Herbal-drug therapy interactions a focus on dementia

In 2007, the Centers for Disease Control and Prevention (CDC), National Center for Complementary and Alternative Medicine, and National Institutes of Health conducted a survey on complementary and alternative medicinal use and found that 17.7% of adults aged 18 and over used herbal medicines.
The content on this website is for information only and is not a substitute for professional medical advice, diagnosis, and treatment.
Vitamins, supplements and herbs have long been used by people with HIV to help manage the side effects of their therapies or improve their general health. The intent of this publication is not to discourage using complementary therapies, but rather to supply some food for thought when making decisions about using them.
Under current law, vitamins, supplements and herbs do not have to be evaluated by any regulatory agency, like the Food and Drug Administration (FDA), prior to their sale. Some manufacturers vaguely refer to "studies" in their literature, but these are seldom more than very small, uncontrolled studies. Herbal supplements can actually contain dangerous chemicals, like arsenic and lead -- both potentially deadly. People should be aware of these things and take measures to reduce their risk of buying contaminated products or ones without active ingredients. On their packages and even their websites, some manufacturers claim their products have been tested for active ingredients.
Generally, if a company shows integrity in some of its products tested by consumer groups, it's a reasonable sign that they maintain similar standards for their other products. At the National Institutes of Health's (NIH) HIV clinic, one woman who started a regimen with ritonavir (Norvir) and then started on garlic supplements developed severe nausea and vomiting, which resolved after stopping the garlic.
A group in Pittsburgh has shown that the common herb, milk thistle, also interacts with the p450 enzyme. A Canadian group has shown that vitamin A supplements (beta-carotene and other retinoids) have an effect on the p450 enzyme. Grapefruit inhibits the p450 enzyme system and in the early days of protease inhibitors some people drank grapefruit juice together with the older version of saquinavir (Invirase), which was poorly absorbed by the body, in hopes of increasing its blood levels and effectiveness.
Vitamins and Potential Side Effects ChartVitamin A and beta-carotenePerhaps the most toxic vitamin. To lessen the chance of herb-drug interactions, experts encourage people to have more in-depth discussions about complementary therapy with their doctors and pharmacists. However, patients also need to be open and honest about what they're using and considering. For example, Chinese herbal remedies that contain deer antler can cause nausea, diarrhea and other stomach upset. Side effects from using herbs, vitamins and supplements may not reveal themselves immediately. Some herbal remedies contain controlled and possibly dangerous substances banned by the FDA. A few years ago a number of Chinese herb supplements to manage diabetes were pulled from the shelves by the California Food and Drug Board. To protect yourself, seek reputable sellers, investigate the product and seek guidance from trained professionals.
Herbal remedies and other vitamins are sold as "food supplements" and do not undergo the rigorous testing that prescription meds do.
There is a great difficulty in evaluating herbs and herb-drug interactions because often the active ingredient in the products and its dose are not known.
Even when the interactions are known for one particular product, it's unclear how they will relate to similar products because of the lack of control over dosing. Whatever the possible benefits of herbs, vitamins and supplements, there's simply no meaningful information to guide making decisions when using them. Nausea, vomiting, diarrhea, cramps, skin irritation, mouth sores and may promote tumor growth. Excitement, loss of appetite and muscle control, diarrhea, labored breath, convulsion, coma and death.3Hypericin (St.
May induce sensitivity to light (photosensitivity), resulting in severe rash following sun exposure.
Depending on the dose, lobeline can cause either autonomic nervous system stimulation or depression. Adverse effects were published in February 1993, of 48 women identified with serious kidney disease associated with the use of a Chinese diet herbal product containing this herb. FDA Document, Illnesses and Injuries Associated with the Use of Selected Dietary Supplements, May 2000. A study conducted by the NIH found a significant interaction between the popular herbal therapy, St.
One possible limitation of the finding is that it is not clear how it applies to the various forms of St.
As this study shows, it's very possible for some herbal and nutritional supplements to lower the effectiveness of anti-HIV drugs or other medications. Several studies suggest that low levels of selenium are related to HIV disease progression. One component of the study was to evaluate the frequency of hospitalizations among those receiving selenium compared to placebo.
Additionally, researchers examined blood levels of selenium in 112 HIV-positive women on anti-HIV therapy. In short, the most that can be concluded from these reports is that it remains entirely unknown if selenium supplements offer any benefit or harm, whatsoever. In general, when used at reasonable doses on their own, nutritional products like vitamin A supplements are considered safe. Deficiencies in vitamin A (retinol, beta-carotene) have been associated with advanced HIV disease.
A team in Canada set out to evaluate whether or not different vitamin A supplements interact with the p450 enzyme. These data suggest that there are possible, real vitamin-drug interactions with potentially harmful results for people taking anti-HIV drugs.
This study suggests that for people taking anti-HIV therapy, vitamin E supplements are likely not necessary. However, trends were noted that children born to HIV-positive mothers who took multivitamins during pregnancy were more likely to be infected with HIV. The use of multivitamins was associated with slightly higher CD4+ and CD8+ cell counts and no overall changes in HIV levels in the blood.
Researchers speculate that using daily multivitamins among women is unlikely to protect them from HIV disease progression and may increase the chances of passing HIV onto others. Another Kenyan study found that vitamin A deficiencies in blood were associated with increased vaginal presence of HIV during pregnancy, increased HIV in breast milk, higher rates of mother-to-child HIV transmission, lower CD4+ cell counts and more rapid disease progression. These findings held true even among the 59% of women with notable vitamin A deficiencies at the start of the study.
Deficiencies in dietary zinc have been associated with decreased immune function and possibly increased HIV reproduction. A team in Florida examined the nutritional and immunologic status of 118 HIV-positive injection drug users. The study also showed that people with lower zinc levels had somewhat lower CD4+ cell counts and were more likely to have counts below 200. It has been well established that the formation of reactive metabolites of drugs is associated with drug toxicity.
Absorption, Disposition, and Pharmacokinetics of Saponins from Chinese Medicinal Herbs: What Do We Know and What Do We Need to Know More? Saponins are a group of amphiphilic glycosides containing one or more sugar chains linked to a nonpolar triterpene or steroid aglycone skeleton, which are believed to be responsible for the pharmacological activities of many Chinese medicinal herbs. Polyphenols present in foods and supplements may contribute to human health by preventing cardiovascular diseases and cancer. Sophora flavescens (SF) is an herbal medicine widely used for the treatment of viral hepatitis, cancer, viral myocarditis, gastrointestinal hemorrhage, and skin diseases.
