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Importance of In Vitro Tools in Drug Interaction Studies

Drug interactions can be defined as the modification of the safety and efficacy profile of a medication following the coadministration of drugs, environmental pollutants, ingredients or additives present in the diet (see 5.35 Modeling and Simulation of Pharmacokinetic Aspects of Cytochrome P450-Based Metabolic Drug-Drug Interactions). Drug interactions are usually defined as being either of pharmacodynamic or of pharmacokinetic origin. These two aspects are closely linked and need to be studied together to evaluate both safety and efficacy in the clinic. Only the latter category, defined also as metabolism-based interactions (i.e., the alteration of the metabolic clearance of a drug by another coadministered drug) will be further detailed in this chapter. With the increasing prevalence of polypharmacy,51'52 these drug interactions have become more frequent,51'53'54 and can lead to serious side effects, e.g., Cerivastatin55 and increased morbidity and mortality.54 It is well recognized...

Use of Various Inhibitor Concentrations for the Prediction of Drug Drug Interactions Metabolic Drug-Drug Interaction Risk Evaluation Figure 2 Qualitative zoning for the prediction of drug-drug interactions (AUC ratio) involving CYP inhibition using the j K ratio. The theoretical curve is based on eqn 14 where F - represents false-negative, T - true-negative, F + false-positive, and T+ true-positive predictions. (Reproduced with permission from Houston, J. B. Galetin, A. Drug Metab. Rev. 2003, 35, 393-415.) Figure 2 Qualitative zoning for the prediction of drug-drug interactions (AUC ratio) involving CYP inhibition using the j K ratio. The theoretical curve is based on eqn 14 where F - represents false-negative, T - true-negative, F + false-positive, and T+ true-positive predictions. (Reproduced with permission from Houston, J. B. Galetin, A. Drug Metab. Rev. 2003, 35, 393-415.) Figure 3 The graph shows 193 studies involving drug-drug interactions for CYP3A4 (filled circle), CYP2D6 (filled triangle), and CYP2C9 (filled square) substrates. Open symbols...

Pharmacodynamic Studies of Drug Drug Interactions

We limit our attention here to several models that attempt to describe adverse effects arising from drug-drug interactions, an increasingly important area in pharmaceutical toxicology. The models involved in these studies cover a wide spectrum of endpoints, including effects on the central nervous system, kidney, cardiovascular, as well as antimicrobial activities. We look briefly at the following distinctive types of pharmacodynamic models sigmoid Emax, isobolo-graphic, and response surface. In each case we briefly mention the purpose of the study and introduce the modeling approach without going into details of the outcome of the studies. The readers are encouraged to consult the original references for additional information. The sigmoid Emax model formed the basis for a number of subsequent pharmacodynamic analyses of drug-drug interactions. For instance, Mandema et al. 82 , used quantitative electroencephalographic effect measurements to study pharmacodynamic interactions among...

How To Use Delmars Dental Drug Reference

Special Concerns This section covers considerations for use with pediatric, geriatric, pregnant, or lactat-ing clients. Situations and disease states when the drug should be used with caution are also listed. Side Effects Undesired or bothersome effects the client may experience while taking a particular agent are described. Side effects are listed by the body organ or system affected and are usually presented with the most common side effects in descending order of incidence. It is important to note that nearly all of the potential side effects are listed in any given clinical situation, however, a client may show no side effects, or one or more side effects. If potentially life threatening, the side effect is indicated by boldface italic print. Drug Interactions This is an alphabetical listing of drugs that may interact with one another. This section focuses on those drug interactions which are of particular concern to dental health and dental practitioners. The study of drug...

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.

Genes and Environment

If we regard a pharmacological agent as one of the extrinsic environmental factors in a common complex disease scenario, with the potential to affect the health status of the individual to whom it is administered, then individually differing responses to such an agent would, under the multifactorial and heterogeneous paradigm of common complex disease elaborated upon earlier, be regarded as the expression of differences in the 'intrinsic' characteristics of these patients. This is true as long as we can exclude variation in the exposure to the drug. This is important, as in clinical practice nonadherence to prescribed regimens of administration, or drug-drug interactions interfering with bioavailability

Roles of Transporters in Pharmacokinetics

Body And Drug Absorption Excretion

This huge network of hepatobiliary transporters can give rise to variations in drug disposition between individuals by modulating the uptake or the exit of drugs and their metabolites from hepatocytes. A change in hepatic uptake may have clinical consequences. It may modulate the pharmacological activity of drugs that act via the intrahepatocellular transduction pathways, it may cause hepatotoxicity, or give rise to drug-drug interactions. The concentration of the cholesterol-lowering HMGCoA inhibitors in hepatocytes must be adequate for their pharmacological activity, and most of the statins (e.g., pravastatin, simvastatin, lovastatin, cerivastatin, and pitavastatin) enter hepatocytes via OATP1B1, and to a lesser degree via OAT1B3.131 Recently identified genetic polymorphisms like the SLCO1B3 haplotype *17 are associated with reduced statin clearance by the liver and lower concentrations in hepatocytes they thus have less effect on cholesterol synthesis.132 Large-scale clinical...

Discharge And Home Healthcare Guidelines

Provide instructions about all medications used to relax the smooth muscles of the bladder or to shrink the prostate gland. Provide instructions on the correct dosage, route, action, side effects, and potential drug interactions and when to notify these to the physician.

Descriptive Epidemiology of Herbal and Vitamin Poisonings

An herb is a leafy plant without a woody stem, but herbal preparations include all natural, alternative, and traditional remedies. Twenty-five percent of current, proprietary pharmaceuticals come from plant-herb sources. As a result of the Dietary Supplement and Health Education Act of 1994, the FDA has no authority over regulating herbal and vitamin products, unless they prove to be toxic. 80 of the world's population use herbal products and vitamins daily most are benign, and offer no health benefit (e.g., vitamin C and Echinacea) or potentially lethal drug interactions (e.g., St. John's wort and SSRIs garlic, ginkgo, and ginseng, and anticoagulants ASA, heparin, warfarin ). The most popular herb sales in the United States include Echinacea (10 ), garlic (10 ), goldenseal* (7 ), ginseng (6 ), Ginkgo (4.5 ), and saw palmetto (4.4 ). * Goldenseal is often used illicitly in unsuccessful attempts to disguise urinary marijuana (THC) metabolites. There are no toxicologic databases on...

In Vitro Toxicological Models And Methods Commonly Used In Drug Discovery

Ligand binding assays for the hERG (human ether-a-go-go-related gene) potassium channel have been developed to identify compounds that may have inhibitory activity and potential cardiotoxicity, especially Torsade de Pointes (see Chapters 13, 16, 19, and 20). The ligands used include 3H astemizole 5 , 3H dofetilide 6 , or other small molecule hERG ligands 7 . Alternatively, functional ion efflux across the biological membrane can be assayed by the nonradioactive Rb+ flux assay 8 . Furthermore electrophysiological techniques such as high-throughput patch clamping has emerged as the whole-cell functional readout for predicting drug interaction potential with these membrane channels 9,10 .

