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Drug Interactions

Drug interactions with hawthorn are theoretically possible with cardioactive medications, but have not been documented (2). In addition, the flavonoid constituents have been shown to have inhibitory and inducible effects on the cytochrome P-450 enzyme system, making other drug interactions possible (20). However, an in vivo study of a potential pharmacokinetic interaction of digoxin and hawthorn demonstrated that concurrent administration had no effect on digoxin pharmacokinetics, suggesting that the two could be safely administered together from a pharmacokinetic point of view (21). However, one must be mindful of additive effects and a potential pharmacodynamic interaction.

Drug Drug Interactions

Drug-drug interactions are divided into pharmacodynamic (PD) and pharmacokinetic (PK) interactions. PD drug-drug interactions can change the pharmacological effect of drugs. Furthermore, the pharmacological effect and, indeed, side effects of two or more drugs can act additively or antagonistically. PK drug-drug interactions are associated with inappropriate plasma concentrations of drugs. Changes in plasma concentrations can be the result of inadequate absorption, transport, metabolism or elimination. In HIV therapy, a considerable number of drug-drug interactions occur during transport via p-glycoprotein or metabolism by isoenzymes of the cytochrome P450 enzyme system (Piscitelli 2001).

Important drugdrug interactions in HIV therapy NRTIs

Drug-drug interactions during intracellular phosphorylation have been shown to occur in vitro when ribavirin is co-administered with zidovudine (AZT), stavudine (D4T) or DDI. Whereas plasma concentrations of AZT and active D4T metabolites decrease in the presence of ribavirin, plasma concentrations of active DDI metabolites increase. The FDA Adverse Event Reporting System describes 24 patients who developed toxic symptoms (pancreatitis, peripheral neuropathy and symptomatic hyperlactatemia lactic acidosis), on average one month after initiation of therapy containing these drugs (FDA Announcement). These symptoms also occur when AZT and DDI are combined (Piscitelli 2001). Pharmacodynamic drug-drug interactions PD drug-drug interactions play an important role within the NRTI class because of the potential for additive side effects. A summary of additive toxic effects within the NRTI class and in combination with comedications is described in table 1.

Application Of Human Hepatocytes In The Evaluation Of Drugdrug Interactions

Mechanism and Clinical Significance of Pharmacokinetic Drug-Drug Interactions Multiple drug therapy is widely practiced either to treat a medical disorder or to treat several concurrently existing ailments in the same patient. It is now known that drugs may interact, resulting in serious pharmacological and or toxicological consequences. Drugs interact mainly by a phenomenon known as pharmacokinetic drug-drug interactions alteration of the metabolic clearance of a drug by a coadministered drug. While pharmacokinetic drug-drug interactions can occur during absorption, metabolism, disposition, and elimination phases after initial drug administration, interference with drug metabolism appears to be the predom inant mechanism. The interference can occur via inhibition or induction of the metabolism of one drug by a coadministered drug. Both mechanisms of pharma-cokinetic drug-drug interactions can have serious clinical consequences. Inhibition of drug metabolism results in an increase...

Drug Metabolism And Resistance

Phase I reactions include oxidation or reduction reactions, usually through the actions of cytochrome P450 oxidative enzymes or reductases. These enzymes prepare fat-soluble molecules for further metabolism via Phase II reactions by creating a reactive group suitable for conjugation. Drug interactions are usually the result of interactions with Phase I drug metabolism mechanisms. Conjugation reactions performed during Phase II metabolism of drugs usually involve the addition of a peptide (glutathione), sugar, or sulfur group to the drug molecule. These groups are usually common and easily accessible in well-nourished cells, so these Phase II reactions are rarely rate-limiting, and therefore rarely involved in drug interactions. Phase I reactions carried out by cytochrome P450 enzymes, flavin monooxygenases, and reductases are more frequently rate-limiting, and are more often the target of clinically significant drug interactions. Phase I oxidative enzymes are mostly found in the...

Adverse Reactions

A systematic review of the herb's safety, published in 2005, analysed data from six electronic databases, postmarketing surveillance studies, spontaneous reporting schemes (including WHO), herbalist organisations and manufacturers (Daniele et al 2005). The review concluded that vitex is a safe herbal medicine and any adverse effects associated with its use tend to be mild and reversible. The most common adverse effects are nausea, headache, gastrointestinal disturbances, menstrual disorders, acne, pruritis and erythematous rash. Additionally, no drug interactions have been reported.

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.