The inhibitory effects of Angelica dahurica root extract on rat liver microsomal cytochrome P450 and drug-drug interactions were studied.
Furanocoumarins (also called furocoumarins and sometimes designated psoralens, after one of the best known furanocoumarins) and compounds of similar structure are found in several Chinese herbs (see Table 2). In vitro inhibition of CYP3A4 metabolism and P-glycoprotein-mediated transport by trade herbal products. The horse chestnut is useful to traditional prevent rheumatism, arthritis and the management of hemorrhoids and varicose. Intro of AIOCMA number of respected practitioners from North America, Australia and China have established the Association of Integrative Oncology and Chinese Medicine (AIOCM). The purpose of the AIOCM is bring together like-minded practitioners to establish protocols, trainings and standards in regards to the application of Chinese Medicine in the treatment of cancer, to increase the profile of Chinese Medicine and to establish research. Chinese Medicine has a contribution to make at every stage in the treatment of cancer, not just the symptoms. The AIOCM is committed to realise this vision so that we stand as equals in the treatment of cancer.
Herbal medicine can support the body to heal itself or while it is undergoing orthodox treatment. Medical herbalists are taught to diagnose medicine in the same way as orthodox doctors but believe in treating a patient holistically to achieve the best results. The herbalist will develop a treatment plan tailored to your particular needs and the appropriate herbal medicine will be dispensed.
A follow-up appointment is arranged for 3 weeks later to monitor progress and supply more medicine. We are the only centre offering this wide range of complementary medicine and alternative therapies in Ayrshire.
The popularity and use of herbal medicines and supplements have increased in the past decade.
In fact, studies suggest that almost 70% of people living with HIV and about half the general population use some form of complementary therapy.
They have not been studied to see how they interact with common medications or whether they add to the overall benefits of anti-HIV therapy. Promoters of supplements and herbs are often the first to criticize prescription drugs as the products of "big business." However, supplements are themselves part of a huge industry -- with annual sales of around $20 billion.
All they need to do is assert that the product is "generally regarded as safe." What this means is that studies are not required to show the effectiveness and safety of these products. Also, these products do not have to be made according to the same Good Manufacturing Practices established for making prescription meds. According to researchers who evaluate these therapies, the quality products that undergo evaluation by the manufacturer are, in general, not the ones you'll find at your average grocery store or pharmacy. John's Wort (hypericin), a popular herb used for mild depression, has possibly serious interactions with protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTI). This information, coupled with knowing that garlic has an effect on p450, suggests that until more is known people should use caution when combining high doses of garlic with anti-HIV drugs that use p450. While this was based on test-tube studies, the information suggests that there might be possible vitamin-drug interactions as well.
At high doses (more than 25,000 IU per day) toxicities are more likely, including loss of appetite, weight loss, bone malformations, spontaneous fractures, internal bleeding, liver toxicities and birth defects.Vitamin B-6 (pyridoxine)Reversible neuropathy has been reported in people taking high doses (500mg to 6 grams a day) over extended periods of time.
One way to capture information about drug interactions and side effects is to record all the supplements you use in a complete drug history. Many people believe that because something is "natural" or sold over-the-counter that it doesn't have side effects. One man stopped all his anti-HIV meds to try to determine which had upset his stomach and quality of life. Taking too many B-6 vitamins can lead to a complication that lands one in the hospital and excessive levels of vitamin A can be highly toxic to the liver. The FDA readily admits that it doesn't have enough enforcement to ensure that these products stay off store shelves.
This followed an incident when a person with diabetes was hospitalized after taking one of the supplements. Other resources that may help are ones that address fraud issues, such as state AIDS Fraud Task Forces and Project Inform's publication, How to Identify AIDS Fraud. Some contend that in order for the body to optimally absorb and use vitamins they need to be delivered through better nutrition, in foods where they exist in complex forms which may help the body to better use the nutrients.
Government, through the NIH, has established two botanical centers to evaluate these types of therapies.
Although drug interaction studies for medications typically take a matter of a week to ten days, drug-herb interaction studies are expected to take much longer. Because no studies have determined the proper or best dose of many complementary therapies, researchers face another challenge in first selecting the dose of herbs to use in studies. For some, the risks are small and only occur when herbs are used in large quantities or for long periods of time. The FDA issued a health warning in 1992 and many companies voluntary removed chaparrel from their products or recalled products containing chaparrel.
May also have interactions with some anti-depressants called Monoamine Oxidase Inhibitors (MOIs). Should also be avoided by individuals with low blood pressure, diabetes, and heart, liver or kidney disease. John's Wort is also likely to have the same effect on other protease inhibitors as well as NNRTIs. People who use complementary therapies should always discuss possible interactions with their doctors and pharmacists. Selenium is a toxic substance that gets spread into the environment through the burning of fossil fuel and other industrial processes. In one case, high levels led to selenium poisoning in a man using supplements as a way to manage his fatigue. One study of 24 children and another of 125 adults has shown that those with these deficiencies were at a greater risk for disease progression and death.
Some have proposed that when HIV uses all the selenium in a given cell, it may leave that cell to find more selenium by infecting other cells. Information about CD4+ cell count, viral load and other parameters were collected at the first study visit and then every six months thereafter for two years. Unfortunately, sloppy data reporting leaves results of this aspect of the study completely not interpretable currently. They looked for links between selenium levels and the risk for pre-cancerous cervical cells (cervical dysplasia).
Risks for cervical dysplasia appear slightly higher when selenium levels are lower, but selenium supplements do not appear to eliminate this risk. New information suggests that when used with other therapies, including anti-HIV drugs and other nutritional products, interactions may occur that alter a product's effectiveness and safety. It remains unclear if taking vitamin A supplements such as retinoids or beta-carotene helps people with HIV beyond correcting the deficiency. Therefore, these products (and possible other nutritional health products) are very likely to interact with anti-HIV drugs.
Much more information is needed to fully understand the scope of these interactions and their impact on the effectiveness and side effects of therapies.
Also, low levels of vitamin E have been associated with increased risk of disease progression. No differences were seen in vitamin A levels either before or six weeks after starting anti-HIV therapy. Moreover, vitamin A deficiencies were not noted with HIV infection, regardless of stage of disease.
This has led to an interest in using multivitamins, particularly in resource-poor settings and those where malnutrition is a problem.
