408-854-1883 starts at $30 per hr home care

Affordable in home care | starts at $28 per hr

We thank our coaches in our lives, from life coach, financial coach to fitness coach

I give thanks to all coaches and trainers who shared their skills unconditionally. Please check out my sales coach, Eric Lofholm

Hi Connie!

I have a favor to ask. I launched my newest book called “Bulls Eye” on Amazon. I am trying a new approach where I am giving away my book for free, and I’m asking you to try them out and see how my books could work for you. This book has my 10-step goal setting process in it. The roots of the process came from Tony Robbins, Zig Ziglar, Napoleon Hill, and Brian Tracy.

I’ve also placed my books “The Power in Asking” and “21 Ways to Close More Sales Now” on the free list as well, normally priced at $2.99. Each book contains great tips for personal development as well as for sales training.

So you can get the Kindle version all of these books for FREE right now on Amazon. I truly believe that there is great content in these books that you will benefit from, all at no cost to you. That’s a win-win!

You can download the books for free on my Amazon Author page at:
http://www.amazon.com/author/ericlofholm

Success,

Eric Lofholm

Rent getting higher and partnering up to get your first home or be a real estate owner

Dear visitors,

I am going to join an auction of tax lien properties in the bay area this August 2016 and is willing to partner up with you if you are interested for positive income cash flow.

We should join forces in the real estate market where rent is getting higher and one cannot do it alone to be a homeowner.

Regards,

Connie Dello Buono

Prevent vascular disease, manage inflammation, get GYV health caps to boost ATP cells performance and speedy repair of your body, email connie to get the caps and join in spreading the benefits with extra income for you at motherhealth@gmail.com and text 408-854-1883

Plavix and Pharmacogenetic test to prevent adverse drug reactions

Contact Connie Dello Buono 408-854-1883 motherhealth@gmail.com , certified rep at medxprime to avail of pharmacogenetic test if you are a doctor, and when prescribing Plavix.

CYP2C19 Genotype Test

Helping predict response to Plavix® (clopidogrel)

Carriers of one or two nonfunctional CYP2C19 variants may have:1-5,a,b

Differential response to Plavix

53% higher risk of a subsequent event in patients with cardiovascular disease (CVD) taking Plavix (300mg loading and 75mg daily mean dosages)

3-fold higher risk of stent thrombosis when taking Plavix

What is the CYP2C19 Gene?

The CYP2C19 gene encodes the cytochrome P450 2C19 enzyme. This enzyme plays an important role in the metabolism of many common drugs, such as the prodrug clopidogrel (Plavix), certain proton pump inhibitors (PPIs), and other drugs.7,a Multiple variants in the CYP2C19 gene have been found to alter the function of the cytochrome P450 2C19 enzyme.

CYP2C19 and Plavix Metabolism

The CYP2C19 Genotype Test identifies several metabolizer types.c The nonfunctional alleles are represented by *2, *3, *4, *5, *6, *7, *8, *9, and *12.  The increased function allele is represented by *17.  These variants alter the function of the CYP2C19 enzyme.d

Potential Clinical Implications

Poor and Intermediate metabolizers taking Plavix may have a higher risk of a subsequent CVD event including stent thrombosis

Ultra-rapid metabolizers have been shown to have enhanced metabolism of certain drugs and may have an increased risk of bleeding associated with Plavix use

Poor or Intermediate metabolizers may benefit from alternative dosing strategies or an anti-platelet medication other than Plavix

The FDA Warning Regarding Plavix

The FDA has placed a warning label on Plavix indicating that patients who are CYP2C19 poor metabolizers may not receive the full benefits of the drug:

“For Plavix to work, enzymes in the liver (particularly CYP2C19) must convert (metabolize) the drug to its active form. Patients who are poor metabolizers of the drug do not effectively convert Plavix to its active form. In these patients, Plavix has less effect on platelets, and therefore less ability to prevent heart attack, stroke, and cardiovascular death.”6 —FDA 2010

FDA Plavix Warning

The CYP2C19 Genotype Test was developed and its performance characteristics were determined by Berkeley HeartLab, a CLIA-certified and CAP-accredited laboratory. This test has not been cleared or approved by the U.S. FDA.

Plavix is a registered trademark of Sanofi-Aventis Corp.

  1. The clinical impact of the CYP2C19 genotype on the metabolism of specific drugs will vary based on non-genetic factors, such as hepatic and renal status, other medications used (including over-the-counter medications, herbals, and other supplements), alcohol or illegal drug use, race, age, weight, diet, and diseases present in an individual patient.
  2. Pharmacokinetic and pharmacodynamic analysis was performed on healthy individuals. Clinical outcomes data was performed primarily in Caucasian patients with acute coronary syndromes with planned PCI undergoing clopidogrel treatment.
  3. Other rare alleles are not detected by this assay. Metabolism of drugs including clopidogrel may also be influenced by race, ethnicity, diet, and/or other medications.
  4. Detection of CYP2C19 genetic variants does not replace the need for assessment of antiplatelet effectiveness and clinical monitoring.

References

Mega et al. Cytochrome P-450 Polymorphisms and Response to Clopidogrel. NEJM. 2009; 360:354-62

Sofi et al. Cytochrome P450 2C19*2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-analysis. Pharmacogenomics Journal. 2010;1-8.

Sibbing et al. Cytochrome 2C19*17 Allelic Variant, Platelet Aggregation, Bleeding Events, and Stent Thrombosis in Clopidogrel-Treated Patients with Coronary Stent Placement. Circulation. 2010;121:512-518.

Simon et al. Genetic Determinants of Response to Clopidogrel and Cardiovascular Events. NEJM. 2009;360:363-375.

Li-Wan-Po et al. Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17. British Journal of Clinical Pharmacology. 2009;69:3:222-230.

US Food and Drug Administration. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm. Accessed February 13, 2012.

US Food and Drug Administration. http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm190848.htm. Accessed February 13, 2012.

Source: http://www.bhlinc.com/clinicians/test-descriptions/CYP2C19

What is pharmacogenetics?

Overview: What is pharmacogenetics?

Some of us respond differently than others to the same medications that we take, or we may experience different side-effects from drugs. The way we respond can be due to the genes we have inherited. With respect to drugs, our unique genetic make-up and our individual response may mean that a drug that is effective for one person may be less effective for another or that a drug that is safe for one person may be less safe for another person—even at the same dosage.

Most drugs are broken down (metabolized) in the body by various enzymes. In some cases, an active drug is made inactive (or less active) through metabolism. In other cases, an inactive (or less active) drug is made more active through metabolism. The challenge in drug therapy is to make sure that the active form of a drug stays around long enough to do its job. However, some people have variable enzyme action so that they may metabolize the drug too quickly or too slowly or not at all — meaning that the drug may not produce its intended effect or it may remain in a person’s system too long and may lead to side effects.

Individual response to a drug may also be related to variability in the drug target, for example a protein that the drug binds to in order to produce its specific effect. Furthermore, individuals may experience side-effects (known as hypersensitivity reactions) from certain medications due to variability in proteins involved in the immune response.

Pharmacogenetics is the study of genetic variability that causes individual responses to medications. By analyzing the genes that produce the specific drug targets or enzymes that metabolize a medication or are associated with immune response, a doctor may decide to raise or lower the dose or even change to a different drug. The decision about which drug to prescribe may also be influenced by other drugs the person is taking, in order to avoid drug-drug interactions.

The terms “pharmacogenetics” and “pharmacogenomics” are sometimes used interchangeably. There are subtle differences in the meaning of the two terms and there is no consensus on the exact definitions. In general, pharmacogenomics refers to the overall study of the many various genes that contribute to drug response. Pharmacogenetics is the study and evaluation of the inherited differences (genetic variations) that affect drug metabolism and an individual’s response to medications. For the purposes of this article, the term pharmacogenetics will be used.

 Why is pharmacogenetics important?

When initiating drug therapy to treat a particular condition, doctors typically prescribe one of several appropriate drugs. Dosages and timing of drugs are usually based upon the anticipated rate of metabolism and clearance from the body in the average person. They prescribe a “standard” dose based on factors such as weight, sex, and age. Clinically, however, each person responds uniquely to treatment and doctors must make adjustments. For example, the doctor may adjust the drug dose or switch to a different therapy, depending on whether the person’s condition is responding to the medication and whether the individual is experiencing unpleasant or dangerous side effects. Sometimes a person may find that a treatment that has been working well for them suddenly causes symptoms when they start taking an additional drug.

The concentrations or effects of some drugs are monitored with blood tests and the drug dosages may be increased or decreased to maintain the drug level in an established therapeutic range. Follow-up of drug concentration is called “Therapeutic Drug Monitoring.” If changing the drug dose is not effective in treating or controlling the person’s condition, or the person still has side effects, then the person may be given a different drug.

In contrast, pharmacogenetics offers physicians the opportunity to individualize drug therapy for people based on their genetic make-up. Testing people prior to initiating drug therapy to determine their likely response to different classes of drugs is a key emerging area of testing. Such genetic information could prove useful to both the doctor and patient when choosing current and future drug therapies and drug doses. For certain medications, pharmacogenetics is already helping physicians predetermine proper therapies and dosages to have a better chance of achieving the desired therapeutic effect while reducing the likelihood of adverse effects.

Testing

How does pharmacogenetic testing work?

Genes are the basic units of genetic material, the segments of DNA that usually code for the production of specific proteins, including the proteins known as enzymes. Each person has two copies of most genes: one copy is inherited from their mother and one copy is inherited from their father. Each gene is made up of a specific genetic code, which is a sequence of nucleotides. Each nucleotide can be one of four different nucleotides (A, T, G, or C). For each nucleotide position in the gene, one of the four nucleotides is the predominant nucleotide in the general population. This nucleotide is usually referred to as “wild type.” If an individual has a nucleotide that is different from “wild type” in one copy of their genes, that person is said to have a heterozygous variant. If an individual has the same variant nucleotide in both copies of their genes, that person is said to have a homozygous variant.

Nucleotide or genetic variants (also called polymorphisms or mutations) occur throughout the population. Some genetic variants are benign — do not produce any known negative effect or may be associated with features like height, hair color, and eye color. Other genetic variants may be known to cause specific diseases. Other variants may be associated with variable response to specific medications.