Pharmacodynamics The Mechanisms of Drug Action

PD is the study of drug action on the biologic and physiologic processes of both cells and biologic systems. The targets of drug interaction are usually specific macromolecules that induce a physiologic or biochemical change DNA, RNA, or other macromolecules involved in cell division (e.g., microtubules) an enzyme found either intracellularly or in the plasma an ion channel protein or structural protein.4 Many newer drugs bind to receptors that normally bind an endogenous regulatory ligand (e.g., growth factors, neurotransmitters, hormones) and drug binding to this receptor alters its function and or its downstream signaling responses. Agonists are drugs that mimic the endogenous ligand for the receptor (e.g., opioids, granulocyte colony stimulating factor (G-CSF), recombinant human erythropoietin (rhEPO). Antagonists are drugs that block the effects of the endogenous ligand (e.g., trastuzumab (Herceptin) monoclonal antibody against HER-2 neu flutamide, an androgen receptor...

Human liver S9 fraction

The liver S9 fractions contain both microsomal and cytosolic fractions. They regroup therefore the same metabolic enzyme profile (phase I and phase II enzymes including their cofactors) as hepatocytes with the exception of the membrane barrier and its transporters. Hence, S9 fractions offer a more complete representation of the metabolic profile compared with microsomes and cytosolic fractions.2 They are therefore of great potential interest for in vitro studies in drug metabolism and drug interaction. However, their low enzyme activities compared to microsomes limit their use for drug metabolism studies.

Use of specific antibodies

The problem of some of the specific inhibitors lies in their poor specificity and potency although they are preferred to antibodies in drug-interaction studies. However, the use of inhibiting antibodies has been recently promoted62,63 in the quantitative assessment of a particular CYP in the metabolic pathway of a drug, in particular when several CYPs are involved.64 Much improvement has been made in their selectivity, with reduced cross reactivity between homologous CYPs (e.g., 1A2 and 1A1).

Use of recombinant enzymes

The microsomal environment, i.e., lipids, apoproteins, level of both cytochrome b5 and NADPH cytochrome CYP reductase, is different in the cDNA-expressed CYP system from the one in human liver microsomes. These differences can affect the turnover number (Vmax) for a given enzyme, although the affinity (Km) of CYP is quite comparable between recombinant enzymes and human liver microsomes (Table 5). A thorough literature search performed with the aid of a drug interaction database (Aurquest database66) can illustrate this aspect (Table 5).

Reversible inhibition

Transformations of the Michaelis-Menten equation (Table 2) are not only used for calculating Ki values but also for graphical depiction of the type of inhibition.28 These equations allow to predict the risk of drug interaction as a change in substrate exposure (AUC) in presence of an inhibitor (AUCi AUC) (Table 2).

Classification Antibiotic penicillin

Special Concerns Safety and efficacy in children less than 12 years of age have not been established. Side Effects At site of injection Pain and thrombophlebitis. GI Diarrhea, N&V, flatulence, abdominal distention, glossitis. CNS Fatigue, malaise, headache. GU Dysuria, urinary retention. Miscellaneous Itching, chest pain, edema, facial swelling, erythema, chills, tightness in throat, epistaxis, substernal pain, mucosal bleeding, candidiasis. Drug Interactions See also Anti-Infectives and Penicillins. How Supplied See Content

Isolated Cerebral Microvessels

In 1975 Goldstein etal.21 reported isolation of metabolically active capillaries from rat brain, and this preparation was used for a number of studies on transport and metabolism, e.g., for hexoses20 and small ions.22 Since Na + -dependent glutamate uptake by the BBB could not be detected in vivo, but was observed in isolated brain microvessels, where the bathing medium mainly has access to the outer vessel surface, an abluminal location for this transport was proposed.54 The vessels were less suitable for studies of processes with high energy demand such as transcytosis, possibly because of the damage caused in vessel isolation and the resultant impairment in ATP production. Recent improvements in technique have led to more physiological preparations of isolated brain microvessels preserving normal polarized (apical-basal) function, and modern confocal imaging techniques using fluorescent substrates have allowed good resolution of real-time transport activity at the single vessel...

Citalopram hydrobromide

GI Nausea, diarrhea. CNS Somnolence, mania, hypomania, seizures, tremor. GU Delayed ejaculation. Miscellaneous Increased sweating, hyponatre-mia, syndrome of inappropriate anit-diuretic hormone secretion. Drug Interactions No drug interactions reported.

Optimization Of Admetox Properties

Considerable research efforts have focused on novel machine learning algorithms that predict ADME Tox properties of new chemical entities. These calculations can be performed with an extremely large number of molecules and act as a form of multidimensional selection filter. For example, comparative molecular fields analysis (CoMFA) and pharmacophore approaches for review, see 84, 85 have been used to model binding modes of metabolizing cytochrome P450 (CYP) enzymes as well as transporters such as P-glycoprotein 86 , nuclear hormone receptors 87 , and ion channels 88 important for drug-drug interactions. Recursive partitioning methods have been used extensively with these large sets of molecules and either continuous or binary data 89, 90 . Kohonen self-organizing maps have only recently been applied to model cytochrome P450-mediated drug metabolism 91 , and -nearest neighbors has been used to predict metabolic stability 92 .

Additional Contraindications

Special Concerns Use of extended-release capsules for attention deficit disorders in children less than 6 years of age and the elixir or tablets for attention deficit disorders in children less than 3 years of age is not recommended. Dosage for narcolepsy has not been determined in children less than 6 years of age. Side Effects See also Amphetamines and Derivatives. Drug Interactions See also Amphetamines and Derivatives. How Supplied Capsule, Extended Release 5 mg, 10 mg, 15 mg Tablet 5 mg, 10 mg

Major Depressive Disorder

Elimination half-life of approximately 6 weeks when considered with its potent metabolite norfluoxetine. Sertraline, citalopram, and escitalopram have few potential drug-drug interactions, but all can have gastrointestinal side effects including nausea, vomiting, and diarrhea, as well as sleep alterations, weight changes, sexual dysfunction, and extrapyramidal effects such as a high-frequency, low-amplitude tremor. The tricyclics produce significant anticholinergic effects and may induce delirium, cognitive slowing, urinary retention, dry mouth, and orthostasis these are not recommended for routine use in this vulnerable population. Similarly, monoamine oxidase inhibitors are not recommended for patients with HIV and AIDS. This class of medications poses an extraordinary risk, since persons with HIV and AIDS are often on complex and frequently changing drug regimens and also have the concurrent risk of hypertensive crisis if exposed to certain foods or other medications. These include...

Physiologically Based Models

Several approaches 29-31 for in silico prediction of the ADME properties useful for PB models have been described. Ekins 32 has described in silico prediction of drug binding properties, useful in understanding drug interactions. Leahy 33 describes how predicted PK parameters might be captured and utilized in PB models. Obach et al. 34 offer a detailed approach to predicting PK parameters from in vitro and preclinical measurements. Houston and Carlile 35 describe how useful hepatic clearance parameters can be elucidated from liver tissue, cell, and cell-component tests. In 1985, Charnick et al. 36 offered a perspective of PBPK models in drug development and discovery. It is interesting to contrast the work of Charnick et al. to the comprehensive view offered by Theil et al. 37 in 2003. A PBPK workshop convened by Malcolm Rowland and Carl Peck under the auspices of Georgetown University attracted many leading practitioners and a useful summary

Phase II clinical trial Therapeutic pilot study designed to

These trials permit investigation of the type and profile of the most frequent adverse effects, as well as the clinically relevant drug interactions and the influence of factors such as age on the results. The trial protocol will preferably be randomised and double-blind, but other designs may be acceptable, especially for long-term safety studies. Generally, the conditions of a Phase III trial should be as close as possible to normal conditions of use.