Because of this, another study was started in Kenya to examine the impact of using daily multivitamins (or placebo) and evaluate its impact on vaginal and cervical presence of HIV.
However, it was also associated with increased vaginal presence of HIV, with about ½ log higher levels of HIV in vaginal swabs. The results are perhaps more relevant to places where anti-HIV therapies are not available or to those who choose not to use them together with multivitamins.
Four hundred women took either placebo or vitamin A at the dose recommended by the World Health Organization for correcting symptomatic vitamin A deficiencies in women of child-bearing potential.
They suggest that while vitamin A deficiencies may be associated with poorer outcomes in passing HIV from mother to child and of HIV disease in general, supplements are unlikely to address these problems.
They found that people whose diets included foods with higher levels of zinc showed higher levels of zinc in their blood.
It would be rash to suggest, however, that low zinc levels are the cause of lower CD4+ cell counts and not merely an effect of disease progression.
The causes of these interactions are mainly divided into pharmacodynamic and pharmacokinetic processes. The purpose of this paper is to summarize the contemporary knowledge of the absorption, disposition, and pharmacokinetics of some important saponins, including ginsenosides, licorice saponins, dioscorea saponins, astragalosides, and saikosaponins. Their known or potential adverse events should be taken into account during treatment with herbal medicines.
Drug-food or drug-herb interactions have recently come into focus but, except for some phytochemicals, few components of food or herbs participate in such interactions. The 2alpha- and 16alpha-hydroxylase activity of testosterone were most strongly inhibited, with 17.2% and 28-5% of their activity remaining, respectively, after oral administration of A. John’s wort, common valerian, common sage, Ginkgo biloba, Echinacea purpurea and horse chestnut were investigated for their in vitro inhibitory potential of CYP3A4 mediated metabolism and P-glycoprotein efflux transport activity. It prevents the breakdown of collagen by inhibiting glycosaminoglycan hydrolases.Its seeds are very toxic but, there have been several methods that can remove this toxicity. It means using whole plants – leaf, root, berry, flower and bark to create medicines. Some people prefer to use herbal medicine as a lifestyle choice.  Some people turn to herbal medicine to assist them with a chronic illness, often where orthodox medicine has been unable to help.
This means treating the person, not the disease and getting to the root cause of the problem not just relieving symptoms. This allows the herbalist to get a complete picture of your overall health as well as focusing on the specific health problem. Please keep this in mind, and be sure to visit other parts of our site for more recent information! Recently, several reports have questioned the safety of some of these therapies in HIV and other diseases. This publication highlights some emerging concerns about using various therapies and addresses ways to limit the possible risks when using them. This leaves the consumer with little or no meaningful information about their benefits or side effects. As a result, these products vary widely in terms of their active ingredients, and even between batches of the same product. However, the best manufacturers make a serious effort to deliver the real product in the amounts claimed. Seek guidance from a trained alternative medicine practitioner, like an herbalist or nutritionist who specializes in HIV, and gather information about the products you're considering.
A second case also reported that garlic supplements may have enhanced the side effects from using ritonavir. Moreover, people using the supplement with anti-HIV drugs who experience serious stomach problems (diarrhea, nausea or vomiting) might consider stopping it to see if these symptoms lessen. For people with previous side effects associated with taking higher doses, symptoms resumed at doses as low as 50mg per day.
Doctors may need to learn to listen and support their patients, in a nonjudgmental way, about using these therapies. It's also important for patients, doctors and pharmacists to keep up-to-date on the latest drug-herb and drug-vitamin interaction studies.

To the contrary, many people with HIV experience side effects from complementary therapies. It turned out that when he stopped his herbal therapy (with deer antler), his problems cleared. These examples illustrate the need to be cautious when adding large doses of vitamins to your diet. Keeping an accurate record of every therapy you take, including when you start and stop them, and documenting the onset of side effects may help sort out which one is causing the problem. Media exposés on this topic in California reveal countless tales of people harmed by products that contain lead, arsenic, anabolic steroids and other dangerous substances.
The other is that people should simply improve their nutrition and increase their vitamin intake through better eating. The use of these therapies has risen almost 400% in the past eight years, and it's estimated that half the people in the U.S. This is a more expensive process since people will probably have to take herbs for a few weeks before an effect is seen. Funding for these studies still remains a problem and a limitation to moving forward rapidly. For others, severe and life-threatening side effects have been seen even at very low doses with a single use. In 2001 the FDA classified it as a Class 1 toxic substance and product recalls were started. In 2002 the FDA issued a warning noting that while liver-related injury associated with kava use is low, consumers should be warned of risks.
Higher doses result in respiratory depression, as well as sweating, rapid heart rate, hypotension, and even coma and death. Symptoms of over dosage include weakness and nervous stimulation followed by paralysis, fatigue, stomach disorders and ultimately death. Indinavir blood levels were greatly decreased when the two were used together, greatly reducing indinavir's anti-HIV activity. It is standard practice for doctors to check selenium levels in people on TPN and supplement as necessary. Investigators analyzed the over-the-counter product and found selenium levels of 500 to 1,000 times the amount labeled for each pill. Interestingly, HIV-positive women with low selenium levels have higher rates of HIV in vaginal secretions. While selenium levels were lower in women who developed dysplasia, using supplements made no difference in the risk of developing dysplasia. Moreover, questions remain as to whether or not vitamin A supplements cause vitamin-drug interactions.
This information would also be needed on how to modify doses of either therapy to reduce the risk of developing drug resistance and increase the chances of benefiting from both.
Researchers in the United Kingdom sought to evaluate vitamin E levels among 33 people before and six weeks after starting anti-HIV therapy.
Moreover, vitamin A levels were in normal healthy ranges, roughly equivalent to those seen in HIV-negative people, both before and after therapy. A study in Tanzania, Africa among HIV-positive pregnant women showed that using multivitamins led to fewer deaths of unborn children, increased birth weights and fewer pre-term births. The percentage of vaginal cells with HIV was higher among those taking daily multivitamins (31%) than those on placebo (17%). The use of multivitamins was linked to improved markers of immune health (slight increases in both CD4+ and CD8+ cell counts).
The study found that the supplements had no effect whatsoever on vaginal presence of HIV, blood levels of HIV, or CD4+ or CD8+ cell counts. As with the other study, this study did not evaluate using supplements together with anti-HIV therapy.
