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Drug Drug Interactions

A drug-drug interaction occurs when one drug interacts with or interferes with the action of another drug. For example, taking an antacid with oral tetracycline causes a decrease in the effectiveness of the tetracycline. The antacid chemically interacts with the tetracycline and impairs its absorption into the bloodstream, thus reducing the effectiveness of the tetracycline. Drugs known to cause interactions include oral anticoagulants, oral hypoglycemics, anti-infectives, antiarrhyth-mics, cardiac glycosides, and alcohol. Drug-drug interactions can produce effects that are additive, synergistic, or antagonistic.

Drugdrug Interactions

These mechanisms of metabolic interactions pertain to the whole organ with the intact blood supply thus, this model may well be a more comprehensive and reliable approach to test for drug-drug interactions. The use of perfusion techniques helps to establish which organ(s) is (are) responsible for the control of the plasma concentration in a class family of structurally analogous drug candidates (whether by metabolism or clearance). This model should be a suitable substitute for whole-animal studies to evaluate potential drug-drug interactions. The advantages include tight control of blood levels of each drug normal binding to plasma proteins and the delivery of each drug to the organ under physiological conditions. When drugs are administered in combination, these drugs show extensive inhibition activation with hepatic microsomes. However, the drugs do not affect the plasma concentration of each other in the perfused liver model or in vivo. In this way, the perfused organ models...

Establishing A New Paradigm For Developing Drug Combinations

To date only minor attention has been given to understanding the role that drug ratios play in governing drug-drug interactions. This is not surprising given that the clinical development of drug combinations pushes the doses of the individual agents to maximum tolerability and hence the final drug ratio arises empirically. Also, until now there was no mechanism to effectively control the drug ratio after administration in vivo and consequently information obtained on drug ratio effects in vitro would have limited utility in prospectively designing dosing regimens in clinical trials. The novelty of the CombiPlex approach to developing drug combinations lies in the concept that one can fix the optimal drug ratio and maintain this ratio in vivo. This opens the possibility to harvest in vitro drug combination informatics and apply it directly to clinically viable drug products in a manner previously not achievable. As such, this strategy represents a new paradigm for developing...

Finasteride Molecular Kinetics

The finasteride 5a-reductase complex is highly stable, and its turnover is quite slow, with a half-life of approx 30 d. The elimination halflife of finasteride is 6 h, and metabolism is achieved by means of the cytochrome P450 system within the liver. Excretion occurs primarily through the bile (20). No clinically significant drug interactions have

Preoperative Evaluation

Ing dental procedures may indicate that extra care should be taken with these patients. The potential of drug-drug interaction with some of the anesthetic agents should be evaluated before any prescription of analgesics. It is important to ask the patients if they have had any undesirable experience with topical, infiltrative, or blocking procedures. Patients should also be asked about the use of any illegal drugs before the administration of any anesthetic medication.

Experimental Approaches

Biotransformation studies have benefited from advances in both molecular biology and biochemistry. Molecular biology provided new reagents for mechanistic studies and screening experiments in the form of expressed drug-metabolizing enzymes 4 . Some of these expression systems include cytochrome P450, glucuronide transferases, and sulfotransferases 5,6 . More recently, drug-transport proteins, such as -glycoprotein, have been cloned and expressed. Transport proteins are now recognized as a major factor that contributes to the ADME of drugs 7 . Drug interactions traditionally thought to occur most frequently with P450 metabolizing enzymes are beginning to be recognized with transport systems as well 7 . Improved cell tissue culture and handling techniques allow for the harvest and cryopreservation of primary hepatocytes that are an important tool for the approximation of in vivo biotransformation 8 . Additionally, the development of human intestinal epithelial cancer cell lines (CaCO2...

The Solution in This Environment

Common to this system is the lack of a uniform approach, often involving a multitude of ways of providing the same treatment, frequently without written guidelines. Other conditions typical of the hospital environment include a dependence on people for vigilance (for example, to follow up on investigation results) and lack of use of available technology, such as electronic prescribing with built-in protections against incorrect drug dosing, drug interactions, etc. (9).

Rational Psychopharmacology for People With Hiv Hcv and Schizophrenia

A large number of medications are prescribed to people with HIV infection, including antibacterial, antifungal, antineoplastic, antiretroviral, and other antiviral agents (Horwath 1996), particularly in later stages of HIV disease, when numerous present or potential complications require active treatment or prophylaxis. Any attempt to diagnose drug-induced neuropsychiatric syndromes requires an appreciation of both the therapeutic use and potential side effects of these medications. Some of these are described in the Practice Guideline for the Treatment of Patients With HIV AIDS of the American Psychiatric Association (2000 access at www.psych.org), but new antiretroviral agents are being developed at a rapid pace, and existing medications to treat HIV-related infections and neoplasms are too numerous to describe fully. Neuropsychiatric side effects of antiretrovirals have been reported most commonly with efavirenz (Sustiva) and occasionally with nevirapine (Viramune). There are many...