Pharmacogenetic tests look for genetic variants that are associated with variable response to specific medications. These variants occur in genes that code for drug-metabolizing enzymes, drug targets, or proteins involved in immune response. Pharmacogenetic tests have the ability to determine if a variant is heterozygous or homozygous, which can impact an individual’s response or reaction to a drug.

 When are the tests ordered?

A doctor may test a patient’s genes for certain variations that are known to be involved in variable response to a medication at any time during treatment (for example, prior to treatment, during initial phase of treatment, or later in the treatment). The results of the testing may be combined with the individual’s clinical information, including age, weight, health and other drugs that they are taking, to help tailor therapy. Sometimes, the doctor may use this information to adjust the medication dose or sometimes to choose a different drug. Pharmacogenetic testing is intended to give the doctor additional information but may not replace the need for therapeutic drug monitoring.

Pharmacogenetic testing for a specific gene is only performed once since a person’s genetic makeup does not change over time. Depending on the medication, a single gene may be ordered or multiple genes may be ordered. An example of a medication for which multiple genes are usually evaluated is warfarin, which can be affected by genetic variation in CYP2C9 and VKORC1.

Testing may be ordered prior to starting specific drug therapies or if a person who has started taking a drug is experiencing side effects or having trouble establishing and/or maintaining a stable dose. Sometimes a person may not experience such issues until other medications that affect the metabolism or action of the drug in question are added or discontinued.

The Pharmacogenetic Tests

There are currently a variety of pharmacogenetic tests that can be ordered on a clinical basis. Some tests may only be applicable to specific ethnic groups. The following are some drugs for which pharmacogenetic tests are available:

Drug      Associated Diseases/Conditions  Gene(s) Tested

Warfarin (see Warfarin Sensitivity Testing)

Excessive clotting disorder            VKORC1 and CYP2C9

Thiopurines (azathioprine, mercaptopurine, and thioguanine) (see TPMT)

Autoimmune/Childhood leukemia              TPMT

Clopidogrel (see Clopidogrel (CYP2C19 Genotyping))

Cardiovascular   CYP2C19

Irinotecan           Cancer  UGT1A1

Abacavir              HIV         HLA-B*5701

Carbamazepine, phenytoin           Epilepsy               HLA-B*1502

Some antidepressants, some antiepileptics             Psychiatric, Epilepsy         CYP2D6,CYP2C9, CYP2C19, CYP1A2, SLC6A4,HTR2A/C

Is there anything else I should know?

For most medications, pharmacogenetic tests are generally not widely ordered for a variety of reasons. However, they may be indicated when the medication of interest has a narrow therapeutic range and/or is associated with a high rate of adverse events.

Pharmacogenetic tests are intended to provide the doctor and patient with additional information when selecting drug treatments and dosages. For a better understanding, patients may want to consult with a genetic counselor prior to and after having a pharmacogenetic test performed. Genetic counseling and informed consent are recommended for all genetic testing.

To learn more about the role of pharmacogenetics in personalized medicine, visit the Personalized Medicine Coalition website.

Common Questions

  1. Should everyone have pharmacogenetic tests performed? Currently they are only indicated if a person is going to take, or is taking, a drug that has an accepted pharmacogenetic test associated with it.
  2.  Is pharmacogenetic testing required before taking certain drugs? No. The FDA may recommend this testing, as in the case of irinotecan, but it is not required.
  3.  Why am I only tested once? Your genetic make-up does not change over time. You may, however, have other pharmacogenetic tests performed if you take a different drug with a different associated pharmacogenetic test.
  4.  Does this mean my drug levels do not have to be monitored? No. Since there are other factors that affect drug levels besides your genetics, therapeutic drug monitoring may still be necessary.
  5.  What type of sample is used? A blood sample is obtained by inserting a needle into a vein in the arm. Saliva samples and buccal swabs, collected by brushing the inner side of the cheek with a swab, can also be used.
  6.  How do pharmacogenetic tests differ from genetic tests? Pharmacogenetic tests are performed to evaluate a person’s potential response to a drug therapy. Most genetic tests have been developed to help diagnose or predict the development of a genetic disease, or to detect bacteria and viruses, for forensic medicine purposes, and in establishing parentage.
  7.  Will I be monitored differently after the test? You may be monitored differently depending on the results of the test, especially when starting the medication, changing the dose, or when adding or discontinuing another medication.
  8.  Should other family members be tested? This is a question to discuss with your doctor and your family members. In some cases it may be useful; in others it may only be relevant if they are going to be taking the same drug or a drug in the same class. Pharmacogenetic test results are useful information for a family member to share with the doctor along with the family’s medical history.
  9.  How do I know whether or not I should have testing done? You and your doctor should consider the condition that you have, your history of drug-related side effects and/or adverse drug reactions, the drug therapies that are available, and the uses the test is intended for. Pharmacogenetic tests are not meant to stand alone but are meant to be used in conjunction with your other clinical findings.

Source: http://labtestsonline.org/understanding/analytes/pharmacogenetic-tests/start/4

http://www.mayoclinic.org/healthy-living/consumer-health/in-depth/personalized-medicine/art-20044300

General Questions

Q: What is genetics? What is genomics?

A: Genetics is the study of inheritance, or the way traits are passed down from one generation to another. Genes carry the instructions for making proteins, which in turn direct the activities of cells and functions of the body that influence traits such as hair and eye color. Genomics is a newer term that describes the study of all the genes in a person, as well as interactions of those genes with each other and with that person’s environment.     Learn more

Q: What does genomics have to do with my health?

A: Genomics plays a part in nine of the Ten Leading Causes of Death in the United States. All human beings are 99.9 percent identical in genetic makeup, but differences in the remaining 0.1 percent may hold important clues about the causes of disease.

We hope that the study of genomics will help us learn why some people get sick from certain infections, environmental factors, and behaviors, while others do not. Better understanding of the interactions between genes and the environment will help us find better ways to improve health and prevent diseases.

 Q: What is the Human Genome Project?

A: The Human Genome Project (HGP) identified all of the genes in human DNA. The project was completed in 2003 by the U.S. Department of Energy and the National Institutes of Health with input from other countries around the world. More information about this project can be found at the HGP Information Web siteExternal Web Site Icon.

 Q: What is stem cell research?

A: Stem cell research is a hot topic in science and the media. Stem cells renew themselves for long periods of time through cell division. When a stem cell divides, it can either remain a stem cell or become another type of cell with a more specialized function such as a blood cell, a muscle cell, or a brain cell. Scientists are investigating using cell- based therapies to treat diseases. To find out more about stem cell research, visit the National Institutes of Health Web siteExternal Web Site Icon.

Q: What is gene therapy?

A: Gene therapy is a technique for correcting faulty genes responsible for disease development. To learn more about gene therapy visit the Human Genome Project Web siteExternal Web Site Icon.

Q: Where can I find out about cloning?

A: The term cloning that you might have heard or read about in the news usually refers only to one type called reproductive cloning. There are actually three types of cloning technologies and they include (1) recombinant DNA technology or DNA cloning, (2) reproductive cloning, and (3) therapeutic cloning. To get more in-depth, reliable information about cloning, visit the Human Genome Project Information Web siteExternal Web Site Icon.

Q: For additional FAQs about Genomics, visit the following Web sites:

A: Genetic Research: Frequently asked questions about genetics research.

Understanding Gene Testing:External Web Site Icon Frequently asked questions about genetic testing.

The Department of Energy (DOE) presents FAQs on the following topics:

  • PharmacogenomicsExternal Web Site Icon
  • Gene TestingExternal Web Site Icon
  • Gene Therapy External Web Site Icon
  • Genetic CounselingExternal Web Site Icon
  • Human Genome Project External Web Site Icon

vistaprint business card

Respect money to get to your financial goals in 2015

Step One: Begin The Goal Setting Process In January

We begin our annual goal setting cycle in the weeks surrounding New Year’s Day. Why? Because it’s virtually impossible to forget or avoid this annual holiday event.

The New Year is a natural time to reflect on achievements from the prior year and start thinking about what we want to achieve in the coming year. In short, it’s a perfect time to begin a goal setting cycle.

Your first task is to review your written goals from the prior year and compare them to your actual results.

 “No one can cheat you out of ultimate success but yourself.”  – Ralph Waldo Emerson

 Inevitably, your results will exceed expectations in some areas, and disappoint in others. The critical point here is to not judge yourself because you’re not your results.

Instead, I suggest positive reinforcement by rewarding yourself for all that you did achieve in the prior year. Take the time to celebrate your wins because you deserve it. Also note areas where you came up short, as that is honoring reality.

What are your results telling you? If you came up short on a goal, then what was the cause?

After all, if you said you wanted a goal, but didn’t achieve it, then there is opportunity for learning.

  • Did something change?
  • Did other goals take a higher priority
  • Did obstacles get in your way?

Maybe you’re just not committed to that goal, and should drop it or change it.

You don’t get to be right or wrong during the review process, as that won’t serve you well. There’s no value in belittling yourself for missing a goal because that will just take away from honoring your successes.

The purpose is simply to get clear on what worked in the prior year and what didn’t. Just notice the facts and make conscious what happened, but don’t judge yourself.

“When defeat comes, accept it as a signal that your plans are not sound, rebuild those plans, and set sail once more toward your coveted goal.”  – Napolean Hill

Where did you meet with success, and where did you come up short? Your objective is to learn from experience and improve your goal setting for next year based on what you discover.

You’re creating an active feedback loop so you can correct and adjust your goals every year to get what you want out of life.

This correct and adjust process works much like rocket guidance systems. When a rocket is launched to a faraway destination, it’s traveling off course more than 80% of the time. Yet, the same rocket will hit its target with pinpoint accuracy. The key is correcting and adjusting.

The rocket knows its goal and is constantly correcting its trajectory during flight until it arrives at the destination. You can do the same thing by reviewing your goals each year and learning from your successes, as well as your failures.

 Step Two: Prepare Financial Statements

The next step during the annual review process is to compose a “quick and dirty” income statement and balance sheet.

This task is particularly easy around the turn of the year because annual tax statements must be prepared showing your assets, income and spending.

When you prepare these statements you are treating your personal finances with the professionalism of a business. You’re respecting your money.

I also suggest plotting your net worth and residual income on a chart so you can track your progress toward your goal of financial freedom. This is very important if you’re working toward the goal of financial independence or retirement security.