These include poor diets, poor absorption of nutrients and poor processing of nutrients by the body. This suggests that, in general, improving a person's diet results in more normalized zinc levels. In general this study is encouraging in that it shows that simply improving diet, without supplements, leads to increased zinc levels in the blood and better immune status. It has been hypothesized that the resultant reactive metabolites following herbal bioactivation covalently bind to cellular proteins and DNA, leading to toxicity via multiple mechanisms such as direct cytotoxicity, oncogene activation, and hypersensitivity reactions. Poor intestinal absorption of saponins is mainly due to their unfavorable physicochemical traits, such as large molecular mass (>500 Da), high hydrogen-bonding capacity (>12), and high molecular flexibility (>10), that underlie poor membrane permeability. In this study, we systematically evaluated the inhibitory effects of 60 polyphenols and related compounds on human cytochrome P450 (CYP) 3A4 and CYP2C9 activity by in vitro assay to investigate whether some polyphenols induce drug interactions.
This herb is popularly utilized in Europe.It is very useful in treating the insufficiency of chronic venus, veins, tension, varicose, tiredness, leg pain, edema and swelling.
Countless drugs are still derived from plant sources and more than 80% of the world’s population still depend on herbal medicine for survival.
Patients with long term conditions can find a new level of wellbeing using herbal medicine either alongside or in place of their orthodox treatment. They can work in partnership with your GP or other health care provider.  As balanced, natural products, herbal medicines have few side effects and are often more gentle on the body than modern drugs. This case demonstrates why it is important that health care practitioners report ADRs to the Food and Drug Administration (FDA). Plant extracts that are used for medicinal purposes are not regulated by the Food and Drug Administration and are available over-the-counter.
In fact, studies show that some products on the market today contain no active ingredients whatsoever. But due to the lack of industry regulations, there's no simple way to know who is telling the truth.
Only taking the word of people selling the products does not guarantee accurate information. John's Wort is processed in the body by the same enzyme used for processing many drugs, including protease inhibitors and most NNRTIs. It is unclear, however, if garlic was increasing the risks of ritonavir-related side effects or if it was the actual cause of them. There are food-drug interactions, which is why certain drugs are absorbed better when taken with or without food.
The additional medication in the claimed "natural" product led to an overdose for that person.
Likely the best approach for people at risk for vitamin deficiencies is one that lies somewhere between these two approaches. Don't assume that just because something is available over-the-counter or is "natural" that it doesn't have side effects or won't interact negatively with your other meds. Every few years, new discussions are held about whether and how to better regulate the marketing of nutritional supplements and herbs. Many companies that sell complementary therapies are reluctant to fund studies which may reveal their products are not useful, have side effects or have interactions with common meds.
A good herbal practitioner should discuss the potential risks of both side effects and herb-drug interactions with you. If you don't see the herb(s) you may be taking on this list, it does not mean that there are no reported or possible side effects from using them.
Panax and Eleutherococcus ginsengs produce morning diarrhea, insomnia, nervousness, depression, confusion, skin rashes and high blood pressure. Further, those with liver disease or taking other drugs that affect the liver should be especially careful. Symptoms from consuming too much selenium include brittleness and loss of hair and nails, skin redness, blisters, vomiting, fatigue, neurological defects and damage to the liver and spleen. Recommended Daily Allowance of selenium (all ages and genders) is 55 micrograms (µg).
This led to warnings noting that unusual diets and vitamin supplements are the most common causes of selenium toxicity in the U.S. Again, it remains unclear if selenium deficiency is a cause or an effect of HIV disease progression and if supplements will help or hurt.
Well-designed research is critical to evaluating the possible benefits (and risks) of selenium supplements. One product had ten-fold less beta-carotene than advertised, and most were at least half as much than stated. Further, no differences were seen in vitamin A levels between healthy HIV-positive people and those with AIDS.
It remains unknown whether the increased vaginal presence of HIV from using multivitamins would be controlled while using anti-HIV therapy. Another study is ongoing to see if zinc supplements will result in improved blood levels of zinc and to see if it has any effect on HIV or immune markers. Metabolic food-drug interactions occur when a certain food alters the activity of a drug-metabolizing enzyme, leading to a modulation of the pharmacokinetics of drugs metabolized by the enzyme.
Rapid and extensive biliary excretion is another primary factor that limits the oral bioavailability of most saponins. In addition, the kinetics of potent CYP inhibitors was investigated by Lineweaver-Burk plot analysis. In the current study, we tested the hypothesis that SF-induced CYP3A expression is mediated by the activation of pregnane X receptor (PXR). 6beta-Hydroxylase activity was also inhibited, with 70% of its activity remaining, under the same conditions. Its extract is helpful in the conjunctive treatment for hemorrhoids, lymphedema and prostrate enlargement. However, herbs are powerful and it is always recommended that you consult a fully qualified medical herbalist rather than self-medicating as the strength and potential interactions of some herbs may be missed.
Taking herbal medicines with prescribed drugs can potentially result in serious or dangerous interactions. This enzyme is called p450, and several diet supplements and herbs have reported effects on it. This underscores that supplementing with vitamins, in pill forms, could carry some risks along with its unknown benefits. Currently, the industry has done very little to document the safe and effective use of its products. However, this shouldn't replace discussing these interactions and side effects with your doctor and pharmacist. Many resources exist on the internet and elsewhere providing even more comprehensive information.
Ginsengs are known to increase effects of some anti-depressants called Monoamine Oxidase Inhibitors (MOIs).
Similar problems with drug interactions may occur between the herb and drugs used to treat other life-threatening illnesses, such as heart disease.