Safety concerns with statins

Cerivastatin 7, an extremely potent third-generation statin, was withdrawn from patients postapproval in 2001 after a higher incidence of severe myopathy and renal failure was observed in cerivastatin-treated patients even though they were taking doses up to 100 times lower than those treated with other statins to achieve their LDLc-lowering target. The mechanistic basis for this increased risk with cerivastatin alone has not been determined. However, more cases of severe myopathy and rhabdomyolysis were observed in clinical trials using cerivastatin in combination with gemfibrozil 13 than with cerivastatin alone. These results have been attributed to drug-drug interactions that occurred as a result of potent inhibition of cytochrome P450-2C8 (CYP2C8) by gemfibrozil 13, one of the key metabolizing enzymes of cerivastatin, resulting in elevated plasma concentrations of cerivastatin.

Initial Considerations for Subset Composition and

There has been an increasing amount of literature discussing reactivity, metabolic toxicity, drug-drug interactions, solubility, cell permeability, stability, and tissue or organ selectivity that can be brought to bear in determining which structural fragments can cause problems. Compounds containing these fragments can then be removed from the screening stream by use of a series of filters. These filters are constructed based on the unwanted structural fragments. Starting in about the mid-1990s organizations began to routinely use automated structural filters to identify unwanted chemical matter and remove it either physically from the screening stream so it is not present in the screening plates, or electronically after a screen has been run during the very early stages of the triage analysis step. For example, Hann et al.16 published a list of SMARTs36 strings used for removing unwanted compounds from the high-throughput screening (HTS) stream. These are found in the supporting...

Ketorolac tromethamine

Use of the ophthalmic solution Transient stinging and burning following instillation, ocular irritation, allergic reactions, superficial ocular infections, superficial keratitis. Drug Interactions Ketorolac may T plasma levels of salicylates due to i plasma protein binding. How Supplied Injection 15 mg mL, 30 mg mL Ophthalmic solution 0.5 Tablet 10 mg

Physiologically Based Models for the Fraction Absorbed

PBPK simulation modeling (see 5.37 Physiologically-Based Models to Predict Human Pharmacokinetic Parameters 5.35 Modeling and Simulation of Pharmacokinetic Aspects of Cytochrome P450-Based Metabolic Drug-Drug Interactions) has developed considerably in recent years.73'74'77'78 In combination with ACAT models it is therefore now possible to simulate the whole body pharmacokinetic events and to predict the human or other species most important pharmacokinetic properties, including estimates of oral absorption. The model parameters are separated into physiological parameters for the species studied and compound-specific parameters, which can be measured or estimated computationally.

Prediction of Phenotype from Other Sources of Data

Advantages Decision Tree Proteins

Parsons et al. (2004) use phenotypic experiments to test sensitivity of yeast singlegene mutant strains to different drugs, building a 'chemical-genetic profile' for each drug, indicating which genes interact with the drug and can buffer the drug target. Genes that appear in the profiles for more than one drug can be said to be involved in multi-drug resistance, and they identified 65 genes involved in drug resistance to at least four compounds. They then went on to make double-gene mutants for selected genes, and scored these for fitness, in order to create profiles that could be compared to the chemical-genetic profiles. The chemical-genetic profiles indicate gene-drug interaction, and the double-mutant genetic profiles indicate gene-gene interaction. Similarities between profiles could be used to identify target pathways. For example, 75 genes showed sensitivity to the drug flucanzole. ERG11 is a target of flucanzole, and making double mutants with this gene showed that 13 of the...

Lidocaine hydrochloride

Drug Interactions See also Amide Local Anesthetic Agents. How Supplied Injection without epinephrine 0.5 , 1 , 1.5 , 2 , 4 , 5 Injection with epinephrine 0.5 , 1 , 1.5 , 2 with epineph-rine concentrations of 1 50,000, 1 100,000, 1 200,000. Usual dental use is 2 lidocaine with 1 100,000 epinephrine

Anspor Velosef [Rx Classification Cephalosporin firstgeneration

Uses Infections of the respiratory tract (including lobar pneumonia, tonsillitis, pharyngitis), urinary tract (including prostatitis and enterococcal infections), skin, skin structures, and bone. Otitis media, septicemia, prophylaxis in surgery, following cesar-ean section to prevent infection. In severe infections, therapy is usually initiated parenterally. Contraindications Hypersensitiv-ity to cephalosporins. Special Concerns Safe use during pregnancy, of the parenteral form in infants under 1 month of age, and of the PO form in children less than 9 months of age have not been established. Hypersensitivity to penicillins. Use in renal impairment. Side Effects See also Cephalosporins. Drug Interactions See also Cepha-losporins.

Severe Mental Illness And Hiv Risk

Currently there is no significant difference between the pharmacologic treatment of schizophrenia in an HIV-infected individual and the treatment of an uninfected person. It is important to take into consideration interactions between HAART medications and antipsychotics psychiatrists and HIV practitioners must work together closely during initiation of or changes in antiretroviral or antipsychotic treatment, as concomitant alterations in dosing may be needed. Many antipsychotics are associated with severe side effects, such as tardive dyskinesia and Parkinsonian syndromes known as extrapyramidal symptoms (EPS). They also have effects on metabolism, including weight gain, increased insulin resistance, and increased lipids that may complicate similar effects produced by antiviral medications. There may be drug interactions with antiviral treatment as well, although these remain unpredictable for the most part (Treisman and Angelino, 2004). Antipsychotic medications have been shown to...

Metformin hydrochloride

Special Concerns Cardiovascular collapse, acute CHF, acute MI, and other conditions characterized by hypoxia have been associated with lactic acidosis, which may also be caused by metformin. Use of oral hypoglycemic agents may increase the risk of cardiovascular mortality. Although hypoglycemia does not usually occur with metformin, it may result with deficient caloric intake, with strenuous exercise not supplemented by increased intake of calories, or when metformin is taken with sulfonylureas or alcohol. Because of age-related decreases in renal function, use with caution as age increases. Safety and efficacy have not been determined in children. Side Effects Metabolic Lactic acidosis (fatal in approximately 50 of cases). Oral Unpleasant or metallic taste. GI Diarrhea, N&V, abdominal bloating, flatulence, anorexia. He-matologic Asymptomatic subnormal serum vitamin B12 levels. Drug Interactions None reported that would interact with dental therapy or oral health. How Supplied Tablet...

Pharmacokinetic parameters

Pharmacokinetics assumes that a relationship exists between the concentration of drug in an accessable site, such as the blood, and the pharmacological or toxic response. The concentration of drug in the systemic circulation is related to the concentration of drug at the site of action. Pharmacokinetics attempts to quantify the relationship between dose and drug disposition and provide the framework, through modeling, to interprete measured concentrations in biological fluids.3 Several pharmacokinetic parameters are utilized to explain various phar-macokinetic processes. It is often changes in these parameters, through disease, genetic abnormalities, or drug interactions, which necessitate modifications of dosage regimens for therapeutic agents. The most important parameters are clearance, the ability of the body to eliminate drug, volume of distribution, a measure of the apparent volume of the body available to occupy the drug, bioavailability, the proportion of drug absorbed into...

