Jan 28
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More research needed to find genetic link to depression risk

By Genetics Research, News

Parsing out the genetic underpinnings of depression remains a challenge for researchers, despite the rise in the number of studies focusing on the human genome, the authors of a new scientific review article report.

The researchers behind the article, published in the January issue of the Harvard Review of Psychiatry, reviewed a number of studies on the genetic link to depression, which is described as one of the most prevalent, disabling and costly mental health conditions in the U.S. According to the Anxiety and Depression Association of America, about 14.8 million American adults (6.7 percent of the U.S. population) suffer from depression.

Depression is known to run in families, study authors Dunn et al. report, with studies involving twins suggesting that genetic factors are responsible for roughly 40 percent of the variation in population risk of depression. Given the genetic complexity of depression, however, even large genome-wide studies have found no consistent association between specific genetic attributes and depression. While multiple genes are thought to be involved in all mental health conditions, an even larger combination of specific genes are suspected to be involved in depression compared with other mental health conditions.

“Given the established heritability of depression, there is every reason to expect that increasingly well-powered studies will indeed identify [genetic] risk loci,” the authors write.

“The genetic and phenotypic complexity of depression, however, may mean that such successes will require samples on the order of tens of thousands of participants.”

The authors call for not just larger studies to help find a link, but also more research that takes into account the role of a person’s environment, in addition to genetics, in the risk of depression. Studies so far looking at both genetic and environmental factors “have thus far failed to provide clarity but have fueled plenty of debate,” the authors write. Environmental factors most often refer to stressful life events, either recently occurring in adulthood or more remote childhood events, such as neglect or abuse.

“Given the enormous burden of depression, identifying its genetic underpinnings may be essential to preventing the onset of this disorder and improving the lives of those who already suffer,” the authors conclude.

While a concrete genetic link to depression risk has proved elusive, how a person’s genetic makeup affects their response to antidepressants is clearer. Most medications used to treat depression are metabolized by just two liver enzymes: CYP2D6 and CYP2C19.

A patient’s genes are a major factor in determining how active these enzymes are in metabolizing these medications. If the drugs are metabolized too quickly, a patient likely won’t receive any benefits from the drug. Too slowly, and the medication could build up and cause adverse side effects.

The YouScript Personalized Prescribing System allows doctors to determine their patients’ unique ability to process medications and select the right drug at the right dose. Learn more on the YouScript website.

To learn more about resources available for those suffering from depression, visit the website of the National Alliance on Mental Illness.

Jan 19
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Genelex announces new genetic testing options

By Genelex News, News, Personalized Medicine, Pharmacogenetics, YouScript Software

Genelex is excited to announce the next chapter in the company’s ongoing mission to improve patient care and reduce adverse drug events. Genelex is unveiling five new panels and 17 new genetic testing options to augment our existing panel of six tests that form the core of the YouScript Personalized Prescribing System.

In conjunction with the YouScript Personalized Prescribing software, all are designed to improve providers’ ability to further personalize medication therapy for their patients.

The five new panels join Genelex’s existing test panels that include testing for variations in the CYP2D6, CYP2C9, CYP2C19, CYP3A4 and CYP3A5 drug-metabolizing enzymes and non-CYP tests for F2 (Factor  II), F5 (Factor V) Leiden, MTHFR, SLC6A4 (5-HTT) and VKORC1.

The new genetic tests (listed below) provide additional testing options and expand coverage to include drugs used for:

Cardiology

  • SLCO1B1, variants which may lead to increased blood levels of statins.

Psychiatry

  • CYP1A2, variants of which have been associated with altered metabolism of the schizophrenia medication clozapine.
  • CYP2B6, variants of which have been associated with the efficacy of the antidepressant bupropion.
  • GRIK4, variants of which have been associated with the efficacy of the antidepressant citalopram.
  • HTR2A, variants of which have been associated with altered response to citalopram as well as differences in risk of side effects in SSRIs.
  • HTR2C, variants of which have been associated with anti-psychotic-induced weight gain in patients with schizophrenia.

