Colchicine modulates calcium homeostasis and electrical property of HL-1 cells

Colchicine (Colcrys®) is a drug typically indicated for gout or familial Mediterranean fever that we learned about in one of our top drugs sessions. Colchicine is a microtubule disruptor, and it can also be used to reduce the occurrence of atrial fibrillation after someone undergoes an operation or ablation. There has not been much research completed on the effects of colchicine on atrial myocytes (cells in the heart muscle), so that is what this study aimed to find out.

The purpose of this study was to determine if colchicine can regulate calcium (Ca2+) homeostasis and reduce the electrical effects of the extracellular matrix on atrial myocytes. HL-1 cells are a specific type of muscle cell. In this study, HL-1 cells derived from mouse atrial muscle cells were treated with and without (control) colchicine over a 24 hour period.

The results of the study were that colchicine-treated HL-1 cells, in comparison to control cells, had a longer action potential duration with smaller intracellular Ca2+ transients and sarcoplasmic reticulum Ca2+ content by 10% and 47%, respectively. The results of this study show that colchicine acts to prevent atrial fibrillation by controlling atrial electrical activity, regulating Ca2+, and reducing the electrical effects of collagen.

I find this study interesting because I learned that colchicine has another use besides treating gout and familial Mediterranean fever. Gout and atrial fibrillation are two very different medical conditions, so it is interesting that some drugs function in ways that can effect many different pathways in the human body. In all honesty, this study was very complicated and difficult for me to interpret. I still don’t understand everything that was tested, but reading over this study was good practice for developing my literature-reviewing skills. I picked out the information that was most relevant to me as a student pharmacist, which was how colchicine physiologically prevents atrial fibrillation. It will be important as a pharmacist to keep up with literature showing alternate uses for medications so we know how to handle our patients that are taking drugs for non-FDA approved uses.

My question posed to colleagues: What are your thoughts about colchicine being used to prevent atrial fibrillation in post-operative patients?

Lu, YY, Chen, YC, Kao, YH, et al. Colchicine modulates calcium homeostasis and electrical property of HL-1 cells. J Cell Mol Med. 2016;20:1-9. 

Association Between Narrow Pharmacy Networks and Medication Adherence

There are narrow or preferred pharmacy networks included within many insurance plans that have in-network pharmacies with reduced prescription prices based on negotiations with the insurance company. These types of insurance plans offer their members reduced cost sharing to incentivize them to use the in-network pharmacies. In 2014, 75% of Medicare Part D (drug coverage plans) and 70% of exchange plan enrollees were in a narrow or preferred network drug plan, so it’s clear that there are many patients who are enrolled in these types of insurance plans. Some professionals have expressed concern that narrow or preferred networks adversely affect medication adherence due to the fact that they might be hard for patients to access based on location. On the flip side, some believe that these types of networks are good for medication adherence because they encourage (and in some cases practically force) members to establish a pharmacy “home” where pharmacists can better support adherence and coordinated care.

The purpose of this study was to assess how narrow pharmacy networks effect plan members’ medication adherence. This study also looked at whether insurancd plans that implemented narrow networks and those that did not were different in the following 2 subgroups: plans with and plans without 90-day prescription programs. These subgroups were included because 90-day prescription programs have shown to be a positive impact on medication adherence.

Data was collected from January 1, 2012, through December 31, 2013, and each subject was studied for only one of the two years from Januray to December. Plans that implemented narrow networks in 2013 were considered intervention plans, while those that implemented them in 2014 were considered control plans. For all plans, CVS/Caremark was the pharmacy benefits manager. The main factors assessed were the differences in members’ medication-possession ratio (MPR) before and after network implementation separately for statins, antihypertensive medications, oral antidiabetic medications, and antidepressant medications. The MPR was defined as the days’ supply from the first through last times that the prescription was filled divided by the days between the first fill date and December 31 of that year. Two narrow network plans (having 67,906 members total) and 3 non-network plans (having 149,989 members total) were included in this study.

The results of the study were that individuals enrolled in narrow network plans had greater increases in MPR than individuals enrolled in non-network plans. In addition, it was found that the difference in MPR improvements before and after network implementation between network plans and non-network plans was greater for plans that had 90-day programs already in place.