The latter was capable of reacting with DNA and proteins, resulting in activation of H-ras oncogene, gene mutation and finally carcinogenesis. However, several saponins, including ginsenosides Ra3, Rb1, Rc, and Rd, and dioscin, are excreted slowly into the bile and in turn have significantly long elimination half lives (7-25 h in rats). John’s wort is known to be a potent inducer of cytochrome P450 (CYP) 3A4 leading to reduced blood concentrations of a number of CYP3A4 substrates. We used two cell lines, DPX2 and HepaRG, to investigate the role of PXR in SF-induced CYP3A expression. In addition, treatment with the extract inhibited the metabolism of tolbutamide, nifedipine and bufuralol. A validated high-performance liquid chromatography methodology was used to quantify the formation of 6-OH-testosterone and scintillation counting was used to quantify the transport of (3)H-digoxin. We will then examine several well-recognized types of drug interactions that are the causes of preventable adverse reactions. Depending on how these products interact with p450, using anti-HIV drugs with them could either raise or lower the blood levels of the anti-HIV drugs. The value of good nutrition for overall health is well known; the value of supplementing with vitamins is not. People with a history of kidney stones should consult a doctor before taking high doses.Vitamin DPotentially very toxic, can cause bone lesions. Pharmaceutical companies are also unwilling to fund these studies for many of the same reasons, and the FDA does not require them. The Institute of Medicine has proposed that the maximum daily intake before causing toxic effects is roughly 400µg for adults. Other examples are pulegone present in essential oils from many mint species; and teucrin A, a diterpenoid found in germander (Teuchrium chamaedrys) used as an adjuvant to slimming diets. Foods consisting of complex chemical mixtures, such as fruits, alcoholic beverages, teas, and herbs, possess the ability to inhibit or induce the activity of drug-metabolizing enzymes. These long-circulating saponins may be used as pharmacokinetic markers to substantiate systemic exposure to the ingested herb extracts.
For many other combinations evidence is sparse but due to a number of case reports of adverse interactions they should only cautiously be combined with certain critical dose drugs until their risk is fully assessed. Lineweaver-Burk plot analysis indicated that apigenin and its dimer amentoflavone and imperatorin displayed a mixed type of inhibition on CYP3A4 or CYP2C9. The DPX2 cell line is derived from HepG2 cells with the stable transfection of human PXR and a luciferase reporter gene linked with a human PXR response element identified in the CYP3A4 gene promoter.
This means she has completed a stringent training regime to degree level, alongside a minimum 500 hours of clinical practice. This section will focus primarily on cytochrome P450-mediated drug interactions, although other types of interactions will also be included, as well as examples of drug-drug, drug-diet, and drug-herbal interactions. Extensive pulegone metabolism generated p-cresol that was a glutathione depletory, and the furan ring of the diterpenoids in germander was oxidized by CYP3A4 to reactive epoxide which reacts with proteins such as CYP3A and epoxide hydrolase. According to results obtained thus far, cytochrome P450 3A4 (CYP3A4) appears to be a key enzyme in food-drug interactions. In addition to biliary excretion for elimination of most saponins unchanged, renal excretion may also be important for certain saponins. Pertinent examples are the immunostimulant Echinacea which could decrease the effect of immunosuppressants. Members must adhere to a strict code of ethics and a robust programme of Continuing Professional Development.
The emphasis will be on current knowledge that can help healthcare providers predict possible drug interactions.
John's Wort, garlic, ginseng, melatonin, milk thistle (silymarin), geniposide and skullcap.
For example, interactions of grapefruit juice with felodipine and cyclosporine, red wine with cyclosporine, and St John’s wort with various medicines including cyclosporine, have been demonstrated. The K(i) value of amentoflavone was significantly lower than that of the CYP2C9 inhibition positive control sulfaphenazole. We used a metabolomic approach to identify the chemical constituents in SF, which were further analyzed for their effect on PXR activation and CYP3A regulation. This will be followed by a discussion of ADR reporting via the FDA’s MedWatch program.
The resultant metabolites lead to CYP inactivation by chemical modification of the heme, the apoprotein, or both as a result of covalent binding of modified heme to the apoprotein. The results indicate the requirement of dosage adjustment to maintain drug concentrations within their therapeutic windows. These findings suggest that some dietary polyphenols may have the potential to inhibit the metabolism of clinical drugs. One chemical in SF, N-methylcytisine, was identified as an individual chemical that activated PXR. In line with the poor permeability, saponin concentrations in most rat tissues are lower than the concurrent plasma level and the brain level is usually very low. It had little effect, however, on the pharmacokinetic parameters of diazepam after intravenous administration at 10 mg kg(-1). CYPs have been known to metabolize more than 95% therapeutic drugs and activate a number of procarcinogens as well. This review article summarizes the findings obtained to date concerning food-drug interactions and their clinical implications.
However, the liver concentrations of many saponins, as well as the kidney levels of certain saponins, can be quite high, which involves transporter-mediated uptake mechanisms.
In HepaRG cells, N-methylcytisine significantly induced CYP3A4 expression, and this induction was suppressed by the PXR antagonist sulforaphane.
Since diazepam showed high clearance, it underwent hepatic blood flow rate-limited metabolism. Recognition and reporting of this arrhythmia in association with terfenadine, astemizole (Hismanal), cisapride (Propulsid), grepafloxacin (Raxar), and mibefradil (Posicor) ultimately led to the removal of these medications from the market.1Monahan BP, Ferguson CL, Cleave ES, Lloyd BK, Troy J, Cantilena LR. Therefore, mechanism-based inhibition of CYPs may provide an explanation for some reported herb-drug interactions and chemopreventive activity of herbs. It seems likely that more information regarding such interactions will accumulate in the future, and awareness is necessary for achieving optimal drug therapy. No correlation was found between the herbs inhibitory potentials towards CYP3A4 and P-glycoprotein activities. Due to the wide use and easy availability of herbal medicines, there is increasing concern about herbal toxicity.
However, the Cmax value after oral administration of diazepam with extract treatment was four times that with non-treatment.
The safety and quality of herbal medicine should be ensured through greater research, pharmacovigilance, greater regulatory control and better communication between patients and health professionals. More research is required for elucidation of the absorption, disposition, and pharmacokinetics of multiple saponins to enhance understanding which saponins are most likely to exert pharmacological effects in vivo, as well as influence of complex herb matrix. John’s wort, are suggested candidates for in vivo intestinal herb-drug pharmacokinetic interactions. On the eighth day of terfenadine therapy the patient began a self-medicated course of ketoconazole (Nizoral—an azole antifungal) at 200 mg twice-a-day for vaginal candidiasis. In addition, research is also needed to characterize the microbiotal deglycosylation and the subsequent aglycone metabolism by the host for more saponins, as well as the hepatobiliary transporter phenotyping for and the interaction with saponins.
Furthermore, in vitro and in vivo studies of saponin-based herb-drug interactions are warranted for a broader range of saponins. Upon admission to the hospital the patient was noted to have a QTc interval of 655 milliseconds (normal is less than 440 milliseconds).
During the hospitalization the patient experienced near syncopal episodes associated with torsades de pointes noted on telemetry.After discontinuing the medications, the QTc interval normalized.
She had no further episodes of torsades de pointes, and she was discharged with no recurrence of syncope.1Monahan BP, Ferguson CL, Cleave ES, Lloyd BK, Troy J, Cantilena LR.
