink too many sodas. I can’t give up my Dr Pepper.”

Pharmacist: “I totally understand. If losing weight is a goal of yours, we can come up with ways to lose weight that don’t involve giving up sodas.”

Joe Smith: “Really? My wife is always telling me I need to give up sodas. If I could lose weight and still drink my sodas, that would be great. My kids are running circles around me, and I just want to be able to keep up with them again.”

Pharmacist: “Keeping up with your kids is a great goal to work towards. Let’s check your blood pressure and brainstorm ways we can help get there.”

~ Then the pharmacist helps the patient take his blood pressure and sets a goal of walking with his kids around the block after dinner to increase his exercise. ~

See how much different those two counseling sessions were? Now, I know what you are thinking. Of course they are different; one is longer. I would love to be able to help more patients, but I can’t afford the time to help every patient take their blood pressure, and not every patient is going to want to anyways. These are the typical arguments that a pharmacist, especially at a large chain store, is going to give. But I would argue that you can’t afford NOT to take the time. You may not always get a positive response, but I have seen patients break down and cry in the pharmacy because a pharmacist took 5 minutes out of their day to listen to a patient. Sometimes this is the first time a healthcare professional has done that for a patient ever. When I was in pharmacy school working for a large chain pharmacy, I made so many changes to a patient’s medication regimen just by talking to them and calling their doctors office. I would never do anything without their prescriber being notified, but it made such a difference in my patients lives they were so thankful for it. I have come up with a few tips and tricks for motivational interviewing to help you better communicate with your patients.

There is a whole art to motivational interviewing and if your pharmacy school was anything like mine the chances of them teaching you motivational interviewing in a meaningful way is not exactly high. APhA has a great (and short) book on motivational interviewing (Get a copy here) that I highly recommend. There is also a great series of videos on motivational interviewing put out specifically on tobacco cessation here. But in case you are looking for something shorter let me give you the highlighted version.

Meet the patient at their level:

One of the most surprising moments for me was when I was talking to one of my professors, a Pharm.D., and she went on a 20 minute rant about how much she hated being counseled.

She is an adrenaline junkie, and had had an accident where she fractured her pelvis. An incredibly painful event by all accounts, leading her to spend an extended amount of time in the hospital. She eventually made it out of the hospital to pick up her pain medication from the pharmacy. When it came time to check out the pharmacist politely checked her out at the register, and began to counsel her. She politely explained that she was a pharmacist and understood how to take the medication.

The pharmacist continued to counsel her and kept her standing at the register with a line forming behind her. She finally had enough of the pain and said “Can I see that prescription for a moment?” The pharmacist said yes and handed her the bottle. She opened it, took out a pain pill, and put it in her mouth. She said “You have about 30 minutes before this kicks in and I can’t drive home anymore. Can you please finish so I can go home?”

If we cannot even get pharmacists to want counseling we are doing something wrong. In her case she had very clearly declined counseling (something patients have a right to do) however the pharmacist ignored her request and continued to talk about her personal medical record in a public space. This is not how counseling should be done. There is a reason in both counseling examples up above the first question asked was “What did your doctor tell you about this medication?” A large part of motivational interviewing is meeting the patient where they are at in their education level.

 

The pharmacist above did not need to know about the medication side effects, she already knew them. She needed to know if the doctor wrote for refills and what else she could do to control her pain besides the medication. In the example with the high blood pressure it was the same scenario. The patient knew how to take the medication and knew the side effects. They did not know how that medication affected their blood pressure and how they could use alternative therapies to reduce their blood pressure. This is critical to listen to the patient.

Treat the patient with respect and use their language:

You will notice that in the blood pressure example the pharmacist used the term high blood pressure instead of hypertension. This is important to use patient friendly terms. The pharmacist also used Mr., and showed respect for the patient. They did not get offended when the patient rejected their idea of alternative therapies as aromatherapy that they did not believe in. The pharmacist simply talked to them about therapies that may be a better fit for this particular patient.

Separate pharmacists from point of sale:

One idea that I would love to see happen would be to separate pharmacists from the point of sale. When we are having to worry about collecting a patient’s money (Something virtually no other doctor would ever do) as well as counseling a patient that has potentially just gotten out of the hospital and is in pain it’s no wonder we aren’t getting heard. We should be meeting the patient in a private area (not the cash register) and sit down with them. This would not only give pharmacists a chance to sit but would also let the patient sit. Setting the expectation that there is time to talk and making a comfortable environment instead of standing with a visible line forming behind you.

Ask open-ended questions:

When I wanted to go to prom with my boyfriend in high school. I knew getting my mom to agree was going to be a tough sell. I did not ask my mom if I could go to prom with my boyfriend for an evening of dancing at a hotel that was known for not checking IDs with it’s liquor sales. The answer would be an absolute no. So I came up with a pretty crazy scenario, where me, my boyfriend and some friends were going to camp on a beach all weekend in a large tent. Having a whole group of teenagers in a tent for a whole weekend sounded worse than me and my boyfriend who she knew and trusted dancing for one night. When presented with the two options, my mom was much more agreeable to one night than an entire weekend. It’s all about perspective. The exact same can be said about counseling patients.