Attention Deficit Hyperactivity Disorder (ADHD)

  • ADRA2A, variants of which have been associated with the effectiveness of the common ADHD medication methylphenidate.
  • COMT, variants of which can directly impact dopamine levels, which may have emotional and behavioral effects.

 Addiction

  • OPRM1, variants of which have been correlated with efficacy of the drug naltrexone in the treatment of alcoholism and opioid addiction

Infectious diseases

  • HLA-A and HLA-B, variants of which have been associated with severe hypersensitivity to the HIV medication abacavir
  • IFNL3, variants of which have been associated with response to drug regimens designed to treat Hepatitis C Virus Genotype 1.
  • NAT2, variants of which have been associated with altered metabolism of the tuberculosis-treating drug isoniazid.

Oncology

  • DPYD, variants of which have been associated with the buildup of toxic levels of the drug 5-Fluorouracil (5-FU), which treats various types of cancer.
  • TPMT, variants of which have been associated with adverse effects of thiopurines, a class of drugs used to treat various cancers.

Smoking cessation

  • COMT, variants of which have been associated with the effectiveness of nicotine replacement therapy.

All the new genes are available for order as single tests or as part of panels geared toward different types of specialty care. The new panels and their included genes (both original and new) are:

  • YouScript Psychotropic: CYP2D6, CYP2C19, CYP1A2, SLC6A4 (5-HTT) and HTR2A
  • YouScript Psychotropic Plus: CYP2D6, CYP2C19, CYP3A4, ADRA2A, CYP1A2, CYP2B6, COMT, HTR2A, HTR2C, GRIK4, MTHFR and SLC6A4 (5-HTT)
  • YouScript ADHD: CYP2D6, COMT and ADRA2A
  • YouScript Cardio: CYP2D6, CYP2C19, CYP2C9, CYP3A4, CYP3A5, VKORC1, F2 (Factor II), F5 (Factor V), MTHFR and SLCO1B1
  • YouScript Analgesic: CYP2D6, CYP2C9, CYP3A4, CYP3A5, CYP2B6, COMT and OPRM1

Learn more about each gene on our test menu page. To find out how to order, contact a member of the YouScript Personalized Prescribing team or call 1-800-TEST-DNA.

Additionally, Pre-register here for upcoming webinars to learn more about the evidence behind these new tests and explore how to use them to improve patient care.

Dec 10
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More older Americans have chronic conditions compared to foreign counterparts, survey finds

By News, Personalized Medicine

An international survey of more than 10,000 adults age 65 or older has found that more Americans had multiple chronic conditions and took four or more prescription drugs than their age mates in 10 other countries.

The survey, the results of which were published in a paper in the December issue of the journal Health Affairs, found that 68 percent of Americans surveyed suffered from two or more chronic conditions; the highest figure among the 11 countries in the study. At 53 percent of those surveyed, the U.S. also topped the list in number of older individuals taking four or more prescription medications.

Researchers polled just more than 15,000 people aged 65 and older in Australia, Canada, France, Germany, the Netherlands, New Zealand, Norway, Sweden, Switzerland, the United Kingdom and the U.S.

Chronic conditions are a widespread problem in the U.S. According to the Centers for Disease Control and Prevention (CDC), about half of all adults are now living with at least one chronic medical condition, while one in four have multiple. The CDC also reports that seven of the top ten causes of death in 2010 were from chronic conditions and that the majority of U.S. healthcare costs are associated with chronic diseases.

Since suffering from multiple chronic conditions and taking multiple drugs typically go hand in hand, this places older Americans at an increased risk for drug-drug, drug-gene or cumulative interactions compared to their international peers. Increased risk of interactions could result in adverse drug events and treatment failures.

Americans were also the most likely (19 percent) to report having any cost-related health care access problems in the last year, according to the international survey results. At 10 percent, New Zealand had the second-highest number of residents reporting this problem. The U.S. also topped the list for older individuals (11 percent) who said they had problems paying or were unable to pay medical bills in the last year.

