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Pharmacokinetic drug interactions

Altered distribution in drug interactions is explained mainly by displacement of drug from plasma proteins or receptor-binding sites. The most common binding proteins are the high-affinity, low-capacity protein a1-acid glycoprotein and the low-affinity, high-capacity protein albumin. Protein-binding displacement interactions after oral and intravenous dosing of low hepatically and nonhepatically extracted drugs are generally clinically unimportant because unbound drug concentrations at steady state in plasma do not change or are only transiently changed by displacement (20-22). Average unbound plasma concentrations at steady state of high hepatically extracted drugs administered orally are also not expected to be affected by displacement, provided that changes in bioavailability and unbound clearance are proportional. Moreover, drugs that are bound to both a1-acid glycoprotein and albumin may show no overall change in fraction of unbound drug in plasma because displacement from...

Evaluation of drug interaction literature

Each report of a drug interaction must be assessed for a variety of criteria (17). Management decisions should be in response to clinically important outcomes resulting from coadministration of drugs. Consideration must be given to the time-course of the interaction (or lack thereof if a negative report is under assessment) to be sure that the occurrence of the most prominent effect is captured. The timing and order of administration of drugs must be evaluated in drug interaction reports because the sequence of administration can determine if an interaction will manifest. Interactions that affect drug absorption can often be mitigated by staggering the dosages and giving the object drug (i.e., drug with the effect that is altered) first. Examples are drug-food (Chapter 12) and quinolone-antacid (Chapter 8) interactions. Dose also affects interactions. A smaller-than-usual dose reduces the chance of observing an interaction, whereas a larger-than-usual dose increases the possibility of...

Pharmacodynamic drug interactions

Pharmacodynamic interactions can be beneficial in that an improved therapeutic response may occur or be detrimental in that toxicity may be heightened. Also, therapeutic activity and toxic effects may occur simultaneously in opposite directions, resulting in a balance between positive and negative responses. Beneficial pharmacodynamic drug interactions abound in infectious disease therapy because of the many of drug combinations used to treat infections. An example of such an interaction is the effective synergistic combination of ampicillin and gentamicin or streptomycin in the treatment of enterococcal endocarditis (26).

Drug interactions affecting distribution

Drug interactions affecting distribution are those that alter protein binding. Generally, the importance of drug displacement interactions has been overestimated, with the extrapolation of data from in vitro investigations without consideration for subsequent physiological phenomena. The lack of well-designed studies has prevented precise quantification of the influence of protein binding on anti-infective therapeutic efficacy in vivo. However, redistribution and excretion of drugs generally occurs quickly after displacement, and the effects of any transient rise in unbound concentration of the object drug are rarely clinically important (82). Depending on relative plasma concentrations and protein-binding affinities, one drug may displace another with clinically significant results. This interaction is much more likely to occur with drugs that are at least 80 to 90 bound to plasma proteins, with small changes in protein binding leading to large relative changes in free drug...

Drug interactions affecting drug metabolism

The majority of oxidative reactions are catalyzed by a superfamily of mixed-function mono-oxygenases called the CYP enzyme system. Although CYP isozymes are located in numerous tissues throughout the body, the liver is the largest source of CYP protein (50). Many significant pharmacokinetic drug interactions involve the hepatic CYP isozymes (87-91) (Table 2).

Example 2 Use of Biomarkers to Assess Drug Drug Interactions

For an analog of clopidogrel with an established concentration-effect relationship, the drug's inhibition of platelet aggregation was used to assess the possible impact of another drug in a drug-interaction study. Absence of a drug interaction was to be declared if the difference in aggregation inhibition, as defined in Example 1, by the clopidogrel analog in the presence and absence of the second drug was < 10 . Using this critical value and the known relationship between plasma concentration and inhibition of platelet aggregation, boundaries for AUC and Cmax of the analog were calculated. It is entirely possible that the so defined upper and lower bounds for Cmax and AUC exceed the traditional bioequivalence range of 80-125 . The criteria for the clinical significance of a drug interaction was defined in this example by a biomarker and not the target clinical endpoint (25).

Mechanisms of Drug Interactions

There are numerous types of drug interaction that are classified in Figure MD.4. They may be desirable (the reversal of neuromuscular blockade by anti-cholinesterases) or undesirable. Two drugs may cause the same effect and the outcome may be simply additive (summation) or synergistic. Synergism is when the combined activity of two or more drugs (or other agents) acting on the same process is such that the effect produced is greater than the sum of the effects of each drug acting alone. Conversely, drugs may reduce the desired effect either by acting in opposite ways or by preventing the other drug from acting. Drugs do not necessarily interact to increase or decrease the therapeutic effect but may cause entirely different effects or may alter the levels of the other agent. Many drugs are given in combination to make use of their interactions. CLASSIFICATION OF DRUG INTERACTIONS

Drug interactions affecting excretion

Renal elimination of drugs involves glomerular filtration, tubular secretion, and tubular reabsorption. Five mechanisms of drug-drug interactions can occur at the site of renal elimination (154). The most common mechanisms are discussed next (Table 3). Potential Mechanisms of Drug Interactions Involving Excretion The most common renal drug interactions occur at the transport site of tubular secretion. Sharing the same proximal tubular active transport system, many organic anionic and cationic drugs and metabolites compete with each other for secretion. A classic example of this interaction, used long ago intentionally for therapeutic benefit, is the combination of probenecid and penicillin to increase antibiotic serum concentrations (157). Examples of other anti-infectives that may exhibit interactions by this mechanism include the sulfonamides, penicillins, and zidovudine (158-160). P-Glycoprotein has been identified in the apical membrane of the proximal tubule and can transport a...

Significance of drug interactions

Many drug interactions are primarily assessed in vitro (see the Preclinical Methods for Predicting Drug Interactions section). However, absolute in vitro in vivo correlations are infrequent. Even with clinical trials, not all statistically significant drug interactions are clinically significant. In particular, drugs with wide therapeutic indices that The greatest risk of documented clinically significant pharmacokinetic drug interactions involving anti-infective-induced altered protein binding, drug-metabolizing enzyme inhibition, and altered renal elimination is the combination of anti-infectives with anticoagulants, antidepressants, and cardiovascular agents (90). The most clinically significant anti-infective drug interactions involving enzyme induction are subtherapeutic concentrations resulting from the combination of rifampin with warfarin (166), cyclosporine (167), and oral contraceptives (168,169). Conversely, the reduction of Cmax or AUC of anti-infectives by other drugs or...

Overview of clinical methods for predicting drug interactions

The primary cause of clinically significant drug interactions is the involvement of drug-metabolizing enzymes. Because great variability exists in drug-metabolizing enzyme activity among subjects, and drug interactions may not achieve clinical significance in all patients, interactions may be better clinically predicted by the knowledge of individual patient isozyme activities. However, there is currently a need for the development of reliable, accurate, and noninvasive methods to monitor drug-metabolizing enzyme expression in humans to guide drug dosage, reduce toxicity, and predict potential drug interactions. Genotyping involves identification of variant genes causing poor- or ultraextensive metabolizer activity or phenotype. Genotyping has been demonstrated to predict the clinical outcome of drug interactions involving both Phase I and II metabolism (194,195). However, drug-metabolizing enzyme activity can be exquisitely sensitive to environmental and physiological influences....