This results of this study are really interesting to me because they show how outside factors can influence how patients take their medications. In this case, the outside factor is one’s insurance plan, and insurance definitely plays an important role in access to medications because it can essentially determine whether a person can afford their medications or not. It bothers me that some people miss out on lower prescription prices simply because they are not in narrow of preferred pharmacy network insurance plans, and I do not like that a person’s insurance plan can be a factor in the affordability of medications which can ultimately influence medication adherence. It is important that pharmacists understand how different insurance plans work so we can help our patients afford their medications in order to help them be adherent in sticking to their medication regimen.

My question posed to colleagues: What do you think about the results of this study? Are there ways in which pharmacists can help patients who are not in narrow or preferred networks afford their medications and also stay adherent?

Polinski, JM, Matlin, OS, Sullivan, C, et al. Association Between Narrow Pharmacy Networks and Medication Adherence. JAMA Intern Med. 2015;1850-1853.

How Do US Gastroenterologists Use Over-the-Counter and Prescription Medications in Patients With Gastroesophageal Reflux and Chronic Constipation?

The purpose of this study was to assess how gastroenterologists use over-the-counter (OTC) and prescription medications to treat gastroesophageal reflux disease (GERD) and chronic constipation (CC) in their patients. This study included a total of 3,600 randomly selected American Gastroenterological Association (AGA) members who were mailed a 27-question survey that assessed their perceptions and use of OTC and prescription medications. A total of 830 gastroenterologists (23.1%) completed the survey.

The results of the study are as follows: For a typical patient with acid reflux, 50% of gastroenterologists recommended OTC proton pump inhibitors (PPIs), 13% recommended an OTC histamine-2 receptor antagonist, and 33% recommended a prescription PPI. In a typical CC patient, 97% of gastroenterologists initially utilized OTC treatments. The vast majority of gastroenterologists felt that OTC brand name and store brand PPIs (76%) and polyethylene glycol (90%) were equally effective. Despite these statistics, very few gastroenterologists “always” or “very often” directed their patients to purchase a store brand PPI (35%) or laxative (40%). In addition, gastroenterologists tended to underestimate the cost savings associated with store brand medicines and had limited knowledge regarding the regulation of store brands.

The results of this study reveal 2 main points: 1) Among US gastroenterologists, OTC medications now dominate the primary therapy for GERD and CC; 2) Despite feeling that name brand and store brand PPIs and laxatives are equally effective, the majority of gastroenterologists recommend brand name medicines and underestimate the cost savings associated with store brands. The results of this study are pertinent to pharmacy practice. Community pharmacists can play an important role in helping patients save money by explaining that store brand OTC medications are usually just as effective as name brand medications. Since pharmacists are medication experts, it is our job to look out for additional factors that come along with using medications such as cost. The cost of medications can pose as a burden to many patients, and affordability is part of the larger picture when we assess medication adherence and access to medications. This study shows that many patients are not recommended to take non-name brand OTCs in many cases, but we could play a role in fixing this situation by explaining that store brand generics are the same medications as the name brand medications.

My question posed to colleagues: What role do you think pharmacists can play in helping patients save money on medications, especially in the case of store brand vs. name brand OTCs as highlighted in this study? Do you think it’s important that pharmacists help patients save money on their medications, or do you think that should not be part of our jobs?

Antibody responses among adolescent females receiving the quadrivalent HPV vaccine series corresponding to standard or non-standard dosing intervals

