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Drug Interactions

In vitro studies suggest that feverfew may inhibit platelet aggregation, leading to recommendations that patients avoid use of feverfew with anticoagulants and medications with antiplatelet activity (4). Platelets from 10 patients who had taken feverfew for at least 3.5 years responded normally to aggregation induced by adenosine diphosphate and thrombin compared to platelets from four control patients who had stopped taking feverfew at least 6 months earlier. In patients who had been taking feverfew for at least 4 years, the threshold for platelet aggregation in response to 11a,9a -epoxymethanoprostaglandin H2 (U46619) and serotonin was elevated (29). Whether these results translate into the potential for drug interactions and bleeding diatheses remains to be documented.

Drug Drug Interactions

No pharmacokinetic or pharmacodynamic drug interactions have been demonstrated between argatroban and aspirin (Clark et al., 1991), erythromycin (Tran et al., 1999), acetaminophen, digoxin, or lidocaine (Inglis et al., 2002). In practice, argatroban coadministered with these frequently used medications should require no dosage adjustments.

Ma Huang and the Ephedra Alkaloids

As with other sympathomimetic agents, theoretical drug interactions with ephedra alkaloids are possible. Despite this potential, only a handful of adverse drug interactions have been reported. This is especially pertinent when considering the extensive use of both ephedra-con-taining supplements and ephedrine- or pseudoephedrine-containing OTC products. The most notable interaction exists between nonselective monoamine oxidase inhibitors and ephedra- or ephedrine-containing products.

Jrgen Borlak A Shift in Paradigm

Fingerprints using bioinformatics to understand the role of gene-drug interactions in disease and dysfunction. The use of DNA microarray technologies enables a genome wide assessment of changes in gene expression and will have a large impact on many fields, including developmental biology and molecular diagnostic. This technology will produce a paradigm shift in biology and toxicology as it allows a global perspective on how an organism responds to a specific stress, drug or toxicant. Data generated in toxicogenomic studies will provide information on cellular networks of responding genes that will help define important target molecules associated with the mechanism of toxicity, provide eventually biomarkers for clinical studies, and support the development of new toxicity screening procedures.

Mechanism of action and efficacy

Apart from gastrointestinal side effects and high pill burden, all PIs used in long-term therapy encounter problems - to a greater or lesser extent, all are associated with lipodystrophy and dyslipidemia (review Nolan 2003). Cardiac arrhythmias (Anson 2005) and sexual dysfunction have also been attributed to PIs (Schrooten 2001), although the data does not remain unchallenged (Lallemand 2002). There is a high degree of cross-resistance between protease inhibitors, which was described before PIs were put on the market (Condra 1995). All PIs are inhibitors of the CYP3A4 system and interact with many other drugs (see Drug Interactions ). Ritonavir is the strongest inhibitor, saquinavir probably the weakest.

Switch for virological treatment failure

A viral load above 50 copies ml does not necessarily mean that resistance mutations have developed. The plasma drug levels may be insufficient (measure the plasma levels ) - which, in turn may be due to drug malabsorption, drug interactions or insufficient dosing (e.g. in very big, heavy patients). Compliance is also critical. Any possible difficulties associated with the taking of the drugs should be openly addressed Is it the number of pills Do restrictions in food intake cause problems Would once-daily treatment be better Are there other reasons, such as depression The risks of resistance developing as a result of non-compliance should be reiter

Change due to virological failure

The same principles apply as when initiating therapy compliance, dosing issues, concurrent diseases, co-medications and drug interactions. It is also essential to consider treatment history and possible existing resistance mutations. Although desirable before any change in treatment, resistance tests are not always practical. It is therefore useful to become familiar with the most important resistance mutations, particularly for nucleoside analogs (see Table 8.1). The basic principles for changing therapy in cases of virological failure apply the faster the change, the better the virus should be given as little time as possible to generate more resistance mutations. In addition the more drugs that are changed, the higher the likelihood of success for the new regimen.

MegaHAART with and without treatment interruptions

Intensified treatment combinations with five or more drugs - described as mega -or giga -HAART - may indeed be effective. However, only well-informed and motivated patients can be considered for mega-HAART regimens. Potential drug interactions are often difficult to predict. Nevertheless, mega-HAART will become less important with the introduction of new drugs and new drug classes.