Instead of asking “Just picking up the one medication?” you could ask “What brings you in today?” These completely different questions will yield completely different answers. One will give you a simple yes. The other will lead the patient to discuss their headaches, or ask you about over the counter medications. It can’t be answered with a simple yes or no. Asking “Do you have any questions?” is the equivalent of asking your mom if you can go to prom with your boyfriend with no parental supervision. The answer will almost always be no. Asking “What other questions do you have for me?” is forcing your mom to choose between letting you be gone for one night with one trusted person or a whole weekend with a wild group of teenagers. It forces her to think and give a much better answer.

I hope these tips have been helpful to you. Please feel free to comment below or contact us if you have any other counseling tips. We would love to hear more advice on connecting to our patients!

Catlina using motivational interviewing while on a medical aid trip to India
Catlina using motivational interviewing while on a medical aid trip to India

Do Drug Expiration Dates Really Matter?

Glitter Pills

I have been sick with the flu for almost an entire week now, and let me tell you, if you ever want a great abdominal workout just get the flu and cough up a lung for a week straight. I’m going to have a 6-pack by the time I am fully recovered! If you would literally do anything else then get the flu like a normal person, just get your flu shot. It’s much more fun than this ‘workout’ I promise. But in all seriousness, when I first got sick I did what everybody does, and looked at my medicine cabinet. I had a whole collection of pills and potions, half of which were expired. Has this ever happened to you? You are terribly sick and only have expired drugs, and debate if it’s worth going to the store to get new ones or just risk using the expired meds you already have? You’re not alone. As much as I would love to say the good pharmacist in me never let any expired drugs into my house I am still human. And this got me to wondering do drug expiration dates really matter?

I want to preface this article with a gentle reminder that while I am a pharmacist, I am not YOUR pharmacist. Medical advice over the internet is never a substitute for discussing your individual health needs with a physician or pharmacist face to face. It is never recommended to take expired meds, however I am fully aware that the temptation is there and I want to do my best to present the facts to you so that you and your medical team can make the best decision for you. This article is written more scientifically than most of our posts as it is my hope that you will print this out and take it to your pharmacist or physician to discuss with them, and use the resources listed to check the claims I make and come to your own conclusions. With that being said, let’s find out if drug expiration dates really matter.

Why Drug Expiration Dates Matter

Under section 501(a)(2)(B) of the federal Food, Drug and Cosmetic Act (FDCA), manufacturers of prescription drug products establish controls for the manufacture, processing, packing, and holding of drug products to ensure their safety. Requirements for these controls are known as current good manufacturing practices (CGMPs), and include the requirement of an expiration date as of 1979. Current requirements include medications to be within 90%-110% of their stated potency.1 The FDA defines an expiration date as “the date placed on the container/label of a drug product designating the time during which a batch of the product is expected to remain within the approved shelf life specifications if stored under defined conditions, and after which it may not be used.”

The expiration date is determined by a review of documentation submitted to the FDA in a New Drug Application (NDA). This includes a stability assessment of the new drug substance and product (dosage form). The stability assessment follows procedures agreed upon by the United States, European Union, and Japan established at the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). How the stability assessments are conducted varies based on the substance and its dosage form, however stress tests are performed evaluating the effects of elevated temperature and humidity, oxidation and photolysis, and hydrolysis over a wide range of pH values.1Expiration dates for prescription drugs (and over the counter drugs) that are subject to premarket approval requirements are based on the amount of real time data available at the time of FDA approval of the NDA.

However, the expiration date may be extended as long as adequate data is provided to the FDA. This is rarely done however, as there is traditionally no incentive to extending expiration dates and extension is strictly voluntary. According to PhRMA, the initial expiration dating for prescription drug products is usually between 18 and 24 months, and expiration dates can range from 12 to 60 months. As of 2006 no drug has an expiration date longer than 60 months. As a general rule, solid dosage forms tend to have longer expiration dates than liquid ones.2

Many studies have proven stability of medications beyond their expiration date. Reducing waste is a key way to reduce healthcare costs and extending expiration dates is one tool through which this can be accomplished. In 1986, the FDA and the Department of Defense (DoD) singed an interagency agreement to “conduct a comprehensive, scientifically sound testing and evaluation program that will determine whether there is justification for extending the shelf life of stored medical items owned by components of DoD or their authorized program partners.”3This created the Shelf Life Extension Program (SLEP) providing the FDA with the largest data source of expired medications to date. From this study, Robbe et al published in 2006 that 122 medications have been tested and 88% were extended past their original expiration date for an average of 66 months.4

