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Around 6.2 million Americans of 65 years and above are ravaged by Alzheimer's. Alzheimer's is characterized by amyloid plaques in the brain. A new study found that people taking certain drugs for type 2 diabetes had less amyloid protein in the brain. Further, people taking these drugs also displayed a slower cognitive decline.
Alzheimer’s is one of the ten leading causes of death in the US. Medically, Alzheimer’s is a progressive neurological disorder, i.e., the nerve cells in the brain start to die, and the brain shrinks.
The area of the brain to get affected earliest is the hippocampus, which is responsible for memory. However, the onset of disease can occur much earlier than the appearance of the first symptoms.
Gradually, neuronal cell death progresses to other areas of the brain. This leads to severe memory impairment and loss of ability to carry out everyday tasks.
To date, there is no cure or treatment for Alzheimer’s. Further progression of the disease ultimately results in death due to severe loss of brain function involving dehydration, malnutrition, or infection.
Xcode Life’s Gene Health Report analyzes 50+ genetic markers for Alzheimer’s disease to give possible predisposition and recommendations. Check your Alzheimer’s Disease risk here.
Biological markers or biomarkers are characteristics that can be objectively measured as an indicator of a pathological or normal physical process.
For Alzheimer’s, scientists usually look for two proteins as the disease’s biomarkers.
Amyloid plaques are stacked forms of the beta-amyloid protein fragment. Beta-amyloid is a protein fragment cut from the amyloid protein precursor (APP). Usually, these protein fragments are cleansed from the brain by microglia.
Image Source: Brain Blogger
The image here depicts amyloid plaques formed around nerve cells in the brain.
In Alzheimer's patients, the beta-amyloid does not get eliminated and starts forming clusters in the brain. In their early cluster stage, the beta-amyloid starts destroying synapses or nerve junctions - leading to memory loss in the individual. Upon forming plaques, the beta-amyloid protein contributes towards brain/nerve cell death.
Tau proteins are part of the neuron’s (nerve cell) internal support and transport system.
Image Source: Utah Public Radio
In Alzheimer’s, the tau proteins change their shape and structure to form tangles in the neuronal fibers. These tangles disrupt normal tau protein functioning and become toxic for the cells, thus leading to cell death.
The most prevalent genetic risk factor for Alzheimer’s is the ApoE (apolipoprotein E) gene. The 4 type of this gene is known to confer the highest risk factor and is present among 50% of Alzheimer’s patients.
The ApoE gene present on chromosome 19 makes a protein that helps transport cholesterol and other fat molecules through the bloodstream.
While there are two other types of the ApoE gene ( 2 & 3), only the 4 variant is associated with increased risk for Alzheimer’s. Having one or both copies of ApoE 4 in the body increases Alzheimer’s risk. The prevalence of individuals carrying one copy is about 25%, while only 2-3% carry both copies.
Know your ApoE gene Status with Xcode Life’s Gene Health Report.
Alzheimer’s is one of the diseases where age, especially old age, plays a significant role. Although Alzheimer’s development is not part of the normal aging process, old age increases the risk.
MCI is characterized by a decline in memory and associated thinking abilities, disrupting an individual's normal societal or work-environment functioning. Usually, an MCI diagnosis with primary memory deficit leads to Alzheimer's associated dementia.
Certain factors which pose a risk for cardiac problems also increase Alzheimer’s risk. Some of them are
Additionally, people with type 2 diabetes are at a higher risk of Alzheimer's disease. This may be due to higher blood sugar levels which have been linked to amyloid plaque buildup.
DPP-4 inhibitors or gliptins are oral diabetes drugs used to block the enzyme dipeptidyl peptidase-4. DPP-4i acts on incretins (a group of hormones that stimulate the release of insulin). In addition, it reduces glucagon (a hormone that increases blood sugar levels), thereby decreasing blood sugar levels.
A previous study exploring the effect of DPP-4i use on dementia among type 2 diabetes patients revealed an increased impact on dementia, albeit not in Alzheimer’s patients.