Mucosalprotective agents

The main mucosal protective agent is sucralfate, which works by binding damaged mucosa, and forming a protective barrier against the erosive action of pepsin and bile. Sucralfate may have a comparable rate of symptom relief and healing of erosive esophagitis to H2B's 2 . The degree of healing with sucralfate correlates inversely with the degree of injury of the mucosa. However, there are significant drawbacks in using this medication for GERD in the elderly. It requires four time a day dosing, and has a potential for drug-drug interactions with digoxin, phenytoin, quinidine, and warfarin. This medication may reduce the absorption of certain drugs, and other medications must be given 2 hours after sucralfate 35 . Due to the increased medication usage in the elderly, this factor makes sucral-fate difficult to effectively utilize in this population.

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.

Histamine2receptor blockers H2Bs

These drugs are generally well tolerated by older adults, however, there are concerns about adverse effects and drug-drug interactions do exist. The overall incidence of adverse events is 3-5 , with most being mild 2 . Cardiovascular events occur most often with cimetidine, and include bradycardia and hypotension. Mental confusion has been reported with cimetidine, with associated factors including high dose, old age, decreased renal function, and cerebral impairment 74 . Other central nervous system effects include delirium, hallucinations, depression, and dyskinesia, seen mostly with the intravenous formulation 31 , 74 . Cimetidine causes a reversible decrease in creatinine clearance in 26 , but does not worsen existing renal failure. Cimetidine also causes a transient increase in serum aminotransferases. Other less common effects include rash, myalgia, and neutropenia with cimeti-dine, and hepatitis, arthralgias, rash, and bone marrow suppression with ranitidine.

Significant Interactions

Because controlled studies are not available, interactions are currently speculative and based on evidence of pharmacological activity. No drug interactions have been reported however, an extract of goldenseal has demonstrated inhibition of cytochrome P450 in vitro (Budzinski et al 2000). Theoretically these findings suggests that any drugs metabolised using this pathway may be affected. The clinical relevance of this possible interaction is unknown. CYCLOSPORIN A

Treatment and prophylaxis of mitochondrial toxicity

Drug interactions may precipitate mitochondrial symptoms and must be taken into account. The mitochondrial toxicity of didanosine (VidexTM) for example is augmented through drug interactions with ribavirin, hydroxyurea and allopurinol (Ray 2004). When didanosine is combined with tenofovir (VireadTM), the didanosine dose must be reduced to 250 mg QD. An impairment of mitochondrial metabolism may also result from comedication with ibuprofen, valproic acid and acetyl salicylic acid - these substances inhibit the mitochondrial utilization of fatty acids. Numerous cases have been described, in which a life-threatening lactic acidosis was triggered by valproic acid, both in HIV infected patients and in patients with inherited mutations of mtDNA. Acetyl salicylic acid may damage mitochondria and such damage to liver organelles may result in Reye's syndrome. Amiodarone and tamoxifen also inhibit the mitochondrial synthesis of ATP. Acetaminophen and other drugs impair the antioxidative defense...

Table 204 Risk of strokeyear in patients with atrial fibrillation

When available, Ximelagatran will be an useful alternative to warfarin in many patients with atrial fibrillation. Two clinical trials comparing this agent to warfarin have shown that ximelagatran is just as effective in stroke prevention with no increased risk of bleeding. Ximelagatran offers the advantage of predicable dosing because of food or drug interactions. The dose is 36 mg. Since 3-6 of patients when starting this drug sill have liver function test abnormalities, these should be monitored. In addition, ximelagatran is renal cleared and there is no data yet on renal dosing.

Secondary psychotic disorders

In addition to that, psychotic symptoms can be caused by medications or drug-drug interactions. The occurring delusional themes are numerous, including somatic delusions, delusions of grandeur, religious delusions, and, most frequently, paranoia or persecutory delusions. Diseases that affect subcortical structures or the temporal lobes are more frequently associated with delusions than others. In hallucinations, every sensory quality (auditory, visual, olfactory, gustatory or tactile) might be affected.

Risk Factors Comorbidity

Patient, thus restricting the general behavioral repertoire of the persons with dementia. Further complicating the use of psychopharmacology with older adults is the fact that many are already taking multiple medications to manage other physical illnesses, making drug-drug interaction effects more likely in this population.