Some manufacturers have extended expiration dates during times of drug shortages. In June, 2017 the FDA posted extended expiration dates for batches of injectable atropine, dextrose, epinephrine, and sodium bicarbonate manufactured by Pfizer. This resulted in one hospital, Newton-Wellesley, saving $7,500 in drugs that were in short supply.2

It is important to note that once the manufacturers container is opened and a drug product is transferred to another container for dispensing and repackaging the expiration date no longer applies. The United States Pharmacopeia (USP) and the American Pharmacists Association (APhA) provide guidance to pharmacists on placing a “beyond use date” on the label of the new container.2

The AMA has resolutions drafted by its house of delegates stating that the AMA “Urges the pharmaceutical industry, in collaboration with purchasers, the FDA, and the United States Pharmacopeia (USP), to determine whether lengthening of expiration dates will provide clinical and/or economic benefits or risks for patients and, if this is the case, to conduct longer stability testing on their drug products.”2They have written many letters and provided many public comments on this topic.T

The SLEP Study

The SLEP study contains the most comprehensive database of long-term stability data in existence. This study published its research on 122 medications (3005 lots) in 2006.5Of the 3005 lots tested, 2650 were extended past their original expiration date. 1237 lots were found to be still viable at 70 months past their expiration date, and were abated before failure and were not studied past this time. Of the 479 lots that eventually failed no lots failed prior to one year past their expiration date, and 312 lots were extended beyond 4 years.

The DoD maintains a stockpile of medications worth around $13.6 billion as of 2016.6Based on the SLEP program and their research the DoD has been able to extend the expiration dates of medications saving $2.1 billion in 2016.6The cost of running the SLEP program in 2016 was $3.1 million resulting in a return on investment of $677 per dollar spent on this program. It is important to note that while many states and hospitals also maintain stockpiles of medications the data used from this study are proprietary to federal agencies such as the DoD, the Center for Disease Control’s Strategic National Stockpile (SNS), and the Veterans Administration (VA).3Non-federal or civilian agencies (including state stockpiles) may not avail themselves of this program.

The medications included in the SLEP study are medications that have been selected specifically for their likelihood of being stable past their expiration dates and have been properly stored under conditions consistent with CGMPs and thus cannot be generalizable to medications that have not been stored under these conditions.3There is much interest in states access to SLEP study data. Kozak et all studied patient attitudes towards unused and expired medication (UEM) in Indiana, and discovered that 40% of patients were unaware of a medication take-back location in their community, and while 77% were willing to drive to a take-back location to return UEM, only 15% had utilized take-back locations.7 Kuspis et all surveyed patients and pharmacies, and out of the 500 people surveyed only 1.4% returned medications to a pharmacy, and out of 100 pharmacies only 5% had consistent recommendations for their customers on drug disposal.8

The SLEP study has evaluated over 500 medications however most of this data is unpublished. Even with the data being unpublished the FDA has used the data to improve manufacturing practices.2,3,9 One study conducted by the Office of Regulatory Affairs (ORA) field laboratory evaluated Mark 1 Nerve Agent Antidote Kits containing atropine sulfate. Five out of every six atropine autoinjectors failed the stability testing due to brown particulate matter or cloudy brown solution.3Further testing revealed that the discoloration was a result of leaching iron from the stopper. The FDA can now use this data to advise the use of non-iron containing stoppers as a potential method of increasing the shelf life of these autoinjectors.

Other Studies

Research on medication stability past it’s expiration date has also been done in the civilian sector. Cantrell et al evaluated 31 expired EpiPens and 9 EpiPen Jrs all of which were 1 to 50 months past their expiration date.10 19 of the EpiPens (65%) and 5 of the Epipen Jrs (56%) contained at least 90% of their stated amount of epinephrine and all of them contained at least 80% their stated amount of epinephrine. This study asked for consumers to donate their autoinjectors. By using donated auto injectors they were able to get a more realistic view, as these medications were commonly stored in cars, humid bathrooms, or other less than optimal settings,

Teder et al evaluated expired and non-expired nifedipine formulations from Estonia and Russia and used IR spectroscopy, HPLC analysis, and evaluation of dissolution rates to compare the drugs to current European Pharmacopeia Standards.11 All tested products had at least 80% nifedipine and did not exceed tolerance limits for impurities. Expired nifedipine formulations did however release faster than their non-expired counterparts.

Binkhathlan et al evaluated tacrolimus extracted from expired Prograf®capsules and established through multiple tests including gas chromatography-mass spectrometry (GC-MS), X-ray diffraction (XRD), and differential scanning that extracted/purified tacrolimus retains its purity and immunosuppressive action.12

Tetracyclines, and their safety past expiration dates, have been highly debated. One report in 1963 by Frimpter et all discovered three cases of Fanconi Syndrome and postulated that the either the tetracycline degradation product epi-anhydrotetracycline or anhydrotetracycline was responsible.13However the SLEP study encountered no toxicity with tetracycline and found batches effective more that two years past their expiration dates.9