The survey also shed light on some positive healthcare trends for older Americans. U.S. respondents were among the most likely to have discussed health-promoting behaviors with a clinician (76 percent), to have a chronic disease plan tailored to their daily life (58 percent), and to have engaged in end-of-life care planning (55 percent).

A common theme among the survey findings, the study authors report, was a lack of coordinated care on the part of providers.

“While each of the health care systems in the surveyed countries has its strengths, all countries surveyed have room for improvement,” the study authors conclude.

“No health system consistently offers older adults accessible, coordinated, and patient-centered care.”

With the health of a particularly vulnerable and growing older population at stake, care coordination is a topic healthcare providers should keep at the forefront. The American Geriatrics Society offers an overview of care coordination for the elderly on their website.

Dec 10
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Study: Falls more common among older adults with pain

By News, Pharmacogenetics

Recurrent falls were more than twice as common in elderly people suffering from pain than those who were not, according to the results of a recent study.

The article, published in the October issue of the Journal of the American Geriatrics Society, found that 19.5 percent of adults 65 and older who reported bothersome pain in the last month also reported falling at least twice in the past year. This compares to 7.4 percent of individuals without pain who reported falls.

The study authors also found that balance/coordination problems and fear of falling increased with the number of specific pain sites reported by participants. For example, roughly 11 percent of participants with pain in one place on their bodies reported problems with balance or coordination that limited activity. At the other end of the spectrum, nearly half (41.4 percent) of participants with four or more pain sites reported balance or coordination issues that limited activity.

The findings strengthen the call for pain management strategies to be developed and integrated into multifaceted fall prevention programs, the study authors write. The authors stop short of assigning a causal relationship between chronic pain and recurrent falls, though these results do confirm findings of past researchers on this topic. The study authors interviewed 7,601 Americans 65 and older, a figure described as “representative of the 35.3 million Medicare beneficiaries living in the United States.”

The study authors say that past studies have shown chronic pain to be associated with falls, though no previous work have sought to characterize the extent of falls-related outcomes according to pain status. Chronic pain might predispose older persons to falling through multiple pathways, the study authors write, including fear of movement, lack of physical activity and muscle weakness.

Overall, falls among the elderly are a source of serious concern. The Centers for Disease Control and Prevention (CDC) cite falls as the leading cause of both fatal and nonfatal injuries among Americans 65 and older. In 2012, 2.4 million nonfatal falls among this age group were treated in emergency departments, and more than 722,000 of these patients were hospitalized. In 2011, about 22,900 members of this demographic died from unintentional fall injuries.

Pain itself affects more Americans that diabetes, heart disease and cancer combined, according to the National Institutes of Health, and is cited as the most common reason Americans access the health care system. Approximately 76.2 million Americans, or one in every four, have suffered from pain that lasts longer than 24 hours.

Effective pain management can be a challenge for any physician, though the YouScript Personalized Prescribing system can help. With the ability to detect genetic variations that can influence how patients respond to pain medications, YouScript can help doctors find the right medication and dose for each patient. Learn more about the system here.

Dec 10
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The Pharmacist’s Corner: Clopidogrel dosing and genetic variations

By News, Personalized Medicine, Pharmacist's Corner, Pharmacogenetics

By Rachel Sass, PharmD

Should providers increase the clopidogrel dose in patients with decreased functioning CYP2C19 enzymes?

Clopidogrel (Plavix) is one of the most well studied medications in pharmacogenetics.  Clopidogrel is a prodrug, meaning that it needs to be converted to an active metabolite in the body to have an effect.

This metabolizing process occurs in part via the polymorphic enzyme CYP2C19. Researchers have found that individuals with decreased CYP2C19 activity have increased major adverse cardiovascular outcomes (e.g., cardiovascular death, heart attack, stroke, and stent thrombosis) compared to those with normal functioning CYP2C19 enzymes.

So what to do? Most prescribers already know the clopidogrel product insert contains a black box warning (effective March 2010) that confirms the increased cardiovascular events rates in patients who are CYP2C19 poor metabolizers who have had acute coronary syndrome or percutaneous coronary intervention (PCI). The warning also recommends considering “alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.” We can certainly identify what alternative treatment means (e.g., alternatives drugs such as prasugrel (Effient) or ticagrelor (Brilinta), but what does “alternative treatment strategy” mean?