Concluding Remarks

Cryopreserved human hepatocytes retain adequate viability and drug-metabolizing enzyme activities 18 , and human hepatocyte-based HrTS assays have been developed. A HrTS assay by definition should have a high capacity and a rapid turnaround time and therefore is not possible with freshly isolated human hepatocytes, as they have limited and unpredictable availability. On the other hand, HrTS assays are compatible with precharacterized cryopreserved human hepatocytes. HrTS assays in 96-well plates are being developed for major drug properties that are critical to the clinical success of a drug candidate metabolic stability, toxicological potential, and inhibitory drug-drug interaction potential. The use of the 96-well plate format allows automation and minimizes the amount of experimental materials (both chemicals and hepatocytes) required. Currently, evaluation of inhibitory pharmacokinetic drug-drug interaction potential is routinely performed using human liver...

Manufacturers Of Herbal Medicines And Natural Supplements In Australia And New Zealand

Blumenthal M et al. The ABC Clinical Guide to Herbs. Texas American Botanical Council, 2003. Bratman S, Kroll D. Natural Health Bible. Rocklin, CA Prima Health, 2000. Braunwald E et al. Harrison's Principles of Internal Medicine. New York McGraw Hill, 2003. Brinker F. Herb Contraindications and Drug Interactions, 2nd edn. Portland Eclectic Medical Publications, 1999.

Proton pump inhibitors

Proton pump inhibitors do have a potential for drug interactions, through the P-450 system 3 , although this is mostly confined to omeprazole and lan-soprazole. PPI elimination is not significantly affected by renal impairment or hepatic dysfunction, and no dosage adjustments are recommended, giving this medication an advantage in older individuals 2 , 61 , 71 , 76 . There are a few potential drug interactions, including digoxin, metoprolol, calcium-channel block-kers, benzodiazepines, phenytoin, theophylline, and warfarin 3 , 61 , 71 . These interactions, however, have not been found to have clinical relevance.

Antidepressants MAOI group

Patients on MAOIs should be given a card listing the items to avoid. It is probable that the risks have been overestimated, and that these effective drugs have been underused as a result. The most recently introduced MAOI, moclobe-mide, is less prone to cause food and drug interactions because it is selective for the MAO-A isoform, which is found in the liver as opposed to the gut. It can be used on a trial basis patients who respond somewhat to it can then be tried on a 'proper', full-strength MAOI.

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.

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.

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-

Oral contraceptives

Macrolide antibiotics, tetracyclines, rifampin, metronidazole (Flagyl), penicillins, trimethoprim-sulfamethoxazole (Bactrim), several anti-HIV agents and many anti-epileptic drugs, can induce the metabolism and decrease the effectiveness of oral contraceptives.

Physical complications

Other physical consequences include peptic ulcer, pancreatitis, gastritis, cardiomyopathy, myopathy, gout, vitamin deficiencies, drug interactions (the effect of psychotropic drugs may be either enhanced or reduced), and raised susceptibility to infections, including tuberculosis and malignancies.

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).

HAART Influence on skin and mucocutaneous diseases

Drug interactions between HAART and agents used to treat cutaneous diseases are frequent and need to be carefully evaluated before being prescribed (see Chapter Drug interactions , Mc Nicoll 2004). Azole derivatives, retinoids and drugs metabolized via the p450 pathway frequently interact with antiretrovirals.

Pharmacologic characteristics see table

Drug interactions drugs that potentiate nondepolarizing relaxants include volatile agents, local anesthetics, calcium channel blockers, aminoglycosides, polymyxins, lincosamines, h e x a m e t h o n i u m , t r i m e t h a p h a n , immunosuppressants, high-dose benzodiazepines, dantrolene, and magnesium.

Drug Delivery System Complications

Typical narcotic side effects include pruritus, nausea, vomiting, urinary retention, constipation, sexual dysfunction, and respiratory depression. The exact mechanism of pruritus is unclear. Histamine release is not thought to be the etiology, but antihistamines, such as diphenhydramine, are often effective. Nausea and vomiting are common with intrathecal opioids. It is thought that the side effects result from interaction with opioid receptors in the area postrema. Nausea could also be caused by unresolved constipation. These symptoms tend to be dose-related and are usually relieved by anti-emetics, such as metoclopramide, prochloroperazine, and ondansetron. Urinary retention is an adverse effect most commonly found in elderly men with enlarged prostates. It is not a dose-related phenomenon, but rather a drug interaction with opioid receptors in the sacral spinal cord. Their stimulation causes detrusor muscle relaxation and an increase in bladder capacity. Adjunctive treatment with...