Classification Antihypertensive depresses sympathetic nervous system

Side Effects CV Edema, pericardial effusion that may progress to tamponade (acute compression of heart caused by fluid or blood in pericardium), CHF, angina pectoris, changes in direction of T waves, increased HR. In children, rebound hypertension following slow withdrawal. GI N&V. CNS Headache, fatigue. Hypersensitivity Rashes, including bullous eruptions and Stevens-Johnson syndrome. Hematologie Initially, decrease in hematocrit, hemoglobin, and erythro-cyte count but all return to normal. Rarely, thrombocytopenia and leu-kopenia. Other Hypertrichosis (enhanced hair growth, pigmentation and thickening of fine body hair 3-6 weeks after initiation of therapy), breast tenderness, darkening of skin. Drug Interactions CNS depressant drugs, especially those used in conscious sedation T Hypotension Indomethaein l Effects NSAIDS l Effects Sympathomimetics l Effects How Supplied Tablet 2.5 mg, 10 mg

Irreversible inhibition

In irreversible inactivation, the inhibitor first acts on the target enzyme before inhibition occurs. In many case, this involves conversion of the inhibitor into a chemically reactive intermediate that forms a covalent bond with the enzyme, inactivating it permanently. For CYP enzymes, irreversible inhibition can be noncovalent occurring through metabolite-intermediate complexes tightly bound to the iron of the heme prosthetic group (quasi-irreversible inhibition). Irreversible inactivation, whether it occurs through formation of covalent bonds or iron complexes, is the underlying mechanism of some high-magnitude drug interactions,16 e.g., CYP2D6 inactivation by paroxetine,81 CYP3A4 inactivation by diltiazem,82 erythromycin, or troleandomycin, CYP2C9 inactivation by tienilic acid,84 etc. It is crucial to distinguish time-dependent inhibition due to the reversible inhibitory effect of a metabolite formed during the incubation from the irreversible inactivation of the enzyme by a...

Safe and Unsafe Medications for Patients with Kidney Failure

Adverse drug reactions and drug interactions are common in renal failure. Since most drugs and drug breakdown products are excreted via the kidneys, even partial loss of kidney function alters the response to a given dose. Kidney disease may change not only drug elimination, but also drug absorption and distribution throughout the body. One such effect often observed is diminished protein binding of drugs in the plasma, owing to low serum albumin level, thereby increasing the concentration of free drugs in the blood. The amount of free drug in the blood is responsible for the drug's effects. If you take a given dose of drug, the extent to which the drug gets bound to your serum albumin will have a major effect on your response The less drug that gets bound to albumin, the greater the drug's effect on your body. Thus a lower dose of the drug may be better for you.

Factors Affecting Pharmacokinetic Parameters

Variability in drug response, which will not be discussed here, other factors that contribute to changes in parameters include drug formulation and route of administration, gender differences, age, weight or body composition, disease, genetic abnormalities, and drug interactions.

Drug and disease interactions

Patients commonly receive two or more drugs concurrently and most individuals who abuse drugs are poly-drug users. Multiple drug use may result in drug interactions. This occurs when the pharmacokinetics or pharmacodynamics of one drug is altered by another. This concept is important to consider because interaction may result in decreased therapeutic efficacy or an increased risk of toxicity. The degree of drug interaction depends on the relative concentrations and therefore dose and time.16 Changes in absorption rate, competition for binding sites on plasma proteins, oral bioavailability, volume of distribution, and hepatic and renal clearance have been demonstrated for therapeutic drugs. Few studies have systematically documented pharmacokinetic interactions between illicit drugs.

Death in the Dental Chair

Naguib et al. produced an extensive review of adverse effects and drug interactions associated with the use of local anesthetics.20 They concluded, as previously noted, that the adverse effects of local anaesthetics were usually caused by excessive dosage, unusually rapid absorption, or inadvertent intra-vascular injection, with the last cause the most common. Severe adverse reactions were caused by either central nervous system or cardiovascular toxicity. The amount ol local anesthetic necessary to produce cardiovascular toxicity is 3.5 to 6.7 times higher than that needed to produce CNS toxicity. High levels of local anesthetics produce direct depression of the myocardium, with impairment of myocardial contractility, and decreased conduction velocity. There is peripheral vasodilatation with hypotension and bradycar-dia. This can progress to arrythmias and cardiac arrest. Bupivacaine and etidocaine are apparently more cardiotoxic than other commonly used local anesthetics, with...

Classification Antihistamine ophthalmic

Contraindications Not to be injected. Not to be instilled while the client is wearing contact lenses. Special Concerns Use with caution during lactation. Safety and efficacy have not been determined for children less than 3 years of age. Side Effects Ophthalmic Burning or stinging, dry eye, foreign body sensation, hyperemia, keratitis, lid edema, pruritus. Nose throat Pharyngitis, rhinitis, sinusitis. Oral Taste perversion. Miscellaneous Headache, asthenia, cold syndrome. Drug Interactions None reported. How Supplied Solution 0.1 Solution in a 5-mL drop dispenser

Role of Human Etheragogo Related Gene in QT Prolongation

Perhaps owing to the unique shape of the ligand-binding site and its hydrophobic character, the hERG channel has been shown to interact with pharmaceuticals of widely varying structure, often at concentrations similar to the levels of on-target activity of the respective compounds. While risk tolerance for QT prolongation may vary significantly depending on indication, development stage, etc., the documented hERG-blocking activity reduces the intrinsic value of the molecule, as it increases risk of clinical failure. Among the indications least tolerant of hERG blockade by the candidate compound are antivirals and antibacterials where high plasma concentrations of the drug are necessary to suppress resistance, and pain management drugs and antipsychotics where overdosing is likely. In addition, drug-drug interactions (e.g., via inhibition of P450 metabolism) may lead to unexpectedly high plasma levels of a drug, which are sufficient to prolong the QT interval. As a general rule, a...

Standard rate method See standardisation

Quantitative composition, the pharmacological properties of the active ingredient(s), therapeutic indications, dosage and method of administration, known adverse effects, possible drug interactions, possible contraindications, and specific precautions for use and storage.

Pulmonary Arterial Hypertension

More recently, endothelin antagonists have been evaluated in the therapy of pulmonary arterial hypertension. There are at least two types of endothelin receptors ETA and ETB. Activation of either receptor aggravates pulmonary arterial hypertension, but activation of ETA receptors appears to be more detrimental. A nonselective endothelin antagonist, bosentan (Figure 5), is used in the therapy of pulmonary arterial hypertension. Its use is based on the evidence that endothelin is overexpressed in patients with pulmonary hypertension and that overproduction of endothelin may lead to pulmonary vascular remodeling. Bosentan is active orally and has been shown to produce short-term benefits in patients with pulmonary arterial hypertension it improves exercise capacity and reduces pulmonary arterial pressure.47 Its side effects include liver toxicity (elevation of hepatic aminotransferase in 7-14 of patients), teratogenicity, and drug interactions, since bosentan is a substrate for and...

Development of Gabapentin for Epilepsy

After the gabapentin product launch, gabapentin was used extensively by physicians for treating epilepsy. Because of a relatively benign adverse event profile and few drug-drug interactions, it was also prescribed for off-label indications, including neuropathic pain, anxiety, and other psychiatric indications, essential tremor, spasticity, postsurgical pain, and prevention of postmenopausal hot flashes. None of these additional indications were supported in the gabapentin product labeling or approved by regulatory agencies until the FDA approved a supplemental NDA for gabapentin to treat postherpetic neuralgia in July 2001 (see Section, below).