Tricyclic antidepressants (TCAs) are one of the few medications that have not been studied past their expiration date. This is potentially due to newer drugs like SSRIs and SNRIs being more common in practice as they have safer toxicity profiles.14According to a review of antidepressant overdose cases gathered from calls to Poison Control Centers, tricyclic antidepressants account for the second highest mortality index of all anti-depressants (40.7 per 10,000 exposures).15Only combination products such as olanzapine/fluoxetine and perphenazine/amitryptyline has a higher mortality index (45.7 per 10,000 exposures). It is worth nothing that the perphenazine/amitriptyline combination product has the highest mortality rate out of the combination products listed (74.1 out of 10,000), and that out of the individual products the TCAs had the highest specifically Amoxapine (124.2 out of 10,000) and Desipramine (141 out of 10,000). This toxicity is due to the cardiac effects of tricyclic antidepressants including dysrhythmias, EKG changes such as prolongation of conduction time, prolonged PR intervals and increased corrected pre-ejection period interval.14

Conclusion

Overall, there is much evidence for the safety and efficacy of medications past their stated expiration date. Many factors are involved in the lack of testing for extension of expiration dates. These include a lack of incentives, the high cost of testing, and the high burden of proof required to be submitted to the FDA. Much can be done to change this, however pharmaceutical companies fiercely fight to keep expiration dates within the traditional two to three year window. Drug manufacturers use patient safety as a defense, due to creation of new marketing materials in that time-frame. They claim patients may get confused between the old and new labeling.

Solid dosage forms tend to be more stable than liquid ones, and many medications, both solid and liquid, have been studied 70 months past their stated expiration dates in the SLEP study. The SLEP study has lead to massive cost savings in the DoD, SNS, and VA systems. This information is proprietary however, and while there is much interest in extending this information to the private sector and states, they argue that such programs would not result in equitable cost savings due to the unique set-up of entities involved in SLEP.

The SLEP study has also provided the FDA with information that can be used in guiding manufacturing pharmaceutical products to improve stability, such as using non-iron containing stoppers. Tetracyclines and tricyclic antidepressants are just a few examples of the need for more research into the safety and efficacy of medication past their expiration dates, as evidence to their harm is inconclusive.

Many medications have been tested past their expiration date, however the FDA, USP, and APhA currently all advise against the use of medications past their expiration date. The AMA also advises against the use of medications past their expiration date, however the have urged the FDA, USP and the pharmaceutical industry to continue to explore the safety, efficacy, risk, and economic benefits of extending expiration dates.

So with all this being said, do drug expiration dates really matter? The answer is honestly, it depends on the drug. There are a few drugs that can become toxic when taken past their expiration dates, however most drugs simply lose potency This means they may not be as effective as usual but will still be marginally effective and may still provide some benefit. I hope this helps! Let us know if you like these types of articles and we will be happy to provide more!

References:

1.     Commissioner, O. of the. (n.d.). MCM Legal, Regulatory and Policy Framework – Expiration Dating Extension [WebContent]. Retrieved October 20, 2017, from https://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/MCMLegalRegulatoryandPolicyFramework/ucm411446.htm

2.     (ProPublica), M. A. (n.d.-a). AMA report_CSA Rep 1 (Pharmaceutical Expiration Dates) a 01 FINAL… Retrieved October 20, 2017, from https://www.documentcloud.org/documents/3671873-CSA-Rep-1-Pharmaceutical-Expiration-Dates-a-01.html

3.     Khan, S. R., Kona, R., Faustino, P. J., Gupta, A., Taylor, J. S., Porter, D. A., & Khan, M. (2014). United States Food and Drug Administration and Department of Defense shelf-life extension program of pharmaceutical products: progress and promise. Journal of Pharmaceutical Sciences, 103(5), 1331–1336. https://doi.org/10.1002/jps.23925

4.     Lyon, R. C., Taylor, J. S., Porter, D. A., Prasanna, H. R., & Hussain, A. S. (2006). Stability profiles of drug products extended beyond labeled expiration dates. Journal of Pharmaceutical Sciences, 95(7), 1549–1560. https://doi.org/10.1002/jps.20636

5.     (ProPublica), M. A. (n.d.). Stability Profiles of Expired Drugs. Retrieved October 20, 2017, from https://www.documentcloud.org/documents/3525372-Stability-Profiles-of-Expired-Drugs.html

6.     (ProPublica), M. A. (n.d.-c). Expired drugs research letter. Retrieved October 20, 2017, from https://www.documentcloud.org/documents/3516397-Expired-drugs-research-letter.html

7.     Kozak, M. A., Melton, J. R., Gernant, S. A., & Snyder, M. E. (2016). A needs assessment of unused and expired medication disposal practices: A study from the Medication Safety Research Network of Indiana. Research in Social & Administrative Pharmacy: RSAP, 12(2), 336–340. https://doi.org/10.1016/j.sapharm.2015.05.013

8.     Kuspis, D. A., & Krenzelok, E. P. (1996). What happens to expired medications? A survey of community medication disposal. Veterinary and Human Toxicology, 38(1), 48–49.