In vitroin vivo scaling of drug interactions

The process of using in vitro models to predict in vivo drug interactions is still in its infancy, and extensive validation of this approach is needed. In vitro models predictive of in vivo drug interactions will be essential for rapid, cost-effective screening of pharmaceutical compounds and are important for reducing risks to patient safety. Currently, these models are constructed from a combination of laboratory and theoretical components. Ideally, in a valid model, the in vivo decrease in clearance caused by coadmin-istration of an inhibitor would be specifically predicted by the decrease in reaction velocity (e.g., formation rate of a metabolite) for the same compound in vitro when the inhibitor is present in the same concentration. To establish the feasibility of in vitro-to-in vivo scaling, most currently reported predictions of inhibitory drug interactions are retrospective. Presently available methods allow a general assessment of what may occur (i.e., an unlikely interaction...

Drug interactions affecting absorption

Mechanisms of absorption include passive diffusion, convective transport, active transport, facilitated transport, ion-pair transport, and endocytosis (9). Certain drug combinations can affect the rate or extent of absorption of anti-infectives by interfering with one or more of these mechanisms (10). Generally, a change in the extent of a medication's absorption of greater than 20 may be considered clinically significant (11). The most common mechanisms of drug interactions affecting absorption are discussed in Table 1. Intestinal blood flow can be modulated by vasoactive agents and theoretically can affect the absorption of lipophilic compounds. However, there is no evidence to date that this results in clinically significant drug interactions (37). A rapidly expanding field of research is that of intestinal transcellular transport. Multiple intestinal transporters located on the brush-border and basolateral membrane of the enterocyte have been identified (38-40). The potential for...

Preclinical methods for predicting drug interactions

Although understanding and anticipating pharmacokinetic drug interactions are important components of rational therapeutics, there is a limit to the number and scope of clinical studies that can reasonably be performed. The development of human in vitro models allows information to be obtained without the expense and potential risks involved in conducting human trials. However, scaling of in vitro data to the clinical situation is not always accurate, and the results of these methods may not be definitive. A primary focus of preclinical screening methods for assessing drug-drug interactions is the identification of isozymes responsible for the metabolism of these compounds and the relative contribution of an inhibited pathway to a compound's overall elimination. Preclinical Methods for Predicting Drug Interactions The following briefly summarizes the strengths and weaknesses of currently available in vitro human methodologies for assessing CYP drug interactions and predicting their...

Drug Interactions

There are a few potential drug interactions to be aware of in the treatment of the stimulant poisoned patient. Since cocaine is metabolized by plasma cholinesterase, coadministration of other drugs such as succinylcholine and mivacurium, which are metabolized by plasma cholinesterase, may have a prolonged duration of effect due to decreased metabolism. This may have significant implications during a failed rapid-sequence intubation with these agents.

Clinical vs statistical significance

The term clinical significance describes the degree to which a drug interaction changes the underlying disease or the condition of the patient (45). The magnitude of An important statistical and clinical consideration is the evaluation of changes in both mean and individual pharmacokinetic and pharmacodynamic variables. Drug interaction reports may conclude that a mean change is statistically and clinically insignificant, but certain individuals may be affected by the drug interaction. Evaluation of individual changes in study participants is therefore important to determine if a particular subset of individuals responds differently to the treatment. Conversely, some individuals are not affected by drug interactions even though significant mean changes may occur. The aim of many interaction studies is to demonstrate that there is no clinically relevant interaction. The currently accepted bioequivalence approach (i.e., the inclusion of the 90 confidence limits for the ratio difference...

Clinical significance grading

The clinical significance grading of a detrimental drug interaction can be difficult. The level of documentation must be assessed to determine the degree of confidence that the interaction exists. The predictability of drug interactions from documentation can be divided into five levels established (well documented), probable, suspected, possible, or unlikely. The data may be from in vitro studies, animal studies, anecdotal case reports, or randomized controlled trials in the target population or healthy volunteers. The Drug Interaction Facts classification scheme combines the three severity levels and five documentation levels into 15 interaction categories, with five levels of clinical significance assigned to those 15 categories (50). A scale of the clinical significance of drug-drug interactions that reflects the professional judgments of practicing pharmacists has been proposed by Roberts et al. (45).

Of in vivo interactions from in vitro data

Although human studies provide the most definitive data on the likelihood and magnitude of a drug interaction, there are important limitations to performing such studies. There is always potential risk to the subject, even if it is small or unlikely. Regulatory requirements for control and monitoring of these studies are becoming increasingly costly and time consuming. Consequently, the number and spectrum of studies that can be performed are limited. A search for alternatives has led to the use of human liver components (e.g., microsomes, hepatocytes) or other tissues to represent or predict the interaction in vivo (53). Chapters 2 and 3 provide an overview of in vitro methods to predict drug interactions. There are now human liver banks that have microsomes and purified or recombinant human cytochrome P450 enzymes available for extensive in vitro study of metabolic pathways of new drugs (54). During early development of a new drug, these in vitro systems can predict if the drug will...

Conclusions and future directions

It is difficult to assess the true incidence and clinical significance of drug interactions. Understanding the mechanisms underlying drug interactions is important for the prediction and avoidance of drug toxicity when initiating combination therapy. Although multiple in vitro methods are currently in use to assess drug interactions, not all have allowed the prediction of clinically significant events (202,203). As drug interactions most commonly result from influences on drug-metabolizing enzymes, future research defining the origins of enzyme activity variability and characterizing individual patient activity will certainly improve our ability to predict these interactions and improve drug therapy.

Pharmacoepidemiology

The reports of overall frequency of drug-drug interactions vary widely in the literature (27). Incidence rates reported in the 1970s and 1980s ranged between 2.2 and 70.3 for ambulatory, hospitalized, or nursing-home patients (28-34). Overall, the incidence of potentially harmful drug interactions is generally low, but certain populations, such as the elderly, extensive or poor metabolizers, those with hepatic or renal dysfunction, and those who are likely to take multiple medications, particularly for offlabel use, are more at risk. Data collected over 1995-1997 suggest that potential interactions are as high as 75 in the population with HIV, with an actual 25 incidence of clinically significant interactions (35). Some studies have attempted to quantify the incidence of symptoms resulting from these potential interactions. A range of 0 to 1 has been reported in hospitalized patients (36), but the incidence is likely increasing (35). Although the number of potential interactions may...

Pharmacoeconomics

The literature suggests that up to 2.8 of hospitalizations result from drug interactions (36). An association also has been found between the risk of hospitalization and interactions of various medications, including anti-infective agents, thus supporting the premise that drug interactions compromise health and incur costs (42). Individual case reports can demonstrate the measurable financial impact of drug interactions. However, quality of life and cost to the patient and society are less apparent but equally or more important (43). Although data are scarce regarding cost increases secondary to drug interactions, the impact of such events remains a concern (44).