Flow Cytometric Assessment of Drug Susceptibility in Leishmania infantum Promastigotes

The flow cytometry approaches described in this unit enable one to detect, differentiate, and quantify cellular changes in Leishmania parasites as a result of treatment with allopurinol or other drugs. In addition, the flow cytometry approaches also demonstrate differences in allopurinol susceptibility between two promastigote forms, thereby expanding the spectrum of flow cytometry applications in the field of parasitology and in studies of parasite-drug interactions as well as cellular toxicity.

Discussion and Conclusion

These safety and efficacy aspects have been discussed in this chapter, trying to show how in vitro metabolism tools can better address, at very early stages, the nature and the importance of metabolites formed throughout species as well as the drug interactions risks. These two issues have been recognized by regulatory authorities as major and the studies to be undertaken have been defined quite precisely for development programs and registration purposes in recent draft guidelines on safety testing of metabolites and predictions of drug interactions. These new requirements will have to be discussed and integrated by research teams. But one has to keep in mind that getting a similar level of understanding in research projects on series of drugs will only be possible if one can further adapt the tools using new technologies and apply different and more global interpretation strategies. Screening programs have in a way broken down the important mechanisms involved in drug disposition...

Pharmaceutical Industry and FDA Perspective

According to the FDA, severe hepatotoxicity is one of the most common causes for pharmaceutical product recalls and labeling changes, and this raises the question of how effective nonclinical and clinical testing are in recognizing such toxicity. Although much attention has been focused on the predictivity of animal models for clinical findings in humans, clinical trials of pharmaceuticals are in fact a relatively poor source of information for ascertaining the probability that an event observed in an animal model is also observed in the human. Of critical importance to avoiding unanticipated toxicity in human is the need to understand why drugs that were judged safe to administer to humans on the basis of animal data sometimes cause unexpected toxicity or drug interactions. In other words, why do animal models in these cases fail to predict human hepatotoxicity It is probably even more important to understand why these models sometimes fail to identify hepatotoxic potential in humans...

Tetracycline hydrochloride

Side Effects See also General Information on Tetracyclines. Additional Side Effects Temporary blurring of vision or stinging following administration. Dermatitis and photosensitivity following ophthalmic use. Use of the tetracycline fiber Oral candidiasis, glossitis, staining of the tongue, severe gingival hyperplasia, minor throat irritation, pain following placement in an abscessed area, throbbing pain, hyper-sensitivity reactions. Drug Interactions See also General Information on Tetracyclines. How Supplied Tetracycline Syrup 125 mg 5 mL. Tetracycline hydrochloride Capsule 100 mg, 250 mg, 500 mg Ointment 3 Ophthalmic ointment 1 Solution 2.2 mg mL

Combinations of statins with highdensity lipoprotein cholesterolelevating agents

Similar beneficial effects were expected with statins in combination with fibrates. However, a heightened awareness of the potential for severe side effects with this combination therapy has occurred as more cases of severe myopathy and rhabdomyolysis were observed in clinical trials administering cerivastatin in combination with gemfibrozil than with cerivastatin alone. These results have been attributed to drug-drug interactions occurring as a result of the potent inhibition of CYP2C8, a key metabolizing enzyme of cerivastatin, by gemfibrozil, resulting in elevated plasma concentrations of cerivastatin. These adverse effects contributed to the withdrawal of cerivastatin from the marketplace.

Pregnancy Category B vaginal

NOTE The injection contains benzyl alcohol, which has been associated with a fatal gasping syndrome in infants. Drug Interactions Antiperistaltic antidiarrheals (opiates, Lomotil) T Diarrhea due to X removal of toxins from colon Ciprofloxacin HCl Additive antibacterial activity

Pharmaceutical Sop Clinical Trial Termination Or Suspension

Chapter 1 provides an overview of clinical development for pharmaceutical entities, drug research and development process in the pharmaceutical industry, regulatory review, and approval processes and requirements. Also included in this chapter are the aim and structure of the book. Chapters 2 to 7 cover the concepts of design and analysis of clinical trials. Chapter 2 introduces basic statistical concepts such as uncertainty, bias, variability, confounding, interaction, clinical significance and equivalence, and reproducibility and generalizability. Chapter 3 provides some fundamental considerations for choosing a valid and suitable design for achieving study objectives of clinical trials under various circumstances. Chapter 4 illustrates the concepts and different methods of randomization and blinding, which are critically indispensable for the success and integrity of clinical trials. Chapter 5 introduces different types of statistical designs for clinical trials. These study...

Three Dimensional Approaches to Predicting Toxicity

3D approaches use knowledge about the shape and volume of either the submitted compound or the binding site thought to be involved in the mechanism of toxicity, or both. They often require knowledge that the chemicals act via a common mechanism or biological event. One example where 3D methods have been applied to predict toxicity is the binding or blockage of the potassium ion channel in the prediction of prolonged QT syndrome, another is the identification of substrates for one or more of the P450 cytochromes and their ability to cause induction or peroxisome proliferation. P450 induction where a patient is taking multiple therapeutic medicines has been linked to causing adverse events through prolonged or increased exposure to one of the drugs or decreased efficacy by increased metabolic clearance. This type of effect is often referred to as a drug-drug interaction (DDI).

Modeling of Phase 1 Metabolism Cytochromes P450

Seven of the 57 known human isoforms of cytochromes P450 (CYP1A2, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) are responsible for more than 90 of the metabolism of all drugs in current clinical use.8 Some of these enzymes (especially CYP2D6 and CYP2C9) show polymorphisms, which can either result in rapid or very poor metabolism.9-11 For example, debrisoquine is extensively metabolized in normal individuals to 4-hydroxydebrisoquine, but poor metabolizers can develop high levels of the parent compound, which may be toxic.12 The impaired metabolic oxidation of at least 30 drugs with diverse structures and pharmacological actions has been associated with the phenotype of poor debrisoquine metabolism. In a few cases, poor metabolizers may be unable to bioactivate a parent drug, such as encaimide, to its therapeutically active metabolites.13,14 Binding of any drug to these cytochromes P450 can cause drug-drug interactions, which can lead to severe side effects. This has in the...

Sleep Disturbance In

Anxiolytics and or antidepressants are usually effective in decreasing anxiety, although the use of anxiolytics in patients with a history of substance abuse may raise another set of issues. The possibility of drug-drug interactions with highly active antiretroviral therapy (HAART) may also limit the choice of agent.

Nfectious Disease

Harn, Jr., pud, 2006 Drug Interactions in Infectious Diseases Second Edition, edited by Stephen C. Directions in Drug Discovery, edited by Philip J. Rosenthal, md, 2001 Drug Interactions in Infectious Diseases, edited by Stephen C. Piscitelli, pharmd


The ABC transporters MDR1, MRP2, and MRP4 are also present on the apical membrane and efflux compounds by secretion. As indicated above, transporters are not evenly distributed along the nephron MDR1, MRP2, MRP4, and MRP6 are found mainly within the three segments of the proximal tubule MRP3 lies in the distal convoluted tubule and MRP1 is found in the epithelial cells of the loop of Henle and the distal and collecting duct tubule cells, but not in proximal tubule cells.114 The regional distributions of the SLC transporters are also specific. OAT1 is found only on the basolateral membrane of the S2 segment cells of the proximal tubule, whereas OAT3 is present on the cells of the S1, S2, and S3 segments. Once again, this raises the question of the most appropriate in vitro kidney models containing the whole transport network. As with Caco-2 intestinal cells, the Madin-Darby canine kidney (MDCK) cell lines are widely used in wild-type or transfected cell systems for examining particular...