9.     Cohen, L. P. (2000). Drugs frequently potent past expiration. Wall Street Journal.

10.  (ProPublica), M. A. (n.d.-b). Epinephrine Concentrations in EpiPens. Retrieved October 20, 2017, from https://www.documentcloud.org/documents/3696595-Epinephrine-Concentrations-in-EpiPens.html

11.   Teder, K., Pepeloshev, A., Matto, V., & Meos, A. (2013). Pharmacopoieal quality of non-expired and expired nifedipine formulations from Estonian and Russian Federation medicinal products market. Acta Poloniae Pharmaceutica, 70(3), 539–546.

12.  Binkhathlan, Z., Badran, M. M., Alomrani, A., Aljuffali, I. A., Alghonaim, M., Al-Muhsen, S., … Alshamsan, A. (2016). Reutilization of Tacrolimus Extracted from Expired Prograf® Capsules: Physical, Chemical, and Pharmacological Assessment. AAPS PharmSciTech, 17(4), 978–987. https://doi.org/10.1208/s12249-015-0433-7

13.  Frimpter GW, Timpanelli AE, Eisenmenger WJ, Stein HS, Ehrlich LI. Reversible “Fanconi Syndrome” Caused by Degraded Tetracycline. JAMA. 1963;184(2):111–113. doi:10.1001/jama.1963.03700150065010

14.  Khalid, M. M., & Waseem, M. (2017). Toxicity, Tricyclic Antidepressant. In StatPearls. Treasure Island (FL): StatPearls Publishing. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK430931/

15.  Nelson, J. C., & Spyker, D. A. (2017). Morbidity and Mortality Associated With Medications Used in the Treatment of Depression: An Analysis of Cases Reported to U.S. Poison Control Centers, 2000-2014. The American Journal of Psychiatry, 174(5), 438–450. https://doi.org/10.1176/appi.ajp.2016.16050523

 

Protein Pirouettes: Part 2

Amyloid

Welcome to our Protein Pirouettes series! This series is designed to teach you about the wonderful world of proteins, so that you too can learn to dance like a protein. If you haven’t read our introduction- check out the first part of the series here. You can also watch this great video here– for expert level dancing on the smallest possible scale. For more information about the author, check out our about us page.

Hello readers! Cooper here! Welcome back to our Protein Pirouettes series. In the last article, I talked a lot about where proteins come from, why they need to fold, and touched on the elaborate dance of protein folding that proteins must perform to function. In this article, we’ll dive deeper into this process, and explore what happens when it goes horribly wrong. 

When you’re stuck in a rut, just keep dancing.

As proteins twist and turn, they take on different shapes that we call conformations. In search of a functional, highly organized, low entropy shape, proteins sometimes get stuck into non-native conformations (intermediately folded states, or simply called intermediates).2These chaotic, entropy laden states are intermediates on the pathway towards fulfillment of the protein’s purpose. Oh, woe is the protein! But do the little dancers give up? Of course not—they do what they always do. They dance

Protein Chain Diagram
Simplified protein folding funnel, showing a handsomely drawn protein perform the Cha Cha slide. Two hops this time!

 

The protein vibrates with wanton abandon, strands of amino acids bumping into each another recklessly and randomly, trying out new moves. It doesn’t give up. Eventually, something just seems to feel right, the protein settles into its groove and becomes more stable, escaping the rut and dancing towards its goal. When faced with a hurdle in life, consider meeting the challenge like a protein: just keep dancing.

Friends don’t let friends dance alone.

Remember the chaperones at your high school prom? Proteins don’t always get to dance without chaperones either. Sometimes, to dance their way to the next conformation, proteins enlist the help of a chaperone.3Chaperones are protein themselves, and when they see a fellow protein dancing, they get up and dance along with them! Cells are like busy night clubs, and it’s hard to dance when there are innumerable other proteins dancing all around you! Just like our high school prom chaperones, protein chaperones facilitate the party so that nothing too-crazy happens. After all, sometimes dancing doesn’t turn out like it should. 

Amyloid
If you’re an amyloid, you’re going to have a bad time.

Go home amyloid, you’re drunk.

Without the safe watch of a chaperone, proteins may accidentally take on a misfolded conformation that is particularly terrible. These misfolded proteins are like that guy at prom that drinks a little bittoo much of the booze he stole from his parents, and ends up vomiting all over the hardwood dance floor of the gym. Don’t be that guy. Proteins don’t want to be that guy either, and, in the world of proteins, that guy’s name is amyloid.3Amyloids form when misfolded proteins get squished together, and they’re dangerous to your health. For example, plaques of amyloid beta proteins are implicated in the development of Alzheimer’s disease.6So, take a tip from proteins: dance responsibly. 