 The person who makes a success of living is the one who sees his goal steadily and aims for it unswervingly. That is dedication.  – Cecil B. DeMille

 Once you’ve updated your financial statements and reviewed your past goals, you’re then complete with the feedback loop portion of the process.

You now have a solid foundation on which to build your new goals. You have a current snapshot of your financial picture, and you understand what worked from the prior year, what didn’t, and why.

 Step Three: Ask The Right Questions

The next step in your annual goal setting process is to decide what you want to create with your life moving forward by asking yourself some questions:

 What do I want this year?

What will it take for this year to rate as a 10 on a scale of 1 to 10?

If failure was not a possibility because I’m guaranteed success, then what would I do? How would I play the game of life differently?

What values do I hold dear that I would like to honor in the New Year?

What’s frustrating or dissatisfying about my life, and how would I like to change it?

If I graded the various parts of my life (relationships, business, money, health, recreation, etc.) on a 1 to 10 scale, what grade would each receive, and what do I want to do this year to create the grades I really want?

What objectives would make the biggest, most profound difference in my life?

Step Four: Compile And Prioritize Your List Of Goals

After I’ve answered these questions, I get together with my wife to create a combined goal sheet for the family. She follows a similar process independent of me and creates her own agenda.

We then compare lists and create a combined family agenda for the year that’s broken into two categories: the first list has business and financial goals, and the second list has our personal and family life goals.

It’s important to note that we don’t just add the lists up to create one summation list. Instead, we negotiate the goals knowing that we must focus to succeed.

Less is more, and this is critical to note. More goals doesn’t equal more success, but more focus on just a few goals that make the biggest difference will equal more success.

Having more goals won’t lead to to success. Focus on fewer goals for the best results instead.

We compare our goals to the “10 Keys To A Winning Goal” checklist found in Step Two of the Seven Steps to Seven Figures course that this article is excerpted from, and we put on the back burner those goals that don’t make it to the top.

After years of practice, we have learned to enjoy greater balance and happiness by focusing on just a few critical goals and actually achieving them, rather than setting ourselves up for disappointment by getting spread too thin with too many goals.

What amazes me about this process is how powerful it is while being deceptively simple.

It never fails to redirect our thinking.

It creates clarity and cohesive focus for both of us to operate as a team, and helps us create a more satisfying and fulfilling life for our family.

It redirects our lives and keeps us from drifting aimlessly or living day to day.

Step Five: Get Into Action To Achieve Your Goals

Once you’ve set your goals, you now have a whole year to achieve them. But how are you going to do that? What is your next step? My suggestion is to divide and conquer.

Keep things simple by picking from the list only those goals that are the most exciting and juiciest of all, so you can focus your limited time and energy resources on them.

What’s your top priority for the year? What’s the most time sensitive or immediately compelling goal on your list?

“The big secret in life is that there is no big secret. Whatever your goal, you can get there if you’re willing to work.”  – Oprah Winfrey

Once your goals are prioritized, then you can pick either of the two strategies from below to begin executing your plan of action.

I offer two different strategies because each is appropriate for different situations, depending on conditions. Certain goals and personality types work best with one or the other approach. Which of the following approaches is best will depend on your personal style and the particular goal you are pursuing.

Next Step Approach: This is a forward looking approach where you just pick the next step to achieve your goal, complete it before figuring out the next step, and so on until your goal is realized. You don’t worry about the big picture with all the planning issues (which might bog you down because too much is unknown, or the whole process is too big to grasp). Instead, you just determine whatever the logical next step is, and trust it’ll take you to the next step until the path becomes clear. You’re like the rocket that’s correcting and adjusting its flight path. This also helps you avoid the “get ready to get ready” syndrome so that you can get started right now and not get stuck in procrastination excuses.

Reverse Engineering: This approach requires you to start with the whole plan in mind from the beginning by reverse engineering it into smaller tasks to complete. You then further subdivide the tasks into additional actionable steps, while continuing to break it down until you have daily actions that will take you to your goal when completed. The advantage to this process is it breaks big tasks down into digestible bite size chunks, making the whole process very easy to grasp. It’s most effective for analytical personality types, or situations where the entire path to the goal can be understood and mapped out in advance.

Both of these approaches help you succeed by reducing the intimidation and confusion that is sometimes associated with larger goals that take us into unfamiliar territory. They reduce your fear factor by transforming goals that are too large to grasp into actionable items that you can easily execute.

Each strategy answers the question, “where do I start?” and “where do I go next?” so that you don’t get stuck in procrastination.

Step Six: Persist Until You Achieve Your Goal

“Let me tell you the secret that has lead me to my goal. My strength lies solely in my tenacity.”  – Louis Pasteur

Once you have picked your goal and developed your plan to achieve the goal, then the rest of the game is simply a matter of getting started and not stopping until you reach it.

Every time you complete an action step, you’re one small step closer to your big goal.

Just keep on correcting and adjusting until you get there with rocket-like accuracy.

Enough said?

Step Seven: Maintain Focus By Reviewing Goals Regularly

Finally, the last part of this annual cycle is you must create a habit of refreshing your goals throughout the year. This means you must review them regularly and rewrite them as necessary.

The purpose of this step is to maintain your focus throughout the year as life’s clutter attempts to distract you from what’s important.

By reviewing your goals regularly, you’re counteracting all the forces outside of your control designed to sideline your plans.

Some people like to post them on their wall, keep a copy on their desk, or post them in their Day Timer or smart phone. Whatever is convenient and will remind you on a regular basis about your goals so that you maintain front of the mind awareness is what’s important.

“It matters not what goal you seek. Its secret here reposes: You’ve got to dig from week to week To get Results or Roses.”  – Edgar Guest

In summary, the seven step process you just learned is designed to do one thing: make goal setting a habit. You must habitually create and refresh your goals to gain all the value from this incredibly effective tool.

By following a habitual goal setting process, you’ll become part of the 3% that outperforms the other 83% by a factor of 10 to 1. You’ll also put yourself firmly on the road to retiring early and wealthy.

It truly works.

Goal Setting System Key Points

There are three major points you should take from this article:

Practicing goal setting and reviewing your goals is necessary to live the greatest version of yourself in this lifetime. Not using goal setting technology to the best of your ability is simply wasteful. It’s the equivalent of flushing opportunity down the toilet.

”You must have long-range goals to keep you from being frustrated by short-range failures.”  – Charles C. Noble

 Goal setting engages your mind in five different ways to achieve your goals. This gives you a distinct competitive advantage over others who don’t regularly set and review their goals. This competitive advantage can make the difference between retiring early and wealthy, or living a lifetime of financial mediocrity.

The most effective way to get all the value out of goal setting available is to make it a habit. Set your goals at least annually, and review them at least monthly. Build a regular cycle out of the process so that it becomes an integral part of your life. If you set goals in a random or irregular fashion, then you will get random and irregular results. If you set and review your goals regularly, you will move them to the forefront of your mental awareness, which will create more consistently profitable results.

The bottom line is if you want to retire early and wealthy, then regular goal setting must become an integral part of your life practice. Financial coaching is a great tool to add accountability, support, and additional insight to not only setting goals, but also following through long enough to actually achieve them.

Source: http://financialmentor.com/

Contact Connie Dello Buono, jr  financial planner to save on your income taxes thru a business structure and financial strategy and have a chat with a sr investment advisor. 408-854-1883 motherhealth@gmail.com

Polypharmacy for older adults, now have pharmacogenetic tests, insurance covered to prevent adverse drug reactions

Dear Doctor,

My older mom and dad are taking more than 6 meds and I wanted to introduce you to my contact Connie Dello Buono 408-854-1883 motherhealth@gmail.com , a certified representative at Medexprime for the pharmacogenetic tests (pactox lab based in California) to prevent adverse drug reactions and to best-personalized care possible. Pharmacogenetic test results will help you doctor consider which medication will work best for my parents.

A Pharmacogenetics test helps in determining the correct medications by evaluating the enzymes in your Liver. Liver enzymes determine how your body absorbs medication. This process will allow you doctor to consider the proper medication now and in the future.

This is what I learned more about this pharmacogenetic test:
Test is accomplished by a Medicare approved laboratory test. Medicare and Medicare replacement plans pay for laboratory tests 100%. Whether you have Medicare or Private Insurance, there is no out of pocket fee to you for this laboratory test. If you are on private insurance and you receive a bill, please provide us a copy of your bill. The testing laboratory has committed to us that they will not hold our patients responsible for any out of pocket money for liver enzyme laboratory work up’s.

  • Prevent Polypharmacy (purportedly excessive or unnecessary prescriptions)
  • Test covered by Medicare and Private Insurance.
  • Reduce negative side effects.
  • No blood work required. Tests performed via simple saliva swab.
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Your support on this matter is much appreciated and hoping this tool will be important for both of us, your practice and my parents health.

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Your patient

Ethnic Differences in Cardiovascular Drug Response & Pharmacogenetics by Julie A. Johnson, PharmD

  • In the early 1980s, clinical differences in response to the blood pressure (BP)-lowering effects of β-blockers and, to a lesser extent, diuretics were noted between ethnic groups. The most convincing evidence at that time came from a Veterans Affairs (VA) Cooperative Trial,1 which, along with other smaller studies, suggested that whites (those of European ancestry) had a better antihypertensive response to β-blockers than blacks (those of African ancestry), whereas blacks had a slight better response to diuretics than whites. Shortly after the first angiotensin-converting enzyme (ACE) inhibitor was approved in the mid-1980s, it was also recognized that whites responded more favorably to ACE inhibitors than did blacks. Over time, these differences in response became well accepted, such that ethnicity began to be used in helping to guide selection of antihypertensive drug therapy.2,3Although the ethnic differences in response between β-blockers and ACE inhibitors in hypertension are perhaps the mostly widely recognized examples of ethnic differences in response to cardiovascular drugs, there are others.

Pharmacogenetics is a field that seeks to unravel the genetic underpinnings of variable drug responses.4 Given the recognized ethnic differences in drug responses and the fact that many genetic polymorphisms differ in frequency on the basis of ethnicity/ancestry, questions about whether pharmacogenetics may also lead to an understanding of the ethnic differences in drug response are not surprising. The present review will summarize the most widely recognized examples of cardiovascular drugs with differential response by ethnicity and the evidence that pharmacogenetics data may aid in our understanding of these differences. Given that there are many examples in the literature of genetic associations that are not replicated, the pharmacogenetic examples discussed herein will come from those for which there is some evidence of replication or for which there have been multiple negative findings.