Working in a Drug Metabolism Environment

Several review articles have been written in the last few years that discuss the role that DM can play as part of a drug-discovery effort 4-10 . The importance of DM involvement in a drug-discovery effort was discussed in a review article by Kennedy 11 in 1997, in which historical data were used to show that a significant percentage of failures in the clinical phase were due to poor human PK properties of the investigational drug. The need for DM support of new drug-discovery efforts is now well accepted and most major pharmaceutical companies include DM input as part of their discovery strategy. What is needed from DM specialists is three types of information (1) the PK properties for the compound in laboratory test animals (typically rats, dogs, and monkeys) (2) the potential human drug-drug interactions for the compound and (3) the predicted human PK properties for the test compound.

Contraindications Precautions And Interactions

The peripheral vasodilating drugs are contraindicated in patients with known hypersensitivity to the drugs, women in the immediate postpartum period (isoxsuprine causes uterine relaxation), and in patients with arterial bleeding. Safe use during pregnancy has not been established (Pregnancy Category C). Cilostazol is contraindi-cated in patients with CHF and during pregnancy (Pregnancy Category C). These drugs are used cautiously in patients with bleeding tendencies, severe cerebrovascu-lar or cardiovascular disease, and after a myocardial infarction. There are no significant drug-drug interactions.

Herbal Alert Warfarin Interaction

Much of the information on drug-herb interactions is speculative. Herb-drug interactions are sporadically reported and difficult to determine. Because herbal supplements are not regulated by the Food and Drug Administration (FDA), products lack standardization, purity, and potency. In addition, multiple ingredients in products and batch-to-batch variation make it difficult to determine if reactions occur as the result of the herb. To assist with the identification of herb-drug interactions, nurses should report any potential interactions to the FDA through its MedWatch program (see Appendix A). Because the absorption, metabolism, distribution, and elimination characteristics of most herbal products are poorly understood, many herb-drug interactions are speculative. It is especially important to take special care when patients are taking any drugs with a narrow therapeutic index (the difference between the minimum therapeutic and minimum toxic drug concentrations is small-such as...

Health Supplement Alert Cranberry

Cranberry juice has long been recommended for use in treating and preventing urinary tract infections (UTIs). Clinical studies have confirmed that cranberry juice is beneficial to individuals with frequent UTIs. Cranberries inhibit bacteria from attaching to the walls of the urinary tract and prevent certain bacteria from forming dental plaque in the mouth. Cranberry juice is safe for use as a food and for urinary tract health. Cranberry juice and capsules have no contraindications, no known adverse reactions, and no drug interactions. The recommended dosage is 9 to 15 capsules a day (400-500 mg d) or 4 to 8 ounces of juice per day. (See Chap. 6 for more information.)

Protein Precipitation Fundamentals

Most biological matrices contain protein to varying extents. Protein-binding phenomena are known to influence drug-drug interactions in the clinical setting. Among the various plasma proteins, serum albumin is the most widely studied and is regarded as the most important carrier for drugs. The presence of these materials for bioanalysis is problematic, and they must be removed before chromatographic separation and detection. When injected into a chro-matographic system, proteins will precipitate upon contact with the organic solvents used in LC mobile phases. The precipitated mass of protein builds up within the column inlet, reduces the column lifetime and increases the system back pressure. When protein is carried through the analytical system, it may reach the mass spectrometer to foul the interface and require frequent cleaning the result is system downtime.

Practical Approach To Nsvt

Any patient with NSVT will need a carefully directed evaluation of both general cardiac issues and the specific arrhythmia. The basic cardiac evaluation can be performed by a general cardiologist, but the management of NSVT should generally be referred to an electrophysiologist. Certainly, if there is impaired (right or left) ventricular function, heart failure, or severe symptoms, if the patient is an athlete, or if the diagnosis is in question (i.e., is it supraventricular or VT), the patient should be referred to an electrophysiologist. Invasive electrophysiology testing and ICD implantation, as well as ICD follow-up, are performed by electrophysiologists. In addition, the use of anti-arrhythmic drugs is becoming more complex. Some drugs are now mandated by the FDA to be initiated in the hospital, and there is a movement (by the FDA) to certify doctors in the use of specific antiarrhythmic drugs because of their potential risk. Drug interactions and metabolism must be considered....