—Cooper

Notes

  1. Video clip of a protein folding simulation.1
  2. Protein folding funnel drawn in Microsoft Paint. The width of the funnel represent entropy, with decreasing entropy as the funnel narrows. The height of the funnel represents Gibbs free energy, with energy decreasing from top to bottom.2
  3. Adapted, surface structure of a 42-residue beta-amyloid fibril (2MXU) visualized in NGL.4-5

References

  1. Theoretical and Computational Biophysics Group at the NIH Center for Macromolecular Modeling and Bioinformatics. Folding of a Three-helix Bundle Protein. Online video clip. YouTube. 2013. Retrieved from https://www.youtube.com/watch?v=XsQgjxMDjNw.
  2. Wolynes PG, Onuchic JN, Thirumalai D. Navigating the Folding Routes. Science. 1995;267(5204):1619.
  3. Dwevedi A. Protein Folding: Examining the Challenges from Synthesis to Folded Form. SpringerBriefs in Biochemistry and Molecular Biology. 2015. ISBN 978-3-319-12592-3. 
  4. AS Rose, AR Bradley, Y Valasatava, JM Duarte, A Prlić and PW Rose. Web-based molecular graphics for large complexes. ACM Proceedings of the 21st International Conference on Web3D Technology (Web3D ’16): 185-186, 2016. doi:10.1145/2945292.2945324.
  5. AS Rose and PW Hildebrand. NGL Viewer: a web application for molecular visualization. Nucl Acids Res (1 July 2015) 43 (W1): W576-W579 first published online April 29, 2015. doi:10.1093/nar/gkv402.
  6. Aisen PS, Cummings J, Jack Jr. CR, et al. On the path to 2025: understanding the Alzheimer’s disease continuum. Alzheimers Res Ther. 2017;9:60. doi:10.1186/s13195-017-0283-5.

When Pills Weren’t Enough

Pills. Image by qimono on Pixabay.
Pills. Image by qimono on Pixabay.

When I became mysteriously ill in 2016, I learned a crucial lesson: pills were not going to be enough.

Formerly a college student of average health, comfortably floating along on Prozac, Adderall, and birth control, I was shocked when I took a lab job and started experiencing nothing short of bodily retaliation soon after. I developed extreme fatigue, had three heavy periods within two months, and suffered panic and anxiety attacks for the first time.

Desperate to find a quick solution, I visited several different medical professionals. The general practitioner took me off Adderall, switched my antidepressant, and told me to take vitamin D. The gynecologist switched my birth control. The BioTE clinic shoved a testosterone pellet into my hip. The others, well, they gave me advice but couldn’t really help me beyond that.

Despite all the pills and the pellet, my health continued to plummet. Eventually, I had an anxiety attack so bad that I was practically bedridden for a couple of days, and during that time, I made the heartbreaking decision to quit my job. My father agreed to financially support me while I rehabilitated myself, and boy did I have my work cut out for me. After all, I’d just spent months trying to do exactly that, but at that point, it became clear to me that pills were not going to be enough.

I was very weak. My body needed fourteen hours of sleep each day, I was extremely depressed, and my confidence and self-esteem had been shattered. I could hardly do any housework, and I mostly laid on the couch for at least the first month. So I had to start very small.

Thought. Image by TeroVesalainen on Pixabay.

The first treatment I could tolerate was Cognitive Behavioral Therapy (CBT) with a licensed counselor, which I had started a couple months before I quit the lab job. I decided to continue meeting my counselor once per week, uncovering the roots of my mental stigmas, venting to get some of my burden off my heart, and most importantly, rewiring my brain by teaching me to view my problems in a different light. That latter component serves as the key behind CBT. Once I learned to reframe my thoughts, I began to see my life much more positively and regain some of my confidence.

Essential oils. Image by monicore on Pixabay.

The second treatment I added to my regimen was aromatherapy, an Eastern medicine practice in which one inhales purified essential oils as a means of boosting health. While many oils can soothe physical problems like headaches or allergies, I used them for their emotional properties. I quickly discovered two favorites: clary sage and lime oil. Clary sage oil helped me calm down and find mental clarity, and occasionally, it inspired me to be creative. Lime oil gave me a little energy and sharpened my focus. Aromatherapy became a critical component to my recovery by encouraging me to get off the couch and search for my next job.

Healthy food. Image by sansoja on Pixabay.

The next thing I worked on (and continue to improve in my life to this day) was cooking healthier. I finally had enough time to cook meals at home instead of ordering takeout, so immediately the quality of my meals leapt upward. After tracking my meals for at least a week on a few different occasions, I learned where I had deficiencies or excesses in certain nutrients, and I would then adjust my weekly meal plan to accommodate for them. This had the biggest impact on my energy levels and overall wellbeing.

(For healthy meal ideas, check out our Recipes page.)

Yoga. Image by StockSnap on Pixabay.

Lastly, once the first three additions to my life inspired me enough, I tried yoga. I practiced short YouTube routines only lasting about 15-20 minutes, but that small start in regular exercise created a lasting impact on me that developed into me doing weekly cardio, strength training, and stretching. Most immediately, learning to control my breathing and balance reduced my anxiety and depression, making me feel calmer and happier. Later on as I added a variety of exercises to my regimen, I regained my confidence.