Many studies have investigated whether increasing the dose of clopidogrel could decrease platelet reactivity, and some studies have investigated if dose increases could overcome genetic resistance (that is, patients who are CYP2C19 intermediate or poor metabolizers). Most of the studies use pharmacodynamic measures, such as platelet aggregation tests, to determine an adequate antiplatelet response.

In CYP2C19 intermediate metabolizer patients, doubling the standard maintenance dose of 75 mg daily to 150 mg daily seemed to be only of limited benefit. Tripling the clopidogrel maintenance dose (225 mg daily) did seem to improve platelet response in CYP2C19 intermediate metabolizers, however CYP2C19 poor metabolizers did not seem to benefit even with doses up to 300 mg daily. See the review article that details these studies here.

In a recent small trial, Hornstein et al. examined 18 patients who were CYP2C19 normal metabolizers, intermediate metabolizers, and poor metabolizers and dosed them at 75 mg, 150 mg, 225 mg, and 300 mg daily for eight days each. The study evaluated the four-hour post-dose maximal platelet aggregation on day eight for each treatment period for each genotype group.

The study authors found that poor metabolizers required 300 mg daily, four times the daily standard dose, to achieve the same platelet aggregation of normal metabolizers taking the standard dose of 75 mg daily. The researchers also found that intermediate metabolizers required 150 mg daily to get the same effects of normal metabolizer on 75 mg daily.

These results differed from the previous studies discussed above in two main ways. The previous studies found that even higher doses (225 mg) were required in intermediate metabolizers and that doses up to 300 mg daily in poor metabolizers did not achieve equal platelet aggregation response to normal metabolizers taking 75 mg daily. This re-emphasizes the fact that we have not yet found the most appropriate clopidogrel dose in patients with decreased functioning CYP2C19 enzymes.

But there is one common theme missing in all these studies. No study has demonstrated an improvement in clinical outcomes (such as a reduction in major adverse cardiovascular events) when looking at increased doses of clopidogrel in patients with decreased functioning CYP2C19 enzymes.

Basically, we know that increased doses have been shown to decrease platelet aggregation, but does this truly help keep our patients from having future adverse cardiovascular events? We might never know for sure until this type of study is conducted.

Additionally, safety of these increased doses will need to be established prior to routinely recommending such doses. Lastly, a standard platelet aggregation test and standard cut-off for adequate response to antiplatelet agents using the standard platelet aggregation test needs to be established, as studies often use different cut-offs and different aggregation tests to determine response to treatment.

There are viable alternatives to clopidogrel available, such as prasugrel and ticagrelor, which the provider can use if the patient has a decreased functioning CYP2C19 enzyme. While the clinical outcomes of switching from clopidogrel to an alternative has not been directly studied in patients with CYP2C19 loss of function alleles, a cohort analysis from the TRITON-TIMI 38 trial demonstrated that cardiovascular outcomes were not different in patients taking prasugrel with or without a CYP2C19 loss of function allele.

This result is in contrast to an increase in ischemic events seen with clopidogrel in patients that had a reduced functioning CYP2C19 enzyme. Additionally, in a subanalysis of the PLATO trial, efficacy of ticagrelor was preserved in patients with decreased functioning CYP2C19 enzymes.

The Clinical Pharmacogenetic Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group both recommend an alternative treatment (both recommend prasugrel, and CPIC recommends ticagrelor as well) in patients with ACS undergoing PCI as long as no contraindications are present. Genelex also makes these recommendations in all CYP2C19 intermediate and poor metabolizers.

Prasugrel and ticagrelor may not be appropriate alternatives for everyone, however, as both have contraindications and warnings in specific patient populations. Knowing that these alternative strategies may not be appropriate in patients who have decreased functioning CYP2C19 enzymes and have specific contraindications to ticagrelor or prasugrel reinforces the need to establish a specific clopidogrel dose that is safe and effective in patients with CYP2C19 variants.