In Vitro Applications

Another higher throughput in vitro assay is the human cytochrome P450 enzyme inhibition assay. This assay is used to make sure that a compound does not have the potential for producing drug-drug interactions in a clinical setting due to the inhibition of one or more human P450 isozymes 61-66 . Often, these P450 assays are carried out in a higher throughput manner using 96-well plates

Prosthetic Heart Valves

Treatment for PVE often involves prolonged therapy (Table 4) (17,21). In elderly patients who are taking coumadin, there may be drug interactions with rifampin. Also, nephrotoxicity with gentamicin is increased in the elderly and in patients taking concurrent nephrotoxins. Guidelines for therapy for infective endocarditis may be found on the Internet at http www.americanheart.org. As many as 65 of patients with PVE may be candidates for surgical valve replacement (22,23). The need for cardiac surgery is increased in patients who have moderate to severe heart failure due to dysfunction of the prosthesis. Uncontrolled bacteremia, fever persisting for more than 10 d during appropriate antibiotic therapy, recurrent arterial emboli, and relapse after appropriate antimicrobial therapy are other indications for surgery. In addition, infections caused by fungi, S. aureus and Gram-negative bacteria often require surgical intervention.

Considerations For Experimental Design Pooling Methods

Clearly the primary risk associated with cassette dosing is the potential for drug-drug interactions that lead to questions that deal with the validity of the results. In addition, precautions must be exercised on the analytical end to avoid analytical interference from metabolites or between analytes. On the other hand, cassette dosing reduces the number of animals used for exposure screening and can dramatically increase the number of compounds that can be analyzed in live-phase experiments.

CTherapeutic approach

Determination is not required but may be useful to detect noncompliance or drug interactions. Indications for reducing the dose should include a decrease in renal function or an increase in blood pressure, not CyA levels. If serum creatinine increases to more than 30 above baseline, the dose should be reduced by 25 to 50 . Blood pressure and serum creatinine monitoring are indicated throughout the treatment period, with appropriate adjustment of dosage of CsA. When the dose is stable, creatinine levels should be measured every 2 to 4 weeks. vii. Drug interactions. CyA serum levels can be increased by drugs that decrease P-450 metabolism, including calcium antagonists, erythromycin, ketoconazole, and histamine2 blockers. Thus, with these medications, the CyA dosage should be adjusted downward. Alternatively, anticonvulsants such as dilantin and rifampicin increase the metabolism of CyA and thus reduce the concentration.

Cyclosporin A Sandimmune Neoral

The dosage should not exceed 5 mg kg of body weight the usual starting dose in RA is 2.5 mg kg of body weight daily. Renal function and arterial blood pressure should be monitored carefully. The serum creatinine should not be allowed to increase by more than 50 of baseline. Hypertension may be controlled with nifedipine or isradipine, but not with verapamil or diltiazem, both of which interfere with hepatic metabolism. Special caution should be taken with concomitant use of MTX, which can decrease the elimination of cyclosporin A. Additional medications to be avoided because of drug interactions include antifungal azole derivatives (ketoconazole, fluconazole, itraconazole), macrolide antibiotics (erythromycin, clarithromycin), and allopurinol, among many others. Grapefruit juice increases the bioavailability of the drug. Cyclosporin A is contraindicated in premenopausal women who do not practice effective contraception, during pregnancy, and in nursing mothers.

Itraconazole

Itraconazole is contraindicated in patients with a known hypersensitivity to the drug. The drug is used cautiously in patients with hepatitis, those with human immunodeficiency virus, impaired liver function, and in pregnant women (Pregnancy Category C). In patients with hypochlorhydria, the absorption of itraconazole is decreased. Multiple drug interactions occur with itra-conazole. Itraconazole elevates blood concentrations of digoxin and cyclosporine. Phenytoin decreases blood levels of itraconazole and alters the metabolism of phenytoin. Histamine antagonists, isoniazid, and rifampin decrease plasma levels of itraconazole. There is an increased anticoagulant effect when warfarin is administered concurrently with itraconazole.

Herbal Medicines

Some issues have arisen with the increased use of herbals, including questions about their purity, safety, concentration, and efficacy. Another issue is drug interactions. Health care providers should ask about the use of herbal remedies when taking a patient's drug history, and patients should report any herbal medicines they take when under treatment. The FDA does not test or regulate herbal medicines, and there are no requirements to report adverse effects. There are, however, restrictions on the health claims that can be made by the manufacturers of herbal medicines. The U.S. government has established the Office of Dietary Supplements (ODS) to support and coordinate research in this field.