Pills. Image from Canva.

All of this is not meant to discredit prescription medications, but rather to emphasize that health is multidimensional, requiring a balance among a wide variety of elements. In my case, I found medications that made me feel somewhat better, but I still needed to improve my diet, exercise regularly, learn healthy coping mechanisms and stress outlets, and reevaluate my career ambitions. Without all of those other things in check, I was weak and unfit to work. Now, I have more confidence and strength than I ever had before.

Pills only make up about half of the health equation, at best. I hope that my experience will encourage you to adopt a more holistic approach with your own health, not just within your body, but with the wide range of treatments and practices available, too!

Sniffle Talk With Your Sickly Tot

 How to communicate with your child when they feel ill

      Life isn’t fun when we are feeling under the weather. As winter has just begun, more of us are prone to catch a cold, stomach virus, the flu and other types of illnesses. Whether it is a sniffle, sore throat or something more serious, feeling ill can influence our work productivity and our family relationships. As adults, we have learned coping mechanisms to help us persevere until we are feeling better again. Children, on the other hand, sometimes need their parents’ or caregiver’s guidance to understand what they are going through. I can remember 15 plus years ago when my two little ones would get sick. “M-o-m-m-y, my throat hurts.” Or “M-o-m-m-y, I feel hot.” And that’s when they were able to speak! But just imagine how difficult it was before they were able to talk! As an infant or toddler it wasn’t always easy to understand what they were trying to communicate to me. That child development course I had in college came in handy through the years. It helped me understand the different stages of development so I could communicate with them more effectively when they were ill. In this article I want to share that information with you, and help explain how to talk about illness with your child.

 

Infants/ Babies:

The infant/baby stage is the hardest to communicate with about their illness. Since babies cannot talk yet, we of course, have to rely on other cues from them such as acting cranky, tugging at their ears (possible ear infection), not eating, and crying more than usual. We have to make educated guesses as to what their ailment is. What we can do at this stage is to comfort them by holding them more and using a soothing voice when we speak to them. Talking about illness comes in later stages, but offering comfort is still very helpful to a child at this stage.

 

Toddlers:

The next stage of development is the toddler stage between 1– 2 years old. At this age, your child is beginning to use just a few words to talk, but not full sentences. It is less difficult to understand how they are feeling than the infant/baby stage. However, sometimes it is still a struggle to nail down exactly what their symptoms are. My little ones, Wyatt and Lily, would sometimes say words like “hot”, meaning they felt hot. They might refrain from eating or playing too. We can communicate with them by using our natural tone of voice, but in a more comforting way. Toddlers love to cuddling at this age when they are feeling sick. Talking about illness is still a struggle in this stage, but it is easier. Using simple words and offering lots of comfort is still a priority.

 

Preschool:

The next stage of development is the preschool stage between 3 – 4 years old. The language development has advanced and they know many words. It is much easier for them to tell you how they feel. I have fond memories of my two at this age. It is really a time when communication between parent and child becomes more developed and determining what illness they have isn’t as difficult as it once was. 


      The school age years from 5 – 11 are characterized by the capability of the child to construct complex sentences and be able to give a more accurate description of how they are feeling. My children had their fair amount of ear infections. At this age, most of the guesswork on what was causing them to feel bad was gone because they would just tell me, “Mom, my ear hurts.” Of course, it was not music to my ears, but at least I was not playing a guessing game. 


The tween and teen stage of development, ages 12 – 18, is characterized by more advanced language skills. They are fully able to tell you exactly how you are feeling and more (smile). While it still important to acknowledge they are not feeling well, you must be careful to not to talk to them like a baby as well. This is the stage of development I guess I struggled with the most because my precious little preschoolers were now almost fully-grown adults. My daughter is nearly 16 and I still have this urge inside to speak to her as though she is a 4 year old. Any other parents out there relate. At this stage of development, our children want to be like an adult. They want us to use a normal tone of voice, not the baby talk I so loved to use.


      No matter what stage of development your child is in, you have to remember that showing concern, empathy, and love at their level of development is so important. It will help them get through their illness easier and hopefully faster. And help you retain some sanity. Here’s to your family’s health!

Protein Pirouettes: Part 1

Ezetimibe

How to Dance Like a Protein: Part 1

Ezetimibe
Pirouettes performed by the target protein of the drug ezetimibe, a medication used to lower cholesterol (a).

Proteins—the practically invisible, molecular dancers that serve as the faithful building blocks of me and you. Yes, it is true that even dancers are made of dancers, and proteins perform some of the most amazing dancing of all by way of folding. Protein folding is actually a lot like belly dancing, with all of its vibrations and shimmying.

Now, I am not—by any leap of the imagination—a dancer, but I do happen to know a lot about nature’s smallest dancers of all. Perhaps you can find some inspiration in learning about our nanoscopic friends, and learn about the science of protein folding along the way!

