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Emtricitabine Drug Interactions

The likelihood of drug-drug interactions with emtricitabine is quite low. In vitro data have shown emtricitabine's benign effect on many clinically relevant cytochrome P450 isoforms (3). In several single-dose healthy volunteer studies combining tenofovir disoproxil fumarate, indinavir, famciclovir, stavu-dine, or zidovudine with emtricitabine, negligible effects were observed, except for a 13 and 17 increase in zidovudine's AUC and Cmax, respectively (3,19). Although statistically insignificant differences may be caused by small sample sizes, the differences are thought to be clinically unimportant (Gilead Sciences, Foster City, CA, data on file). A regimen of didanosine and efavirenz at typical doses coadministered with emtricitabine to treatment-naive patients did not change the pharmacokinetic profile of emtricitabine after 4 wk of therapy (19).

Drug Interactions

A drug interaction study has also been conducted evaluating the combination of 300 mg tenofovir DF daily with ritonavir-boosted atazanavir (100 mg ritonavir daily plus 300 mg atazanavir daily) in 10 HIV-infected volunteers. The AUC for 300 mg atazanavir daily decreased 25 when atazanavir was administered with ritonavir plus tenofovir DF, but the trend did not reach statistical significance (46). To assess potentially significant drug interactions between adefovir dipivoxil and drugs used frequently by patients with chronic HBV infection, a phase I randomized, open-label, multiple-dose, three-period crossover pharmacokinetic drug-drug interaction study was performed in healthy subjects. The findings suggest coadministration of 10 mg adefovir dipivoxil once daily with lamivudine, paracetamol, ibuprofen, or systemic trimethoprim sulfamethoxazole does not result in clinically significant drug interactions, but systemic adefovir AUC levels were notably higher when coadministered with...

Indications in sleep disorders

Modafinil is a selective wakefulness promoting drug which appears to be effective in relieving excessive daytime sleepiness whatever its cause (Table 4.5). It is indicated when this persists after sleep hygiene advice and treatment of the cause, and if there has not been any response to first-line stimulant treatments such as caffeine. It is preferable to amphetamines and related drugs, because although they are equally effective, it has a more specific effect on sleep-wake control, fewer side-effects, low potential for dependence, no withdrawal symptoms, few drug interactions and is safer in overdose. Its main indications are as follows.

Problems with use

Drug interactions The metabolism of barbiturates by microsomal enzymes in the liver underlies most of the drug interactions. The rate of metabolism of warfarin, phenytoin, tricyclic antidepressants and the oral contraceptive pill is increased, and conversely MAOIs inhibit these enzymes and reduce the rate of barbiturate metabolism.

Membrane Based Systems

Immobilised artificial membrane (IAM) surfaces are constructed of phospholipid analogs which are covalently bound by an alkyl chain to silica particles at high molecular surface densities, mimicking fluid phase phospholipid bilay-ers (Pidgeon and Venkataram, 1989 Taillardat-Bertschinger et al., 2003). Even given the advantages of IAM, including the ease of automation, the speed of screening, and the possibility to study pH-dependent partitioning, the data obtained with IAM chromatography may not always reflect biological permeation but only drug interactions with the membrane surface. Other shortcomings associated with the method include column variability and instability.

PH Bile Salts and Proteins for Biorelevance pH Adjustment

Yamashita and coworkers studied the effect of medium pH on the transport rate of several passively and actively transported drugs in Caco-2 cells (including antipyrine, theophylline, hydrochlorothiazide, atenolol, terbutaline, nadolol, salicylic acid, furosemide and cephalexin). Transport was studied in the absence (apical and basolateral medium buffered at pH 7.4) or presence (apical medium buffered at pH 6.0, basolateral medium buffered at pH 7.4) of a pH-gradient. The observed differences in apparent permeability were attributed to both difference in drug partitioning and modification of carrier-mediated transport (Yamashita et al., 1997). A similar study was run in the PAMPA model (Sugano et al., 2001). The permeation of 30 model compounds, expected to be passively tran-scellularly transported, was assessed as a function of pH. For both models, it was concluded that a better prediction of the fraction absorbed in humans would be obtained under pH-gradient conditions. Although...