An important privilege pharmacists have is to administer and counsel patients about vaccinations they should receive. A relatively new (new meaning it’s been on the market for roughly 10 years) but very important vaccine called Gardasil is a vaccine that protects patients against multiple strains of the human papillomavirus virus (HPV). HPV is an STD virus that can cause genital warts, cervical cancer (only in women), anal cancer, throat cancer, and penile cancer (only in men). HPV is spread through skin-to-skin contact, especially when mucous membranes come into contact with each other (e.g. kissing, intercourse, and oral sex). Most people in the United States contract some form of HPV in their lifetime, and a person usually contracts it by the age of 26 years. The Gardasil vaccine, also known as quadrivalent human papillomavirus vaccine (HPV4), is recommended as a 3-dose series administered at 0, 1–2, and 6 months. The vaccine is administered to both boys and girls, and it is recommended to be administered to children between the ages of 9 and 13 years. The reason for administering the vaccine to children at such a young age is because there is a high chance that they will contract some form of HPV during their teenage or young adult years through skin-to-skin contact. The vaccine can be administered to girls between the ages of 9 and 26 years, and it can be administered to boys between the ages of 11 and 21 years (boys between the ages of 21 and 26 years can be given the vaccine under the special circumstances of engaging in male-male sexual activity or if they have a suppressed immune system).

The purpose of this study was to asses if administering doses 2 and 3 of the Gardasil vaccine later than recommended would affect antibody titers. The reason for this study is that the Gardasil dosing schedule is often not followed, and children/adolescents often receive doses 2 and 3 later than recommended. The study assessed antibody titers to HPV4 when dose 2 and/or dose 3 were administered on schedule or delayed. 331 Healthy females aged 9–18 years were enrolled at the time of receipt of HPV4 dose 2 or 3. Participants were classified as belonging to one of four groups depending upon timing of receipt of HPV4: both doses on time; only dose 2 delayed later than 90 days; only dose 3 delayed later than 180 days; or both doses 2 and 3 delayed. Pre- and post-dose 3 blood samples were taken to test HPV antibody titers.

The results of the study were that post-dose 3 geometric mean titers (GMTs) for all HPV types were NOT significantly lower for any of the delayed dosing groups when compared to the on time group. When compared to the on time group, the post dose 3 GMTs in the delayed dose 3 group were actually significantly higher for HPV types 6, 11, and 16. These results suggest that delays of dose 2 or 3 do not interfere with immune responses to the vaccine after completion of the 3-dose series. These results are important because they support current recommendations to not administer additional doses of HPV4 vaccine if dose 2, dose 3, or both doses have been administered late.

I think this study highlights an important factor in vaccinations that we as pharmacists will have to be aware of, which is inappropriately administering a repeat vaccination. This study proves the importance of checking a patient’s antibody titer before administering a repeat dose of a vaccine. We should never assume that a patient’s antibody is low because the vaccine was not administered in the correct timeline or certain recommendations assert that vaccines given during a specific time period need to be readministered. As pharmacists, we will need to use our analysis skills to determine which vaccines our patients need and which vaccine antibodies should be tested via titers before readministering any vaccines.

My question posed to colleagues: How do you think this study applies to pharmacists administering and recommending vaccinations? Are the results of this study surprising to you?

Russel, K, Dunne, EF, Kemper, AR, et al. Antibody responses among adolescent females receiving the quadrivalent HPV vaccine series corresponding to standard or non-standard dosing intervals. Vaccine. 2015;33:1953-1958. 

Serum anti-Mullerian hormone production is not correlated with seasonal fluctuations of vitamin D status in ovulatory or PCOS women

Polycystic ovarian syndrome (PCOS) is a disorder in women that is characterized by ovarian cysts from anovulation and is associated with hyperandrogenism and infertility. The most common symptoms of PCOS include polycystic ovaries, amenorrhea, hirsutism, obesity, insulin resistance, and infertility.

Anti-Mullerian hormone (AMH) is a glycoprotein produced by the ovary, and it plays an important role in maintaining ovarian reserve and modifying the follicles’ response to follicle stimulating hormone (FSH). Recently, there has been an increase in interest about the role that AMH plays in reproductive physiology. Many women of child-bearing age are now being tested for their AMH levels as a measure of both ovarian reserve and PCOS status.

Vitamin D’s role in reproduction has also sparked a lot of interest in recent years because many studies have come showing a correlation between vitamin D deficiency and many pregnancy-related disorders, including PCOS. Vitamin D is primarily produced by the skin in response to UV light exposure, and it can be supplemented in our diets. Earlier studies have shown that seasonal fluctuations in ovulation in countries of high latitude correspond to large seasonal fluctuations in serum vitamin D levels.