Rachel Sass, PharmD, is a board-certified pharmacotherapy specialist who has worked at a Genelex as a personalized prescribing clinical pharmacist for one year.

Nov 20
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Public-facing genetic registry launched

By News, Personalized Medicine

geneticA genomic research project funded by the National Institutes of Health (NIH) dedicated to finding which genetic variants are most relevant to patient care has launched a registry where people can enter de-identified information about their genetics.

The Clinical Genome Resource project has launched its GenomeConnect patient portal, the PharmGKB Blog reports. The patient portal, or registry, is a repository for voluntarily-provided genetic information that has been stripped of all personal identifiers, such as name, birthdate and contact details. Members of the public can enroll and, once a personal account is created, provide medical history information through a survey and upload genetic test results if available.

The overall goal of the project is to harness both research data and information collected from the hundreds of thousands of clinical genetic tests performed each year to advance knowledge of how genetics affect patient care. According to the GenomeConnect website:

“A patient portal (also called a registry) is a secure place for patients to voluntarily share and store detailed information, so that connections can be made between that information and healthcare providers and researchers who wish to study it. Registries make medical discoveries possible by bringing together information from a large number of patients.”

De-identified health and genetic information will be studied by Clinical Genome Resource staff and made available to interested researchers and select databases to allow the scientific community to learn from the data. The compiled information will help researchers interpret genomic data more accurately.

Personal identifying information, such as name, birthdate and contact information, will never be shared. GenomeConnect states that thay are “very serious about protecting the privacy of particpants.”

Why share this sort of information? Many pharmacogenetic studies are unable to draw conclusions on the effect of a certain genetic variant due to insufficient patient numbers. What’s more, including large numbers of patients in clinical trials can be overwhelmingly expensive and can hinder a site’s ability to conduct a desired study.

As the PharmGKB Blog writes, including this information in the GenomeConnect database allows it to be part of large-scale studies designed to further the understanding of the impacts of genetics on health. In addition, researchers can use the same pool of data to study different outcomes, which may help control costs and facilitate more studies. The more data made available, the more effectively researchers can identify patterns and draw conclusions.

The pharmacogenetic testing offered through the YouScript Personalized Prescribing System is just one type of genetic testing available on the market. Visit the Clinical Genome Resource project website for more information on how to get involved.

 

Nov 20
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Raising awareness of diabetes in November

By Cytochrome P450, News, Personalized Medicine

November is diabetes awareness month in the U.S., a time to learn more about a disease that affects an estimated 30 million American children and adults.

According to data from the Centers for Disease Control and Prevention (CDC), the number of adults with diabetes nearly tripled between 1980 and 2011, going from 5.6 million people to 20.9 million. The American Diabetes Association estimates the total national cost of diagnosed diabetes at $245 billion.

Proper nutrition, physical activity and control of blood sugar levels are the cornerstones of treatment and prevention of diabetes, says the National Diabetes Education Program, with diabetes medications also being a key player in these strategies. The CDC reports that between 1997 and 2011, the percentage of people with diabetes taking both insulin treatment and pills increased from 9.1 percent to 13 percent.

Researchers are recognizing the role of an individual’s genetics in response to many common medications used to treat diabetes. Variants of the gene CYP2C9, which codes for drug-metabolizing enzymes in the liver, have the potential to alter blood levels of certain diabetes drugs, possibly necessitating a change in dosage.

For example, a 2013 review study in the scientific journal Biochema Medica reviewed studies that found that those who had CYP2C9 variations were not able to clear the diabetes drug glyburide as effectively as those with normal CYP2C9 activity. This could lead to buildup of the medication in the blood stream and increased risk of low blood sugar. This risk would be even more dangerous in those with “hypoglycemia unawareness,” or having low blood sugar without feeling symptoms.

Though the authors cite “significant evidence” to demonstrate an association between specific gene variants and differing responses to diabetes medications, they call for more clinical trials to further assess the utility of pharmacogenomics for individualized treatment. Pharmacogenomics generally refers to the study of genetic variations that influence individual response to drugs.