In light of the socially charged issues that surround race and genetics, we will typically refer to groups either as ethnic groups (meaning groups who may have similar ancestral origins and who share certain social or cultural practices) or will refer to continental ancestry, referring to the 3 major continental populations from which the human population mainly derives (namely, European, African, and Asian ancestry).

Ethnic Differences in Response to Warfarin Therapy

Ethnic differences in the warfarin dose required for an international normalized ratio (INR) between 2 and 3 are well documented in the literature but do not appear to be widely appreciated by clinicians. For example, the anticoagulation consensus guidelines that relate specifically to warfarin do not mention the influence of ethnicity on the typical maintenance dose,5 a fact that may result from trials conducted predominantly in white populations. Figure 1 depicts average warfarin dose requirements for Asians, Hispanics, whites, and blacks to maintain an INR of 2 to 3.6 Although these data were derived from a relatively small sample, average daily doses of 3.4 mg in Asians, 5.1 mg in whites, and 6.1 mg in blacks are representative of the literature for these ethnic groups. Given that most dosing algorithms recommend initiating therapy at 5 mg daily, it is apparent from Figure 1that this is a reasonable estimate of the starting dose in whites but likely an excessive dose in Asians and an inadequate dose in blacks. The lower dose requirement in Asians was sufficiently recognized to warrant special notation in US Food and Drug Administration (FDA)-approved labeling for warfarin, which indicates requirements for a lower dose in Asians.7 Although some would argue that initiation of therapy with an inappropriate dose will be corrected quickly on the basis of close monitoring of INR, data clearly suggest the risk of bleeding is highest in the first 30 days of therapy, when the appropriate dose is typically still being determined.8 This would suggest that more accurate initial dosing may have the potential to reduce the early risk of bleeding.

Figure

Figure 1. Average warfarin dose requirements, by ethnicity, to maintain a therapeutic INR.2,3Reproduced from Dang et al,6with permission from the Annals of Pharmacotherpy.
 In addition to differences in dose, there are questions about whether the risks of warfarin therapy also differ by ethnicity. The large trials that established an INR range of 2 to 3 to balance the benefits (reduced thromboembolic events) with the risks (bleeding) of warfarin therapy were conducted almost exclusively in whites. Thus, it is not clear whether this is the most appropriate INR range across ethnic groups, although some data suggest it may not be in Asians. For example, in a study of 563 Taiwanese patients with mechanical valve replacements (for whom the usual INR range is 2.5 to 3.5), investigators found the risks of thromboembolism were not different for those with an INR >2 versus <2.9 In a study of 491 Chinese patients treated with warfarin, the INR associated with the lowest hemorrhagic and thromboembolic rate was 1.8 to 2.4.10 These data suggest Asians may have greater thromboembolic protection at lower INRs than whites. Finally, in a study of 667 Japanese nonvalvular atrial fibrillation patients studied for 1 year, INR ≥2.27 was associated with an OR of 4.33 (95% CI 1.30 to 14.39) for major bleeding. Furthermore, despite low-dose warfarin therapy (target INR 1.6 to 2.6), the rate of major bleeding and intracranial hemorrhage was similar to the rate observed in Western populations with full-dose anticoagulation (target INR 2 to 3) and approximately double the rate observed in Western populations for low-intensity warfarin therapy.11 Combined, these data suggest that Asians might require a lower INR for protection from thromboembolism and might be at increased risk of bleeding at lower INRs.

Warfarin Pharmacogenetics

Among cardiovascular drugs, warfarin has the strongest pharmacogenetics data, which may also help explain ethnic differences in dose requirements for a stable INR. Two genes have been clearly associated with a variable warfarin dose: those encoding the major enzyme responsible for the metabolism of warfarin (cytochrome P450 2C9, CYP2C9) and the protein on which warfarin exerts its pharmacological effect (vitamin K epoxide reductase, VKORC1). The first report of genetic association with warfarin dose and CYP2C9 genotype was in 1999,12 and numerous studies since that time have documented this association across a variety of ethnic populations (see reviews by Wadelius and Pirmohamed13 and Sanderson et al14). Specifically, there are 2 polymorphisms, commonly called CYP2C9*2 and CYP2C9*3, both of which reduce the normal metabolic activity of the enzyme, although the *3 polymorphism does so to a greater extent than the *2 polymorphism. In a 2005 meta-analysis, which included 2775 patients and 8 different studies that related the polymorphisms to warfarin dose, the analysis suggested that carriers of at least 1 variant copy of the *2 allele required 0.85 mg less of warfarin daily (95% CI −1.11 to −0.60 mg), and those carrying at least 1 copy of the *3 allele required 1.92 mg less of warfarin daily (95% CI −2.47 to −1.37 mg).14 Several studies have also documented that individuals with CYP2C9 variant alleles require a longer period of time to achieve a stable dose and are at increased bleeding risk, particularly during the period of therapy initiation (ie, first 1 to 3 months).12,14–16 Data on the influence of CYP2C9 variants are available from multiple populations in the United States, Europe, and Asia, and all consistently show a genetic association with CYP2C9 polymorphisms. What differs is the frequency of the polymorphisms and thus their overall impact in that ethnic population. Table 1 depicts allele frequencies for the CYP2C9 variant alleles and shows there are clear differences by ethnicity. Specifically, variant alleles forCYP2C9 are much more common in whites than other groups; thus, at a population level, the impact of CYP2C9 variants on warfarin dose is greater in whites. This may help to explain the slightly lower doses in whites versus blacks but does not explain the very low doses typically required by Asians.

Differing warfarin sensitivities by ethnicity are perhaps better explained by variant alleles in VKORC1. A number of different polymorphisms have been studied in this gene, and evidence currently points to a promoter polymorphism (referred to in the literature as 3673 G>A or −1639 G>A) as the most likely candidate for the functional polymorphism.19,20 Importantly, many different polymorphisms have been studied, and because of a high degree of linkage disequilibrium (inheritance of single-nucleotide polymorphisms [SNPs] together) between these SNPs in whites and Asians, the various SNPs tested all gave similar genetic associations. However, as with many other genes, the degree of linkage disequilibrium in VKORC1 is lower in blacks than in other groups. In analyses in our laboratory of a variety of VKORC1SNPs, only 3673 and 6484 were significantly associated with warfarin dose in blacks, whereas numerous SNPs were associated with dose in whites. This is explained by high levels of linkage disequilibrium across numerous SNPs in whites but only these 2 SNPs in blacks. This emphasizes the importance of studying the functional polymorphism, because reliance on linkage disequilibrium between SNPs can be problematic across different ancestral populations. Table 1 also provides a comparison by ethnicity for the presumed functional VKORC1 polymorphism and reveals striking differences, such that the “variant” (ie, less common allele) in whites and blacks (with approximate frequencies of 45% and 10%, respectively) is the major allele in Asians, with a frequency of 90% to 95%.17

To date, there have been >30 studies published on the genetic association betweenVKORC1 SNPs and warfarin dose, and all have shown a significant association, with the variant allele being associated with a lower warfarin dose.13,19–26 These studies have included numerous white populations from the United States, Europe, and Israel, along with Japanese, Chinese, Indians, and Malays. In whites, across a variety of studies, the average dose for GG homozygotes (using −1639 as the reference) was 6.1 mg daily, whereas those with a GA genotype required 4.5 mg daily, and AA homozygotes required 3.0 mg daily. Among Asians, doses for GG and GA have often not been reported separately (owing to low G allele frequency), but across studies, AA homozygotes required 2.8 mg daily, similar to the dose required by whites with the AA genotype. In the single study with a reasonably sized black cohort, daily dose requirements for GG, GA, and AA genotypes were 5.7, 4.5, and 3.1 mg, respectively, nearly identical to that in whites.21 Given that most blacks have the GG genotype and most Asians the AA genotype, these data suggest genetics may contribute substantially to the ethnic differences in dose.

Taken together, there is little doubt that genetic variability helps explain differences in warfarin dose requirements, particularly the VKORC1 polymorphisms. Numerous different investigative groups have attempted to determine the amount of variability in warfarin dose that can be explained by genetic, demographic, and clinical factors. These studies suggest that between 30% and 60% of warfarin dose variability can be explained, with genetic factors responsible for explaining approximately two thirds of that variability. Clinical/demographic factors that have also been associated consistently with warfarin dose variability are age (reduced dose with increasing age), body size (increased dose with increased body size, assessed as body surface area, body mass index, or weight), and, in most studies, smoking status and interacting drugs. Given the well-known effect of high-content vitamin K foods on warfarin dose requirements, it is also possible that dietary differences between ethnic groups contribute to differences in warfarin sensitivity. It is also possible, although not tested to date, that there may be significant gene-diet interaction, particularly with VKORC1 or other genes in the vitamin K pathway, that may also contribute to variability and might differ by ethnicity. Thus, in addition to genotype, there are a variety of other demographic, clinical, and environmental factors that may contribute to ethnic differences in warfarin dose requirements.

To advance the clinical translation of these findings, several groups have suggested warfarin dosing equations that incorporate genetic and nongenetic factors, some of which have been tested prospectively in small cohorts.22,18,27–29 Two studies have tested prospectively a genotype-guided versus usual-dosing control group, with 1 study considering only CYP2C930 and the other considering both CYP2C9 andVKORC1.31 Both studies were relatively small (≈200 subjects each) and had mixed results regarding significant differences in specified outcomes between genotype-guided versus usual-care approaches. However, these studies and others clearly support the need for an adequately powered randomized clinical trial.