The purpose of this study was to clinically test if there is there a relationship between serum AMH levels and seasonal variations in serum vitamin D in women with ovulatory and polycystic ovary syndrome (PCOS). There was little research looking at the clinical relationship between AMH and Vitamin D before this study. The design was a retrospective cohort study that included 340 women aged less than 40 years, with 58 women having PCOS and 282 women having an ovulatory syndrome.  This data was collected as part of the subjects’ routine fertility assessment between January and December 2013 at a private fertility clinic in Adelaide, South Australia. The data collected from the subjects included age, BMI, cause of infertility, antral follicle counts (AFC), serum AMH and vitamin D levels, smoking status, and menstrual cycle length for women aged less than 40 years of age. Their serum AMH and vitamin D levels were sampled within the same 4-week period and were retrieved from a database. The hours of sunlight per day and daily UV index were extracted from a database at the South Australian Bureau of Meteorology which is located South Australia. The data analysis was done by analyzing serum vitamin D levels were against seasonal variation in sunlight and UV exposure and serum AMH levels.

The results of this study were that seasonal variations in serum vitamin D were observed between summer and winter, but serum AMH levels were NOT affected by the seasonal fluctuations in serum vitamin D in either the PCOS or ovulatory cohort. It was also found that serum vitamin D levels were not significantly related to the underlying cause of infertility . These results were contradictory to in vitro studies which have shown that vitamin D has the potential to modify AMH production.

I think the results of this study are interesting because previous evidence from in vitro studies would make one believe that serum vitamin D most likely has a direct effect on serum AMH. I think this study is a good example for health care providers and pharmacists that we can not always assume from related studies that drugs, hormones, disease states, etc. have direct effects on each other. It is important to conduct thorough research on topics that do not have direct evidence or findings because it is certainly not appropriate for health care providers and pharmacists to make assumptions based on related literature when treating patients’ disease states. As for the actual topics discussed in the study, I find it interesting that vitamin D deficiency has been previously found to effect problems associating with pregnancy and contraception. I would like to learn more about vitamin D’s role in pregnancy and how women with reproductive disorders are treated for problems with conceiving because I could potentially recommend women to take vitamin D supplements as a pharmacist to help them conceive.

My question posed to colleagues: Do you know anything about how vitamin D deficiency can be related to pregnancy disorders? What are your thoughts about the finding of this study in relation to the previous research completed about factors related to AMH and vitamin D?

Pearce, K, Gleeson, K, Tremellen, K. Serum anti-Mullerian hormone production is not correlated with seasonal fluctuations of vitamin D status in ovulatory or PCOS women. Hum Reprod. 2015;30:2171-2177.

Quality care in epilepsy: Women’s counseling and its association with folic acid prescription or recommendation

       This study focused on women of child-bearing age who are being treated for epilepsy with antiepileptic drugs (AEDs). Taking folic acid during the pre-conceptual period has been found to decrease the risk for congenital malformations in babies born to women with epilepsy who take AEDs. The purpose of this study was to determine if annual counseling about contraception and pregnancy in a treatment setting for women with epilepsy is associated with increased recommendations or prescriptions for folic acid.

        This was a retrospective cohort study that collected the data by abstracting medical records from the subjects. 77 women of childbearing age were included in this study who had two or more visits for epilepsy at a neurology clinic. The assessment included a review of documentation from the first three visits for epilepsy within a 24-month follow-up window. The women in this study were placed into 2 groups based on the type of counseling they received about pregnancy and contraception in relation to their epilepsy treatment: one group received something called DFCW (N=28) while the other group did not receive DFCW (N=49). DFCW was defined as the health care provider perfectly adhering to annual counseling about the impact of epilepsy treatment on contraception or pregnancy during their sessions with the patients. A recommendation from the provider that the patient take over-the-counter (OTC) folic acid or a prescription for folic acid was independently abstracted from the chart at each visit.