Clinical management

After assessing the level of documentation in the literature and the significance grading of the interaction, consideration must be given to the onset and offset of the event, the mechanism, the change in outcome, management suggestions, and any discussion in the available literature concerning the interaction. When a patient has been identified to be at risk of experiencing a clinically relevant drug interaction, steps must be taken to prevent or minimize this potential event (17). If possible, the combination should be avoided or one or more of the agents stopped. The medication(s) may be replaced by noninteracting medication(s) that are therapeutically equivalent, doses may be staggered, dose strength or interval may be modified, or the route of administration may be changed. Classification Scheme for Management of Drug Interactions Class 4 Potential for harm is low and no specific action is required other than to be aware of the possibility of the drug interaction.

Conclusion

With the increasing appreciation of known and potentially important drug interactions covering the broad spectrum of infectious diseases, the need for clarification of This volume is intended to provide an in-depth review of drug interactions related to a number of topics in infectious diseases. An emphasis on the clinical approach with specific examples and cases will guide the reader in developing skills for identifying drug interactions and problem drugs as well as strategies for circumventing of drug interactions.

Cyp2e1

Drug oxidation can be accounted for by the activities of CYP1A2, CYP2C8 9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 5 (Fig. 1). Drug interactions involving these isozymes result from enzyme inhibition or induction, although genetic polymorphism can attenuate these interactions (96). Poor-metabolizer phenotypes can be at high risk for toxicity from drugs that require CYP inactivation and at high risk for therapeutic inefficacy from prodrugs that need CYP activation (98). However, they are at low risk for drug interactions that involve enzyme inhibition or induction because their activity is preemptively compromised and cannot be induced. In addition, because of the large variability (e.g., 40-fold or greater) in enzyme activity documented in extensive metabolizers (99), drug interactions may not manifest in all subjects with this phenotype. Inhibition of drug-metabolizing enzymes may result in more significant effects in those with high initial enzyme activity, and induction of...

Pglycoprotein

P-gp is the first known and best studied of the adenosine-triphosphate (ATP)-bind-ing cassette (ABC) proteins, which also include MRPs 1-8 (8,9). P-gp-mediated drug extrusion was initially identified as a mechanism by which chemically diverse anticancer agents were ejected from tumor cells, resulting in multidrug resistance (10). In addition to tumor cells, P-gp is also located on the canalicular surface of hepatocytes, the apical surface of renal tubular epithelial cells, the apical surface of intestinal and placental epithelial cells, and the luminal surface of capillary endothelial cells at the blood-brain barrier (BBB) (2,6,9). P-gp is also localized on a number of lymphocyte subsets, including CD4+, CD8+, CD19+, and CD56 NK cells (7). Because of its presence in multiple anatomic locations, P-gp may influence the absorption, distribution, metabolism, and excretion of drugs that are P-gp substrates. As such, modulation of P-gp activity by one drug may affect the pharmacokinetics of...

Structure And Model Of Drug Transporters

Because of the involvement of transporters in all facets of drug absorption, excretion, and toxicity, characterization of transporter structure can provide a scientific basis for understanding drug delivery and disposition, as well as the molecular mechanisms of drug interactions and interindividual and interspecies differences. However, compared to soluble proteins, the atomic resolution crystal structures of membrane transporters have been extremely difficult to obtain, for several reasons. First is the amphipathic nature of the surface of the transporters, with a hydrophobic area in contact with membrane phospholipids and polar surface areas in contact with the aqueous phases on both sides of the membrane second is the low abundance of many transporters in the membrane, making it impossible to overexpress them, a prerequisite for structural studies and third is the inherent conformational flexibility of the transporters, making it difficult to obtain stable crystals.

In Vitroin Vivo Correlation Of Drug Behavior

One of the important kinetic properties that needs to be determined in assessing the drug interaction potential of any drug is the value of its KI with each of the major cytochrome P450s. The standard equation for determining competitive inhibition of an enzyme is Eq. (3.24). Since a drug does not need to be a substrate for any specific P450 to be a potent inhibitor of that enzyme, its potential for inhibition can only be assessed and evaluated by in vitro studies. Such studies not only help in determining which P450s are susceptible to inhibition but also to what degree. If the inhibitory drug is coadministered with another drug whose metabolism is primarily dependent upon a P450 that is subject to inhibition by the inhibitor, the potential for a serious interaction would be predicted. Fortunately, in order for a metabolically-based drug interaction to become therapeutically significant three criteria must be met (6). First, the substrate drug should have a narrow therapeutic index...

For Behavioral Insomnia Therapies

As might be surmised by the above discussion, sleeping pills remain the most popular treatment for those chronic insomnia suffers who report sleep complaints to their physicians. Indeed, as many as 50 of those patients who complain of insomnia to their physicians are treated with sedative hypnotics or sedating antidepressant medications to address such complaints. Although these agents may be useful in the management of transient insomnia, they generally fail to provide long-term relief for those with more chronic sleep disturbances. Patients who use hypnotics on a long-term basis often suffer such unwanted effects as drug tolerance, dependence, hangover, short-term memory loss, and a gradual return of their sleep problems. Side effects may be particularly problematic among elderly hypnotic users who are at increased risk for toxic drug interactions and serious falls resulting from oversedation. Although some recently developed sleeping pills hold the promise of reduced side effects,...

Disposable Electrode Materials

Highly oriented pyrolytic graphite electrodes (HOPGE) have also been attractive for electrochemical DNA biosensor research. 9-12 The renewal of HOPGE surface is also simple and rapid. A freshly cleaved surface of HOPGE can easily be prepared by contacting a piece of adhesive tape to the graphite surface, and then removing a thin layer of graphite with the tape. Thus the same electrode can be used for several different measurements. DNA and DNA-drug interaction were examined on thin-film mercury-coated HOPGE by Hason et al. 9 Voltam-metric microanalysis of DNA adducts with osmium tetroxide,2,2'-bipyridine (Os,bipy) using a HOPGE provided the detection of 140 pg of DNA-Os,bipy after a 5-min accumulation period. 10 Anodic voltammetry and atomic force microscopy (AFM) imaging were performed for the detection of adriamycin and DNA interaction on HOPGE surfaces. 11 Atomic force microscopy surface characterization of the effect of pH and applied potential on the adsorption of DNA on HOPGE...

Antiretroviral Therapy

The goal of antiretroviral therapy is to reduce HIV viremia as much as possible for as long as possible. The best time to start therapy and the best drugs to use are not known with certainty, and treatment strategies will continue to evolve. General guidelines include initiation of antiretroviral therapy in persons with CD4 cell counts of less than 500 cells pL. However, therapy must be tailored to individual patients with attention to suppression of viral replication, preservation of immune function, drug side effects, drug interactions, and the patient's preference. Education and counseling also constitute an integral part of antiretroviral therapy. For these reasons, decisions regarding initiation of and changes in antiretroviral therapy should always be made in consultation with the primary care physician and an infectious disease consultant.