One of the challenges regarding clinical use of warfarin pharmacogenetic information is the lack of availability of a dosing algorithm/equation that has relevance across various geographic and ethnic groups. On the basis of this and other issues, investigative teams with warfarin pharmacogenetics data have shared their data in a common database, with the primary goal of defining a warfarin pharmacogenetics dosing equation with validity across the globe. It is anticipated that this dosing equation will incorporate information not only on VKORC1 andCYP2C9 genotypes but also on various clinical and demographic factors that influence warfarin dose requirements. The group, called the International Warfarin Pharmacogenetics Consortium, comprises 21 research groups from 11 countries and 4 continents, and combined, they have contributed warfarin genotype and phenotype data on nearly 6000 individuals, with all 3 major ethnic groups well represented. After publication of the first report from this group, all data will be made publicly available on a World Wide Web site for the Pharmacogenetics and Pharmacogenomics Knowledge Base (www.pharmgkb.org). An additional aim of the International Warfarin Pharmacogenetics Consortium is to test questions relating to genetic associations and ethnicity, given that the combined group will have greater power than single-site studies to test a variety of hypotheses relating to ethnicity and warfarin pharmacogenetics.

Utilization of genetic information for warfarin dosing made headlines in both the medical and lay press in the summer of 2007 when the FDA product labeling (package insert) for warfarin was changed to include suggestions on (but not require) the use of genetic information to guide early warfarin dosing. There is great controversy about whether these data are to the point that such clinical utilization is appropriate, because there have been only 2 small randomized prospective studies testing the prospective use of genetic information to guide warfarin dosing.30,31 These questions will be addressed more comprehensively by a study from the National Heart, Lung, and Blood Institute, which will conduct a prospective clinical trial that tests genotype-guided warfarin dosing against usual-dose-initiation approaches. The study is intended to launch in late 2008 and last ≈18 months. This trial will not be powered to test (as a primary end point) for reductions in incidence of bleeding or prevention of thromboembolic events with the randomized dosing strategies. That the CYP2C9 genotype is associated with bleeding risk seems clear, but it is not known whether prospective use of genetic information will reduce bleeding events. To the extent that some clinicians will judge reduced risk for bleeding to be the only meaningful end point for prospective warfarin pharmacogenetic testing, this may represent a long-term limitation of the data. Other clinicians will judge other end points to also be clinically meaningful (eg, time to stable INR or time to INR >4), and these should be well addressed by the planned trial. In the meantime, clinicians will be faced with deciding whether and how to use genetic information with warfarin in the clinical setting. In the absence of genetic information, it seems clear that ethnicity should be considered as a factor when initial warfarin doses are selected.

Ethnic Differences in Responses to Antihypertensive Therapies

As described above, antihypertensive drugs were the first cardiovascular therapies for which there was wide recognition of clinical differences in response based on ethnicity. The Fourth Report of the Joint National Committee (JNC-IV) on the Detection, Evaluation, and Treatment of High Blood Pressure, published in 1988, was the first to recommend consideration of race/ethnicity in selection of antihypertensive therapy,32 and the 3 subsequent sets of JNC guidelines have contained similar recommendations. The most notable differences are in response to β-blockers, ACE inhibitors, and angiotensin receptor blockers (ARBs). The widespread clinical recognition of such differences followed the 1982 VA Cooperative Study Group finding that 62% of whites and 54% of blacks achieved their BP goal with propranolol, whereas such goal was attained with hydrochlorothiazide in 55% of whites and 71% of blacks.1 Another VA cooperative study a decade later similarly found that atenolol and captopril were less effective at BP lowering than hydrochlorothiazide and diltiazem, particularly in older blacks.33,34 A meta-analysis, published in 2004, evaluated 15 clinical trials published between 1984 and 1998 that reported differences in antihypertensive response between blacks and whites and that met other specified criteria.35 Its analysis is summarized in Table 2 and highlights the fact that blacks generally respond more favorably to diuretics or calcium channel blockers, whereas whites tend to respond similarly to all the drug classes. In comparisons between groups, blacks respond slightly better than whites to diuretics and calcium channel blockers, whereas whites respond slightly better than blacks to ACE inhibitors and β-blockers. More recent data on lisinopril, quinapril, and losartan support the differences with ACE inhibitors and ARBs suggested by the meta-analysis.36–38

Thus, the literature suggests there are consistent, although perhaps small, differences in responses between blacks and whites, particularly for ACE inhibitors, ARBs, and β-blockers. However, an important point from the meta-analysis and several other reports is that although a mean difference in response between groups exists, there is also a large degree of overlap in responses between the 2 groups, as depicted in Figure 2.39 Viewed in this way, therapy decisions based on ethnicity appear less reasonable.

Figure 2. Representative decrement in BP among whites and blacks after administration of antihypertensive drug. Shaded area represents white and blacks who have similar responses. Differential responses are representative of those observed with ACE inhibitors, ARBs, or β-blockers. Reproduced from Sehgal,39 with permission from Lippincott Williams & Wilkins. Copyright 2004, American Heart Association.

Perhaps the more important question is whether these arguably small differences in BP response translate into differences in outcomes. Only a few trials have addressed this question, the largest being ALLHAT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial).36 In the case of amlodipine versus chlorthalidone (the reference therapy), there was no difference in outcomes between blacks and nonblacks; however, for lisinopril, there were some outcomes for which there were significantly different treatment effects by ethnicity. Specifically, lisinopril (versus chlorthalidone) was associated with a significantly increased risk of stroke in blacks (relative risk 1.40), but no such effect was observed in whites (relative risk 1.00). There were also significant differences between blacks and nonblacks in the risk of combined cardiovascular disease (relative risk 1.19 in blacks versus 1.06 in nonblacks). Many have suggested that some of these differences were likely explained by the differences in BP achieved by blacks and nonblacks, although the ALLHAT analysis that controlled for BP did not suggest this to be the primary explanation.36 In the INVEST trial (International Verapamil SR and Trandolapril Study), which randomized patients to a calcium channel blocker or β-blocker strategy, there were no differences in outcomes (composite of death, myocardial infarction, or stroke) by drug strategy for blacks, whites, or Hispanics.40 In the LIFE trial (Losartan Intervention For Endpoint reduction in hypertension), losartan was superior to atenolol in nonblacks (hazard ratio 0.83, 95% CI 0.73 to 0.94), whereas it was associated with increased risk in blacks (hazard ratio 1.67, 95% CI 1.04 to 2.66).41 The African American Study of Kidney Disease and Hypertension (AASK) found that outcomes were better or not different with ACE inhibitor versus β-blocker or calcium channel blocker therapy in blacks.42,43 Although this study did not provide comparisons between ethnic groups, it does suggest a lack of difference in outcomes by drug therapy in blacks. Most of the large, outcomes-driven hypertension trials do not provide insight into therapy-related differences in outcomes, either because they do not include sufficient numbers of nonwhites, or because they do not report such differences in a meaningful way in the manuscript. As such, one must conclude that on the basis of the available evidence, there are not clear differences in outcomes between blacks and whites with various antihypertensive regimens, and thus treatment decisions, as they relate to outcomes, should not be based on ethnicity.

Pharmacogenetics and Ethnic Differences in Antihypertensive Drug Responses

Overall, the literature suggests ethnic differences in the BP-lowering response to antihypertensive drugs, with less evidence for differences in outcomes. The question is whether these differences can be explained by genetic polymorphisms. The hypothesis is that a “responsive” genotype might differ in its frequency in different ethnic populations, leading to differences in response, such as is depicted in Figure 2. The more clinically relevant issue is that at present, many clinicians use ethnicity to guide selection of drug therapy. As suggested in Figure 2, a certain proportion of blacks and whites will respond well to the therapy. Even if, as suggested in Figure 2, whites are overrepresented among the “good responders,” and blacks are overrepresented among the “poor responders,” it is clear that ethnicity does not sufficiently separate those for whom a given therapy will be effective versus ineffective. The potential promise of pharmacogenetics is that it may present a more effective way of identifying responders and nonresponders, allowing clinicians to begin to move away from use of ethnicity as a method for selecting therapy. Although it appears that genetic differences are an important potential explanation for differences in response, ethnic or cultural differences can also influence response to antihypertensive medications. For example, some antihypertensive drugs are more or less effective in the presence of a high-salt diet, and dietary differences by ethnicity or geographic region are well documented. Thus, in the future, it will likely be a cadre of genetic information along with demographic and other information (eg, dietary information) considered together that might be most effective at targeting therapy, as is evident with warfarin. Whether ethnicity will be an appropriate surrogate for the cultural or dietary components or whether more refined tools to capture such information will be needed remains to be seen.

ACE Inhibitors and ARBs

The literature does not provide much insight regarding genetic polymorphisms and response. Despite the fact that there have been many studies evaluating the associations of numerous candidate genes with ACE inhibitor or ARB response, none have been consistently associated. Most studied is the ACE gene, and most of the studies with this gene have focused on an insertion/deletion (I/D) polymorphism, with equivocal data. The most convincing study in this area is the pharmacogenetic substudy of ALLHAT, called GenHAT. This study tested the association of various outcomes in ALLHAT with the I/D polymorphism in 37 939 patients. No association was found between this polymorphism and BP lowering (with lisinopril or any other study drugs) nor with any of the study outcomes, either when considered in combination or stratified by drug therapy.44 As discussed with warfarin, ethnic differences in linkage disequilibrium between blacks and whites may be diminishing the ability to document associations with this gene, because the I/D is not believed to be the functional polymorphism. Although this gene remains of interest, any polymorphism that influences the ACE inhibitor or ARB response remains to be identified.

Another gene that has been widely studied relative to the ACE inhibitor and ARB response is the gene for the angiotensin type 1 receptor, AGTR1. Similar to ACE, there have been no consistent findings with this gene, and we recently reported no association with BP response to trandolapril in whites, blacks, or Hispanics.45 There are also clear ethnic differences in the risk for angioedema from ACE inhibitors, with blacks being at greater risk,36 but there are no pharmacogenetic studies to provide insight into these differences.