Adults and adolescents1

1 These dosages are in common clinical use. The dosages in this table were selected on the basis of the best available clinical evidence, and dosages that can be given on a once or twice daily basis were preferred in order to enhance adherence to therapy.The doses listed are those for individuals with normal renal and hepatic function. Product-specific information should be consulted for dose adjustments that may be indicated with renal or hepatic dysfunction or for potential drug interactions with other HIV and non-HIV medications. 4 Dosage adjustment when combined with an NNRTI is indicated but a formal recommendation cannot be made at this time. One consideration is to increase the RTV component to 200 mg wice daily when EFZ or NVP is used concomitantly. More drug interaction data are needed.

Searching For Biomarkers In A Sea Of Human Variability

Metabolomics-based analysis of serum and other surrogate biofluids offers certain unique advantages over transcriptomics- and proteomics-based approaches. For example, there is a higher possibility that small molecules can either be transported or diffuse across cell membranes and into the bloodstream more readily than transcripts, whole proteins, or peptides. Since metabolite levels are a direct reflection of enzymatic activity, using metabolites as biomarkers should, in theory, have higher levels of specificity and more accurately reflect the true physiological state of a cell or organism than transcript or protein profiles. Proteomics is further complicated by the fact that proteins, even if overexpressed, are subject to a myriad of regulatory processes (post-translations modifications, drug interactions, environmental carcinogens, etc.), which may or may not be important in a biological context, or produce phenotypic changes. Metabolites are not subject to these processes, since...

Clinical Decision Support

Various forms of clinical decision support functionality have been implemented in clinical systems used by healthcare delivery organizations. This functionality has been implemented in the context of various applications, where decision support logic supported by these applications is embedded within the invoking application and an attempt has been made to automate complex guidelines for clinical care 22 . Examples of typical applications are (a) Computerized physician order entry (CPOE) applications, which allow physicians to enter orders (e.g., medications, laboratory and radiology tests) into the computer system interactively providing real-time decision support as part of the ordering process (b) automatic alerting, which automatically identifies serious clinical conditions and notifies the patient's attending physician while suggesting potential treatments for patient's condition (c) Adverse drug-events monitor (ADE), which reviews patients' medication profiles for pairs of...

Pharmacokinetic Profile

A summary of drug interactions with delavirdine has been published elsewhere (41), and is nicely presented in a continuously updated format at As would be expected, coadministration of delavirdine increases circulating levels of amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir (39) (Table 1). However, nelfinavir causes a significant reduction in peak delavirdine levels as well as a less-significant reduction in total drug exposure (42), and the efficacy of this combination would have to be carefully evaluated in clinical trials before its use could be recommended in

Adjunctive Medication

Judicious use of additional medications may be appropriate in selected schizophrenic patients and is very frequently utilized. The basis for the use of adjunctive medication may be treatment of side effects, refractory psychotic symptoms, comorbid conditions, or specific nonpsychotic symptoms such as agitation, anxiety, depression, or mood elevation. Careful consideration of potential side effects, additive effects, and drug interactions is essential.

Discussion Pneumonia and HIV

**Multidrug-resistant (MDR) tuberculosis (resistant to isoniazid and rifampicin) is becoming an increasing problem among HIV positive individuals in North America. Antituberculous treatment requires careful monitoring for drug interactions and toxicity, especially if the patient is on HAART. Interactions such as those between the rifamycins and protease inhibitors or non-nucleoside reverse transcriptase inhibitors can lead to lower efficacy or increased toxicity of the anti-retroviral regimen.4

Impact of early HAART

The success of HAART has led to a reappraisal of the role of prophylaxis for opportunistic infections such as PCP, CMV, and M avium. This is due to the decreased risk of opportunistic infections in the face of a reduced viral load and sustained or increased CD4 T cell levels, and because of problems of drug interactions between HAART and prophylactic therapies.4 15-20 45-48 The Adult Adolescent Spectrum of HIV Dis