How may selection bias affect trial findings

Exclusion of high-risk patients in clinical trials has other ramifications. Several post myocardial infarction studies that evaluated prophylactic beta-blocker therapy included patients with a broader spectrum of risk. Contrary to what one would expect, these trials showed that the benefits of beta-blockade were more pronounced in patients with complicated infarcts (and no contraindications to beta-blocker therapy) than in patients with uncomplicated infarcts.1 By excluding high-risk patients, beneficial effects may be missed. Selection bias may also increase the chances of finding favorable treatment effects. Study subjects typically have above-average education, as well as a personal interest in the research project. As a consequence, their level of adherence with the study medication is usually high. Additionally, since study subjects are usually free of other conditions and take few if any other medications (healthy volunteer effect), the likelihood of drug- drug interactions is...

Reasons Against Prophylaxis

These studies were conducted in the mid-1980s, and national guidelines have since been revised to tailor prophylaxis to at-risk patients. No study has since demonstrated whether the risk-benefit ratio has been modified by the latest recommendations. Nonetheless, the potential for adverse drug reactions must always be borne in mind. Such a consideration should also include non-allergic toxicities (e.g., amino-glycoside-induced nephrotoxicity), as well as potential drug-drug interactions.

TABLE 1511 Nontoxic Ingestions

In 1996, there were 2,155,952 toxic exposures reported to poison centers in the United States 1,137,295 (52.6 percent) involved children younger than 18 years of age. Some authors currently list poisoning as the third leading cause of death in the United States and, between 1985 and 1995, the incidence of toxin-related deaths is said to have increased approximately 300 percent. Although many of these exposures were referred to as accidents, most were preventable or avoidable by modalities such as increased awareness and education, increased parental control over children, instituted checks and balances in hospitals and pharmacies, computer networking and recognition of potential drug interactions, better hospital protocols to ensure patient identification, detailed procedures to check proper dosing, better warning labels and packaging on products with potential toxicity, and better access to mental health care by the underinsured. The public must be made aware of the potential tragedy...

General Principles Of Newer Antidepressants

Since all of the newer antidepressants are metabolized primarily by the liver, hepatic dysfunction can lead to elevated drug levels and subsequent drug toxicity. Also, drug interactions are possible when the newer antidepressants are combined with other drugs dependent on hepatic metabolism.

Admission Criteria

All intentional MAOI overdoses and accidental exposures of greater than 1.0 mg kg require admission to an intensive care unit. Accidental exposures of less than 1.0 mg kg still require hospital admission but are unlikely to develop life-threatening complications. Therefore, these patients can be admitted to a less acutely monitored bed. It is important to remember that even a single MAOI pill may produce life-threatening drug interactions, such as serotonin syndrome, under the right circumstances. Therefore, emergency physicians should have a very low threshold to admit all MAOI exposures. Asymptomatic patients should be monitored for at least 24 h before medical clearance. Vital sign abnormalities should be recognized early and treated appropriately. Dietary and medication restrictions should be meticulously followed during the hospitalization. All patients should be instructed to avoid contraindicated foods and medications for a minimum of 2 weeks. Consultation with a medical...

Factors Enhancing Toxicity

A variety of factors increase susceptibility to digitalis toxicity. True end organ sensitivity is seen with myocardial disease or ischemia, and metabolic or electrolyte abnormalities. Hypokalemia, hypomagnesemia, and hypercalcemia all predispose to increased toxicity.3 The elderly are more susceptible to toxicity. Decreased renal function, hepatic disease, hypothyroidism, chronic obstructive pulmonary disease, and drug interactions can all augment toxic effects. 5 Drug interactions potentially resulting in digitalis toxicity include quinidine, procainamide, b blockers, calcium channel blockers, amiodarone, spironolactone, indomethacin, clarithromycin, and erythromycin.

TABLE 1541 Drugs Contraindicated with MAOIs

Drug interactions involving MAOIs can be grouped into three categories pharmacodynamic, pharmacokinetic, and idiosyncratic. The most common pharmacodynamic reaction involves indirect-acting sympathomimetics. They have the potential to produce a hyperadrenergic condition similar to the tyramine reaction (see above) and can be found in over-the-counter preparations, drugs of abuse, and some prescription products. Pharmacokinetic drug interactions have been noted with MAOIs because they are metabolized through the cytochrome oxidase enzyme system and thus can inhibit the metabolism of other drugs. The potentiation of opiate and sedative-hypnotic drugs is an example of this type of enzyme inhibition. Tranylcypromine and phenelzine have been shown to increase insulin release and predispose to hypoglycemia, especially in patients taking oral sulfonylureas agents. Insulin dosage may also warrant reduction. Serotonin syndrome is a rare, potentially life-threatening idiosyncratic reaction. It...

Animal Toxins and Plant Toxicants

Overall, healthy individuals can tolerate naturally occurring toxicants. However, there are several conditions under which natural toxicants can create problems. Inborn errors of metabolism or certain drug interactions can make individuals prone to problems caused by natural toxicants. Whereas nutrients can be beneficial to most, they can be deleterious to some, e.g., consumption of lactose by lactose-intolerant people. Other examples include individuals with celiac sprue, sucrase deficiency, fructose intolerance, galactosemia, and phenylketonuria. Individuals taking drugs that inhibit monoamine oxidase enzymes can be affected when eating cheeses or drinking wines, which are high in tyramine. Individuals with sensitivities due to allergies can be affected by foods. Hypersensitivity to a particular substance produces anaphylactic shock. Examples of foods that cause allergies include milk, wheat, nuts, citrus, strawberries, fish (shellfish), and egg. Some individuals have bizarre food...

Treatment M avium Complex

The newer macrolides are the mainstay of therapy for MAC pulmonary and disseminated disease (Table 4). Intermittent streptomycin for the first 2-3 months of therapy for the first 8 weeks has also been used. For disseminated disease in AIDS, treatment regimens should include clarithromycin or azithromycin and ethambutol and a third agent rifabutin can be used, but drug interactions exist between rifabutin and protease inhibitors. Prophylaxis for MAC, with either azithromycin (1200 mg once weekly) or clarithromycin (500 mg twice daily, BD), is now recommended for all AIDS patients with CD4 cell counts < 50 cells mm3. 23 Rifabutin (300 mg day) or a combination of azithromycin (1200 mg once weekly) plus rifabutin (300 mg day) has been proven to be effective.

Pharmacokinetics and convenience

An early investigational CXCR4 inhibitor, the bicyclam compound AMD-3100, was found to have potent in vitro antiviral activity against X4 viruses but was not orally bioavailable 29 . Fortunately, some other chemokine pathway inhibitors have shown recent promise as orally bioavailable small molecules, and this may turn out to be a pivotal breakthrough for the entry class as a whole. Both SCH 351125 (Schering C) and another CCR5 inhibitor, aplaviroc, although orally bioavailability 30, 31 , were not further pursued due to potential toxicity. Vicriviroc (Schering D), another CCR5 antagonist in clinical trials 33 , is dosed orally and is being pursued as a stand-alone formulation when given as part of a first antiretroviral regimen, and in the setting of treatment-experienced patients when given with ritonavir as a pharmacokinetic booster. Although clinicians and patients have become accustomed to co-administering mini-dose ritonavir with selected protease inhibitors, especially for...