β-Blockers

Unlike ACE inhibitors and ARBs, the β-blocker pharmacogenetics literature may provide some insights into ethnic differences in response. There are at least 6 papers in the literature reporting the association between BP lowering with β-blockers and 1 of 2 genetic polymorphisms in the β1-adrenergic receptor gene (ADRB1): Ser49Gly and Arg389Gly. All but 1 of the papers reported significantly greater BP lowering in the Arg389Arg individuals, with the other report showing differences that did not achieve statistical significance.46 Studies have generally reported that alone, the Ser49Gly polymorphism does not importantly influence response, but when considered in combination with the Arg389Gly polymorphism, it may be more informative than Arg389Gly alone.47,48 Regarding the Arg389Gly polymorphism, there is concordance of this association in the literature. Additionally, because these have been documented as functional polymorphisms, the challenges of studying a nonfunctional polymorphism and ancestral differences in linkage disequilibrium are not believed to be an issue. Whether these polymorphisms help explain differences in β-blocker response between ethnic populations was only addressed in 1 paper, because the other studies were composed of mostly or only 1 ethnic group.47 In multiple regression analysis of the determinants of the BP response to metoprolol, ADRB1 genotypes were significant determinants of response, but ethnicity was not. Figure 3 depicts BP responses to metoprolol considering the Ser49Gly and Arg389Gly polymorphisms in a US-based study that included blacks and whites and a study in Chinese. As is evident fromFigure 3, the 2 most responsive diplotypes (genotype combinations for the 2 polymorphisms) were consistent across the 2 studies. Of interest is that the frequency of these 2 most responsive diplotypes varies by ethnicity. Specifically, 54% of Chinese and 44% of whites but only 23% of blacks carry 1 of the 2 most responsive diplotypes shown in Figure 3. This is not direct evidence that this gene helps explain ethnic differences in β-blocker response, but it does provide preliminary evidence in support of such a hypothesis. The Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study is an ongoing National Institutes of Health-funded pharmacogenetic study of β-blocker and thiazide diuretic that is accruing a large cohort of black and white hypertensive individuals, and it should be able to address this question more directly.

Figure

Figure 3. Antihypertensive responses to metoprolol among various ADRB1 diplotype groups (genotype combination for Ser49Gly and Arg389Gly), among whites and blacks (A) and Chinese (B). S indicates Ser49; R, Arg389; G, Gly49 (when the first of 2 letters) or Gly389 (when the second of 2 letters); DBP, diastolic BP; SBP, systolic BP; and MAP, mean arterial pressure. Reproduced from Johnson et al47 and Liu et al,48 with permission.

 Thiazide Diuretics

There are limited examples in the literature of replicated associations with the response to thiazide diuretics. The strongest example, which may also provide insight into ethnic differences in response, is a functional SNP in the G protein β3 subunit gene (GNB3), which has been shown in at least 2 studies to be associated with the antihypertensive response. Although 1 study was conducted only in whites,49 the other included blacks and whites.50 In the latter study, ethnicity was a significant predictor of diuretic response in univariate analysis, but when genotype was included in a multivariate analysis, genotype remained a significant predictor, whereas ethnicity did not. Thus, similar to the β-blocker data, these data suggest that genotype may be a better predictor of response than ethnicity. The contribution of dietary sodium intake and its potential ethnic differences was not addressed in the study. As with the β-blockers, these findings do not provide direct evidence that pharmacogenetics may help explain differences in response, but they are suggestive. Also as with the β-blockers, the PEAR study should provide more specific evidence in this regard. Nonetheless, studies with β-blockers and diuretics provide the conceptual framework that genetics may represent a significant (albeit not the only) factor in ethnic differences in response and, more importantly, may be superior to ethnicity in separating responders from nonresponders.

Ethnic Differences in Responses to Heart Failure Therapies

Heart failure therapies have been among the most controversial with regard to ethnic differences in response. This is largely due to the African American Heart Failure Trial (A-HeFT), which enrolled only self-declared African Americans to test the efficacy of isosorbide dinitrate-hydralazine (I-H) versus placebo and led to the eventual FDA approval of I-H for treatment of African Americans with heart failure. This represents the only FDA-approved therapy with explicit labeling for a single race/ethnicity group, and it caused great controversy about the appropriateness of clinical trials conducted exclusively in 1 race/ethnicity group and FDA labeling of drugs in a single group.

Isosorbide-Hydralazine

The A-HeFT trial was stimulated by data from the V-HeFT (Vasodilator-Heart Failure Trial) I and V-HeFT II trials, which suggested that blacks derived greater benefit from I-H than whites.51 Specifically, in V-HEFT I, I-H significantly reduced mortality compared with placebo in blacks but not whites (Table 3), although there were no statistical differences in response by ethnicity. In V-HeFT II, again, there were no significant ethnicity-by-treatment interactions, although enalapril provided significant benefit compared with I-H in whites but not in blacks. Furthermore, mortality rates with I-H were numerically higher in whites than blacks.51 This led the investigators to conduct the A-HeFT trial, enrolling only African Americans, because the previous data suggested this group might obtain the greatest benefit.

ACE Inhibitors

Ethnic differences in response to ACE inhibitors were also suggested by the investigators reporting differences in response by ethnicity from the V-HeFT trials (Table 3).51 However, it is not clear that the data support this contention. Specifically, the report does not present statistical comparisons of mortality in enalapril-treated blacks and whites, and although mortality was numerically lower in whites than blacks, it appears unlikely this difference was statistically significant (Table 3). In a matched cohort analysis of blacks and whites from the Studies Of Left Ventricular Dysfunction (SOLVD) prevention and treatment trials, investigators found that enalapril was associated with a significant 49% adjusted risk reduction in heart failure hospitalization in whites and a nonsignificant 14% adjusted risk reduction in blacks, for a significant treatment-by-ethnicity interaction (P=0.005).52 They did not, however, observe differences in mortality reduction between ethnic groups. In both the V-HeFT II and SOLVD analyses, whites had greater BP reduction with enalapril than blacks, which may have contributed to the observed differences in outcomes. A subsequent analysis that only involved the SOLVD Prevention Trial did not observe any differences between blacks and whites in the risk reduction associated with enalapril in progression to symptomatic heart failure.53 Finally, a meta-analysis did not suggest any differences in ACE inhibitor efficacy in reducing adverse cardiovascular outcomes in heart failure between blacks and nonblacks in heart failure.54

β-Blockers

Over a period of a couple of years, the efficacy of bisoprolol, metoprolol CR/XL, and carvedilol in heart failure were all documented.55–57 Thus, it came as a surprise when the large clinical trial with bucindolol (called BEST, Beta-Blocker Evaluation of Survival Trial) failed to achieve the primary end point.58 There were 2 hypotheses put forward by the authors to explain why bucindolol failed to reduce mortality in heart failure, when other drugs had shown such benefit. Specifically, they hypothesized it might be due to differences in the patient populations for the various trials, or there were ancillary pharmacological properties of bucindolol that reduced its efficacy. Regarding the differences in study populations, the most notable difference was that BEST enrolled substantially more blacks than any other trial (ie, 23% in the bucindolol trial, <1% in the bisoprolol trial, and 5% in the metoprolol CR/XL and carvedilol trials).59 Furthermore, in the BEST subgroup analysis, there was no benefit evident in blacks (hazard ratio 1.17, 95% CI 0.89 to 1.53), whereas there was a significant mortality reduction in nonblacks (hazard ratio 0.82, 95% CI 0.70 to 0.96). This prompted a variety of subsequent analyses to evaluate whether there was lower efficacy with β-blockers in blacks in the treatment of heart failure. A reanalysis of the carvedilol data by ethnicity suggested no differences in outcomes, with blacks having estimates of risk reduction similar to whites.60 Nonetheless, there were only 217 black participants in the trial, and a lack of or reduced efficacy in blacks cannot be ruled out by these analyses. Subgroup analyses of the metoprolol CR/XL data were not as convincing with regard to the lack of a difference by ethnicity.61 Although all hazard ratios in blacks were <1.0, for total mortality, the hazard ratio point estimate was 0.79 in blacks (not significant) and 0.67 in whites (significant). Similarly, for mortality plus heart failure hospitalization, the point estimate was approximately 0.98 in blacks and 0.70 in whites.54,61 Thus, although the authors concluded there were no differences between blacks and whites, it is not apparent this is the case. Whether the study was simply underpowered to test for ethnic differences or no such differences exist is unknown. Interestingly, the FDA package labeling for metoprolol CR/XL indicates that among the US-based participants in the metoprolol CR/XL clinical trial (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure [MERIT-HF]), no benefit was evident. Given that nearly all the blacks in MERIT-HF came from the United States,61 it is possible that reduced efficacy in this population led to the failure to observe a benefit among the US population for this trial. Thus, although there is reasonable evidence for a lack of ethnic difference in response to carvedilol, it is less clear for metoprolol CR/XL. There was also a meta-analysis that included 2 carvedilol trials, the metoprolol CR/XL trial and BEST.54 As suggested by the previous analyses, point estimates for blacks and nonblacks were similar, except for bucindolol. In the meta-analysis that included BEST, there was significantly less relative risk reduction in blacks than whites, whereas in the meta-analysis that excluded BEST data, there was no significant difference in the relative risk reduction. However, in this meta-analysis and in 3 of the 4 trials, the risk reduction ratio (blacks/whites) was greater than 1.0, which suggests less risk reduction in blacks (albeit nonsignificant except in BEST). Given that even when combined, the other 3 trials included 82 fewer blacks than BEST, it is difficult to exclude a reduced efficacy with β-blockers in blacks. Finally, the BEST investigators conducted an analysis in which they created a subgroup in BEST that closely matched the demographics of the other trials.59 In the BEST comparison subgroup, they showed a significant reduction in mortality (hazard ratio 0.77, 95% CI 0.65 to 0.92), which made the findings similar to the trials with the other drugs. This comparison subgroup included no blacks, which supports their initial hypothesis that differences in their study population, particularly a larger black population, may have influenced the inability to show a significant reduction in mortality with bucindolol.

Pharmacogenetics and Ethnic Differences in Responses to Heart Failure Therapies

Isosorbide-Hydralazine

If one accepts that I-H is more efficacious in blacks than whites, a potential explanation for such a finding is that there might be a “responsive” genotype that occurs exclusively or more commonly in blacks. Work is ongoing in the A-HeFT genetic substudy to address this question. However, equally likely as a genetic or ethnic explanation for the I-H findings is that response differences highlight differences in 2 different heart failure phenotypes, which happen to differ by ethnicity. Specifically, blacks are significantly more likely to have hypertensive heart failure, whereas the underlying cause is more likely to be ischemic heart disease in whites. Thus, it is possible that blacks and whites with hypertensive heart failure would respond equally well to I-H and that ethnicity per se is not the source of response differences. It is unlikely that there will be future studies that sufficiently dissect the role of genetics versus differences in phenotype in the response differences to I-H. However, whichever of these might be the explanation, either would highlight that a proportion of whites would be expected to benefit from I-H, and a proportion of blacks would be expected to not benefit.