Toward Algorithms in Individualized Medicine

The efforts to establish a modern platform for individualized therapy is a demanding challenge to medicine. The evaluation of a rational approach to identify and handle a complex set of variable factors, which may influence drug treatment and responses, is critical. These factors include genetic variability of the drug metabolizing enzymes, drug transporters, drug targets and their signaling pathways, and as well drug-drug interactions and food-drug interactions in addition to disease state and phase, organ function dysfunction, age, body weight, and gender. A future direction in pharmacotherapy might be to develop treatment algorithms (Fig. 1) for single drugs or drug regimens taking into account the relevant subset of critical determinants with adjustments to the single patient and further linked to practical implementable procedures. Algorithms aiming to integrate the premises of advanced pharmacological therapy can support a higher precision in individual treatment both with...

Richard Ogden and Gail Skowron

Many of the drugs described in the preceding chapters represent milestones in HIV treatment history for reasons other than that they were the first agents to save or prolong lives of adults and children worldwide. There has been an unprecedented effort by the pharmaceutical industry to surmount the hurdles associated with coformulation of these drugs into regimens that have the convenience of a lower daily pill burden. The first agent approved, zidovudine, is now available coformulated with lamivudine, as combivir, with abacavir, as epzicom and with both as trizivir. It has undoubtedly helped up to this point that the commercialization of these coformulated drugs has been driven by common ownership of the component medications. The benefits to patients, in terms of convenience, have been huge. Recent coformulation of emtricitabine and tenofovir as truvada and the ongoing work to formulate and gain approval for a triple combination of truvada with efavirenz has not only brought one of...

Regulatory Clinical Pharmacology Perspective

Plasma concentration profiles with single-dose pharmacokinetic data and models, and estimating the clinical consequence (change in effectiveness and toxicity) of changes in pharmacokinetics in special populations or due to drug-drug interactions and other intrinsic or extrinsic factors based on pharmacokinetic and pharmacodynamic relationships. Examples of the second application include estimating the power of population pharmacokinetic pharmacodynamic studies, and efficacy safety conclusions.

Central nervous system stimulants and wakefulness promoting drugs

Caffeine is the usual first-line mild stimulant for excessive daytime sleepiness, and is often taken in tea, coffee, cola or 'energy' drinks, or as caffeine tablets. Nicotine is a stimulant in high doses and has a useful alerting effect. If excessive daytime sleepiness is more severe, modafinil should be considered before amphetamines and related drugs. It has a more specific sleep-promoting action with fewer central or peripheral nervous system stimulant effects. Side-effects and drug interactions are uncommon and it has little potential for dependency. It has a more gradual onset and a longer duration of action than dexam-phetamine, but lacks the 'lift' that amphetamines give. It is as effective as dexamphetamine as a wakefulness promoting drug, but should not be taken late in the day since its long duration of action may lead to insomnia.

Psychotropic Medications

The somatizing patient is often sensitive to medication side effects therefore, the physician should discuss in advance common side effects, explaining that these are normal responses to such medications. It is also important for the physician to inquire about other drugs, such as herbal preparations, that the patient may be taking, because drug interactions have the potential to cause adverse reactions.

Drugdrug And Drugfood Interactions

The results of drug interaction studies with EFV are shown in Tables 3 and 4 (17,21-30). Relatively few of these pharmacokinetic interactions seem to require dosage adjustments. There may be an interaction with ritonavir that may potentiate the toxicity of ritonavir. There are no specific guidelines for dosage adjustment, but there is a need for vigilance regarding any possible drug-associated toxicity. Administration of EFV with saquinavir as the sole PI is not recommended because plasma concentrations of saquinavir are markedly decreased however, a triple-drug combination of EFV plus saquinavir plus ritonavir was not associated with any significant changes in steady-state concentrations of either saquinavir or ritonavir, and dosage modifications with this triple combination seem unnecessary (31). When EFV is administered with the combination of lopinavir plus ritonavir, an increase in the dosage of the PI