Physicochemical Properties of Excipients in Dry Powder Inhalers

Increased drug deposition is generally observed with smaller carrier size (61-65). Manufacture method may have significant effects depending on carrier excipient particle size. For example, poor dispersion of nedocromil was obtained using coarse carrier systems, whereas the use of fine carrier particles and high shear mixing techniques physically disrupted the drug-drug contacts and promoted deaggregation (66). Nedocromil sodium powder performance is considered to be dominated by cohesive drug-drug interactions. By decreasing the particle size of the lactose carrier, deaggregation and fine-particle drug dispersion were significantly improved. The carrier's functional effects were achieved by intercalating within the drug self-agglomerates and disrupting the cohesive drug-drug interactions (66).

Postapproval Maintenance

As described earlier, during the final phases of the approval process, the FDA may require the sponsor to do additional work on the drug product after it has been approved. These postapproval commitments range from generation of additional safety and or efficacy data to generation of additional data on the manufacture and control of the drug or biologic product (Fig. 7.28). During initial drug development, studies are conducted in a relatively small number of patients selected under strict inclusion and exclusion criteria with limited long-term safety data. Special patient populations, such as patients with concurrent diabetes or heart conditions, renal failure or hepatic failure, or pediatric and geriatric patients, may not have been specifically studied during the development program. Subpopulations within a general disease indication may need further exploration (e.g., at different disease stages or levels of severity). Due to the exclusivity provisions for studying products in a...

Mobile Health Delivery Systems

EPocrates Rx Pro, a popular PDA program for e-prescription services, is an example of a mobile health delivery system. Information is available for each drug, including dosage recommendations, administration routes, cautions, typical patient reactions, drug interactions, metabolism information, retail costs, manufacturer, safety data, and recalls. EPocrates Rx Pro will also recommend alternative and substitute drugs, particularly when a patient's formulary does not cover the initial option this is known as e-prescription referencing. Multicheck, another useful feature of the Rx module, evaluates two or more drugs and compiles a list of drug interactions. The SUNY Upstate Medical University, located in Syracuse, New York, has been educating students to become qualified physicians for over 160 years. The university comprises the medical center with a teaching hospital, a Level 1 trauma center, a burn unit, the Center for Evidence-Based Practice, many specialty clinics, and an expanding...

Bile acid sequestering agents resins

As 25 , have also been reported.56 Colesevelam does not cause constipation, which is likely to improve patient adherence,55 and is formulated as a tablet, which should eliminate the palatability problems that some patients have with resin powders.56 In drug-interaction studies, colesevelam was coadministered with digoxin, warfarin, sustained-release metoprolol and verapamil, quinidine and valproic acid, and no clinically significant effects on absorption were reported.57

TABLE 2021 Potential Etiologies of Hypoglycemia in Adults

Common scenarios in diabetic patients include inadequate food intake, increased physical exertion, incorrect medication dosing, or drug interactions. The characteristics of diabetic patients who are more likely to experience hypoglycemia include male gender, adolescent and very elderly age groups, African American heritage, a past history of hypoglycemia, intensive diabetic medical therapy, insulin use (compared with OHA therapy), polypharmacy (more than five agents), and recent hospitalization.12 and 3

Enantiomers their importance in psychopharmacology Introduction

In addition to metabolic interactions, consideration should be given to drug-protein binding interactions, although there is little clinical evidence to suggest that such interactions are of any consequence with the SSRIs. It must be stressed that many liver enzymes are non-specific for their substrates and that most drugs are metabolized by multiple pathways. Good therapeutic practice demands that drug interactions should be considered carefully, particularly in subpopulations of depressed patients such as the elderly or those with hepatic dysfunction or a history of alcoholism. Despite the limited value of measuring plasma psychotropic drug concentrations to assess clinical response, a knowledge of the pharmaco-kinetics of such a drug can be of value in predicting drug interactions.

Summary of the pharmacological properties of antidepressants in general use in Europe

Sertraline Muscarinic

Slight dopaminomimetic effect which may contribute to its alerting effect, while paroxetine is a muscarinic receptor antagonist. Both fluvoxamine and sertraline have affinity for sigma 1 receptors, the precise importance of which is uncertain but could contribute to the motor side effects which all the SSRIs are reputed to have, albeit very rarely. Fluoxetine, by activating 5-HT 2C receptors, may cause anxiety at least in some patients. Thus differences between the SSRIs are due not only to their different potencies as 5-HT reuptake inhibitors, but also because of their actions on other receptor systems. A comparison of the pharmacokinetic differences between the SSRIs is summarized in Table 7.10. These differences may be of clinical importance in terms of the special populations to whom the drugs should be administered (for example, the elderly may benefit particularly from citalopram because of its slightly sedative profile, and its lack of inhibition of cytochrome P450 enzymes in...

TABLE 987 Etiology of Postmenopausal Bleeding

Hormone replacement therapy is commonly used to relieve symptoms associated with menopause and to reduce the risk of cardiovascular disease. Most therapeutic regimens deliver sequential progestins to induce withdrawal bleeding and protect the endometrium from atypia. Other therapies use continuous administration of estrogen and progesterone to achieve an atrophic endometrium and amenorrhea.12 In patients treated with sequential hormonal therapy, heavy or prolonged bleeding at the end of the cycle or breakthrough bleeding in two or more cycles should be investigated. Of patients on continuous therapy, 40 percent will have abnormal bleeding in the initial 4 to 6 months. There is no acceptable criteria for abnormal bleeding on these therapies, and investigations are warranted if bleeding continues beyond 6 months or recurs after amenorrhea is established. Although bleeding is frequently caused by an unstable or atrophic endometrium, other causes must be considered. Important conditions...

Absolute contraindications to OCs

The metabolism of OCs is accelerated by phenobarbital, phenytoin and rifampin. The contraceptive efficacy of an OC is likely to be decreased in women taking these drugs. Other antibiotics (with the exception of rifampin) do not affect the pharmacokinetics of ethinyl estradiol.

Dietary Sources High Intakes and Antimetabolites

There are various medical conditions and drug interactions that can increase the requirement for niacin. Examples are Hartnup disease, in which tryptophan transport in the intestine and kidney is impaired carcinoid syndrome, in which tryptophan turnover is increased and isoniazid treatment, which causes B6 depletion and hence interference with niacin formation from tryptophan. Hartnup disease (the name of the first patient being Hartnup) is a rare genetic disease in which the conversion of tryptophan to niacin is reduced, partly as a result of impaired tryptophan absorption. Affected subjects exhibit the classical skin and neurological lesions of pellagra, which can be alleviated by prolonged treatment with niacin. Another genetic disease which may respond to niacin supplements is Fredrikson type I familial hypercholesterolemia nicotinic acid is effective in reducing the raised blood cholesterol levels associated with this abnormality.