Knowing The Providers

Geriatric patients often have multiple care providers. It will also be advantageous and necessary for the patient's other care providers to be informed of the treatment plan and therapeutic goals. This can prevent inadvertent duplication of therapy or potential therapeutic interaction. Drug interactions increase exponentially with the number of medications used (39-46). Statistically, the average patient older than 65 years takes nine prescription medications frequently, these medications are prescribed by several prescribers. Over-the-counter medications further complicate this issue.

Assessment of Efficacy

Overall, based on clinical experience and the available scientific data, SSRIs and TCAs may be considered useful for the treatment of depression in PD, and the agent that provides the best overall clinical benefit-to-risk profile should be selected (168). Amoxapine and lithium should be avoided, given the propensity of these agents to worsen motor symptoms and the availability of safer agents (169,170). Additionally, the nonselective MAO inhibitors (e.g., isocarboxazid, phenelzine, and tranylcypromine) should be avoided in levodopa-treated patients due to the risk of hypertensive crisis. Several antidepressants, such as bupropion, fluoxetine, fluvoxamine, nefa-zodone, and paroxetine, are potent in vivo inhibitors of various cytochrome P450 (CYP450) drug-metabolizing isoenzymes (171,172). These antidepressants may increase the risk for drug interactions.

HAART lipodystrophy syndrome and cardiovascular risk

Of lipid lowering drug therapy in these patients. Most importantly, the information about drug interactions of lipid lowering and antiretroviral drugs is still incomplete. The accumulation of pre-existing and drug-related risk factors will get more clinical attention, because, by improving the HIV-associated morbidity and mortality, HAART consequently increases an additional relevant cardiovascular risk factor the age of patients who are effectively treated with antiretroviral drugs.

Caco2 Drug Transport Assays

The Caco-2 cell line is heterogeneous and was derived from a human colorectal adenocarcinoma. Caco-2 cells are used as in vitro permeability models to predict human intestinal absorption because they exhibit many features of absorptive intestinal cells. This includes their ability to spontaneously differentiate into polarized enterocytes that express high levels of brush border hydrolases and form well-developed junctional complexes. Consequently, it becomes possible to determine whether passage is transcellular or paracellular based on a compound's transport rate. Caco-2 cells also express a variety of transport systems including dipeptide transporters and P-gps. Due to these features, drug permeability in Caco-2 cells correlates well with human oral absorption, making Caco-2 an ideal in vitro permeability model. Additional information can be gained on metabolism and potential drug-drug interactions as the drug undergoes transcellular diffusion through the Caco-2 transport model.

Daniel Berkner and Leo Sioris

Echinacea remains a popular supplement used as an immunostimulant in the prevention and treatment of infection. Despite inconsistent results from clinical trials attempting to assess effectiveness, its relatively wide margin of safety makes the herb an attractive alternative for prevention and treatment of common infections such as upper respiratory infections. Given the herb's inherent ability to inhibit various CYP450 enzymes, further studies to identify the clinical implications for herb-drug interactions are needed.

Potential Advantages of Therapeutic Antibodies

In addition, several of the currently used antiretrovirals (protease inhibitors, nonnucleoside reverse transcriptase inhibitors) are substrates or inducers of cyto-chrome P450 enzymes and thus can substantially perturb metabolic pathways (Cressey et al. 2006). Several of these drugs are indeed associated with significant drug-drug interactions between antiretroviral drugs used in combination and between additional medications the patient may require for other conditions (de Maat et al. 2003 Winston et al. 2005). Antibodies could in this setting be advantageous as they are not metabolized by cytochrome P450 enzymes, and thus could simplify the selection of combination treatment regimens. Lastly, mAbs may efficiently block protein-protein interactions or other targets that are not readily drugable with small molecules. For example, there presently are no licensed small-molecule drugs that target the CD4, CCR5, gp120, and gp41 epitopes recognized by the mAbs TNX-355, PRO 140, 2G12, and...

Fixed Combination Drugs

Attempts to develop effective fixed combinations of glaucoma medications date back several decades. Few such combinations have emerged, due in part to limitations such as differences between the component optimal dosing frequency, indications and contraindications, additive side effects, and drug interactions of the components (table 7.1).