“With recent scientific and technological advances, pharmacogenomics has a great potential to yield therapeutic advances leading the way towards personalized diabetes care,” the review study authors write.

A 2012 position statement from the American Diabetes Association and the European Association for the Management of Diabetes on the management of hyperglycemia also recognized the potential of pharmacogenetics to improve diabetes treatment decisions, and the need for more clinical trials in this area.

“Pharmacogenetics may very well inform treatment decisions in the future, guiding the clinician to recommend a therapy for an individual patient based on predictors of response and susceptibility to adverse effects,” the position statement authors write.

More information for patients on preventing and treating diabetes can be found on the CDC’s website and through the American Diabetes Association.

Nov 19
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Study shows 50% drop in serious bleeding with DNA-guided warfarin treatment

By News, Pharmacogenetics

A new meta-analysis of clinical trials scrutinizing warfarin dosing methods found that warfarin treatment guided by individual genotypes reduced instances of serious bleeding by more than half compared to standard dosing approaches.

The work lends support to the importance of genetic testing for the genes CYP2C9 and VKORC1, variations of which can influence warfarin’s therapeutic effect. In August 2007, the U.S. Food and Drug Administration revised the drug labeling for Coumadin, a brand name of the anticoagulant warfarin, to describe the genetic factors that affect dose requirements.

The new study, appearing in the September issue of the Journal of Thrombosis and Haemostasis, reviewed nine randomized controlled trials involving 2,812 patients that compared genotype-guided vs. clinically-guided warfarin dosing. Meta-analysis authors Franchini et al. found that the pharmacogenetic-guided dosing of warfarin and other similar medications (collectively referred to as VKAs) reduced major bleeding episodes by 52.5 percent.

Multiple pharmacogenetic-guided dosing algorithms have been developed to guide VKA therapy, the study authors write, as the role of CYP2C9 and VKORC1 variants in VKA response has been realized. Other more general recommendations regarding CYP2C9 and VKORC1 testing also exist, such as a 2008 American College of Medical Genetics policy statement commenting on the the appropriate use of these tests in the context of warfarin treatment.

“The [working group that developed the policy] determined that the analytical validity of these tests has been met, and there is strong evidence to support association between these genetic variants and therapeutic dose of warfarin,” the policy statement says.

“Although the routine use of warfarin genotyping is not endorsed by this work group at this time, in certain situations, CYP2C9 and VKORC1 testing may be useful, and warranted, in determining the cause of unusual therapeutic responses to warfarin therapy.”

Franchini et al. write that some previous studies on this topic, such as large 2013 study in the New England Journal of Medicine (NEJM), found little to no difference in the percentage of time in the therapeutic range of warfarin when clinical and genotype-based dosing strategies were compared. However, the meta-analysis authors contend, reduction of major bleeding may be the more important measure.

“…the right question for the clinician is not how much time patients spend within the therapeutic range during the initial phase of VKA treatment but whether or not the use of pharmacogenetic testing reduces the incidence of clinical complications as compared with clinically-guided dosing,” Franchini et al. write.

The PGx In Practice blog took a look at the 2013 NEJM study earlier this year and made a similar point about the use of time in therapeutic range as a measuring stick for the effectiveness of warfarin dosing guided by pharmacogenetic testing. While the 2013 NEJM study by Kimmel et al. provided valuable information, examination of adverse drug events such as major bleeding may be the more important endpoint for patient safety.

Learn more about CYP2C9 and VKORC1’s influence on warfarin here.

Nov 19
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Gene Spotlight: 5HTT and antidepressant medications

By News, Pharmacogenetics

about one in 10 Americans aged 12 and older takes antidepressant medications.

The majority of these drugs are metabolized by the body’s highly genetically variable CYP2D6 and CYP2C19 pathways. Response to selective serotonin reuptake inhibitors (SSRIs), a commonly prescribed type of antidepressant, may also be affected by variations in the 5HTT gene.