Pharmacogenetics and psychopharmacology

At the practical clinical level, individual differences in the pharmaco-kinetic characteristics of antidepressant drugs have been more successful. It is well established that the enzymatic activity of different allelic forms of the cytochrome P450 oxidase system in the liver is particularly important in the metabolism of many psychotropic and non-psychotropic drugs (see pp. 91-94). Of the major forms of cytochrome P450 in man, the 2D6 isozyme is particularly important in the metabolism of antidepressants and a potential cause of drug interactions. Three of the five commonly available SSRI antidepressants (fluoxetine, paroxetine and sertraline) undergo autoinhibition of this isozyme and can therefore increase the tissue concentration of a more toxic drug (for example, an antiarrhythmic or beta-blocker) should it be given concurrently. pharmacokinetic features of the drugs, the effect of diet, drug interactions, etc. One would therefore anticipate that the effects of individual genes on...

Organization of a Pharmaceutical Company

Collaboration Mapping Diagram

The diagram in Figure 1.24 displays a core group of representative functions in a research division. Disease biology is a starting point in discovery process to explore disease patho-physiology, especially to understand existing and new mechanisms for disease. Targets for disease intervention are identified and validated in other laboratories. Molecules are created or discovered in yet other laboratories (hits) that need validation, resulting in leads and later drug candidates. Animal testing is done (preclinical work) for pharmacology and toxicology of the drug candidates. The metabolism and pharmacokinetics group examines drug disposition and drug interactions in animals and then humans. The pharmaceutics group formulates a product into a specific dosage form (e.g., oral capsule or injectible liquid), a container system (e.g., bottles and vials), and a delivery system (e.g., a syringe), based on the disease, patient, and health care system. A variety of specialty research groups may...

Clinical Features

Picture Ringworm Palm Hand

Bullous tinea pedis often does not respond to topical treatment. If the patient is experiencing minimal discomfort, a topical agent can be tried initially. In more severe cases, oral antifungal treatment is necessary. Itraconazole 200 mg qd for 14 days or terbinafine 250 mg po for 14 days are effective. The prescribing physician should be familiar with the potential drug interactions and the uncommon but serious side effects (hepatotoxicity and erythema multiforme toxic epidermal necrolysis) prior to prescribing these medications.

Key References for Further Reading

Are pharmacokinetic drug interactions with SSRIs an issue Int. J. Psychopharmacol. 11 (Suppl. 1) (1996) 23-27. Fugh-Berman, A. Herb drug interactions. Lancet 355 (2000) 134-138. Fuhr, U. Drug interactions with grapefruit juice extent, probable mechanism and clinical relevance. Drug Safety 18 (1998) 251-272. Stockley, I. H. Drug Interactions A source book of adverse interactions, their mechanisms, clinical importance and management (Fifth Edition). London Pharmaceutical Press, 1999. Spina, E. and Perucca, E. Newer and older antidepressants a comparative review of their drug interactions. CNS Drugs 2 (1994) 479-490. Finley, P. R. Clinical relevance of drug interactions with lithium. Clin. Pharmacokinetics 29 (1995) 172-187.

How is the harm of a treatment documented

Many drugs are metabolized in the liver and an emerging area of concern is the possibility of drug-drug interactions. Toxicity may occur when one drug inhibits the metabolism of another drug, or when two drugs compete for the same metabolic pathway. Of all the potential interactions, only those between the most commonly prescribed drugs can be evaluated prior to marketing. In 1997, the FDA approved mibefradil (Posicor) for marketing in the U.S. The product was withdrawn within one year, after multiple serious drug interactions were documented, the most important one with simvastatin (Zocor).

What determines interchangeability for safety

Practolol, one of the first marketed beta-blockers, was shown to improve survival in post-infarction patients but was subsequently taken off the market for safety reasons. The late introduced calcium channel blocker, mibefradil, was approved for treatment of hypertension, but was later removed from the market due to adverse effects linked to drug-drug interactions. Troglitazone, the first marketed glitazone for treatment of Type 2 diabetes, was taken off the market due to liver toxicity, but was replaced by rosi-and pioglitazone.

Guide for Separating Food Folklore Facts from Fiction in Clinical Situations and A Practical Example

In the late 1980s, in a study examining the interaction between alcohol and felodopine (a calcium antagonist used to lower blood pressure), it was accidentally discovered that grapefruit juice, which was being used as a placebo, dramatically altered the drug's metabolism. The drug was a common one, the juice dose - about 6 ounces (180 ml) - was within the range many people drink, and the effects were large (similar to a doubling of the drug dose). Therefore, it was of potential clinical importance. Since then, more than 200 scientific papers have been published in peer-reviewed journals on the issue of drug interactions with grapefruit, confirming the original observations. By the mid-1990s, the finding had received a great deal of media coverage and the notion that grapefruit juice was dangerous for those on prescription drugs had become a subject of food folklore. This particular bit of folklore is an example of a strongly held belief for which there is some scientific evidence....

Animal Models For Pharmacological And Toxicological Studies

Due to the differences in the primary sequence of the ligand-binding domain of PXR between humans and mice, drugs recognized by human PXR, such as rifampi-cin, are not necessarily recognized by mouse PXR therefore, the predictive value of using only mice as a model system to learn about drug metabolism in humans is less than ideal (Jones et al., 2000). In addition, the enhancer elements that are recognized by PXR in controlling Cyp3A gene expression are only partially conserved between humans and mice, leading to differential action of Cyp3A genes in response to xenobiotics. In order to create a mouse model that recapitulates the specificity and regulatory pattern to that of a human, a line of PXR homozygous knockout was first created and then followed by replacing the deleted mouse gene with that of human PXR (Xie et al., 2000). These humanized mice can then recognize the plethora of drug molecules that would lead to undesirable activation of the Cyp3A gene. Thus, it is now possible...

Basic Concepts

This chapter focuses on Phase I studies that are designed to provide preliminary but essential information on safety, tolerability, PK and if possible the pharmacological actions of a compound. The term Phase I has two connotations one refers to the earliest, first-time-in-humans (FIH) studies, while the other encompasses studies of PK, metabolism, drug interactions, special populations, and other clinical pharmacology trials (ICH-E8, 1997). Dose selection is a critical activity for Phase I studies to ensure that the data collected in these clinical trials are at doses to support the recommended therapeutic dose. The purpose of dose-finding studies in Phase I is to evaluate the compound's mechanism of action in humans, the compound's metabolic actions and PK, AEs associated with increasing doses of the compound and to gain early evidence of the compound's effectiveness (Code of Federal Regulations, 2004). A well-designed and executed Phase I program permits the design of...

Pharmacokinetics

In multiple ascending dose studies, subjects are usually treated for several days beyond that needed to achieve steady state. PK data from the single dose FIH study is used to estimate the dosing frequency for the multiple dose study. These data are used to predict accumulation and the time required to reach steady-state plasma concentrations. In a broad qualitative sense, the appearance of metabolites are characterized in humans and compared with animal data. As drug development progresses, the PK profile of a compound is continuously refined such that predictions can be made about routes of elimination and potential drug interactions, and special populations can be identified.