       The group of subjects who received DFCW and the group who did not receive DFCW had no significant differences in respect to age, disease duration, baseline history of drug-resistant epilepsy (DRE), presence of concurrent psychiatric disease, epileptologist involvement, number of AEDs prescribed, types of seizures experienced, and etiology. The results were that 71.4% of subjects (20 women) in the DFCW group and 85.7% of subjects (42 women) in the non-DFCW group were NOT recommended or prescribed folic acid by their health care provider. These results show that providers are missing a big area of counseling for their female patients with epilepsy who are of child-bearing age. Even though many of the providers counsel their female epilepsy patients about how epilepsy treatment may affect contraception and pregnancy, they often times do not mention or actively recommend their patients to take folic acid if they are thinking about trying to conceive.

     I think the results of this study are interesting and very eye-opening. It is concerning to me that many health care providers are not mentioning the benefits of taking folic acid to their female epilepsy patients of child-bearing age because previous studies have proved that folic acid can prevent congenital malformations in babies born to women with epilepsy who took AEDs during their pregnancies. I am wondering if this finding about folic acid is relatively new in the treatment of women with epilepsy and that many providers, especially those who have been practicing for many years, are simply not aware of this finding. Whatever the reason is, I hope this study has been reviewed in the world of epilepsy treatment and that more providers start recommending the use of folic acid in their female epilepsy patients of child-bearing age in order to prevent more congenital malfunctions from the use of AEDs during pregnancy from occurring.

My question posed to colleagues: How can pharmacists play a role in making female epilepsy patients of child-bearing age taking antiepileptic drugs aware of the fact that taking folic acid could decrease the risk for their children having congenital malfunctions?

Moura, LMVR, Mendez, DY, De Jesus, J, et al. Quality care in epilepsy: Women’s counseling and its association with folic acid prescription or recommendation. Epilepsy Behav. 2015;44:151-154.  

Tiotropium/Olodaterol: A Review in COPD

This article reviews the efficacy of a new inhaler for COPD (chronic obstructive pulmonary disease) that was approved by the FDA in May 2015 and has since been out on the market. This new inhaler is named Stiolto Respimat (tiotropium/olodaterol), and it was developed by the company Boehringer Ingelheim.

For a quick review, COPD is an overarching term that describes a group of diseases that affect the lungs. People with COPD have difficulty breathing and receiving necessary airflow through their lungs. Patients who receive treatment for COPD typically use long-acting inhalers that are used to improve their chronic state of limited breathing along with “rescue” inhalers that are used to treat acute asthma attacks as needed. Some examples of common, long-acting inhalers already on the market are Advair and Symbicort, and some examples of commonly used “rescue” inhalers already on the market are albuterol inhalers sold under the brand names of Ventolin, ProAir, and Proventil.

Stiolto Respimat is a long-acting inhaler that is a combination of 2 drugs used to treat respiratory problems, which are tiotropium and olodaterol. Tiotropium (bromide) is a long-acting antimuscarinic agent (LAMA), so it works by blocking muscarinic acetylcholine receptors to dilate the bronchioles. Olodaterol is the new drug in this inhaler that has allowed Boehringer Ingelheim to patent and manufacture Stiolto Respimat. Olodaterol is an ultra long-acting beta 2-adrenoreceptor agonist (LABA) that works on beta 2 receptors in the lungs to dilate the bronchioles.

 

This article reviewed clinical trial data and compared Stiolto Respimat to the commonly used inhaler, Advair (fluticasone/salmeterol), that is also a long-acting inhaler for the treatment of COPD. The article determined that Stiolto Respimat seems to be a relatively safe inhaler that has minimal side effects when used correctly and does not have any adverse cardiovascular side effects. It was found to work more efficiently than Advair over a 24 hour period for bronchodilation and lung functioning. The article determined that the combination of tiotropium and olodaterol was more effective when used in combination compared to using the two drug components monotherapeutically. This inhaler can be used once daily, which is convenient in comparison to other long-acting inhalers that must be administered twice daily. Stiolto Respimat was also found to increase exercise capacity in COPD patients and the amount of gas they can inhale into their lungs.

In conclusion, this article has shed a positive light on Stiolto Respimat as it makes it way into the medical world through the new few years. It seems to be a great addition to current therapies for COPD, and could be a good alternative to COPD patients who are allergic to drugs in some of the other inhalers. I find it interesting how drug developers have combined drugs with different mechanism of actions in inhalers to maximize the efficacy of inhaled therapies. These newer combination therapies have been very popular in the treatment of COPD since they came out a few years ago (I’m thinking of inhalers such as Advair, Symbicort, and Ventolin). I am thinking that I want to become a community pharmacist, so I am interested in learning more about the treatment options for COPD and all of the side effects that come with these treatments.