The recent expansion of our knowledge of the involvement of drug transporters in pharmacokinetics has added a new layer of complexity to our understanding of the mechanisms underlying the absorption, distribution, and elimination of drugs. New transporters undoubtedly remain to be identified, and the functions of some identified transporters remain poorly understood. Nevertheless, it is clear that the drug transporters in organs such as the intestine, liver, brain, and kidney are significant determinants of variations in drug responsiveness between individuals. Together with the drug-metabolizing enzymes, they determine drug-drug interactions, drug-induced organ toxicities, and diseases. Detailed knowledge of genetic polymorphisms in transporters and how they affect transporter function will help to optimize drug therapies and identify unknown, residual factors that influence intersubject variations.


Chronic overdose Chronic renal failure (CRF) in the elderly and alcoholics bleeding and cognitive dysfunction and dementia in elderly. Constellation of side effects Gastrointestinal, renal, hypersensitivity reactions, (acetic acids and phenylbutazone piroxicam propionic acid) pulmonary, CNS, hematologic, drug-drug interactions.


The substrate specificities of transporters are often very broad, as indicated by the many overlaps of substrates and inhibitors, much like the specificity of the drug metabolism enzymes. Thus, probenecid was initially known to produce many drug interactions by blocking the secretion by the kidney of many drugs, including the penicillins and the antiviral Tamiflu.116 Probenicid is today known to be a polyspecific inhibitor of several MRPs, OATs, OATPs, and even OCTs.117 Similarly, MRP1, MRP2, and MRP3 have broad, overlapping substrate specificities, while OCT1, OCT2, and OCT3 transport a wide range of similar OCs. P-gp interacts with a multitude of xenobiotics, many of which are metabolized by CYP3A4 5, and some of them are also substrates of MRP1 and BCRP.21 The tyrosine kinase inhibitor imatinib is effluxed by both P-gp and BCRP, and imported by OCT1.118 Thus all ionized chemicals, peptides, and nucleosides that cannot diffuse freely across membranes are very likely to interact with...


Sufficiently to cause symptoms or even life-threatening hypoglycemia. Side Effects GI Abdominal pain, diarrhea, flatulence. GI side effects may be severe and be confused with paralytic ileus. Drug Interactions Charcoal l Effect of acarbose Digestive enzymes l Effect of acar-bose


Special Concerns Use with caution during lactation, in the elderly, and in clients with asthma. Side Effects Respiratory Increased incidence of bronchospasm in clients with asthma. Increased amount of liquefied bronchial secretions, which must be removed by suction if cough is inadequate. Bronchial and tracheal irritation, tightness in chest, bronchoconstriction. Oral Stomatitis. GI N&V. Other Rashes, fever, drowsiness, rhinorrhea. Drug Interactions Acetylcysteine is incompatible with antibiotics and should be administered separately.

Alendronate sodium

GI Abdominal pain, nausea, dyspepsia, constipation, diarrhea, flatulence, acid regurgitation, esoph-ageal ulcer, vomiting, dysphagia, abdominal distention, gastritis. Miscellaneous Musculoskeletal pain, headache, rash and erythema (rare). Drug Interactions Antacids l Absorption of alendro-nate


An examination of a database containing data assembled from the literature on substrates inhibitors for various transporters indicates how the research community has scored their relevance for drug transport (Figure 5).99 Clearly, the extensively studied efflux protein P-glycoprotein (P-gp) has the highest number of substrates inhibitors, followed by other efflux transporters of the ATP-binding cassette (ABC) transporter family, various transporters for organic anions, cations, and the oligopeptide transporter PEPT1.99 This rating can probably be explained by the role of ABC transporters in drug resistance,100'101 brain uptake,102'103 and drug-drug interactions,104-106 and by the importance of ABC transporters and organic anion and cation transporters for drug transport and elimination in the liver, kidney, and, perhaps, the intestine,107 and by the exploitation of PEPT1 as a (pro)drug target for enhanced absorption.108 Examples of successful exploitation of PEPT1, which is...


Additional Side Effects Serious CV side effects, including death, cardiac arrest, QT interval prolongation, torsades depointes and other ventricular arrhythmias have been observed in clients exceeding the recommended dose of astemizole. Syncope may precede severe arrhythmias. Overdose may be observed with doses as low as 20-30 mg day. Drug Interactions Concomitant use of astemizole with erythromycin, itraconazole, or ketoconazole may cause serious CV effects, including death, cardiac arrest, torsades de pointes, and other ventricular arrhythmias (including QT interval prolongation).


Ness, drowsiness, fatigue, hallucinations, insomnia, lethargy, mental changes, memory loss, strange dreams. GI Diarrhea, ischemic colitis, nausea, mesenteric arterial thrombosis, vomiting. Hematologic Agranulocytosis, thrombocytopenia. Allergic Fever, sore throat, respiratory distress, rash, pharyngitis, laryngos-pasm, anaphylaxis. Skin Pruritus, rash, increased skin pigmentation, sweating, dry skin, alopecia, skin irritation, psoriasis. Ophthalmic Dry, burning eyes. GU Dysuria, impotence, nocturia. Other Hypoglycemia or hyperglycemia. Respiratory Bronchospasm, dyspnea, wheezing. Drug Interactions See also Drug Interactions for Beta-Adrenergic Blocking Agents and Antihypertensive Agents.

Calcium carbonate

Uses Mild hypocalcemia, antacid, antihyperphosphatemic. Special Concerns Dosage has not been established in children. Drug Interactions May interfere with the absorption of anticholiner- Captopril gics, ketoconazole, tetracyclines, ----and sodium fluoride. How Supplied Capsule 500 mg, 600 mg, 900 mg, 1250 mg Chew Tablet 300 mg, 420 mg, 500 mg, 600

Drug History Taking

If the patient is on an antiretrovi-ral, the patient may stop taking the medication because he or she is feeling uncomfortable symptoms of opioid withdrawal. Other drug-drug interactions, including those with psychotropic medication, are also significant. A patient with comorbid HIV and hepatitis C who stops all alcohol use during interferon treatment and eagerly resumes daily use after successful treatment and eradication of hepatitis C virus puts his or her hepatic function in jeopardy once again. For individuals who have unprotected sexual encounters in the context of alcohol or drug use, history-taking has public health implications. For individuals exposed to drug- or alcohol-related domestic violence, the implications are both tragic and obvious. Hence, for medical, psychological, and social reasons, a comprehensive drug history is essential in persons with HIV and AIDS.

Amphotericin B

Imidazoles Miconazole, clotrimazole. Toxicity Increased drug-drug interactions Drug-drug interactions Azoles inhibit CYP3A4, responsible for metabolizing many drugs, including statins, H1-blockers, steroids, benzodiazepines, calcium channel blockers (CCBs).