Hypoventilation

Hypoventilation in postsurgical patients is extremely common but is most often mild and not noticed. Specifically, it is defined as a PaCO2 less than 45 mmHg on an arterial blood gas measurement, although the test is not often done and the patient's baseline measurement must be taken into account. Clinical signs of mild-to-moderate hypercarbia and respiratory aci-dosis include tachycardia, hypertension, and ventricular ectopy. Neurologic depression and circulatory collapse may result if the hypercarbia is severe and untreated. In a review of 13,000 postoperative patients, 0.02 percent developed serious respiratory failure, 77 percent in the first hour. Most of the cases were identified primarily by pulse oximetry or by alert nurses and were attributed to upper airway obstruction, excessive fluid administration, and residual drug effects, mostly sedatives, anesthetics, and muscle relaxants. Other contributing factors included hypothermia, electrolyte abnormalities, magnesium therapy...

Bacterial Infections

Mycobacteria tuberculosis occurs in renal transplant patients both as a primary and as a reactivation disease.12 Risk factors for mycobacterial infection include malnutrition, history of inadequate treatment, or recent exposure to a contact with tuberculosis. There is no typical presentation for a transplant patient with tuberculosis. Instead, a highly variable presentation has been described, including cavitary pulmonary disease, miliary disease, and multiorgan involvement. Diagnosis is rarely aided by tuberculin skin testing. Definitive diagnosis is by organism identification and culture from sputum, pleural effusions, and bronchoalveolar lavage, lung, or bone marrow biopsy. Therapeutic options are complicated because of the CYA drug interactions with many antituberculosis medications.

Animal Models

As noted earlier, the evidence accumulated indicates that OAT1 and OAT3 manifest functional properties and anatomical localization consistent with a critical role in the basolateral uptake step of renal secretion of organic anions by the classical pathway. However, most of this evidence has derived from in vitro studies, so that the actual in vivo function of OATs, in the context of the whole kidney and or the entire organism, has remained uncertain. Recently, mice containing null alleles for OAT1 or OAT3 were generated using homologous recombination. Studies of OA transport in these knockout mice have begun to define the role of OAT1 and OAT3 in vivo61'62 and their potential role in nephrotoxicity and drug-drug interactions (Figure 4.9). Some of these results are discussed below.

Seizures

Seizures are present in 50 percent of children with cerebral palsy. With increasing severity of cerebral palsy, there are often more frequent and complex seizures. Multiple seizure types may occur in a single individual. This may cause difficulty in eliciting a complete seizure history if the physician is unaware that different seizure presentations are documented historically. Multiple anticonvulsant medications may be required to adequately control seizures. When multiple anticonvulsants are required, the physician should be alert to the possibility of multiple seizure types, interactions of the various anticonvulsant medications, and the possible fragility of seizure control. Contact with the managing neurologist is strongly advised in such cases. The treatment of medical problems should be evaluated with regard to drug-drug interactions whenever a medication is recommended. Anticonvulsant medications may affect or be affected by many other drugs. Theophylline is known to lower...

Drooling

The control of saliva may be impaired in children with severe spastic quadriplegia. Poor head control and oromotor deficits are the cause. With the head held flexed or to the side, there may be pooling of oral secretions in the anterior portion of the oral cavity. If bolus formation is not initiated, these secretions will spill over the lips and onto the face and body. Although primarily thought of as a social or cosmetic issue, drooling may lead to skin problems such as chapping on the face. Families and physicians have used a variety of techniques to stem the drooling when it persists in childhood and is perceived as a problem. As a side effect, some common medications are noted to decrease secretions. These drugs, including scopolamine, atropine, imipramine, trihexyphenidyl hydrochloride (Artane), glycopyrrolate (Robinal), benztropine mesylate (Cogentin), and antihistamines, have been used with limited success. 3 Side effects of these medications, toxicity (if the family should...

Mirtazapine

Mirtazapine has a similar pharmacokinetic profile as other atypical antidepressants. It is rapidly and completely absorbed following oral administration. Bioavailability is approximately 50 percent due to significant first-pass hepatic metabolism. Peak levels occur within 2 h after ingestion. Mirtazapine is metabolized by the hepatic oxidase enzyme system (P-450), with only minor active metabolites. Theoretically, since mirtazapine is metabolized by the P-450 enzyme system, drug interactions with other P-450-dependent medications is possible. Presently, no such interactions have been reported, although experience with mirtazapine is very limited. The elimination half-life for mirtazapine averages 26 h for males and 37 h for females. The difference in mirtazapine half-life between men and women is attributed to decreased P-450 metabolism in females. Mirtazapine is highly protein bound (85 percent) and has a large volume of distribution (5 L kg). Plasma levels are unlikely to be...

Serotonin Syndrome

5-HT2) is required for full expression of this syndrome. Drugs (like ondansetron) that block serotonin postsynaptic receptors are incapable of inducing this syndrome. The majority of cases occur at therapeutic levels, with fewer than 13 percent of cases being associated with drug overdose. Serotonin syndrome is characterized by alterations in cognition and behavior, autonomic nervous system function, and neuromuscular activity. The degree of abnormality in any one area is highly variable. Serotonin syndrome usually occurs either relatively soon after the dose of a potent serotonin agonist (MAOI or SSRI) has been increased or shortly after a second serotonergic agent (e.g., dextromethorphan) has been added. The importance of serotonin syndrome in emergency practice is twofold. First, the diagnosis of serotonin syndrome is very challenging due to its nonspecific symptomatology. Mild cases of serotonin syndrome are frequently attributed to other psychiatric and medical disorders. Severe...

Buspirone

Experience in overdose may be limited by the drug's wide margin of safety. Patients have taken up to 3 g (which is 150 times the average anxiolytic dose) in overdose without lasting ill effects. Most common clinical symptoms in overdose are nonspecific drowsiness and dysphoria. Rarely, hypotension, bradycardia, seizures, GI upset, dystonia, and priapism also have been described. Spontaneous acute hypertensive reactions have developed in patients coprescribed buspirone and monoamine oxidase inhibitors. No other adverse drug interactions or unexpected toxicities have emerged with buspirone use. 18

Glucocorticoids

Cyclosporine has been used for renal transplants in cats in combination with glucocorticoids it has been used in human and more recently canine atopic dermatitis (Matthews & Gregory, 1997). The mode of action involves the inhibition of T-cell activation the synthesis of various cytokines, especially IL-2, inhibits T-cell proliferation and the formation of cytotoxic lymphocytes. The drug is available as either an emulsion or a capsule formulation and consists of a microemulsion preconcentrate of cyclosporine (e.g. Neoral Novartis). Initial reports of its use in cats with EGC, as a manifestation of allergic skin disease, used a dose of 7.5-10 mg kg per day for up to 1 month. There are studies of feline asthma that report the use of the drug administered with food. It is unclear what role, if any, food has on the absorption of cyclosporine in cats. Side-effects include a poor appetite and long-term use may predispose to bacterial and fungal infections. Some renal transplant cases have...