Secondary psychotic disorders

Characteristic symptoms of a secondary psychotic disorder are prominent hallucinations or delusions. They are caused by an organic disorder of the central nervous system (CNS) as a consequence of a general medical condition. In HIV patients this could, for example, be an opportunistic infection, cerebral lymphoma or HIV en-cephalopathy. In addition to that, psychotic symptoms can be caused by medications or drug-drug interactions e.g. in HAART (Foster 2003). Therefore an exact

Progress in Drug Development

Historic approaches to anticoagulation have relied on partially purified or chemically derivatized natural products, such as heparin and warfarin. The utility of these agents, however, is limited by interpatient variability in pharmacologic effect, the requirement for laboratory monitoring, and, for warfarin, various food and drug interactions. The association of heparin and warfarin with prothrombotic complications immune heparin-induced thrombocytopenia (HIT) and warfarin necrosis are particularly troublesome.

Reasons For Noncompliance

While age as an independent variable is not significantly related to the level of compliance, age is often accompanied by diseases that may influence adherence. Elderly patients are more likely to suffer from multiple chronic diseases, and approximately 20 to 30 take three or more medications.25 Polypharmacy is associated with increased risk of adverse drug reactions, drug interactions, and poor compliance.25 Forgetfulness, poor visual acuity, parkinsonism, tremor, and hemi-

Complementary Therapies For Parkinsons Disease What Do We Really Know

There are very few well-designed studies and consequently very little evidence to support or refute the use of most complementary therapies for the treatment of PD. This does not mean that alternative therapies cannot help someone with PD, but for Western-trained healthcare providers treating someone with PD who is considering alternative therapies, it is difficult to know what and how to advise them. The first rule in medicine is do no harm, so if a particular therapy such as massage therapy is not thought to be harmful then it might be recommended. On the other hand, ingesting an herb, injecting glutathione, or ingesting a homeopathic remedy without any proof that it is beneficial and without knowing the potential harmful effects or drug interactions may not be in the best interest of a person with PD. Specific complementary therapies that are commonly prescribed by alternative practitioners are reviewed in the following section. As the majority of these therapies, especially those...

Salvage Antiretroviral Therapy

Clinicians should have a comprehensive knowledge of the toxicity profile of each agent before replacing a failed regimen. Clinicians are advised to change an entire regimen, especially when there has been viral rebound associated with resistance. A change in one drug or addition of a drug to a failing regimen is suboptimal. The new regimen should include at least three drugs if possible, and the potential for cross-resistance between antiretroviral drugs must be considered in choosing new medications. It is particularly important when a protease inhibitor is being utilized since there is cross-resistance to multiple protease inhibitors. Multiple drug interactions exist between antiretroviral therapies and other medications used for the treatment of infection and opportunistic prophylaxis this must be considered when a change in regimen occurs. Considerations for terminal care and the intensity of an antiretroviral regimen need to be taken in the context of a multidisciplinary...

Pathophysiology of HHV6 reactivation in DRESS

Many factors are probably implicated in DRESS as recently summarized by Wong and Shear (2004) drug exposure, genetic predisposition, drug interactions, concomitant illness, host immune response with generation of drug-specific T cells, cytokines, transient hypogammaglobulinemia, reactivation of latent viral infection, viral infection, etc.

Pointof Care Systems

Depending on the POC system, a clinician may enter some subset of the data listed in Table 6.1. A clinical information system that has POC functionality has the potential to become paperless as each clinician, the laboratory, and the radiology department contribute to the collection of data about a patient. Advantages of POC systems to a hospital include quicker access to clinical information, the ability to communicate orders more quickly, elimination of the difficulties involved in reading the products of poor penmanship, and the ability to harness integrated decision-support tools such as electronic formularies, drug interaction warning databases, and electronic implementations of practice guidelines. POC systems are the future of biosurveillance. A POC system facilitates the electronic capture of key diagnostic data (and usually in a computer-interpretable form rather than English). POC systems typically include decision-support capabilities (discussed in Chapter 13) that alert...