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

Nography to measure the thickness of the carotid intima media or endothelial function to predict the cardiovascular risk. Some of these investigations found abnormal test results (e.g. reduced flow-mediated dilation) that correlated either with the use of protease inhibitors or the presence of dyslipidemia (Currier 2003). Long-term follow-up results will be necessary to substantiate these preliminary observations. While there is some indication of an increased rate of coronary artery disease during HAART, the benefit of suppressed viral replication and improved immune function resulting in reduced morbidity and mortality, clearly argues for the use of antiretroviral drugs according to current international guidelines. It seems obvious however, that pre-existing cardiovascular risk factors in individual patients need to be considered more carefully before starting or switching HAART. Recommendations such as the National Cholesterol Education Program (NECP) have been proposed for...

Treatment of Deep Venous Thrombosis

Recently, it has been reported that the direct thrombin inhibitor ximelagatran in the dose of 36 mg twice a day can be used instead of heparin warfarin in therapy of DVT PE. Ximelagatran offers the advantage of more predicable dosing and lack of drug interactions. This agent is described in more detail in Chapter 23.

Nmda Receptors And The Development Of Opiate Sensitization

Recent research from others appears to present a more complicated picture. Vanderschuren et al. (98), for example, reported that only high doses of MK-801, which produced considerable lethality in combination with morphine, had the ability to inhibit sensitization to the locomotor-stimulant effect of morphine in rats. Lower doses, which did not produce lethality, did not affect sensitization. These authors therefore suggest that the effect may be a nonspecific drug interaction, rather than an inhibition of neural and behavioral plasticity.

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...

Mechanism of action and efficacy

Apart from gastrointestinal side effects and high pill burden, all PIs used in long-term therapy can be implicated in lipodystrophy and dyslipidemia (review in Nolan 2003). Smaller randomized studies have shown that elevation of lipid levels is more pronounced in ritonavir-containing regimens (full, not booster dose) than with saquinavir or nelfinavir (Roge 2001, Wensing 2001). In addition, there may be significant drug interactions on ritonavir and with boosted regimens. Sexual dysfunction has also been attributed to PIs (Schrooten 2001), although data is inconclusive (Lallemand 2002). hibitors of the CYP3A4 system and interact with numerous other drugs (see Drug Interactions chapter). Ritonavir is by far the strongest inhibitor, saquinavir probably the weakest.

Mega and GigaHAART Treatment Interruptions

The success of these mostly uncontrolled studies is debatable. On five- or six-drug regimens, sufficient suppression of viral load was achieved only in a variable percentage of patients (22-52 Grossman 1999, Miller 2000, Montaner 2001, Piketty 2002, Youle 2002). First and foremost, these studies indicate that there are some patients who are capable of tolerating such intensive combinations. But a lot remains to be criticized only well-informed and highly motivated patients can be considered for mega-HAART regimens, and such approaches are often unrealistic in clinical practice. It is important to consider that potential drug interactions are difficult to predict for such combinations, and therefore plasma levels should be measured whenever possible. However, most PIs can be combined quite well without causing significant interactions or toxicity (van Heeswijk 2001, Eron 2001). Despite all the discussions concerning mega- or giga-HAART, the primary...

Safety of medical therapy

Interactions with concomitant medication. In respect to drug interactions, PPI can be regarded as safe drugs with little interaction all compounds alter pH-dependent absorption of other pharmaceuticals (e.g. konazoles), and some PPI (e.g., omeprazole, esomeprazole) show interaction with drugs which plasma concentration (phenytoin) or clinical effect (warfarine) is under strict control under any circumstances.

Advantages of Primary Hepatocytes in Drug Metabolism

Hepatocytes in culture retain active uptake as well as biliary excretion similar to hepatocytes in the liver in vivo. Drugs that are bioaccumulated will have a higher intrahepatocyte concentration than plasma concentration, or be actively excreted, and will therefore have a lower intrahepatocyte concentration than plasma concentration would behave similarly in cultured hepatocytes. For these drugs that have differential plasma and intracellular concentrations, values critical to in vitro-in vivo extrapolation of drug-drug interaction, e.g., Ki values, derived from hepatocytes, would be more relevant to those obtained with microsomes. CYP inhibition and induction are the two major mechanisms of drug-drug interactions. While CYP inhibition can be studied with microsomes and hepatocytes, CYP induction can only be studied in a living cell, i.e., hepatocytes. Induction protocols for CYP induction, especially for CYP1A and 3A, are well established 19-21 . Known human in vivo inducers such...