Studies revealed an increased risk of inflammatory bowel and hypoglycemia when combined with another class of diabetic drug, sulphonylureas (like glipizide and glimepiride), in type 2 diabetic patients.
Know your body’s predisposition to the metabolism of DPP-4i and sulphonylurea drugs with Xcode Life’s pharmacogenomics report, Personalized Medicine.
Scientists at the American Academy of Neurology explored the effect of DPP-4i use in Alzheimer’s patients who may/may not suffer from type 2 diabetes (T2D).
The study involved 282 people with either pre-clinical, early, or probable diagnosis of Alzheimer's. Individuals were of an average age of 76 and were followed for a six-year period. These people comprised of:
Researchers measured the amyloid content in the individuals’ brains using a brain scan.
Study participants were made to take a common thinking and memory test called Mini-Mental State Exam (MSME) every 12 months for 2.5 years to track cognitive decline. The test consisted of questions like counting backward from 100 by sevens or copying a picture on paper. The score ranged from zero to thirty.
Between the three subgroups, Alzheimer’s individuals having T2D and on DPP-4i drugs:
Further adjustment of factors that could affect MSME scores, the same Alzheimer’s individuals with T2D and using DPP-4i drugs scored even lower decline by 0.77 points per year.
Xcode Life’s Personalized Medicine report targets genes that are associated with your response to drug therapies. This will help your physician understand your metabolic responses and prescribe the right drug.
Your genes produce drug-metabolizing enzymes, drug targets, and other proteins related to the action of drugs. Each individual has a unique genetic makeup. Hence, they might respond differently to certain medications.
Pharmacogenomic tests provide information about a person’s genetic makeup to help the physician decide which medications and what doses might work best for him or her. It also helps to reduce the cost and time associated with a trial-and-error approach to treatment.
Some interesting facts about genes and your medications:
The report can be used to optimize therapy for nearly 200 commonly prescribed drugs in multiple treatment categories,including statins, platelet aggregation inhibitors, biguanides, sulfonylureas, anticoagulants, beta blockers, antihypertensives, proton pump inhibitors, non-steroidal anti-inflammatory drugs, and antiarrhythmics.
The results of this report can be used as a supplement to the clinical decision-making process and reduce the cost and time associated with a trial-and-error treatment. In this report, we profile gene variants that influence your metabolic response to various drug therapies.
Based on the results of your genetic test, the report provides an insight into your genetic type.
Your results, along with the possible outcome, are mentioned. The numbers in your result column signify which variant allele you carry and how that influences the metabolism of the drug. For example, *1/*1 is used to denote a normal metabolizer. This will help you understand your genetic type for each drug.
This section walks you through the list of drugs we test you for.
The drugs are classified into various categories that include:
Depending on the gene type you carry, your metabolizer status is assigned for each drug. Normal or extensive metabolizers break down drugs at a normal rate. These people are likely to metabolize the drugs normally and experience the intended effect of the drug.
Poor metabolizers break down the drugs at a much slower than normal rate. The standard doses may not be as effective for them. They also may experience undesired side effects.
Ultra-rapid metabolizers break down drugs at a faster than normal rate. As a result, they may experience some undesirable side effects. They may also require a higher dosage of the drug.
The evidence level and strength are also mentioned, along with the gene analyzed in relation to drug metabolism. Treatment and dosage recommendations are provided for each drug covered in the report.
The report analyzes your response to 270+ drugs, including ACE Inhibitors, Caffeine, Carbamazepine, Codeine, Fentanyl, Ibuprofen, Metformin, Morphine, Selective serotonin reuptake inhibitors, Simvastatin, Tamoxifen, and Warfarin. For a comprehensive list of the traits covered, click here.
Amlodipine is a drug used to treat high blood pressure (hypertension). It belongs to a class of drugs called calcium channel blockers.
The main goal of this class of drugs is to widen the blood vessels and improve the blood flow through them.
When the blood vessels are widened, the pressure applied by the blood on the vessel walls is reduced.
Image: Blood vessels constrictions vs. relaxation and blood pressure
Apart from hypertension, Amlodipine is also used to reduce the frequency of chest pain (angina) and other diseases that affect the blood vessels in the heart.