Butterfly Protein
The humble butterfly protein. Or two chicken legs pressed together? Choose your own adventure (b).

A reason to dance. What, you think that the protein above woke up looking that beautiful? To understand how and why a protein folds, it’s important to remind ourselves of how they come to exist in the first place—the central dogma of molecular biology. DNA is transcribed into mRNA, and mRNA is translated in proteins. That probably sounds like an awful lot of alphabet soup, but let’s simplify things with an analogy: your cell is a small company called Cell Incorporated®. Every company needs a CEO to boss everybody around, and that’s “DNA” (deoxyribonucleic acid), whose office is located in the center (nucleus) of Cell Inc.®. However, even a visionary leader is powerless if they cannot communicate that vision, so they employ messengers called “mRNA” (messenger ribonucleic acid). Now, the company needs to produce something to make a profit, and that product is called “proteins.” Ergo, the central dogma of molecular biology: DNA -> mRNA -> proteins.

To make their product, Cell Inc.® needs raw materials—these are chemicals called amino acids, the steel from which proteins are made. As a protein is being constructed (or translated from the “language” of nucleic acids to amino acids), it is formed piece by piece in a long chain. Imagine that every component that makes up a cell phone was attached to one another by a tiny string; if you laid out that string, it would look nothing like a cell phone (let alone work like one), and the same is true for proteins. Unfortunately for them, cells don’t have the benefit of assembly lines and blue collar workers; therefore, the product must put itself together.

Understand the immense difficulty of this task for a moment: Cell Inc.® needs to make a product out of steel blocks connected by string that, due to the unique properties of each block, will self-assemble into something useful, something beautiful (cell phones are beautiful, okay?).

Wow.

Fortunately for them, however, cells possess the most powerful allies in the entire universe: the laws of physics (c). And it is these laws that govern what is possible, what is probable, and what isn’t. Using physics, Cell Inc.® came up with a solution to make its products self-assemble—to make the pieces of the protein fold nicely together: they dance.

Dancing with purpose. There, I said it: protein folding is dancing. Proteins jiggle, wiggle, twist, and turn, always moving, vibrating, and colliding with themselves and anything else around. Although the motions may be random, the dance itself is done with an immense sense of purpose, guided by the very nature of the protein itself. From chaos and entropy, proteins allow their amino acid bodies to guide their movements towards the native structure, the final, functional form of proteins that we’re familiar with (see the image above). From the very moment that a protein is born, it begins to fold—dancing, you might say, is an integral part of the nature of what it means to be a protein.

There’s an important life lesson to be learned from the humble protein, here. We should allow our natural talents and capabilities to guide our decisions, rather than force upon ourselves choices that deviate from the desires of our hearts. In the early moments of a protein’s birth, it seems impossible to foresee anything of worth or interest arising from a tangled mess of amino acids slapped together, moving erratically in the dark loneliness of a cell. However, perhaps if we live our lives like a protein—following our hearts, listening to our bodies, and maybe even a little dancing—we can find fulfillment, and become the best, most beautiful version of ourselves that we can be.

You do you, aquaporin. You do you (d).

To learn more about proteins, check out my second article here. I’ll be exploring protein folding in greater detail, and discuss how even one false move on the dance floor can transform an otherwise contributing member of cellular society into a murderer.

—Cooper

TL;DR:

  • Proteins are made up of amino acids
  • Central dogma of molecular biology: DNA -> mRNA -> proteins
  • During and after translation, proteins must fold to become functional
  • Protein folding happens as a consequence of the protein’s inherent chemical structure

Notes

(a) Adapted, surface structure of human NPC1L1 (3QNT) visualized in NGL. (1-2)

(b) Adapted, surface structure of human DNA topoisomerase IIa ATPase/ADP (1ZXN) visualized in NGL. (1-2)

(c) This is ultimately where biochemistry comes from; biochemistry is the study of biological chemicals, chemistry is the study of chemicals and how they interact, and those interactions are governed by the law of physics. Biochemistry is basically biological chemical physics. The laws of physics, as they apply to biological chemicals (biochemistry), govern the movements and interactions of proteins (which are also biological chemicals, albeit bigger ones)—just as they govern the movements and interactions of us.

(d) Adapted, surface structure of bioassembled human aquaporin (4CSK) visualized in NGL. (1-2)

References

(1) AS Rose, AR Bradley, Y Valasatava, JM Duarte, A Prlić and PW Rose. Web-based molecular graphics for large complexes. ACM Proceedings of the 21st International Conference on Web3D Technology (Web3D ’16): 185-186, 2016. doi:10.1145/2945292.2945324.

(2) AS Rose and PW Hildebrand. NGL Viewer: a web application for molecular visualization. Nucl Acids Res (1 July 2015) 43 (W1): W576-W579 first published online April 29, 2015. doi:10.1093/nar/gkv402.

Part 2 coming soon!