Ketoconazole has not been associated with development of torsades de pointes when used by itself.
How did ketoconazole interact with terfenadine to cause QT prolongation and torsades de pointes in this patient? That question will be answered during the course of this module.1Monahan BP, Ferguson CL, Cleave ES, Lloyd BK, Troy J, Cantilena LR. The Institute of Medicine reported in January of 2000 that from 44,000 to 98,000 deaths occur annually from medical errors.1 Of this total, an estimated 7,000 deaths occur due to ADRs.
Incidence of adverse drug reactions in hospitalized patients: A meta-analysis of prospective studies.
Again, methodological constraints limit making completely accurate estimates, but one estimate of the cost of drug-related morbidity and mortality is $136 billion annually,1 which is more than the total cost of cardiovascular or diabetic care in the United States. This will allow us to make the most appropriate choices in prescribing and avoiding preventable ADRs.1Schappert SM. Ambulatory care visits to physician offices, hospital outpatient departments, and emergency departments: United States,1997.

However, some drugs cause serious ADRs at very low frequencies and would require many more exposures to detect the reaction. For example, bromfenac (Duract) was a non-steroidal anti-inflammatory agent (NSAID) that was removed from the market in 1998, less than 1 year after it was introduced. Bromfenac caused serious hepatotoxicity in only 1 in 20,000 patients taking the drug for longer than 10 days.1 To reliably detect the toxic effects of a drug with a 1 in 20,000 adverse drug reaction frequency, the new drug application database would have to include 100,000 patient exposures. A drug that is tested in a few thousand people 11 may have an excellent safety profile in those few thousand patients.
However, within a short time after entering the market, the drug may be administered to several million patients.
The complete safety profile of a new drug will be defined only after it has been approved and is in use on the market.1Friedman MA, Woodcock J, Lumpkin MM, Shuren JE, Hass AE, Thompson LJ. However, the temporal relationship of a reaction with regard to the administration of a new medication can be helpful. Also, biological plausibility (asking if the drug’s mechanism of action makes this possible or likely) can also be helpful. A health care provider does not have to be absolutely certain that a drug caused a reaction. In the example case in this module, a single report ultimately led to the removal of terfenadine from the market.
This report potentially saved many lives and led to a better understanding of the mechanism involved in causing torsades de pointes. Almost all drugs are now evaluated prior to being released on the market for their potential to induce cardiac arrhythmias, also as a result of this single case report.1Figueiras A, Tato F, Fontainas J, Gestal-Otero JJ. Each of these drugs has value in the pharmaceutical marketplace, and each has value to patients. Although the respondents were very concerned about suffering from pain and the cost of filling prescriptions, they were most concerned about being given the wrong drug or that a drug interaction would occur. The public in general has a much greater level of concern about ADRs than most health care providers would suspect.
These data demonstrate that drug interactions and reactions are not only a concern to health care providers but to patients as well.1American Society of Health Systems Pharmacists.
Bethesda, MD.Types of Drug InteractionsThe previous slides have reviewed information about the magnitude of adverse drug reactions and the burden they place on the health care system. How much do drug interactions contribute to the total number of preventable ADRs? Again, estimates of the numbers of patients injured due to drug interactions vary widely. 2Raschetti R,  Morgutti M, Menniti-Ippolito F, Belisari A, Rossignoli A, Longhini P, et al.
Suspected adverse drug events requiring emergency department visits or hospital admissions. More significant is the fact that, although this information is avail-able, it is not uniformly or optimally incorporated into decision making.
A fundamental understanding of the clinical pharmacology of drug interactions and a framework for avoiding preventable drug interactions remains critically important.
Thus we need to overlay technologic solutions on a base that is strong in basic principles of clinical pharmacology and drug interactions. Incorporation of up-to-date computerized databases is valuable, and frequent consultation with other members of the healthcare team, such as nurses and pharmacists, is essential.1Bates DW, Leape LL, Cullen DJ ,Laird N, Petersen LA, Teich JM et al.
Effect of computerized physician order entry and a team intervention on prevention of serious medication errors. Contraindicated use of cisapride: impact of food and drug administration regulatory action. Both slow the heart rate by different mechanisms, and the combination is relatively contraindicated because heart block can result. Because of this interaction many textbooks and computer pro-grams warn against concomitant use of any beta-blocker and any calcium channel blocker.
This creates a great deal of confusion and distrust of drug interaction warnings, because most health care providers know that drugs in these two classes are often employed successfully and safely in patients with hypertension.The next few slides will review some of the mechanisms for drug interactions in more detail. Several examples of drug interactions that occur prior to drug administration are listed here.
When phenytoin is added to solutions of dextrose, a precipitate forms and the phenytoin falls to the bottom of the IV bag as an insoluble salt. Amphotericin is still used widely as a urinary bladder perfusion to treat aggressive fungal infections. If it is administered in saline, the drug precipitates and can erode through the bladder wall if not removed. The clinical presentation of such cases is an acute abdomen due to perforation of the bladder.1 Lastly, it is recommended that aminoglycosides not be co-mixed in IV fluids with betalactam antibiotics. Women taking iron supplements often do not consider them as a medicines, and should be specifically questioned about whether they are taking iron if they are to be prescribed a quinolone or azithromycin. Drugs such as ketoconazole (Nizoral) and delavirdine (Rescriptor) require an acidic environment to be in the non-charged form that is preferentially absorbed. The previously cited examples have subsequently been shown to be due to inhibition of elimination, not plasma protein displacement.Drug MetabolismThe next few slides will focus on drug metabolism. Some important preventable drug interactions are due to their effects on drug metabolizing enzymes, resulting in either inhibition (reduced activity) of the enzyme or induction (increased activity) of the enzyme.
Of the remaining drugs, some are converted to metabolites that retain the same activity as the parent.
An example of this is fexofenadine (Allegra), the active metabolite of terfenadine that has equal potency at the histamine receptor and now is on the market and used clinically for allergic rhinitis. On the other hand, if the parent drug needs to be metabolized to the active compound and metabolism is inhibited, then a therapeutic failure could result. Induction of drug metabolizing enzymes could similarly result in a subtherapeutic effect by reducing drug levels below that required for efficacy.1Woosley RL, Chen Y, Freiman JP, Gillis RA. In addition to cytochrome P450, there are other enzymes in microsomes such as flavin monooxygenase (termed FMO3). Since Phase II reactions generally result in conjugation of a drug to a water-soluble group like a sugar, peptide (glutathione) or sulfur group, and, because there is a large excess of these groups in well nourished cells, these reactions are rarely rate-limiting.