Discovery Techniques Not Suited For

Without question, electrophysiological methods have revolutionized our understanding of the properties and behavior of ion channels and their interactions with drugs 57 . Patch clamp electrophysiology refers to a technique for forming a tight seal on the cell surface with a pipette containing a small electrode. This allows the current flow through this small patch (several m2) to be recorded for analysis of single-channel properties or whole-cell electrical properties. However, traditional electrode-based methods clearly fall short of a testing rate of thousands of compounds per day, owing to challenges involved in providing suitable biological preparations, establishing stable recordings with the desired characteristics, and delivering test compounds in a controlled manner. Several studies have, however, introduced extensions of the traditional methods with the aim of providing sufficient throughput. One study employed capillary electrophoresis for the delivery of putative...

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.

Metabolism Studies A InVitro Studies

The glucuronide metabolite of AZT was isolated from rat and human liver microsomal incubations (177), and the formation of a toxic metabolite of AZT was demonstrated in rat hepatocytes and liver microsomes (177). The metabolism of tamoxifen was examined in human liver homogenate and human Hep G2 cell line preparations by LC API MS (178). Several metabolites were detected in the human liver homogenate extracts, namely, N-didesmethyltamoxifen, a-hydroxy-tamoxifen, 4-hydroxytamoxifen, N-desmethyltamoxifen, and tamoxifen N-oxide. All of these metabolites, except the N-didesmethyltamoxifen, were observed in the samples after incubating tamoxifen with the human Hep G2 cell line. In-vitro studies have also used MS to examine potential drug-drug interactions. For example, (179) demonstrated that the a2-agonist, dexmedetomidine, inhibited metabolism of the anesthetic alfentanil, whereas clonidine had no effect.

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.

Anaplastic Oligodendroglioma

Temozolomide is an alkylating agent which is quickly well absorbed after oral administration, reaching peak plasma concentrations (Cmax) one hour after administration. It is spontaneously converted to the cytotoxic mono-methyl 5 triazino imidazole carbox-amide (MTIC), the active form of the drug. It does not require metabolic activation by the liver and crosses the blood-brain barrier, achieving excellent concentration within the central nervous system 43,44 . Its cytotoxicity is thought to be due to methylation of primarily DNA at the O6, N7, and N3 positions, inhibiting DNA replication. Dosage is 150-200 mg m2 day for 5 days per 28 day cycle. There is an absence of drug interaction between temozolomide and cytochrome-P450-inducing agents, an advantage in this population of patients, many of whom are on anticonvulsant drugs. Chemotherapy naive patients are started at 200 mg m2 day. Patients previously treated with chemotherapy are started at 150 mg m2 day, but are usually allowed to...

Methylguanine Methyltransferase

The effectiveness of any drug regimen depends not only on the intrinsic resistance shown by the tumor cells, but also on the possibility of acquired resistance that can occur during therapy. To identify mechanisms of resistance that could arise during treatment, a number of studies have been conducted in vitro 97-101 . This work has demonstrated that MGMT resistance to the inhibitory effects of O6-BG can arise due to mutations in the binding site of MGMT 97,98 . Furthermore, work by Ueda et al., 102 showed that dexamethasone induces MGMT, most likely through 2 glucocorticoid-response elements located in the gene promoter. Thus, studies designed to increase alkylating agent efficacy by depleting MGMT should consider the drug interactions that occur not only between chemotherapeutic agents, but also between chemotherapeutic agents and other medications. In addition, depletion of MGMT may require combinations of multiple inhibitors such as O6-BG and or other derivatives and...

Renal problems 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 body mass index (Meraviglia 2002), drug interactions and individual fluctuations of the drug plasma level. In one study, the intake of indina-vir ritonavir 800 100 mg with a light meal reduced the indinavir nephrotoxic maximum plasma concentration, probably reflecting a food-induced delay in the absorption of indinavir (Aarnoutse 2003). More than 20 of patients have persistent asymptomatic leukocyturia associated with a gradual loss of renal function without urological symptoms (Dielemann 2003). However, renal failure is rare (Kopp 2002).

Virological Treatment Failure

A viral load above 50 copies ml does not necessarily mean that resistance mutations have developed. It may also indicate insufficient plasma levels (measure these if possible ). This may be due to drug malabsorption, drug interactions or simply insufficient dosing (e.g. in very big, heavy patients). Compliance is also critical. Any possible difficulties associated with the regimen 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 reiterated. If plasma levels are sufficient and viral load remains detectable (monitor blips at short intervals - within a few weeks ), treatment should definitely be changed as soon as possible.