Conclusion

Anticoagulation is recommended for almost all patients presenting with AF. Rate control is essential to alleviate symptoms and prevent deterioration in cardiac function or clinical status. The decision to initiate antifibrillatory agents should be made on an individual case-by-case basis. When drugs are used to convert or suppress atrial arrhythmias, factors such as structural heart disease, comorbid diseases, drug metabolism and elimination, and drug-drug interactions must be considered to reduce the risk of proarrhythmia. Even when these factors are taken into account, medication side effects often limit the use of an individual agent. With the future availability of novel antifibril-latory agents, drug therapy may be safer and more easily tolerated. In highly symptomatic individuals who fail antifibrillatory agents and cannot tolerate rate control (with anticoagulation), consideration should be given to either ablation of the AV node and insertion of a permanent pacemaker or...

Medication Training

Medication training is an important part of allowing patients to take a greater part in their own management. Unfortunately, many patients do not fully understand the medication regimens they are on, and often do not use their inhaled medications properly (24). The education should include discussions regarding the types of medications commonly used, discussed by class with in-depth review of mechanisms of action and side effects. Another important part of the education program is a review of drug interactions, especially with an eye to the issue of over-the-counter medications that often have significant effects that can harm the uninformed individual. A review of the proper use of inhaled medications is also appropriate as a part of the training program. Group education sessions can be used for the overall didactic portions of the program, whereas the inhaler education can often be best done in individual settings.

Antiinfection drugs

An LC-LC-MS-MS method for fully automated and direct analysis of voriconazole (a novel broad-spectrum antifungal agent) in raw human serum. The raw serum sample is first fractionated using a size-selective extraction column, followed by LC (C18 column) and ESI-MS-MS detection. Using parallel extraction and chromatographic separation, analysis time is 13 min. Lower quantification limit 0.05 g ml. Eliminates the need for complicated sample pretreatment, and requires only 5 l serum. A novel XLC-MS-MS (extraction liquid chromatographic + tandem mass spectrometric) technique for the simultaneous measurement of two samples from diluted human plasma samples for the monitoring of HIV AIDS patient samples. Analysis time 3.3 min detection limit 2-70 ng ml lower limit of quantification 78-156 ng ml. Good linearity is achieved in a wide concentration range (from the lower limit of quantification to 10,000 ng ml). Intra- and interday precision values 7.5-13.5 (depending on the concentration)...

Issues of Competency

Issues of competency are more problematic in older schizophrenic individuals because the demarcation of incapacity becomes murkier. In younger schizophrenic persons, incapacity is typically due to psychotic processes, although substance abuse can confound the etiology of the disturbance. In older schizophrenic persons, in addition to the effects of psychoses, the effects of neuropsychological deficits and medical disorders must be carefully considered. Whereas as many as three-fourths of schizophrenic people evidence some neuropsychological deficits within the first few years of their illness, roughly one-fifth of persons have a very poor long-term outcome with respect to psychopathology and cognition (Davis 2002). In their seventh and eighth decades of life, such persons reach levels of cognitive deficits comparable with persons with moderate to severe Alzheimer's disease, although no Alzheimer's disease neuropathology is present (Davis 2002). In a larger group of schizophrenic...

Drug Therapy

The antiviral drugs amantadine and rimantidine are highly specific for the type A influenza virus and are ineffective against type B or C influenza viruses. These drugs block viral replication by inhibiting the M2 channel from the external side of the membrane (Pinto et al, 1992). The mechanism is not clearly understood. One idea is that amantadine simply plugs the channel pore. However, the slow onset of the amantadine block suggests instead that the drug may influence the channel allosterically (Chizhmakov et al., 1996). Amantadine is very effective at alleviating the symptoms of influenza and has been used clinically as a prophylactic in nursing homes, or for those particularly at risk from infection. Unfortunately, the virus mutates very rapidly and amantadine-resistant strains quickly develop. In addition, amantadine is a teratogen and therefore cannot be administered in pregnancy. Analysis of the mutations associated with amantadine resistance has yielded information not only...

Hivaids

Diagnosis and treatment of HIV are beyond the scope of this review. The treatment of HIV in the elderly is more challenging than in the younger population, however, due to drug interactions with other medications the elderly may require and the altered pharmacokinetics of drugs seen with age. Patients should be managed by a clinician who is familiar with the treatment of HIV in order to appropriately monitor for side effects and response to treatment.