Codeine sulfate

Contraindications Premature infants or during labor when delivery of a premature infant is expected. Special Concerns May increase the duration of labor. Use with caution and reduce the initial dose in clients with seizure disorders, acute abdominal conditions, renal or hepatic disease, fever, Addison's disease, hypothyroidism, prostatic hypertrophy, ulcerative colitis, urethral stricture, following recent GI or GU tract surgery, and in the young, geriatric, or debilitated clients. Additional Drug Interactions

Erythromycin base

Special Concerns Use of other drugs for acne may result in a cumulative irritant effect. Additional Side Effects When used topically Erythema, desquamation, burning sensation, eye irritation, tenderness, dryness, pruritus, oily skin, generalized urticaria. Drug Interactions Antagonism has been observed when topical eryth-romycin is used with clindamycin. How Supplied Enteric coated capsule 250 mg Enteric coated tablet 250 mg, 333 mg, 500 mg Gel Jelly 2 Ointment 2 Ophthalmic ointment 5 mg g Pad 2 Solution 1.5 , 2 Swab 2 Tablet 250 mg, 500 mg Tablet, Coated particles 333 mg, 500 mg

Suspenion Tablets

Adults Add felbamate at a dose of 1,200 mg day in divided doses t.i.d.-q.i.d. while reducing current antiepileptic drugs by 20 . Further decreases of concomitant antiepilep-tic drugs may be needed to minimize side effects due to drug interactions. The dose of felbamate can be increased by 1,200-mg day incre imize side effects due to drug interactions. The dose of felbamate may be increased by 15-mg kg day increments at weekly intervals to 45 mg kg day.


The successful introduction of HMG-CoA reductase inhibitors for lipid lowering sparked intense competition in the field. pravastatin 4 (Figure 7) is made in a two-step fermentation process that first generates compactin with Penicillium citrinum, and after hydrolysis of the lactone, employs a biological hydroxylation with Streptomyces carbophilus to introduce the allylic 6-alcohol group regioselectively. Pravastatin has higher water solubility and provided several potential advantages over the more hydrophobic analogs, lovastatin and simvastatin. Unlike lovastatin and simvastatin, pravastatin sodium is administered as the sodium salt of the corresponding open-chain hydroxy-acid. The polar nature of pravastatin, however, limited its overall human absolute bioavailability to 17 , presumably due to incomplete absorption and firstpass metabolism. However, pravastatin has been used to demonstrate the facilitated cellular uptake of compounds through organic anion transporter proteins....

Lamivudine Zidovudine

See also Lamivudine, Zidovudine, and Antiviral Drugs. Content Each Combivir tablet contains Antiviral Lamivudine, 150 mg and Antiviral Zidovudine, 300 mg. Action Kinetics Both drugs are reverse transcriptase inhibitors with activity against HIV. Combination results in synergistic antiretroviral effect. Each drug is rapidly absorbed. Uses Treatment of HIV infection. Contraindications Use in clients requiring dosage reduction, children less than 12 years of age, CCR less than 50 mL min, body weight less than 50 kg, and in those experiencing dose-limiting side effects. Side Effects See individual drugs. Drug Interactions See individual drugs.


Side effects and drug interactions are possible with the use of Asian ginseng and Siberian ginseng. Both herbs may produce sedation and may conceivably worsen MS fatigue or accentuate the sedating effects of medications and alcohol. Asian ginseng may interact with steroids, which sometimes are used to treat MS attacks. Asian ginseng and Siberian ginseng may increase bleeding tendency and should be avoided by people who are undergoing surgery, people who have blood-clotting disorders, and people who take blood-thinning medications or aspirin.


Treatment of anxiety disorders in HIV-positive patients follows guidelines similar to those for treating persons with other chronic medical illnesses, with particular attention to medication dosing, metabolism, potential for drug interactions, and potential for side effects (Farber and McDaniel, 2002). This will be discussed further in Chapter 32. While the DSM-IV guidelines prove helpful in diagnosing specific disorders, it is generally more appropriate to treat the anxiety on the basis of a patient's symptoms and symptom severity. To minimize adverse effects, medications should be started at low doses and titrated up slowly to the desired effect. Side effect profiles should also be taken into account. Selective serotonin reuptake inhibitors (SSRIs) are useful as first-line therapy for treating chronic anxiety disorders (Ferrando and Wapenyi, 2002, Pollack et al., 2004), although benzodiazepines are most frequently used (Cabaj, 1996). Benzodiazepines are especially useful as an...

Chloral hydrate

Chronic toxicity is treated by gradual withdrawal and rehabilitative measures such as those used in treatment of the chronic alcoholic. Poisoning by chloral hydrate resembles acute barbiturate intoxication the same supportive treatment is indicated (see Barbiturates). Drug Interactions CNS depressants Additive CNS depression concomitant use may lead to drowsiness, lethargy, stupor, respiratory collapse, coma, or death How Supplied Capsule 500 mg Suppository 325 mg, 500 mg, 650 mg Syrup 250 mg 5 mL, 500 mg 5 mL


CYPs may be induced by a structurally diverse range of xenobiotics including rifampicin, omeprazole, and phenobarbital, as well as cigarette smoking and alcohol.49 The induction of CYPs leads to two different problems effects on self, and coadministered drug-drug interactions. On chronic administration ritonavir induces CYP3A leading to a decrease of its own AUC.50 Regarding the latter effect, an inducible drug can influence the pharmacokinetics of a coadministered drug which shares the same metabolic pathway. For example, rifampicin induces metabolism of ethynylestradiol which can lead to the failure of contraceptive therapy.49 More sophisticated approaches accounting for drug interactions with transporter proteins51,52 and metabolizing enzymes are required to enable accurate predictive models to be developed.


The total elimination of a parent compound and metabolites requires the integrity of these three separate processes, which themselves depend on plasma pH, urine pH, and renal blood flow. All active processes may be restricted by the amount of available transporters and energy supply, which may lead to competitive drug-drug interactions.


AurSCOPE is a collection of annotated structure databases that capture biological and chemical information related to a given therapeutic or biopharmaceutical topic from literature, mostly patents and journals.146 These databases capture in vitro and in vivo biological data, together with chemical information and structure-activity relationships. Complete descriptions of the biological test methods are provided. AurSCOPE GPCR (500 000 bioactivities for 106000 ligands and 2300 targets) contains biological and chemical data relating to GPCR chemistry, pharmacology, and physiology AurSCOPE ADME Drug-Drug Interactions (97000 bioactivities for 4520 molecules, 1770 metabolites, and 420, targets) contains biological and chemical information related to metabolic properties of drugs, which enables the identification of potential drug-drug interactions. AurSCOPE Ion Channel is focused on drugs described as ion channel blockers, openers, or activators, that captures all ion channels (calcium,...


Special Concerns When given with sulfonylurea or insulin, miglitol causes further decrease in blood sugar and increased risk of hypogly-cemia. Safety and efficacy have not been determined in children. Side Effects GI Flatulence, diarrhea, abdominal pain, soft stools, abdominal discomfort. Dermatolog-ic Skin rash (transient). Drug Interactions No drug interactions reported that would impact on dental health or the dental process. How Supplied Tablets 25 mg, 50 mg, 100 mg

In Silico Approaches

The application of in silico approaches for the modeling of drug-protein interactions has several stages, depending on the level of knowledge available on the structure and function of the modeled protein. Lack of detailed information about the 3D structure of the multidrug transporters and the binding sites involved in the drug interactions precludes the use of in silico tools that are based on the so-called structure-based drug design approach (e.g., docking and, related to it, virtual screening). Instead, they are commonly restricted to ligand-based drug design methods. Among the mostly used are different versions of the classical quantitative structure-activity relationship (QSAR) analyses by Hansch118 and Free-Wilson119 three-dimensional quantitative structure-activity relationship (3D-QSAR), comparative molecular field analysis (CoMFA),120 and comparative molecular similarity indices analysis (CoMSIA).121 Furthermore, correlations with molecular descriptors can be generated from...