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.

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

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).

Conclusions

Inhibition of drug metabolism by cytochromes P450 (CYP) is a principal mechanism for pharmacokinetic drug-drug interactions. In vitro methods for quantitatively measuring the extent of CYP inhibition have been utilized for several years. Classical methods use drug molecules as substrates and time-consuming, HPLC-based analysis. There has been a need to develop methodologies that do not require HPLC separations for data acquisition.

Practicality

A drug's side effects, both short-term and known long-term, profoundly influence its practicality. The taste of the preparation when in liquid formulation can sometimes be masked by other flavours but some anti-retrovirals (or the excipients required to hold them in liquid form) have an extremely unpleasant taste that cannot be adequately masked. Known drug-drug interactions with other antiretrovirals must be considered along with interactions with other medications which the child is receiving, in particuar TB treatments. Knowledge of drug interactions continues to increase rapidly and use of one of several websites that frequently update information about them is recommended when considering addition of other drugs (e.g.,

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).

Inducers

Inducers increase the production of enzymes and thus accelerate metabolism. Consequently, the plasma levels of substrates are lowered, producing subtherapeutic concentrations. This has particular relevance for HIV therapy as this can lead to loss of virological control and development of resistance. CYP3A4 inducers include carbamazepine, phenytoin, rifabutin, rifampicin and St John's Wort. The maximal inducing effect is usually achieved after one to two weeks of intake. After stopping therapy with an inducer, the effect of this drug interaction will continue for a few days or weeks until the enzyme quantity returns to the baseline level (Haefeli 2000).

Prokinetic agents

Mild to moderate disease, and may have had a role in maintenance therapy 28 . The combination of cimeti-dine with a prokinetic agent resulted in improved healing compared to either agent alone 20 . Cisapride not only has prokinetic effects, but it stimulates salivation via a cholinergic mechanism. Orr et al 38 looked at acid clearance with cisapride in patients with symptomatic GERD, and found a significant decrease in the number of swallows required for acid clearance compared to baseline. These authors concluded that the main efficacy of cisapride in treating GERD actually results from its ability to stimulate saliva, not from its relatively weak prokinetic effects. The removal of this medication from the US market was due to a drug interaction with azole antifungals, macrolide antibiotics, and procaina-mide, resulting in a prolonged QT interval and risk of cardiac arrhythmias. An investigational limited-access program is available for patients whose disease has failed to respond to...

Depression in PD

Treatment of depression in IPD includes the use of a wide range of antidepressants, only a few of which have been shown to be effective in this population in controlled studies. Selection of which antidepressant to use should be based on side effect profile of the drug and potential drug interactions. Antidepressants with more anticholinergic properties such as amitriptyline can produce cognitive disturbances in the elderly and should generally be avoided. Tricyclic antidepressants with fewer anticholinergic properties and cardiovascular side effects such as nortryptiline are generally better tolerated in the elderly population. The serotonin reuptake inhibitors have little effect on the cholinergic system and only minor action on norepinephrine and dopamine. They have few side effects and may offer some advantage in the treatment of depression in this patient population. A few relatively small-scale studies have shown them to be effective in this patient population. In a recent study...

Pcv And Oligodendro

The action and, therefore, cytotoxicity of this metabolite is thought to be methylation of DNA at the O6, N7, and N3 positions, which inhibits DNA replication 45,46 . Temozolo-mide achieves high measured concentrations in cerebrospinal fluid, approximately 35 to 39 per cent of that measured in plasma 45,47,48 . As temozolo-mide is not metabolized in the liver, there are no drug interactions between it and cytochrome P450 inducing agents. This imparts a significant advantage to this drug in the brain tumor population, as many patients are on antiepileptic drugs. Temozolomide is administered at a dose of 150-200 mg m2 per day for 5 days per 28 day cycle. Chemotherapy naive patients are started at 200 mg m2 per day. Patients who have been previously exposed to chemotherapy are started at 150 mg m2 per day, and usually are advanced to the higher dose if the medication is tolerated with mild or no toxicity.

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.