Amlodipine is usually recommended for adults and children who are at least six years old.
One can take Amlodipine with or without other blood pressure-lowering medications.
Amlodipine is available in the tablet and suspension (or liquid) form that can be taken by mouth (orally).
It is usually recommended to be taken once a day and at the same time each day.
High blood pressure (or hypertension) is a prevalent health condition that can arise from both lifestyle and genetic factors.
Blood pressure is essentially the pressure of circulating blood against the walls of the blood vessels.
If not controlled or treated in time, hypertension can damage other organs in the body such as the brain, kidneys, blood vessels, etc.
Damage to these organs can result in heart disease, heart attack, heart or kidney failure, liver failure, and vision loss.
Medications used to treat hypertension are called antihypertensives and are of different types depending upon their mechanism of action.
Amlodipine belongs to a class of antihypertensives called calcium channel blockers.
This drug primarily acts on the blood vessels and widens their diameter.
Amlodipine blocks calcium entry into smooth muscles of the blood vessels and cardiac muscles.
This allows the blood vessels to relax, improves blood flow through them, and lowers the force of blood on the vessel walls.
As a result, blood pressure levels are reduced.
In most cases, Amlodipine is a safe drug to consume.
However, some side effects of this drug have been noted.
The common side effects of Amlodipine are:
Many of these common side effects may subside within a few days to weeks of taking the Amlodipine.
However, if they do not reduce, consult with your doctor.
Some severe side effects that may occur on taking Amlodipine are:
If you experience any of the above side effects on taking Amlodipine, report the same to your doctor immediately.
Before taking Amlodipine, you must inform your doctor about any medications, nutritional supplements, and herbal medicines you may be taking to avoid any drug interactions.
An interaction is when a substance changes or modifies the way a drug works. This may cause harmful effects or prevent the drug’s required effect.
Amlodipine interacts with a wide range of drug groups:
Taking diltiazem (another calcium channel blocker) with Amlodipine may increase the level of Amlodipine in the body and cause more side effects.
Taking antifungal medicines like ketoconazole, itraconazole, or voriconazole with Amlodipine may increase Amlodipine levels in the blood.
Taking clarithromycin with Amlodipine may increase Amlodipine in blood, increasing the risk for more side effects due to the medicine.
Taking medicines like sildenafil, tadalafil, avanafil, or vardenafil along with Amlodipine may increase your risk of low blood pressure.
Taking Amlodipine with simvastatin (a cholesterol-lowering drug) may result in higher levels of simvastatin in the blood.
This could result in more side effects due to the drug.
Taking Amlodipine with medications like cyclosporine and tacrolimus may result in higher levels of these medicines in the blood.
This can increase the risk of immune system-related side effects.
Other drugs that are known to show severe interactions with Amlodipine are:
Cytochrome P450 Family 3 Subfamily A Member 4 or the CYP3A4 gene is a member of the cytochrome P450 family.
The CYP genes participate in drug metabolism (chemical alteration of the drug in the body), production of cholesterol, steroids, and other lipids.
Amlodipine is metabolized in the liver by CYP3A4 and CYP3A5 genes.
Therefore, any changes in the activity of these genes can lead to a modified effect of Amlodipine.
A study published in JAMA (Dec 2018) states that coadministering Amlodipine and clarithromycin or erythromycin increases the risk of hypotension (low blood pressure) and acute kidney injury.
This effect is said to be due to decreased metabolism of the drug by the CYP3A4 enzyme.
Another study reports that CYP3A4 gene types partly determined blood pressure response to Amlodipine in high-risk African-American patients.
Natriuretic Peptide A or NPPA gene is a gene that belongs to the natriuretic peptide family.
This family of genes is responsible for maintaining salt and water balance in the body.
This gene is located on chromosome 1.
rs5065 (also called T2238C) is a single nucleotide polymorphism or SNP in the NPPA gene.
A study published in JAMA in 2009 stated that SNP rs5065 played a role in modifying the antihypertensive medication effects on blood pressure and the cardiovascular system.
According to the study, patients with the C allele showed favorable cardiovascular disease outcomes on taking diuretics.