The Scope Of Proteomic And Chemical Proteomic Studies

In order to simplify the complexity of a proteome, it is often useful to group proteins into families based on similarities in their binding sites. Once this is done, many of the spectral techniques presented in this book (reviewed in chapter 3) can be used to characterize protein-protein (part III) or protein-ligand (part IV) interactions, one protein family at a time. To achieve the full benefit of this approach to proteomic studies, Villar et al. (chapter 2) noted the need for more sophisticated tools to extract information on protein interactions and to identify the relationships across datasets and disciplines. They note the importance of striving towards this goal, since it is crucial to understanding the selectivity issues associated with drug-drug interactions, environmental challenges, and toxicological risk assessment. The interface of chemistry and the proteome is defining the field of chemoproteomics (chemical proteomics) and is an underlying theme in many chapters of this...

Treating TB and HIV together

Infection, who does not appear to be at high risk of dying, it may be safer to defer ART until the initial phase of TB treatment has been completed. This decreases the risk of immune reconstitution syndrome and avoids the risk of drug interaction between rifampicin and a PI.

The Role Of Delavirdine In Clinical Practice Table

A number of options are currently available for the use of delavirdine in initial HAART regimens. It is unfortunate that limited data are available on the short-and long-term potency of delavirdine-based regimens in this setting. However, even if this information were available, it is unclear how much delavirdine would be used, because the other drugs in this class have a lower pill count and can be administered once a day. One could argue that delavirdine could be used in patients who cannot take either efavirenz or nevirapine for reasons of toxicity, and in whom there is a desire to avoid the use of PIs. This may include intravenous drug users who could be at increased risk of hepatic toxicity (because of intercurrent hepatitis C virus infection) and who may also experience drug interactions when receiving methadone with efavirenz and or nevirapine. This may represent an area for future research, especially if additional data can be generated on the efficacy of delavirdine as part...

Learned Helplessness and 5HT

It is probably worth reiterating that the SSRIs are relatively, not absolutely, selective for 5-HT, since some of these agents have appreciable effects on other neurotransmitters as well. Interestingly, newer in vivo studies suggest different biogenic amine reuptake blockade profiles for the SSRIs than those reported by the earlier receptor binding studies (see also Chapter 10). Since in vivo studies examine the brain as a whole, with neuronal connections intact, they may be a more accurate reflection of actual brain-drug interaction than studies of post-mortem tissue. Using in vivo microdialysis, we showed fluoxetine to increase extracellular levels of both noradrenaline and dopamine similar to imipramine, whereas fluvoxamine had negligible effects on the catecholamine neurotransmitters.12 Of course, the extent to which these factors influence therapeutic effects or adverse effects is not known, and may be irrelevant.

Pharmacology And Toxicology Of Spirulina

The pharmacokinetics and pharmacodynamics of Spirulina in humans have not been thoroughly investigated. However, the proteins, lipids, and carbohydrates in Spirulina are digested, absorbed, and metabolized by the humans upon oral consumption. Spirulina can be consumed at a dose of 3-20 g day without manifestation of any adverse effects.91 Studies on the acute, subchronic, and chronic toxicity and mutagenicity of Spirulina have revealed no specific body or organ toxicity or genotoxicity.92,93 Studies in animals fed with large quantities of Spirulina have shown that the alga is neither toxic nor causes adverse health effects.94 Dietary ingestion of very high levels of Spirulina during pregnancy has not caused any fetal abnormalities or birth defects.95 Independent feeding tests have shown no toxic or adverse effects in the humans, rats, pigs, and chickens.92,96,97 Feeding experiments with rats conducted in Japan have revealed no acute or chronic toxicity or reproductive toxicity of...