Comedication

Table 2 Common side effects caused by drug-drug interactions between comedications and protease inhibitors (Dresser 2000) Azithromycin is a macrolide, which possesses a low potential for drug-drug interactions with antiretroviral drugs, with the exception of NFV (Piscitelli 2001). NNRTIs reduce methadone plasma concentrations within the first 14 days of intake, therefore opiate withdrawal can occur in these patients. In these cases, doses of methadone should be increased in 10 mg steps. Drug-drug interactions between methadone and PIs are not particularly predictable. Reduced methadone concentrations are described with RTV, NFV and LPV r. However, reduced methadone concentrations are not always associated with opiate withdrawal. When coadministered, reduced concentrations of APV and methadone have been reported therefore APV TDM is recommended (Antoniou 2002). Drug interactions involving drugs of abuse are of particular concern due to an increased risk of life threatening side...

Linezolid

Pharmacokinetic data are available in children from all age groups, including premature neonates (Jungbluth et al., 2003). Linezolid is available in both parenteral and oral formulations. The oral bioavailability is virtually 100 , allowing clinicians to use an oral dose identical to that which is administered intravenously. Data suggest that absorption of linezolid following ingestion is somewhat delayed in those who are fed concurrently, compared with those who receive antibiotic without food, although the child's total drug exposure is not significantly effected. Protein binding in serum is 31 the drug is cleared by the kidneys, both unchanged and after oxidation of the parent compound, with an elimination half-life of about 3 hours. Oxidation is the primary mechanism of inactivation of linezolid, therefore no dose reduction is recommended for children with renal insufficiency, and cytochrome P450 system drug-drug interactions are not of concern.

Anticonvulsants

Six-week controlled study in 21 outpatients with BPSD associated with severe AD, who were treatment resistant to antipsychotics. Greater improvement was seen on the Clinical Global Impression of Change (CGIC) and the Brief Psychiatric Rating Scale (BPRS) hostility item with a trend for the hallucination item for the carbamazepine group over placebo. It is likely that side effects seen in other populations, such as rashes, more serious sedation, hematologic abnormalities, hepatic dysfunction, and altered electrolytes, for example, would be more evident with widespread use of this agent in the elderly, which may limit its use (Tariot, Frederiksen, et al., 1995). Further, it has considerable potential for significant drug-drug interactions. The carba-mazepine studies help provide proof-of-concept for the anti-agitation efficacy of anticonvulsants.

Sertraline

Serotonin, one of the neurotransmitters, is a brain chemical that carries nerve impulses from one nerve cell to another. Researchers think that depression and certain other mental disorders may be caused, in part, because there is not enough serotonin being released and transmitted in the brain. Like the other SSRI antidepressants, flu-voxamine (Luvox), fluoxetine (Prozac), and paroxetine (Paxil), sertraline increases the level of brain serotonin (also known as 5-HT). Increased serotonin levels in the brain may be beneficial in patients with obsessive-compulsive disorder, alcoholism, certain types of headaches, post-traumatic stress disorder (PTSD), pre-menstrual tension and mood swings, and panic disorder. Sertraline is not more or less effective than the other SSRI drugs although selected characteristics of each drug in this class may offer greater benefits in some patients. Fewer drug interactions have been reported with sertraline, however, than with other medications in the same...

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.

Depression

The clinical description of depression is complex, covering a broad range of symptoms that lack a unifying biological hypothesis. Depression has both genetic and environmental components, with linkage studies suggesting it is a polygenic disor-der.131 Here again, effective therapeutics are contributing to an understanding of its underlying molecular mechanisms.132 Modern treatment for depression, which focuses exclusively on agents that modulate monoamine neurotransmission, began with a monoamine oxidase inhibitor (MAOI) originally developed to treat tuberculosis. MAOIs increase serotonin and norepinephrine concentrations in the brain by inhibiting the MAO enzyme. They are highly effective in treating depression but are used only rarely due to potentially dangerous drug interaction effects.

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).

How to Change HAART

The same principles apply as when initiating therapy compliance, dosing issues, concurrent diseases, comedications 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.

Histoplasmosis

Crommentuyn KM, Mulder JW, Sparidans RW, Huitema AD, Schellens JH, Beijnen JH. Drug-drug interaction between itraconazole and the antiretroviral drug lopinavir ritonavir in an HIV-1-infected patient with disseminated histoplasmosis. Clin Infect Dis. 2004 Apr 15 38(8) e73-5. http amedeo.com lit.php id 15095234

Delavirdine

Delavirdine is rarely used, due to impractical dosing and drug interactions. However, the drug has theoretical potential. It is fairly well tolerated (no hepatotoxicity, no CNS problems), and increases levels of indinavir and saquinavir. Disadvantage It has the usual NNRTI cross-resistance, and high pill burden.