In contrast, TT allele carriers showed promising cardiovascular results on taking calcium channel blockers like Amlodipine.
If you suffer from liver disease or heart valve problem (arterial stenosis), inform your doctor about the same before taking Amlodipine for hypertension.
If you are allergic to Amlodipine or experience a hypersensitivity reaction due to it, avoid taking the drug and report to your doctor immediately.
Studies conducted on animals show that taking Amlodipine during pregnancy may have adverse effects on the fetus.
Though there aren’t many human studies to determine how Amlodipine affects human pregnancy, it is best to inform your doctor if you are pregnant or planning a pregnancy while taking the drug.
Though limited, research states that Amlodipine may pass into breast milk and may cause side effects in a breastfed child.
If you are breastfeeding your child, inform your doctor about the same before taking Amlodipine.
As you age, your body’s ability to process Amlodipine reduces, making it stay in your body longer.
This increases the risk of side effects in older patients.
Genetic testing helps your doctor understand how your body may react to a particular drug.
It also helps your doctor determine the appropriate dosage of a drug for you.
For safe consumption of Amlodipine, you may need to get CYP3A4 gene testing done.
Gene testing may also be recommended if you need to take any other medication with Amlodipine, especially antibiotics like clarithromycin or erythromycin.
Analyze Your Genetic Response to Amlodipine
References:
Amphetamine is a central nervous system (CNS) stimulator used to treat medical conditions like Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy.
CNS stimulators affect the chemicals in the brain and cause hyperactivity and impulse control.
ADHD is a complex psychological disorder caused by genetic and non-genetic factors.
It is the most common neurodevelopmental disorder occurring in childhood.
Children with ADHD have trouble paying attention, controlling impulsive behaviors, and being overly active.
Aside from its medical uses, Amphetamine is also a habit-forming (highly addictive) substance with a long history of abuse.
Apart from a few brands, Amphetamine is not recommended for children below the age of three years.
Today, Amphetamine is also being used for treating obesity, depression, and chronic pain, although off-label.
Amphetamine is a CNS stimulant that increases the amount of neurotransmitters (chemical messengers) like dopamine, norepinephrine, and serotonin in the synapse via different mechanisms.
A synapse is a small gap between two nerve cells where transmission of electrical impulses occurs.
Amphetamine enters the nerve cell at the synapse by diffusion and is taken up by transporter molecules at the synapse.
Once inside the nerve cell, Amphetamine disrupts the electrochemical gradients required for standard impulse transmission.
Amphetamine also inhibits the metabolism of monoamine neurotransmitters (chemical modifications that monoamine transmitters undergo) by inhibiting Monoamine Oxidase (MAO) enzymes.
MAO inhibitors are responsible for degrading neurotransmitters. So, if Amphetamine inhibits MAO, the quantity of specific neurotransmitters increases.
Though Amphetamine is safe when taken legally and in doses strictly prescribed by the doctor, some people may experience mild to severe side effects on taking it.
These side effects may be physical or psychological.
Physical side effects of Amphetamine include:
Psychological side effects of taking Amphetamine may include:
Some studies have also shown that when Amphetamine is used to treat ADHD in children, it can retard or slow down growth.
Some minor effects have also been observed in the cardiovascular system, including increased heart rate and blood pressure.
However, more research is required to confirm this.
When Amphetamine is taken at higher doses or through routes not prescribed by a doctor, the risk of adverse effects increases.
Taking excess Amphetamine increases dopamine levels in the brain.
Overuse or abuse of Amphetamine may lead to:
People who take Amphetamine for recreational purposes may also experience withdrawal symptoms like depression and sleep disturbances when they stop taking the drug.
Many drugs, nutritional supplements, and herbal supplements may interact with Amphetamine.
Therefore, you must always inform your doctor about medications or supplements you are currently taking.
Drug interactions may change how drugs work and increase the risk of adverse reactions.
Some drugs that interaction with Amphetamine are:
Monoamine Oxidase Inhibitors of MAO inhibitors are a class of drugs used to treat depression.