Interactions

In vitro evidence suggests that kava components may inhibit the metabolism of drugs by cytochrome P450 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (40). However, in vivo studies were not confirmatory except for the case of CYP2E1. Gurley and colleagues studied the ability of kava to inhibit in vivo metabolism by several of these enzymes and found that kava coadministration had no effect on CYP1A2, CYP2D6, or CYP3A4 activity but did significantly inhibit CYP2E1 activity (41). Because very few drugs are metabolized by CYP2E1, the clinical significance of this interaction is lessened. It appears that pharmacokinetic interactions with kava are unlikely and any drug interactions will likely be related to an additive pharmacodynamic effect (e.g., sedation).

Ginkgo biloba

Controlled studies suggest that administration of Ginkgo biloba (GB) extract has limited effectiveness in improving memory and cognition, either in elderly subjects with dementia or healthy subjects. GB administration does seem to reverse sudden hearing loss in patients with mild cases of this disorder. Additionally, GB administration may blunt the rise in blood pressure in response to stress and may blunt the glycemic response after an oral glucose tolerance test. Despite the lack of evidence of effects on coagulation in vivo, a number of case reports of excessive bleeding in patients taking GB have been reported. Finally, GB does not appear to be prone to causing drug interactions, except for agents metabolized by cytochrome P450 2C19 (in which case, induction is observed).

GenMAPP

The single most important contribution of genomics to toxicology is the rapid identification of mechanisms of toxicity, knowledge of which provides insight into potential drug-drug interactions. These mechanisms may also indicate which animal models and metabolic pathways should be targeted for further investigation. Deductions require links between expression profiles and functional annotations. A visualization tool is required to gain insight (Figure 3.6). The best known repository of

Indinavir

Renal problems occur particularly on indinavir treatment, and are caused by indina-vir crystals, which may be found in the urine of up to 20 of patients. Approximately 10 of patients develop nephrolithiasis, which is not visible on X-ray, accompanied by renal colic. Nephrolithiasis is primarily caused by high indinavir levels in relation to a low BMI, drug interactions and individual fluctuations of the drug plasma level. In one study, the intake of indinavir ritonavir 800 100 mg with a light meal reduced the indinavir plasma concentration, probably reflecting a food-induced delay in the absorption of indinavir (Aarnoutse 2003). In case of suspected high indinavir levels, therapeutic drug monitoring should be performed and the dose adjusted (Collin 2007). Interruption of therapy, following a single incidence of colic, is not usually necessary. More than 20 of patients have persistent asymptomatic leukocyturia associated with a gradual loss of renal function without urologi-cal...

Steroids

Another issue regarding steroids is their possible interaction with chemotherapeutic drugs and AEDs. Because decadron is a CYP3A4 inducer it can potentially affect other drugs that also undergo hepatic metabolism. If steroids act to decrease brain edema by affecting the blood-tumor and blood-brain barrier, then steroids might also affect the delivery of chemotherapeutic drugs to the central nervous system (CNS). Weller et al. (43) have gone so far as to recommend that, if possible, steroids be withdrawn from glioma patients so as to maximize the therapeutic effect of chemotherapy agents. It is common for patients on DMS to often require very high doses of phenytoin. Lachner (44) presented the case of a patient requiring 10 mg kg d of phenytoin to maintain therapeutic concentrations while on dexamethasone. Once the steroid was discontinued the phenytoin plasma level tripled. For these reasons, close monitoring of AED levels should be undertaken when drug interactions are known.

Tuberculosis

Despite a steadily increasing prevalence of HIV-1 infection in Western Europe and North America in recent years, the incidence of TB has continuously declined in countries where antiretroviral therapy (ART) against HIV-1 are available (Kirk 2000, Girardi 2000). However, clinical management of MTB-HIV co-infected patients is complicated due to a wide range of drug interactions, overlapping side effects of ART and antituberculous medications and low compliance caused by pill burden.