β-Blockers

As described, there appears to be reasonable evidence for differences in response to bucindolol between blacks and whites, and although the studies with the other β-blockers did not provide convincing evidence for differences in response, the number of blacks included was small, and such a difference cannot be excluded. As with the antihypertensive response, the pharmacogenetics data with β-blockers may be considered consistent with a potential mechanistic explanation for such differences in response. For example, studies have shown that the ADRB1Arg389Gly polymorphism is significantly associated with the improvement in left ventricular ejection fraction (LVEF) associated with carvedilol,62 metoprolol CR/XL,63 and bisoprolol.64 Specifically, in all these studies, the Arg389Arg genotype group had the greatest improvement in LVEF, and given that improvement in LVEF is considered a good surrogate for improvement in survival, such differences may have clinical relevance. The first 2 studies were conducted in the United States, whereas the latter was conducted in China, which also suggests these associations are consistent across ethnic groups.

Consistent with the associations between genotype and improvement in LVEF are data from BEST, which showed that Arg389Arg homozygotes had a significant mortality reduction with bucindolol compared with placebo, but such a benefit was not evident in the Gly389 carriers.65 Of importance is that the frequency of the Arg389Arg genotype is lower in blacks than whites, which is consistent with the potential ethnic differences in response. Specifically, among whites, ≈55% of the population has the Arg389Arg genotype, compared with ≈30% to 35% of blacks. This would not appear to explain the literature that suggests a lack of difference by ethnicity for carvedilol and a more dramatic difference with bucindolol. However, studies by Liggett and colleagues65 on the effects of genotype on ex vivo ventricular contractile responses may be insightful. They found that in precontracted ventricular trabeculae, bucindolol behaved as an inverse agonist in the Arg389Arg hearts only, whereas carvedilol was a neutral antagonist in Arg389Arg and Gly389 carriers.65 These data suggest that ancillary properties of the drugs might also vary by genotype and thus may influence the variable efficacy between drugs and across ethnic groups.

Another ancillary property of bucindolol that may have influenced its failure to reduce mortality in the overall population is its sympatholytic properties. Specifically, it was shown that a portion of the bucindolol-treated population had dramatic reductions in norepinephrine, due to its sympatholytic effects, and those with the greatest decline in norepinephrine were at increased mortality risk.66 Of interest is that the sympatholytic effects of bucindolol may be associated with the amino acid 322 to 325 I/D polymorphism in the α2C-adrenergic receptor (ADRA2C), with deletion (Del) carriers having greater norepinephrine reductions with bucindolol.67 Additionally, in BEST, ADRA2C Del carriers had no benefit from bucindolol relative to placebo, whereas insertion/insertion (Ins/Ins) homozygotes had a significant benefit from bucindolol therapy. The group with the greatest benefit was those with both ADRA2C Ins/Ins and ADRB1 Arg389Arg genotypes. As with the Arg389Gly polymorphism, there are significant ethnic differences in theADRA2C 322 to 325 I/D polymorphism. Specifically, in BEST, 66% of blacks were Del carriers versus 8% of whites. Thus, 2 genes have been associated with different outcomes for bucindolol, and in both cases, blacks are less likely than whites to have the favorable response genotype.

Of interest is that among the β-blockers used to treat heart failure, the sympatholytic effects appear to be confined to bucindolol, so these findings would not translate to the other β-blockers. This may help explain why bucindolol appears to be the most extreme with regard to ethnic differences in response. For example, we found that ADRA2C Del carriers had significantly greater improvements in LVEF with metoprolol than Ins/Ins homozygotes.68 Additionally, when considered with the ADRB1 Arg389Gly polymorphism, it appeared that the LVEF improvement in Arg389Arg homozygotes/Del carriers was synergistic relative to those carrying just 1 of the favorable genotypes. This finding is also consistent with the known functional effects of the ADRA2C polymorphism, in which the Del carriers have impairment in the normal autoinhibitory function of the receptor, which leads to enhanced norepinephrine release.69 In the absence of sympatholytic effects of the drug, Del carriers would be expected to have a greater response to β-blocker therapy. When data from the 2 drugs are considered together, they suggest that the most favorable genotype combination for bucindolol (Arg389Arg plus Ins/Ins) is different from the most favorable combination for metoprolol (Arg389Arg plus Del carrier). Blacks are more likely to have the latter rather than the former genotype combination, consistent with the data suggesting a more minimal difference in response to metoprolol CR/XL between blacks and whites than with bucindolol. Data considering both genes are not available for carvedilol, so it is not possible to know what the most favorable genotype combination might be for this drug.

The pharmacogenetics data for β-blockers in heart failure suggest several things. First, it appears the observed ethnic differences in response in clinical trials might be explained to some degree by pharmacogenetics. The data also suggest that it might be possible to more precisely select β-blocker therapy on the basis of genotype and that such an approach would appear to be superior to selecting therapy on the basis of a patient’s ethnicity. Specifically, although one might conclude from the literature that bucindolol would be a suboptimal therapy in blacks, certain blacks will carry the genotype combination for which it might be an effective therapy. A small pharmaceutical company has purchased the rights to bucindolol and will be filing a new drug application with the FDA, with the drug being most strongly recommended for Arg389Arg plus Ins/Ins genotype patients. Thus, use of genetic information to guide β-blocker selection in heart failure may soon be a clinical reality and would be expected to be a more reliable predictor of response than reliance on data regarding differences or similarities in response by ethnic group.

Challenges to Defining the Role of Pharmacogenetics in Ethnic Differences in Drug Response

Ethnic differences in responses to cardiovascular drugs have been recognized for several decades, and in some cases, ethnicity is used to make decisions about drug therapy. It is intuitively attractive to speculate that pharmacogenetics may contribute to our understanding of ethnic differences in drug response, and some of the examples cited herein support that pharmacogenetics may contribute to such differences. However, there are certain challenges to defining the role of pharmacogenetics in ethnic differences in drug response that must be recognized. First, the heritable contribution to drug response variability is rarely defined experimentally, but if one assumes that it is approximately the same as the heritable contribution to the diseases the drug treats, then on average, this would represent 30% to 60% of variability that has a genetic basis, with the remaining being environmental or demographic. Additionally, it is expected that for most drug responses, the genetic underpinnings will be explained by a variety of genes, thus making any calculation of the role of pharmacogenetics in ethnic differences in response more challenging. It is possible that the examples provided herein are ones for which the genetic contribution from a single gene is larger than normal, thus making the potential contribution of that gene to ethnic differences in response more evident. Additionally, as genetic studies move toward a tag SNP approach, in which the functional polymorphism is unknown, differences in linkage disequilibrium between ancestral populations will add to the challenge of defining an association across different ethnic groups and defining the role of that polymorphism in ethnic differences in response. This has been clearly evident with warfarin and the VKORC1 SNPs. The contribution of environmental factors to drug response, particularly diet for many of the cardiovascular drugs, and how this may confound the search for the genetic underpinnings of ethnic differences in response remains to be clarified. Finally, there are the challenges associated with translation of any finding or technology to practice. This includes accumulating sufficient data that the genetic (and probably other) information is predictive enough to be useful clinically, followed by the education required of clinicians for adoption to practice.

Despite the many challenges, it appears that in at least some cases, pharmacogenetic findings may help to explain ethnic differences in response. As the goals of personalized medicine begin to be realized, it is possible that use of genetic and other patient-specific information, including environmental factors, will be superior to use of ethnic information and will help guide drug therapy decisions for certain drugs.

http://circ.ahajournals.org/content/118/13/1383.full

How do we metabolize pain medications?

What role does genetics have in pain?
Research shows that  genetic factors account for a substantial proportion of all elements contributing to a patient’s response to drugs (others include age, sex, weight, general health and liver function).

Genes provide your body with instructions for making enzymes, which help break down drugs in your system, allowing your body to benefit from the medicine. Differences in your enzymes can affect how your body metabolizes a drug and how long the drug stays your body – and thus, how well drugs may work in an individual.

In particular, common pain medications require activation by an enzyme called CYP2D6 to become effective. Approximately half of patients have genes that alter the function of CYP2D6. Testing for these gene alterations allows for changes to dosage regimens in order to compensate for altered metabolisms –  and optimizes the safety and efficacy of pain medications.

Without knowing an individual’s specific genetic code, physicians may often need to go through months of trial-and-error prescribing to find the right drug and dose. Physicians are often baffled when a drug will work for one person but not for another with the same diagnosis. The fact of the matter is that physicians really do not know how to predict drug effectiveness or toxicity because everyone is different.  Genetic testing helps assess drug responsiveness. An individual’s genes can be a map that serves as a guide for physicians.

What is Pharmacogenetic Testing (PGT)?
A simple saliva test can evaluate an individual’s ability to metabolize or process drugs. Pain medications such as hydrocodone, oxycodone, diazepam and morphine utilize the CYP2D6 enzyme in order to metabolize the drug. As a drug gets metabolized, it is broken down into harmless pieces and eventually cleared. The activity of your clearance system is based on your genetic code. Once tested, this knowledge about an individual’s unique drug metabolizing system can help guide physicians.

What is the purpose of PGT?
Physicians would like to be able to anticipate how one may respond to a drug instead of relying on a trial-and-error process. By knowing the specific way one may break-down drugs, a physician can tailor treatment according to an individual’s unique metabolism and immediately find the right drug. Not only will this information help physicians predict which drug will best treat pain, a physician will also be able to predict the effective dose and potential for toxicity. In theory, this knowledge has the potential to save time, money and lives.

Pharmacogenetic testing (PGT), specifically, is exceedingly important for the proper management of pain because finding the precise drug and dose for each patient is so critically important. The groundbreaking development of PGT testing provides more individualized drug treatment for patients while also reducing adverse effects.

Pharmacogenetics and pain management by Maria Chianta and Maria Guevara PharmDs

Chronic pain affects approximately 100 million U.S. adults at a cost of up to $635 billion annually in direct medical costs and lost productivity.  As clinicians attempt to reduce pain and improve functionality in patients with chronic pain, pharmacotherapy remains a cornerstone of treatment. Typically, several medications with different mechanisms of action are employed to target different physiological pain pathways. Thus, polypharmacy is common in patients with chronic pain, exposing patients to increased risk of drug-drug interactions.  Another challenge clinicians face is wide inter-patient variability in responses to prescribed medications.