Side Effects Oral Ulcerative sto-matits. GI Nausea, abnormal LFTs, diarrhea, abdominal pain, hepatitis. CNS Headache, fatigue, paresthesia. Hematologic Decreased hemoglobin, decreased platelets, decreased neutrophils. Miscellaneous Rash (may be severe and life-threatening), fever, peripheral neuropathy, myalgia. Drug Interactions None reported that may have potential dental concerns. However, nevirapine can induce cytochrome P450 enzymes. How Supplied Tablet 200 mg

Treatment Strategies

Underlying depression should be treated with selective serotonin reuptake inhibitors (SSRIs), which are generally better tolerated than tricyclic antidepressants by patients with HIV and AIDS (Elliot et al., 1998 Schwarz and McDaniel, 1999). The notable exception is fluvoxamine, which is less well tolerated despite its efficacy in treating depression (Grassi, 1995). Since fatigued patients with HIV and AIDS are especially sensitive to antidepressant side effects compared to patients without fatigue (Sharpe and Wilks, 2002), treatment should be initiated at very low doses. Because concomitant antiretroviral therapy is frequently used, drug-drug interactions should also be carefully monitored by prescribing physicians. Excellent reviews of such psychopharmacologic considerations have been carried out by Robinson and Qagish (2002) and

Clinical features

An MSLT performed alone has the same drawbacks as does pupillography -it measures sleepiness regardless of its cause, which may simply be sleep deprivation. The MSLT also ignores repetitive microsleeps that can lead, in borderline cases, to daytime impairment not scored by conventional analysis. To be clinically relevant, the test must be conducted under specific conditions. Subjects must have abstained from medication for a sufficient period (usually 15 days) so that drug interaction is avoided. On the basis of sleep diaries, their sleep-wake schedules are stabilized. On the night preceding the MSLT, the subjects undergo a standard nocturnal polysomnogram. Throughout the total nocturnal sleep period, any sleep-related biological abnormalities responsible for sleep fragmentation and sleep deprivation are recorded. A nocturnal polysomnogram is useful for eliminating other possible causes of excessive daytime sleepiness such as periodic leg movements and obstructive sleep apnea. The...


Lower number of false positives in drug profiling and also avoids expensive labeling processes. Initially, optical biosensors have been mainly applied in secondary profiling and kinetic analyses of protein-protein or protein-drug interactions, but more recently high-throughput applications have been developed (for review see1'45).

Sulfacetamide sodium

Contraindications In infants less than 2 months of age. Use in the presence of epithelial herpes simplex keratitis, vaccinia, varicella, and other viral diseases of the cornea and conjunctiva. Mycobacterial or fungal infections of the ocular structures. After uncomplicated removal of a corneal foreign body. Special Concerns Safe use during pregnancy and lactation or in children less than 12 years of age has not been established. Use with caution in clients with dry eye syndrome. Ophthalmic ointments may retard corneal wound healing. Side Effects When used topically Itching, local irritation, periorbital edema, burning and transient stinging, headache, bacterial or fungal corneal ulcers. NOTE Sulfonamides may cause serious systemic side effects, including severe hypersensitiv-ity reactions. Symptoms include fever, skin rash, GI disturbances, bone marrow depression, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, photosensitivity. Fatalities have occurred....


Erythema, worsening of psoriasis, skin pain, irritation, rash, desquamation, contact dermatitis, skin inflammation, fissuring, bleeding, dry skin, localized edema, skin discoloration. Drug Interactions T Risk of photo-sensitivity when used with fluoro-quinolones, phenothiazines, sulfon-amides, tetracyclines, thiazides.


Additional Side Effects Doses of 360 mg or more may cause serious CV effects, including death, cardiac arrest, torsades de pointes, and other ventricular arrhythmias (including QT interval prolongation). Syncope may precede severe arrhythmias. Drug Interactions Azole antifungal drugs T Risk of serious CV effects, including death, cardiac arrest, torsades de pointes, and other ventricular arrhythmias Clarithromycin T Risk of serious CV effects, including death, cardiac arrest, torsades de pointes, and other ventricular arrhythmias Erythromycins T Risk of serious CV effects, including death, cardiac arrest, torsades de pointes, and other ventricular arrhythmias Itraconazole T Risk of serious CV effects, including death, cardiac arrest, torsades de pointes, and other ventricular arrhythmias Ketoconazole T Risk of serious CV effects, including death, cardiac arrest, torsades de pointes, and other ventricular arrhythmias Macrolide antibiotics T Risk of serious CV effects, including death,...

InLife Testing

However, pervasive computing will ultimately do much more it will change the very way in which new drugs are tested. At present, all drugs go through three clinical phases, but the process is both very costly and very inefficient. Clinical trials cannot detect rare side effects and drug interactions, or sometimes even fairly common reactions. In fact, one recent study conducted by Harvard Medical School and Public Citizen, the US consumer advocacy In-life testing has various practical and economic advantages. It will dispense with the need to expose patients to placebos or dosing levels that are pharmacologically ineffective. It will be better able to pick up rare side effects and drug interactions, thus making the move from the laboratory to real life much safer. It will also reduce the frequency of the visits patients need to make to their doctor or hospital. Travel was one of the two biggest obstacles cited in a recent survey of potential trial patients. Similarly, it will reduce...


More recently the crystal structure of the LBD of human PXR was elucidated and showed the existence of an extensive hydrophobic ligand-binding cavity containing several polar residues, which allow hPXR to bind to a variety of structurally diverse ligands including small and large molecular weight compounds 54 . Furthermore mutagenesis analyses indicated that alteration of four amino acids in the ligand-binding pocket of mPXR to the corresponding hPXR amino acids (Arg203 Leu, Pro205 Ser, Gln404 His, and Gln407 Arg) was sufficient to switch the original PCN responsive mPXR to a human-like receptor, which could be activated effectively by SR12813 but no longer by PCN (Figure 4.66). Using trans-species transfection assays, Xie et al. 11 demonstrated that co-transfection of hPXR into primary rat hepatocytes resulted in a significant induction of rat CYP3A23 reporter gene by compounds known to be human PXR activators and CYP3A4 inducers, including rifampi-cin, clotrimazole,...


As discussed above, the primary disadvantage of sulfonylurea use is a risk of hypoglycemia, especially in individuals with hepatic or renal dysfunction. Drug interactions between sulfonylureas and other pharmacologic agents (salicylates, sulfonamides, fibric acid derivatives, and warfarin) can prolong the activity of either medication, and requires both close glucose monitoring and measurement of serum drug levels when possible. The activity of metabolites prolongs the drug effect, which can be beneficial in improving glycemic control, but dangerous if buildup of the metabolites occurs. Finally, weight gain is common in persons on sulfonylurea therapy.


Thrombocytopenia, anemia, infections, bleeding, packed cell transfusions, platelet transfusions. CV Bradycardia and hypotension (including during the infusion), hypertension, severe CV events (including asymptomatic ventricular tachycardia, bigeminy, syncope, completeAVblock), abnormal ECG (including nonspecific repolarization abnormalities, sinus tachycardia, premature beats). Muscu-loskeletal Peripheral neuropathy (including mild paresthesia), myalgia, arthralgia. Oral Mucositis. GI N&V, diarrhea. Miscellaneous Alopecia, fever associated with severe neutropenia infections of the urinary tract and upper respiratory tract as well as sepsis due to neutropenia. Drug Interactions Ketoconazole Inhibition of metabolism of paclitaxel by ketoconazole How Supplied Injection 6 mg mL