Phase 4 Studies

R Identify variables in existing indications r Identify new dosing schema r Explore real-world effectiveness (e.g., in the office) r Define effects in special populations (elderly, children) r Examine impact of concurrent diseases r Post-marketing surveillance r Drug interactions Objectives of phase 4 studies are manifold (Fig. 5.10) determining efficacy and safety compared with competitor drugs, defining mechanisms of disease that often are performed as investigator-initiated studies (see below), exploring real-world effectiveness (e.g., in the office), defining effects in special populations (e.g., the elderly, children, concurrent disease), providing postmarketing surveillance for unsuspected or low-frequency adverse events, further defining potential drug interactions, and possibly pharmacogenetic assessments (to be discussed below). Some objectives done during phase 4 period may require FDA agreement and may be classified technically as phase 3b or even phase 2 studies, such as...

PD Processes

In order to produce any pharmacological response, the drug should bind to its biological targets. For short we will call them receptors, keeping in mind that they are not necessarily membrane-bound proteins (classical receptors), which specifically bind drug molecules (11,12). The drug interaction with receptors produces a primary signal that triggers a series of pharmacological events, ultimately leading to clinical effects. This biosignal may consist in perturbing an intrinsic biochemical process (or processes) in the body. For example, formation or sequestration of certain mediators (hormones or proteins) may be accelerated or suppressed. Changes in the mediator level may, in their turn, initiate a cascade of events that we call transduction, resulting in observable changes in body characteristics, or clinical effects.

Preservative Agents

Polymer-drug interactions Drug loading matrix and subsequently the release rates Excipients present in the matrix may slow down or increase the drug-release rates by changing the microclimate pH, matrix porosity, or polymer-drug interactions Phase changes (e.g., crystallization of drug or carrier) within the matrix and or chemical degradation of the matrix and drug may affect the release profile

S epidermidis

As discussed previously, Q D (quinupristin daltopristin) is a combination of two semi-synthetic derivatives of pristinamycin. This combination antimicrobial binds to the 50S bacterial ribosome, resulting in irreversible inhibition of protein synthesis, with subsequent bactericidal effects 141 . Its spectrum of activity is limited to Gram-positive bacteria however, it has good activity against MRSE. In one study analyzing Q D activity against 658 isolates of CoNS, > 97 of tested isolated had Q D MICs of < 4 g L 270 . Of the 186 clinical isolates of S. epidermidis specifically, resistance rates to Q D were < 1 270 such rates have been confirmed in other studies 271 . As well, clindamycin susceptibility appears to be predictive of Q D susceptibility 270 , which may allow for clinical laboratories to use clindamcyin as a surrogate antibiotic for Q D during antimicrobial susceptibility testing. Animal models of endocarditis to determine the efficacy of Q D have focused on S. aureus...

Small peptides

53 Zhou-Pan XR, Seree E, Zhou XJ, Placidi M, Maurel P, Barra Y, Rahmani R (1993) Involvement of human liver cytochrome P450 3A in vinblastine metabolism drug interactions. Cancer Res 53 5121-5126 55 Zhou XJ, Zhou-Pan XR, Gauthier T, Placidi M, Maurel P, Rahmani R (1993) Human liver micro-somal cytochrome P450 3A isozymes mediated vindesine biotransformation. Metabolic drug interactions. Biochem Pharmacol 45 853-861 60 Chan JD (1998) Pharmacokinetic drug interactions of vinca alkaloids summary of case reports. Pharmacotherapy 18 1304-1307 63 Tobe SW, Siu LL, Jamal SA, Skorecki KL, Murphy GF, Warner E (1995) Vinblastine and erythromycin an unrecognized serious drug interaction. Cancer Chemother Pharmacol 35 188-190 66 Sathiapalan RK, El-Solh H (2001) Enhanced vincristine neurotoxicity from drug interactions case report and review of literature. Pediatr Hematol Oncol 18 543-546 117 Jamis-Dow CA, Klecker RW, Katki AG, Collins JM (1995) Metabolism of taxol by human and rat liver in vitro a...

Venlafaxine

Peak levels occur 2 h after ingestion. It is poorly protein bound (27 percent), and it has volume of distribution of 6 to 7 L kg and a half-life of approximately 5 h. The majority of venlafaxine undergoes hepatic P-450 oxidation, but it is a weak inhibitor of P-450 enzyme activity. To date, no significant pharmacokinetic drug interactions have been reported. It has one active metabolite, O-desmethylvenlafaxine, which is pharmacologically similar to its parent drug, except for a longer half-life of 11 h. The adverse effect profile for venlafaxine is similar to the aforementioned one for SSRIs. The only notable exception is the occurrence of mild to moderate hypertension when doses exceed 225 mg day, which is probably secondary to inhibition of norepinephrine reuptake. Venlafaxine has the same potential as other serotonin agonists to produce serotonin syndrome. Therefore, it should not be combined with MAOIs or other serotonin agonists. Because of its shorter half-life, venlafaxine...

Tuberculosis and HIV

Treatment of tuberculosis in coinfected individuals is generally effective, but some reports have indicated higher mortality rates in coinfected patients. 7 The incidence of adverse drug reactions to antituberculosis chemotherapy is higher in HIV-infected than in HIV-negative patients. 8 Due to the number of medications taken by patients with HIV, potential drug interactions must also be of concern.

Neurologic Problems

SEIZURES Thirty to 50 percent of all developmentally delayed individuals have seizure disorders. Often, an individual experiences several different types of seizures, which may have complicated presentations such as Lennox-Gastaut seizures. Occasionally, patients, particularly those who are verbal, also have pseudoseizures. As with any other patient, the priorities are to insure adequate oxygenation and to stop the seizure. Subsequently, one must determine the precipitants for the seizure, specifically whether the precipitant is medication or infection. Seizures are commonly precipitated by a change in medications. Frequently, in an effort to reduce side effects and potential drug interactions, efforts are made to reduce the number of anticonvulsants or to switch from an older agent such as phenobarbital even though the patient's seizures are under good control. Occasionally, unintentional medication changes occur when the developmentally disabled individual moves to new living...

Aspergillus spp

Itraconazole, an azole with activity against Aspergillus spp., appears more efficacious than monotherapy with AmB in animal models 434 . However, its pharmacology (i.e., variable intestinal absorption, unpredictable drug interactions) has limited its use in primary treatment of Aspergillus endocarditis. It has been used successfully, however, as antifungal prophylaxis against recurrence once primary treatment was completed 431,433 .

Treatment Issues

When symptoms first start in children and adults, an extensive physical exam from a qualified physician is immediately required. Both depression and manic symptoms can stem from problems ranging from vitamin deficiencies or excess to major autoimmune, cardiovascular, gastrointestinal, endocrine, hematolo-gic, neurological, and pulmonary diseases or malignancies. Additionally, a long list of medications and drug interactions can cause manic-depressive behaviors. Commonly, bipolar symptoms caused by medical problems other than a neuropsychiatric disorder will improve as the person recovers from the primary physical illness. Once alternative medical problems are ruled out and the person is diagnosed with a bipolar disorder, psychotropic medications become the first and fundamental treatment method.