In contrast, the Phase I reactions carried out by cytochrome P450 enzymes, flavin monooxygenases, and reductases are more frequently rate-limiting.
These are the target of clinically significant drug interactions, such as the inhibition of cyclosporine metabolism by erythromycin.Six cytochrome P450 isoforms have been well characterized in terms of drug metabolism in humans.
The predominant enzymes responsible for Phase I reactions are those involving the microsomal mixed function oxidation system. These enzymes are companions and part of a cascade that shuttles electrons from molecular oxygen to oxidize drugs. Because many drugs are metabolized principally by these enzymes, important interactions between drugs can be predicted by using a list of drugs that are inhibitors or inducers of that enzyme.
This simplifies the search for interacting drugs and provides a framework for prediction of interactions. Next we will review how these enzymes are named.Cytochrome P450s were named by molecular biologists and protein chemists. Because of this great sensitivity, small changes in amino acid sequence can result in huge changes in substrate specificity for the cytochrome P450 enzymes. For example, 2C19 is the principal metabolic enzyme for omeprazole (Prilosec) metabolism, but a closely related enzyme, 2C9, has no catabolic effect on omeprazole. Thus, little functional similarity is imparted by the similarity in amino acid sequence on which this nomenclature is based.
However, as will be seen later, there is some concordance between classes of drugs and the P450 family that metabolizes them. The focus of the subsequent slides will be to outline the role of the cytochrome P450 isozymes in metabolism of commonly used drugs and to identify tools that can be used in clinical practice to avoid cytochrome P450-mediated drug interactions.The graph on the left lists the major isoforms of CYP450 and their relative roles in drug metabolism (not relative amounts found in the liver) based upon the number of drugs that are known to be metabolized by that particular isozyme. CYP2D6 accounts for less than 2% of the total content of P450 in the liver, but as shown on the left, is responsible for the metabolism of a large fraction of drugs.
A large amount of cytochrome P450 has not yet been characterized.There is tremendous variability between individuals in terms of expression of cytochrome P450 isozymes. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. As a result, the enzyme may be absent or have low, or no, metabolizing activity for drugs that are usually metabolized by that enzyme. If the mutation is relatively common (more than 1%) it creates a polymorphism—this is a trait that has genetic variation that results in more than a single population being represented in greater than 1% of the total population. On the graph, PM means poor metabolizer, EM means extensive metabolizer, which is the normal or usual phenotype, and URM means ultra-rapid metabolizer. Ultra-rapid metabolizers usually do not appear as a separate distribution in most phenotypic data but are important because a usual dose of drug in these people will be cleared more quickly than in the rest of the population and will result in lower blood levels of the drug and, perhaps, less therapeutic effect. For CYP2D6, it is known that these individuals have very high activity because they have multiple copies of the CYP2D6 gene (up to13 copies have been reported).Second, people that have usual drug metabolizing ability (EM) can become phenotypic poor metabolizers if they are given a substance (drug or food as we will see later) that inhibits the enzyme. If this occurs, metabolism of any drug that is a substrate for that isozyme will be metabolized more quickly resulting in lower plasma concentrations of the drug. Also, if the drug is metabolized to a toxic compound, the toxic metabolite may accumulate to higher levels.The P450 isozymes will now be reviewed in more detail.
The laminated card in the pocket of the module can be used as a reference for the next few slides.CYP3A is responsible for metabolizing the greatest number of marketed drugs. These include a wide range of important medications including cyclosporine and HIV protease inhibitors, as well as cisapride (Propulsid) and the no longer marketed non-sedating antihistamines terfenadine (Seldane) and astemizole (Hismanal). Although CYP3A is not polymorphic in its distribution (it doesn’t have a distinctly separate population as seen on the previous graph), its activity varies over 50-fold in the general population.
Terfenadine, one of the first non-sedating antihistamines, is metabolized by CYP3A to fexofenadine. When the CYP3A-mediated metabolism of terfenadine is inhibited by ketoconazole, as in the case described, terfenadine accumulates to high levels. At these high levels, terfenadine is a blocker of potassium channels in the heart.2 Potassium channels are important for repolarization of the heart.
Once these channels are blocked, QT interval on the electrocardiogram can be prolonged and torsades de pointes can  develop, as was seen in this case. This important enzyme has been the basis for most of the fatal drug interactions that have gained so much publicity in recent years. For terfenadine, as well as astemizole and cisapride, recognition and reporting of torsades de pointes in association with the drug and its interactions ultimately led to withdrawal of these drugs from the market.The vast majority of drugs that may cause cardiac arrhythmias by prolonging the QT interval are metabolized by cytochrome P450 3A. While the biological basis for this remains unclear, it does make it easier to remember!Also note that CYP3A is found in the liver and also in the GI tract. Drugs that are substrates of CYP3A can be extensively metabolized in the GI tract, and ,in fact, the GI tract is responsible for a large part of the metabolism that was formerly attributed totally to the liver!
Inhibition of GI tract CYP3A also results in higher plasma levels of substrate drugs.1Thummel KE, Wilkinson GR.
Azole antifungal drugs, in general, are potent inhibitors of CYP3A, although fluconazole is a weak inhibitor and inhibits CYP3A only at high doses. All the macrolide antibiotics, except azithromycin, are also potent inhibitors of this cytochrome P450 isoform.
The role of grapefruit juice in drug interactions will be discussed later.Several commonly used drugs have been characterized as inducers of CYP3A. Use of these drugs could potentially result in lack of therapeutic efficacy of a CYP3A substrate. Study of CYP2D6 has led to understanding the failure of codeine to relieve pain in some patients. Codeine itself is much less active as an analgesic, but causes nausea and other adverse effects.
These include quinidine3 as well as haloperidol and some other antipsychotics.4,5 The well-described pharmacokinetic interaction between selective serotonin reputake inhibitor (SSRI) antidepressants and tricyclic antidepressants appears to be due to the fact that fluoxetine and paroxetine are both potent inhibitors of CYP2D66,7 and render patients metabolically equivalent to people who do not have the enzyme.
This increases the plasma levels of tricyclic antidepressants and increases the potential for side effects.