My question posed to colleagues: How are the mechanism of action between Advair (fluticasone/salmeterol) and Stiolto Respimat (tiotropium/olodaterol) different?

Dhillon, S. Tiotropium/olodaterol: A review in COPD. Drugs. 2016;76:135-146.

 

Accelerating Medicines Partnership: Alzheimer’s Disease (AMP-AD) Knowledge Portal Aids Alzheimer’s Drug Discovery through Open Data Sharing

The Accelerating Medicines Partnership (AMP) was developed in 2014 as a way to address 3 main problems in the development and testing of new medications. These 3 problems are that drug development and testing are very expensive, they can take a long time, and they often times fail completely.  AMP was developed by Dr. Francis Collins, Director of the National Institutes of Health (NIH), in conjunction with the heads of many pharmaceutical companies. AMP’s efforts focus on 3 diseases, which are Alzheimer’s disease (AD), Type II Diabetes, and rheumatoid arthritis/lupus erythematosus. This article focuses on the role of AMP in AD and how it could change the development of new drugs for AD through 2 projects, which are the Biomarkers Project and the Target Discovery and Preclinical Validation Project.

Biomarkers Project: The goal of this project is to develop novel imaging techniques and to identify fluid biomarkers in people who are clinically determined to have a greater risk of developing AD later in their life (to make this clear, these people DO NOT have AD already!). People are determined to have a greater risk of developing AD if they have one of the three gene mutations that produces early-onset dominantly inherited AD, because they have two copies of the late-onset genetic risk factor for ApolipoproteinE-ε4 , or because they already have beta-amyloid in their brain that was detected by a PET scan (beta-amyloid is the characteristic “plaque” that builds up in the brains of those with AD). This project aims to develop clinical trials in people with a predisposition to AD so that drugs can be developed to prevent the onset of AD.

Target Discovery and Preclinical Validation Project: The main goal of this project is to discover, select, and characterize novel therapeutic targets for AD. In order to reach this goal, AMP is focusing its research on gaining a better understanding of gene, protein, and metabolic networks in human brains where these novel targets would operate and interact, identifying biologic nodes and networks that are linked to the development or progression of AD, and by evaluating the drugability of the targets in multiple model organisms. This project is using genomic, epigenomic, RNA sequencing, and proteomic data derived from studies of over 2000 postmortem human brains from people who had AD or were cognitively normal.

A critical aspect of AMP is how it utilizes an IRB-approved data sharing platform where data can be stored, accessed, and collaboratively analyzed by all members of the AMP-AD research team. There has not been a new therapy approved by the FDA for the treatment of AD since 2003, so AMP’s hope is that this new and comprehensive research platform will help produce a much needed new drug(s) for the treatment of AD. AMP’s hope is ultimately that their platform will stretch to many AD researches across the globe so that a vast communal effort can be put forth to develop new medicinal therapies for treating AD.

I think this is a great new platform in the fight against Alzheimer’s disease. AD is so common in older adults, and it is pretty astounding to think that there has not been any new drugs approved for the treatment of AD since 2003! We learned in Anatomy and Physiology I that AD is starting to be recognized possibly as “Type 3 Diabetes” because researchers are starting to find that beta-amyloid “plaque” in AD patients’ brains may be caused by insulin issues. I personally think AMP’s platform is an innovative way to approach research on a global scale because it seems like AD is so complicated that it may take a widespread effort among researchers from different parts of the world to truly figure out how to combat the disease through medicinal therapies.

My posed question to colleagues: What do you think are the risks and benefits of having a platform like AMP’s to further research in hopes of developing new drug therapies for specific disease states such as AD?

Hodes, RJ, Buckholtz, N. Accelerating Medicines Partnership: Alzheimer’s Disease (AMP-AD) knowledge portal aids Alzheimer’s drug discovery through open data sharing. Expert Opin Ther Targets. 2016;20:1-4.