ART and TB therapy

Drug interactions There are many pharmacological interactions between ART and antituberculous drugs (Table 3 and 4). Both RMP and protease inhibitors (PIs) are metabolized by cytochrome P450 3A. As RMP and PIs serum levels are unpredictable when they are administered simultaneously, concomitant therapy with PIs and RMP is generally not recommended (exception ritonavir saquinavir and ritona-vir-hyper boosted lopinavir) (OARAC DHHS Panel Guidelines, October 2006) (Table 3). Either the combination of 2 nucleoside reverse transcriptase inhibitors (NRTIs) with the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz or the suboptimal combination of 3 NRTIs are possible therapeutic options for treating HIV infection during TB treatment with RMP. As an alternative to RMP, RB (another rifamycine) can be co-administered with PIs as it is a weaker inductor

Malaria

The efficacy of antimalarial therapy is not influenced by HIV. Accordingly, recommendations for malaria therapy generally apply to HIV patients. As described above though, drug interactions of antimalarial and HIV drugs are not well-established. The treatment of complicated malaria is problematic since the indicated drugs, quinine, quinidine, or artemisinin derivates, are all metabolized by CYP3A4. The coadministration of these drugs with CYP3A4 inhibitors as protease inhibitors,

Lopinavir

Effective PI in treatment-naive as well as treatment-experienced patients. Disadvantages include gastrointestinal side effects (diarrhea) and the often significant dyslipidemia, which is more extreme than with some other PIs. As with all PIs, lipodystrophy and various drug interactions should be considered. Comments Warnings drug interactions are numerous. All drugs metabolized by the CYP3A or CYP2D6 enzyme systems are contraindicated flecainide, propafenone, astemizole, terfenadine, ergotamines, cisapride, pimozide, midazolam, triazolam. Rifampin and St. John's wort reduce the efficacy of lopinavir. Caution with lovastatin, simvastatin (myopathy, rhabdomyolysis), carbamazepine, phenobarbital, phenytoin or sildenafil (hypotension), amiodarone, warfarin, lido-caine, tricyclic antidepressants, quinidine, cyclosporine, tacrolimus. Measure plasma levels in patients with reduced liver function tests.

Lack Of Reporting

This seems somewhat reasonable given that the average 70-year-old takes seven to nine different medications (18-20). The addition of analgesics to a complex medication regimen is even more likely to cause drug interactions in an older individual (19,20).

Policy

Demonstration products and outcome-based research of such systems is needed and should be part of the Request for Proposals program at the National Institutes of Health as well as other government-funded research programs. Practices that use EMR systems with the ability to reduce drug-drug interactions, facilitate communication, provide instant data retrieval, facilitate acquisition of information, reduce adverse events, and so on should also receive reductions in malpractice insurance rates, reduced medical society dues, improved reimbursement as incentive for transitioning a busy office practice to such systems, which are likely to also improve quality of care and quality improvement practices (6,7).

Conclusion

Infect Genet Evol 7 333-342 Davey RT Jr, Boenning CM, Herpin BR, Batts DH, Metcalf JA, Wathen L, Cox SR, Polis MA, Kovacs JA, Falloon J, et al (1994) Use of recombinant soluble CD4 Pseudomonas exotoxin, a novel immunotoxin, for treatment of persons infected with human immunodeficiency virus. J Infect Dis 170 1180-1188 De Cock KM, Fowler MG, Mercier E, de Vincenzi I, Saba J, Hoff E, Alnwick DJ, Rogers M, Shaffer N (2000) Prevention of mother-to-child HIV transmission in resource-poor countries translating research into policy and practice. JAMA 283 1175-1182 de Maat MM, Ekhart GC, Huitema AD, Koks CH, Mulder JW, Beijnen JH (2003) Drug interactions between antiretroviral drugs and comedicated agents. Clin Pharmacokinet 42 223 Decker JM, Bibollet-Ruche F, Wei X, Wang S, Levy DN, Wang W, Delaporte E, Peeters M, Derdeyn CA, Allen S, Hunter E, Saag MS, Hoxie JA, Hahn BH, Kwong PD, Robinson JE, Shaw GM (2005) Antigenic conservation and immunogenicity of the...

Nutraceuticals

In a US survey, one in four adults took at least one nutritional supplement of the patients who took prescription medication, nearly half also took nutraceuticals (96a,96b). Many of these nutraceuticals have potent pharmacological effects from the natural products they contain. Therefore, before initiating any analgesic agents, an accurate nutraceutical history must be obtained from the patient to avoid inadvertent drug interactions or adverse effects.