Roughly 40 percent of the North American population carries a 5HTT variation that may make them less likely to respond to SSRIs. 5HTT codes for a protein found in neurons that helps regulate serotonin levels at the main site of action —the same chemicals many antidepressants (includ­ing Prozac and Paxil) target. Genetic variations to 5HTT may decrease the efficacy of these medications.

Genelex added 5HTT testing to its core panel of five CYP tests last year. 5HTT testing is generally not used to predict changes in blood levels of SSRIs. Rather, the testing is best used to help predict future response or tolerance to SSRIs or better understand past or current drug response.

Who would make a good candidate for such a test? In general, prescribers with patients who are starting SSRIs or other therapies targeted at 5HTT, or who are experiencing adverse effects or low efficacy of prescribed SSRIs, should consider 5HTT genotyping.

More specifically, Caucasians with the 5HTT variant that limits serotonin transport may see a better response and decreased adverse drug events with non-SSRI medications compared to treatment with SSRIs. A prescriber may consider adjusting therapy by prescribing a non-SSRI drug for treatment of depression for patients with decreased 5HTT activity.

5HTT joins a list of tests Genelex offers that are geared toward specialized prescribing. These includes HLA-B*5701, which tests for sensitivity to the HIV medication abacavir (Ziagen). Find out more about Genelex’s entire test panel here.

Nov 18
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All that wheezes is not asthma: Doctor uses YouScript to solve puzzling patient case

By Case Studies, DNA Today Newsletter, Fall 2014, News, Personalized Medicine

As cardiopulmonologist Mark Pamer, DO, goes about his day at his South Florida practice, one adage from medical school that sticks in his mind is: “All that wheezes is not asthma.”

“[As doctors], we probably all heard that. Did we understand it? You know, probably not,” said Dr. Pamer. “We understood it later on in residency or fellowship or in life.”

This adage proved itself during Dr. Pamer’s treatment of a puzzling patient case involving a 59-year-old man who came into his practice with all the classic signs of asthma. It was worse in the winter and around animals, and included nasal congestion. The patient also had history of gastroesophageal reflux disease (GERD) also known as acid reflux, hypertension, irritable bowel syndrome and tremors.

The patient was on multiple medications, including fluticasone/ salmeterol (Advair) for asthma, dexlansoprazole (Dexilant) for GERD and primidone (Mysoline) for tremors, in addition to a rescue inhaler.

The patient came to Dr. Pamer complaining of worsening asthma symptoms, so the dose of Advair was increased. A month later, the asthma symptoms had not changed. Pulmonary function tests and chest x-rays simply did not point to asthma.

Dr. Pamer stopped the Advair and had the patient evaluated for asthma-mimicking states, which can include acid reflux. These tests showed the patient’s reflux was not being controlled by the Dexilant, which is metabolized by the highly variable CYP2C19 enzyme pathway.

Fortunately, Dr. Pamer knew the value of the YouScript Personalized Prescribing System in figuring out tough cases. Genotyping and YouScript analysis revealed the patient to be a CYP2C19 rapid metabolizer, which was predicted to decrease the blood levels of Dexilant.

Primidone, being an inducer of both CYP2C19 and CYP3A4, was likely decreasing Dexilant blood levels even more. Together, these factors resulted in a clinically significant increase in Dexilant metabolism and a decrease indrug effectiveness.

This analysis, in combination with a 24-hour pH probe on the patient, revealed his asthma symptoms were actually a result of acid reflux. The reflux, in turn, was the result of both the patient’s genetics and a drug-drug interaction that was drastically reducing the blood levels of Dexilant.

“I wouldn’t have learned any of this from talking to him,” Dr. Pamer explained. “It just seemed that he had horrible asthma.”

After Dr. Pamer consulted with the patient’s neurologist, the 59-year-old was titrated off primidone. Additionally, his Dexilant was replaced with rabeprazole (Aciphex), which is not as dependent on the CYP2C19 pathway for drug metabolism. The patient’s “asthma” was controlled, and his cough went away.

“I’ll tell you that your knowledge base improves exponentially once you start to use this test,” Dr. Pamer said of YouScript.