Future Prospects

A critical need in molecular pharmacology is the development of a better understanding of protein binding similarities and the dynamic process that occurs during the recognition process.50 The arrangement of proteins and compounds into classes is a central problem in drug discovery, and the vast amount of data being accumulated requires new ways to classify proteins and ligands. The importance is not merely theoretical, but has great practical implications. Problems of selectivity are squarely in this realm. Adverse events, environmental challenges, drug-drug interactions, and toxicological risk assessment are all related to this central problem Small molecules interact with multiple proteins in ways that are not necessarily anticipated. If we are to increase the efficiency of the drug discovery process, we need to understand how those interactions come about and apply our expanding knowledge base in drug design to reinforce desirable characteristics and avoid unwanted ones.

The Elderly

The increased vulnerability of elderly subjects to side-effects of tricyclic antidepres-sants, particularly cardiac problems, orthostatic hypotension, sedation and cognitive impairments often causes clinicians to consider the use of SSRIs as an alternative treatment to tricyclic antidepressants in the elderly. While a detailed discussion of pharmacokinetic and pharmacodynamic changes with aging is outside the scope of this chapter (but see Chapter 2) it is important to note that some important differences exist between SSRIs. For example, some SSRIs show linear kinetics (citalopram and sertraline) while others do not. Age-related changes in plasma concentrations also vary, with fluvoxamine and sertraline showing little change with age while levels of citalopram and paroxetine may be double in the elderly. They also differ in their potency to inhibit different subtypes of the cytochrome P450 system, an important system involved in oxidative metabolism of many drugs. This results in...


If the patient and the physician are aware of the possibility of liver and other toxicity, then a 200-mg tablet once a day for 9 months might be curative. Close patient monitoring is necessary. Many drug interactions, very expensive. 3. Itraconazole (Sporanox) therapy has been reported to be curative, 200 mg b.i.d. for 7 days, repeated monthly for 4 to 6 months. Available as a Pulse Pak. Many drug interactions. 2. Itraconazole (Sporanox) may be used. A dosage of 200 mg b.i.d. for 7 days, repeated monthly for 4 to 8 months, has been suggested. A Pulse Pak is available. Drug interactions must be watched for. Monitoring of the patient is necessary for rare liver toxicity. Very expensive

Iu Introduction

ART results in dramatic reductions in morbidity and mortality in HIV-infected people. There are several requirements for successful use of ART. These include considerable efforts to maintain adherence to lifelong treatment and to monitor response to treatment, drug toxicities and drug interactions.

Binding Studies

The examples described in the previous section demonstrate how NMR spectroscopy can be used as a tool to study the behavior of proteins inside living cells and that significant differences between the in vitro and in vivo behavior of a protein can exist. Furthermore, the sensitivity of the chemical shift to changes in the chemical environment of a nucleus can also be used to study binding events such as the interaction of proteins with small molecules or with metal ions 10 . This feature has made high-resolution liquid-state NMR spectroscopy a widely used tool for screening protein-drug interactions in the pharmaceutical industry. In vitro NMR screens have, however, the disadvantage that an interaction that is observed might not occur in the same way in vivo. Binding of a drug to its intended target protein in vivo could, for example, be prevented due to the inability of the drug to cross the cellular membrane, its rapid metabolism inside the cell, its binding to other cellular...


Several types of prescription antidepressants are available, and newer generations become available each year. Please refer to our resource section in Appendix B for more information on antidepressants. We also urge you to review Chapters 10 and 11, which discuss drug interactions, as well as Chapter 21 on informed consent.


Stavudine (also known as d4T) is available as an immediate-release product (Zerit) and has been investigated as a once-daily extended-release formulation (Zerit XR). The absorption of stavudine is not significantly affected by food. Although no clinically significant drug-drug interactions occur between stavudine and didanosine, lamivudine, or nelfinavir, concurrent use of zidovudine and stavudine is not recommended in clinical practice, because of intracellular antagonism. Because of the potential for overlapping toxicities, the use of the combination of stavudine plus didanosine in therapy-naive patients is decreasing and is not recommended.