Due to these variables, clinicians must consider multiple factors when determining optimal pharmacotherapy for patients, including the pharmacokinetics/pharmacodynamics of a medication and the patient’s comorbid medical conditions, age, and concomitant medications.

Pharmacogenetics is the study of how genes affect the response to medications. Pharmacogenetic information may be used to predict a patient’s genetically driven response to a specific medication. Genetic variances account for 20% to 40% of inter-individual differences in metabolism and responses to medications and can exacerbate drug-drug interactions, hinder a pro-drug from bio-activation, or induce metabolism through alternative, potentially deleterious pathways.3 The goal of pharmacogenetics is to deliver improved pharmacotherapeutic treatment for an individual by distinguishing between patients who may be more or less likely to respond to a specific drug and identifying patients who may be at higher risk for adverse events and certain drug interactions.3

The human body breaks down or metabolizes medications in order to eliminate them. Many medications commonly used in the treatment of chronic pain are broken down in the liver via hepatic enzyme metabolism. The cytochrome P450 (CYP450) enzymes are responsible for the metabolism of the majority of medications and associated with genetic variations (i.e., polymorphisms) that can affect an individual’s response. During the past several years, the ability to test for polymorphisms in these hepatic metabolic enzymes has become more convenient, more commercially available, and reimbursable by third-party payers, leading to increased clinical use.  The ability to identify polymorphisms in an individual’s genotype can now be used to predict a phenotype for these hepatic metabolic enzymes. The phenotype is the observable trait encoded by the genotype, which in this case describes how a patient metabolizes medications that are processed by the enzyme that is tested. The test for a particular hepatic enzyme is referred to as a pharmacogenetic test.

When patients undergo pharmacogenetic testing, they are categorized into one of four phenotypes: ultra-rapid metabolizer (UM), extensive metabolizer (EM), intermediate metabolizer (IM), or poor metabolizer (PM). Extensive metabolizers are considered to have normal enzyme activity and metabolism through the enzyme pathway tested and, based on pharmacogenetics alone, would be expected to have a typical response on standard medication doses.  Ultra-rapid metabolizers will metabolize medications faster through the enzymatic pathway tested compared to an extensive (normal) metabolizer. Intermediate metabolizers have a decreased capacity to metabolize medications through the enzymatic pathway tested, and poor metabolizers have very little to no ability to metabolize medications through the enzymatic pathway tested.5

The clinical consequence of each phenotype will depend on whether the medication is inactivated by metabolism or needs metabolism to produce an active metabolite (i.e., a prodrug). For example, a poor metabolizer, unable to metabolize certain medications, is at risk for accumulation of the active parent compound and increased toxicity, or lack of conversion of a prodrug into an active metabolite and decreased efficacy.

When deciding which patients may benefit from pharmacogenetic testing, considerations include the clinical consequences of a genetic polymorphism, whether the medication(s) prescribed or to be prescribed are metabolized by the enzyme(s) tested, and salient information from the patient’s medical history (response to medications, personal or family history of adverse events to medications, response to anesthesia, response to alcohol and history of genetic diseases).4  If a genetic variant is identified, the predicted clinical consequences should be assessed and clinical adjustments, such as modifying the dose, modifying the dosing schedule, or changing the medication should be considered. In some cases, the genetic variant may support the dosing regimen or drug choice(s), and no change is required.3

Chronic pain is a major burden to the healthcare system, and it lacks many objective tests available to help guide treatment. Pharmacogenetic testing is a tool that is available today that, when applied to patient care, may lead to improved selection of medication(s) for the individual and optimal pharmacotherapy. Benefits of using pharmacogenetic testing may include fewer medication-related side effects, avoidance of drug-drug interactions, and a reduced number of opioid rotations by avoiding the use of medications that repeat negative outcomes due to a genetic variant. Testing may also provide documentation to support a decision to change or continue a medication regimen.7 Pharmacogenetic testing brings us one step closer to the ideal treatment: personalized medicine.

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Statins and pharmacogenetic test to lessen side effects

LONDON, Ontario— Strikingly wide variation among patients in plasma levels of atorvastatin and rosuvastatin (Crestor, AstraZeneca), even with consistent dosing, is likely related to gene variants that affect the drugs’ uptake by the liver in some patients, suggests a prospective study[1]. The researchers propose that selective screening of some statin candidates for the presence of the specific polymorphisms could help individualize atorvastatin and rosuvastatin dosing with the goal of lowering the risk of statin side effects, especially myopathy.

In the study of 399 patients taking either statin, senior author Dr Richard B Kim (University of Western Ontario, London) toldheartwire ,”We were surprised at the extent of interpatient [plasma-level] variability at the same dose. Tremendous variation–45-fold. That is to say, there were some people with very low blood levels and an excellent response to statins, and people with unexpectedly high levels and a reasonable response to statins.” It’s the latter group that appears to be at increased risk, given that statins affect lipoproteins in the liver, but the side-effect risk goes up with plasma levels.

“We also were surprised by the role of age. It really did look like, in our patients older than aged 75 with the wrong genetic makeup, the higher doses were particularly bad in terms of risk.”

The study was published online July 22, 2013 in Circulation: Cardiovascular Genetics with first author Dr Marianne K DeGorter (University of Western Ontario).

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The group devised a potential management algorithm that includes genotyping and is aimed at avoiding adversely high statin plasma levels, acknowledging that whether it would prevent side effects has yet to be demonstrated. But Kim said it could add to efforts to avoid significant muscle enzyme elevations or actual rhabdomyolysis.

It really did look like, in our patients older than aged 75 with the wrong genetic makeup, the higher doses were particularly bad in terms of risk.

“It’s really an additional decision support tool that incorporates clinical and pharmacogenetic variables that I think gives the prescribing physician a point of reference regarding when to switch [treatments], how to switch, and dose considerations, with a mechanistic point of view in terms of drug level,” Kim said. The current study “does say that if you’re thinking high-dose in an older person, the [algorithm] might be particularly useful.”

In the 165 patients taking rosuvastatin, nearly all the explainable variability in blood concentrations could be attributed to two reduced-function polymorphisms, one in the uptake transporter gene SLCO1B1 (p<0.001) and the other in the efflux transporter gene ABCG2 (p<0.01), the group writes. In the 134 patients on atorvastatin, explainable blood-level variability was split between two polymorphisms in SLCO1B1 (p<0.01 and p<0.05, respectively) and the activity of cytochrome P3A (CYP3A). The analyses were adjusted for gender, age, body-mass index, ethnicity, statin dose, and time from last dose, and echo a 2008 study which concluded that two SLCO1B1variants were associated with simvastatin-related myopathy, as reported by heartwire . The screening concept is currently being applied to simvastatin therapy at least at one major center.

The group retrospectively tested their ideas, looking at the relationships between genotypic and clinical variables and statin dose, in a validation cohort of 579 patients taking either drug in a primary care setting in the US and at a referral clinic in Canada.

The group found that the transporter genotypes that raise statin concentrations were homogeneously distributed among patients taking a range of atorvastatin and rosuvastatin dosages. That is, the prescribing physicians, armed primarily with their clinical judgment to decide dosage levels, failed to achieve optimal dosing with respect to serum drug levels. But it seemed to be only patients receiving the highest dosages who showed higher-than-safe serum levels according to genotype- and age-based criteria.

“Although we didn’t quite get to the sample size we needed, it did seem like people with the wrong genetic makeup are more likely to stop a statin or switch to [another dyslipidemia drug],” Kim said, at least among patients on the highest statin dosages.

The group’s proposed management algorithm recommends a maximum statin dosage that will result in plasma concentrations below the 90th percentile (reflecting an assumption that 10% of patients will have statin-related muscle issues) based on patient age and transporter-related genotype.

The algorithm is based on data predominantly from whites; the group cautions that some other ethnicities, “particularly Asians,” have increased sensitivity to statins.

The research was supported by grants from the Canadian Institutes of Health Research, Drug Safety and Effectiveness Network, Academic Medical Organization of Southwestern Ontario Alternate Funding Plan Innovation Fund, and US National Institutes of Health. Neither Kim nor DeGorter had any disclosures; disclosures for the coauthors are listed in the paper.

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Why you need pharmacogenetic tests when taking Vancomycin

Vancomycin

Antibacterial obtained from Streptomyces orientalis. It is a glycopeptide related to ristocetin that inhibits bacterial cell wall assembly and is toxic to kidneys and the inner ear.

Indication

For the treatment of serious or severe infections caused by susceptible strains of methicillin-resistant (beta-lactam-resistant) staphylococci.

CPIC Dosing Guideline for rasburicase and G6PD

Summary

Rasburicase is contraindicated in G6PD deficient patients with or without chronic non-spherocytic hemolytic anemia (CNSHA). In patients with a negative or inconclusive genetic test result an enzyme activity test is recommended prior to rasburicase treatment to determine whether a patient is G6PD deficient. The G6PD gene is X-linked and therefore males only have one copy, whereas females have two copies. See full guideline for disclaimers, further details and supporting evidence.

Annotation

Aug 2014

Accepted article preview online May 2014, advance online publication 11 June 2014

  • Guidelines regarding the use of pharmacogenomic tests in determining whether rasburicase treatment should be undertaken have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
  • Excerpt from the 2014 rasburicase guideline:
    • “As stated above, rasburicase is contraindicated by the FDA, the EMA, and PMDA in those with G6PD deficiency (32-34) (see Table 2). If, on the basis of genotyping, a deficient status can be unambiguously assigned to a patient, that would be a sufficient contraindication to the use of rasburicase. However, due to the limitations of genetic testing (discussed above), in most cases it is necessary to perform G6PD enzyme testing to assign G6PD status.”
  • These guidelines are applicable to
    • neonates
    • pediatrics
    • adults
  • ———–

Pharmacogenetic tests

  • We are working with doctors and medical sales reps, medxprime.com to prevent adverse drug reactions and promote patient safety. Contact Connie Dello Buono 408-854-1883 motherhealth@gmail.com if you want to add this service /test as added tool in your practice and  for medical sales reps (as we are hiring in all states in the USA).