Taking MAO inhibitors with Amphetamine may cause serious and possibly fatal drug interactions.
Therefore, you must avoid taking Amphetamine with MAO inhibitors like isocarboxazid, linezolid, metaxalone, methylene blue, etc.
You must also avoid taking MAO inhibitors for two weeks before taking Amphetamine.
Speak to your doctor to know when you should stop taking MAO inhibitors before starting on Amphetamine.
If you are taking drugs like methadone, dextromethorphan, or methylenedioxymethamphetamine (also called ecstasy) that increase serotonin production, taking Amphetamine can lead to serotonin syndrome or toxicity.
Amphetamine is similar to dextroamphetamine or lisdexamfetamine.
To avoid adverse effects or overdose, you must not take these medications together.
Amphetamine may interfere with routine lab tests like blood, urine analysis, and brain scan for Parkinson’s disease and give false results.
So, you must inform your doctor if you are taking Amphetamine before undergoing these tests.
The CYP2D6 gene gives instructions for the production of Cytochrome P450 Family 2 Subfamily D Member 6 enzyme.
The CYP2D6 enzyme plays a vital role in the metabolism of most psychostimulants (drugs that can stimulate the central nervous system), including Amphetamines.
Over 100 forms of the CYP2D6 gene have been identified.
They are classified as normal function, decreased function, or no function.
Though most people carry two copies of the CYP2D6, a few people might have more than two copies.
Individuals who carry one decreased function allele and one no function allele of the CYP2D6 are called intermediate metabolizers of Amphetamine.
Individuals who have two no-function alleles of the gene are called poor metabolizers of the drug.
A majority of people carry two normal function alleles of the CYP2D6 and are normal metabolizers of Amphetamine.
The DRD2 gene gives instructions for producing the Dopamine Receptor D2 subtype.
A particular mutation or abnormal change in this gene may cause myoclonus dystonia whereas other mutations may cause schizophrenia.
The DRD2 is also called the ‘pleasure-seeking gene due to its association with addictions.
People with the A1 type of the DRD2 gene are more prone to addictions of various kinds, including Amphetamine drug addiciton.
Some medical conditions can make it unsafe to take Amphetamine. Inform your doctor about any medical conditions that you may have, particularly:
If you have a history of sensitivity or allergy to Amphetamine, you must avoid taking the drug.
If you have a history of drug abuse or addictions, you must not take Amphetamine and inform your doctor about the same.
Inform your doctor if you are pregnant or are planning a pregnancy. Taking Amphetamine during pregnancy may cause premature birth, low birth weight of the baby, or withdrawal symptoms in the newborn.
Since Amphetamine can pass into breast milk and harm your baby, you must inform your doctor if you are breastfeeding before taking the drug.
Genetic testing helps your doctor understand how a particular drug may affect you. It can also help them determine the appropriate dosage for you based on your medical history, medications you are taking, and history of addictions.
Before taking Amphetamine, genetic testing for the CYP2D6 and DRD2 genes may be helpful to determine how you will metabolize the drug without causing side effects.
Analyze Your Genetic Response to Amphetamine
References:
Pharmacogenomics, sometimes called as pharmacogenetics, is the study of how genes affect a person’s response to drugs. It is a combination of two fields - pharmacology (the science of drugs) and genomics (the study of genes and their functions).
Just like how genes determine our eye color, height, etc. they also partly influence how our body responds to drugs. Some chemical changes in these genes can elicit unwanted side effects upon drug consumption.
The long-term goal of pharmacogenomic research is to design drugs best suited for each person, in order to avoid these undesirable side effects.
Genes influence multiple steps involved in your response to drugs. They include:
Drug Receptors: Some drugs require a type of protein called the receptors, to which they bind and get activated. Your genes can influence the number and effectiveness of these receptors.
Example: T-DM1 is a drug used to treat breast cancer. This drug works by attaching to a receptor called the HER-2 receptor. However, not all breast cancer cells express this receptor. So, this drug may not be effective for all individuals with breast cancer.
Drug Uptake: Certain drugs are activated only after they are taken into the cells and tissues. If your genetic makeup leads to reduced uptake of the drug, it may accumulate in other parts of the body.