Ritonavir

Due to its gastrointestinal side effects, the therapeutic dose of ritonavir is hardly acceptable and rarely prescribed. However, ritonavir has become an important drug for boosting other protease inhibitors. In these combinations, when lower doses are used, side effects of ritonavir are tolerable. Numerous drug interactions must be considered. Comments Warnings even the low boosting doses used in combination with other PIs have multiple drug interactions The following are contraindicated rifampin, amiodarone, astemizole, bepridil, terfenadine, encainide, flecainide, cisapride, triazolam, ergotamine, simvastatin, lovastatin, quinidine, and St. John's wort. Silde-nafil should be avoided

Drug Selection

Many brain tumor patients take antiepileptic drugs (AED) for seizure prophylaxis. Some anticonvulsants may induce the hepatic cytochrome P450 system and alter the metabolism of a treatment agent being studied 17 . Such drug interactions may alter the type and severity of toxicity that patients experience. For example, it has been discovered that patients taking paclitaxel or CPT-11 while taking enzyme-inducing antiepileptic drugs (EIAED) may have lower-than-expected plasma levels and higher-than-expected tolerated doses 18,19 . Thus, phase I studies of agents known to be metabolized by this enzyme system should stratify patients into two different dose-escalation cohorts of those on and off EIAED. A more recent approach in early-phase studies in neuro-oncology is to initiate a phase II study in brain tumor patients using the established phase II dose from other systemic cancer patients not taking EIAEDs. Only if some measure of activity is

Ultrafiltration

Membrane filters can also be used to separate protein from plasma samples. This method differs from the other techniques, however, in that protein-bound drug is removed along with the proteins. In precipitation methods, liquid-liquid extraction, or solid-phase extraction techniques the protein and the solvent conditions undergo changes that release the drug from the protein, thus resulting in total drug concentration (sum of bound and free). Ultrafiltration is therefore the most common choice if the free drug concentration is needed. This measurement in combination with total plasma concentration allows the study of protein-drug interactions (44).

Practical Management

For cancer patients who require an AED, the selection of an appropriate AED must be based on effectiveness, side effect profile, cost, and available routes of administration. To add to this complicated decision-making, we must consider the potential for drug-drug interactions, particularly with CTAs. The ideal AED for neuro-oncology patients would have a long half-life to allow once daily dosing to improve compliance, would have a low incidence of tolerable or transient side effects, would be highly effective as monotherapy for both partial and generalized seizures, would allow a rapid titration to a therapeutic dose, would have minimal interaction with other medications, and would be low cost. No currently available agent meets all of these requirements. Table 3.3 summarizes some of the considerations when choosing an AED. The advantages and disadvantages of specific AEDs in treating cancer patients (see Table 3.3) vary with the clinical situation. For surgical candidates, the...

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).

Treatment

The medical and surgical treatment of GERD in the elderly population generally follows the same principles as for any adult patient with reflux 10 . The basic goals of treatment are relief of symptoms, early detection of lesions, healing of esophagitis, prevention of relapses, and prevention of complications 28 . Evaluation and management of the elderly patient does require attention to more subtle, atypical, or non-specific symptoms, recognition of the importance on maintaining function, and patience in the interaction and in the pace of progress 1 . Education of the patient about the nature of GERD and the factors that may precipitate reflux continues to be the cornerstone of therapy. Characteristics of an ideal agent for the treatment of a chronic condition in an elderly patient include high safety and efficacy, minimal side effects, no need for dose adjustment with age, safety in renal and hepatic insufficiency, a simple dosing regimen, no significant drug interactions, and cost...

Phenelzine

Phenelzine is effective for treating depression, especially complicated types of depression that have not responded to more traditional antidepressants. However, phenelzine also affects the MAO enzyme in many other areas of the body. This accounts for the large number of serious side effects and drug interactions it causes.

Malaria

The efficacy of antimalarial prophylaxis and therapy is not influenced by HIV. Accordingly, recommendations for malaria therapy are generally applicable in HIV patients. As described above, drug interactions of antimalarial and HIV drugs are insufficiently established. The treatment of complicated malaria is specially problematic since the indicated drugs, quinine, quinidine, or artemisinin derivates, are all CYP3A4 metabolized. The coadministration of these drugs with CYP3A4 inhibitors, especially protease inhibitors, efavirenz, and delavirdine, requires intensive care monitoring and, when possible, drug level monitoring.