Treatment

The new azole drugs represent an exciting advance for the treatment of serious fungal diseases (29,30). For the first time, oral agents with reliable efficacy are now available for the treatment of several of the fungal diseases. Fluconazole is a relatively nontoxic drug that has good efficacy in the treatment of Candida and some other fungal infections. It is available in both an oral and an intravenous form. Itraconazole has a broader spectrum of activity, including activity against some Aspergillus organisms, as well as Candida, Blastomyces, and Histoplasma. New azole drugs such as voriconazole appear promising. Azoles have effects on the P450 system, and other medications should always be reviewed to prevent adverse drug interactions.

Endemic Mycoses

Symptoms Blastomycosis

Drug interactions, many of which have serious implications for older adults, are frequently encountered with the azole antifungal drugs. Interactions with warfarin, phenytoin, and carbamazepine occur in varying degrees with all of the azole drugs in current use. Itraconazole can increase serum digoxin levels with subsequent toxicity, and ketoconazole and fluconazole can increase the effect of oral hypoglycemics. The antihistamine astemizole and the motility drug cisapride should never be used concurrently with azoles because of QT prolongation and ventricular arrhythmias.

DNADrug Complexes

Recently, a thorough review of noncovalent interaction studies of DNA and RNA with MS was prepared by Hofstadler and Griffey 5 . Compounds that bind to DNA are useful as antitumor, antiviral, and antibiotic drugs. DNA binding drugs interact with duplex DNA principally as minor groove binders (at the rich A and T regions of DNA), as intercalators (at the rich G and C regions of DNA), or in a mixed mode of the two processes. In recent work by Gross 32-34 , Gabelica 35,36 , and their co-workers, ESI-MS has been shown to be a simple, sensitive, and reliable tool for characterizing noncovalent DNA-drug interactions in the gas phase. (These MS studies were shown to be consistent with similar studies in the condensed phase with other spectroscopic tools.) The authors claim that the native state of the annealed duplex DNA was maintained in solutions prepared for ESI-MS containing 50-100 mM NH4Ac and up to 50 methanol to aid in spraying. The optimum concentration for a model dodecamer DNA was...

Spiking Autosampler

The other higher throughput in vitro assay that is supported by LC-MS MS is the enzyme inhibition potential assessment, which is used as a predictor of human drug-drug interaction potential for NCEs 7,9,12,35 . Kumar and Surapaneni 7 provide a detailed discussion of how enzyme inhibition potential can be used as part of the drug-discovery process and provide examples of marketed drugs that have drug-drug interactions as a liability. As shown in Figure 12.9, Eddershaw et al. 9 show how enzyme inhibition fits into the overall absorption, distribution, metabolism, and excretion (ADME) assessment that is typically required for NCEs before a compound can move into development. Several authors, including Chu et al. 36 and Testino and Patonay 37 , have described higher throughput LC-MS MS assays that are used as part of the enzyme inhibition potential measurement.

Etanercept Enbrel

Caution should be used during pregnancy, and the drug should be discontinued in nursing mothers. Etanercept is contraindicated in the setting of sepsis or in patients with known hypersensitivity to any component of the preparation or to latex. No drug interactions are known, but concurrent live vaccinations should not be given. The risk for the eventual development of neutralizing antibodies is not known.

Acquired Lqts

The ever-expanding list of drugs associated with acquired LQTS presents the practitioner with several dilemmas. In the case of non-cardiac drugs that possess I&-blocking activity, meticulous attention is required to avoid drug interactions that may result in QT prolongation. It is also reasonable to avoid these drugs in individuals with baseline QT prolongation, and to ensure that electrolyte levels are normal. The approach to these patients is complicated by the fact that these drugs are most commonly prescribed by non-cardiologists, who are less likely to screen patients in this manner.

In Vivo Applications

Cassette Dosing

One of the issues that is still debated is whether or not to use cassette dosing as a way to increase the throughput for discovery PK studies. As shown in Fig. 13.4, cassette dosing (also called N-in-one dosing) is the practice of dosing multiple NCEs into one laboratory animal and then collecting blood samples from the animal and using HPLC-MS MS for analysis of the samples 78 . It is the ability of HPLC-MS MS to assay multiple compounds in one sample that has allowed this technique to be utilized. As discussed recently by Manitpisitkul and White 78 , although cassette dosing is still used by about half of the major pharmaceutical companies, it does have problems that should be considered before implementing it as part of a drug discovery strategy. For example, drug-drug interactions between the multiple compounds dosed into one animal can lead to erroneous PK conclusions for one or more of the dosed compounds. Indeed, the possibility of drug-drug interactions from cassette dosing...