In contrast, patients co-prescribed fluoxetine or paroxetine with codeine may experience no analgesic benefit, since codeine requires CYP2D6 for metabolism to morphine.1Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. Frequent distribution of ultrarapid metabolizers of debrisoquine in an ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced halo-peridol. Effect of antipsychotic drugs on human liver cytochrome P-450 (CYP) isoforms in vitro: preferential inhibition of CYP2D6. Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients. It is the major enzyme responsible for metabolism of many of the non-steroidal anti-inflammatory drugs (NSAIDs), including the second generation cyclooxygenase-2 (COX-2) specific inhibitors. A number of other important medications have their metabolism primarily catalyzed by CYP2C9.
An important drug metabolized by this enzyme is warfarin (Coumadin), and almost all inter-patient variability in warfarin levels and anticoagulant effects can be explained on the basis of CYP2C9 activity (not the differences in protein binding as originally thought).The azole antifungal agent fluconazole (Diflucan) is a potent inhibitor of CYP2C9.
Contrasting effects of fluconazole and ketoconazole on phenytoin and testosterone disposition in man. This enzyme metabolizes many anticonvulsants, diazepam (Valium), omeprazole (Prilosec) and several of the tricyclic antidepressants. Asians have reduced clearance of diazepam compared to Caucasians,1 and, in fact, a survey of Asian and Western physicians demonstrated the use of lower doses of diazepam in Asians.2 Asian patients may have a lower omeprazole dosage requirement for effective treatment of Helicobacter pylori.
Do Oriental psychiatric patients receive different dosages of psychotropic medication when compared with occidentals. Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer.
Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin. Effects of ketoconazole on the polymorphic 4-hydroxylations of S-mephenytoin and debrisoquine.
Comparison of the interaction potential of a new proton pump inhibitor, E3810,versus omeprazole with diazepam in extensive and poor metabolizers of S-mephenytoin 4'-hydroxylation. Inhibition of cytochrome P450 (CYP450) isoforms by isoniazid: potent inhibition of CYP2C19 and CYP3A.
The clearance of theophylline, imipramine, propranolol and clozapine are all increased by smoking.
Thus, people who smoke may require higher doses of some of the medications that are substrates of CYP1A2. In contrast, a smoker would require a decrease in theophylline dosage if, for example, smoking were discontinued and the enzyme no longer induced. Ciprofloxacin increases serum clozapine and N-desmethylclozapine: a study in patients with schizophrenia.
An evaluation of the quinolone-theophylline interaction using the Food and Drug Administration spontaneous reporting system. Fortunately there are aids to help health care providers to anticipate and prevent drug interactions, such as the tool shown here.
This table includes a listing of the 6 major cytochrome P450 isozymes involved in drug metabolism and the drugs that are metabolized by them.
We recommend using this or another table as a quick reference for detection of potential drug interactions.If 2 drugs are metabolized by the same cytochrome P450 isozyme, it is very possible that competitive inhibition could lead to higher than usual levels of either or both of the drugs. If a drug is metabolized by a specific cytochrome P450 and is taken with an inhibitor or inducer of that isozyme, an interaction is also likely.The following are examples of how to use this card.
Suppose your patient is taking amiodarone and you want to add a statin agent to decrease the patient’s cholesterol (follow red circles and arrows above).
We also note that lovastatin and simvastatin are metabolized by CYP3A and that if given with amiodarone (which is inhibiting the enzyme) a toxic level of the statin may occur.
Another example would be if your patient were taking an HIV protease inhibitor and wants to take St. At the website, it is possible to easily obtain the reference for a given drug by clicking on the drug.
The website hyperlinks to PubMed and searches for a list of the relevant publications.In addition to the drug-drug interactions just reviewed, drug-disease interactions can occur. Severe liver disease can be associated with reduced metabolic clearance and higher plasma levels of drugs extensively metabolized by the liver.1 Although liver disease reduces drug clearance on average, the change is relatively small and usually not clinically relevant except in patients with near terminal liver disease. Pharmacokinetics of theophylline in hyperthyroid and hypothyroid patients with chronic obstructive pulmonary disease.
Higher incidence of elevated body temperature or increased C-reactive protein level in asthmatic children showing transient reduction of theophylline metabolism.
One of the early observations was the reduced absorption of tetracycline when taken with milk products. The chelation of tetracycline by calcium prevents it from being absorbed from the intestines. Dietary sources of vitamin K, such as spinach or broccoli, may increase the dosage requirement for warfarin by a pharmacodynamic antagonism of its effect. Grapefruit juice contains a bioflavonoid that inhibits CYP3A and blocks the metabolism of many drugs.
This was first described for felodipine (Plendil)2 but has now been observed with several drugs.3 This interaction can lead to reduced clearance and higher blood levels when the drugs are taken simultaneously with grapefruit juice. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression.
Compared with water, there is an increase in felodipine plasma concentrations, as well as a decrease in systolic and diastolic blood pressure.
This demonstrates a potentially clinically significant effect of the grapefruit juice-felodipine interaction.1Dresser GK, Bailey DG, Carruthers SG. It is therefore important that health care providers obtain a complete drug history that includes herbal remedies and other natural products and dietary supplements and that they be alert to potential interactions.1Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J.
Pharmacokinetic interaction of digoxin with an herbal extract from St John’s wort (Hypericum perforatum). John’s wort, a 57% reduction was observed in the indinavir area under the plasma concentration-time curve (AUC), indicative of reduced exposure to indinavir.
The potential for loss of therapeutic efficacy due to this interaction suggests the importance of taking a complete medication history.
This history should include questions about herbal therapy and other natural products as well as over-the-counter medications.1Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. The first goal is to increase awareness of drug, device and other medical product induced disease and the importance of reporting.The second goal of MedWatch is to clarify what should (and should not) be reported.
This is important both in improving the quality of individual reports and enabling the FDA and the manufacturer to focus on the most significant reactions. Introducing MedWatch: a new approach to reporting medication and device adverse effects and product problems. It is therefore important to develop a stepwise approach to preventing adverse reactions due to drug interactions.First, taking a good medication history is essential. Studies show that the rate of adverse drug reactions increases exponentially in patients taking 4 or more medications.1 Importantly, some categories of drugs are especially at high risk for interactions.
Depending upon the practice setting, this may be a clinical pharmacologist, a hospital pharmacist, a specially trained office staff nurse, or the nearby pharmacist in community practice.Fifth, use one of the computerized databases available. Palm Pilot) and can be configured to automatically update each time you synchronize with the desktop computer.

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