Example: Statins are a class of drugs commonly used to treat high cholesterol levels. For the drug to work, it must be transported to and taken up by the liver efficiently. SLCO1B1 gene influences this process. A change in this gene results in a reduced transport of statins to the liver. This can result in statin buildup in muscles resulting in pain and weakness.
Drug breakdown/metabolism: If your genetic makeup results in a faster breakdown of drugs, it gets clear from the body faster. This may warrant an increased dosage of the drug or a different drug. On the other hand, if your drug metabolism is slow, it stays in your body for a longer period. In this case, a lower dosage may do the work.
Example: Amitriptyline is an antidepressant drug. Two genes, namely, CYP2D6 and CYP2C19, are involved in its metabolism. If you carry a change that slows down or boosts the metabolism, you may need to alter the drug dosage accordingly.
Patients can respond differently to the same medicine.
Commonly used drugs to treat some medical conditions need not be effective for everyone. Some examples are:
- Antidepressants drugs (SSRIs) are ineffective in as many as 38% of patients who are prescribed these drugs
- Asthma drugs are ineffective in as many as 40% of patients who are prescribed these drugs
- Diabetes drugs are ineffective in as many as 43% of patients who are prescribed these drugs
- Arthritis drugs are ineffective in as many as 50% of patients who are prescribed these drugs
- Alzheimer’s drugs are ineffective in as many as 70% of patients who are prescribed these drugs
- Cancer drugs are ineffective in as many as 75% of patients who are prescribed these drugs
- Cardiac Arrhythmias drugs are ineffective in as many as 40% of patients who are prescribed these drugs
Source: Brian B Spear, Margo Heath-Chiozzi, Jeffrey Huff, Clinical application of pharmacogenetics, Trends in Molecular Medicine, Volume 7, Issue 5, 2001, Pages 201-204, ISSN 1471-4914, https://doi.org/10.1016/S1471-4914(01)01986-4.
The purpose of pharmacogenomic testing is to find out if a medication is right for you. A pharmacogenomic test will help in knowing:
Efficacy - Whether a medication may be an effective treatment for you.
Dosage - What is the best dose for you for specific medications.
Toxicity - Whether you could have serious side effects from a medication.
CYP enzymes or the Cytochrome P450 enzymes are the major drug-metabolizing enzymes in the body. The P450 enzymes contain a protein called heme (iron-containing compound) and are commonly present in hepatocytes (cells of the liver). This is why drugs are mostly broken down or metabolized in the liver.
From a clinical perspective, the most commonly tested CYPs are:
- CYP2D6
- CYP2C9
- CYP2C19
- CYP3A5
Changes in CYP enzymes can influence the metabolism and clearance of drugs.
The CYP450 Test categorizes individuals into one of the four known metabolic profiles, called “predicted phenotypes.”
What are the limitations of a CYP test?
- Pharmacogenomic research is still in its infancy. Therefore, tests are available only for certain drugs.
- Any change in medication will require a new CYP test - this is because different enzymes are responsible for metabolizing different drugs
- The test reveals how genes affect the drugs and not what the drug does to the body (for example, we cannot determine how the drugs change certain receptors in the brain to alleviate the symptoms)
- Some drugs are metabolized and cleared by more than one CYP enzyme. For example, antidepressant drugs like the SSRIs (Selective Serotonin Reuptake Inhibitor) are metabolized by serotonin receptor molecules as well. This can limit the predictive value of the test.
Who should take the PGx test ?
If you answer yes to any of the below questions, you are an ideal candidate for a PGx test.
1. Are you currently taking four or more medications monthly?
2. Have you or anyone in your family ever been hospitalized for taking medication?
3. Have you or anyone in your family ever felt ill after taking a new medication?
4. Has your doctor changed your dose of medication due to a lack of response or a reaction to the medication?
5. Do you take your prescribed medication, and you still aren’t feeling better?
6. Are you taking or is your doctor considering prescribing to you pain medicine, tamoxifen, or Plavix?
7. Do you take herbal supplements regularly in addition to your medication?
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