Set Up Your Free Medication Profile

Bernard Testa Urs A Meyer

This book tries to give an overview on present knowledge about pharmacological and clinical aspects of antidiabetic drugs. In this connection it was found to be important to include chapters on the regulation of glucose homoeostasis and pathophysiology of Type-I and Type-II diabetes mellitus. Since diabetes mellitus is a disease of inadequate insulin secretion and inadequate action of insulin, especially in Type-II diabetes mellitus, special emphasis has been put on the molecular basis of insulin secretion and insulin actions. Several experts have contributed different topics. The clinical part was written by H. Laube, and insulin action by H. U. Haring, M. Kellerer and L. Mosthaf. The secretory machinery and mechanisms of sulphonylurea actions were contributed by H. P. T. Ammon. The author of pharmacodynamics of other antidiabetic drugs, side effects and drug interactions is E. J. Verspohl and finally M. A. Wahl added the pharmacokinetic properties of antidiabetic agents. Only...

Cell Based Assays to Predict Toxicity and Resistance Aspects

Before an antiviral agent becomes a drug, advanced toxicity testing, pharmacological combination, and drug-interaction studies are needed. The use of new cell-based assays that can predict mitochondrial toxicity, lactic acidosis, peripheral neuropathy, anemia, hypersensitivity, lipodystrophy, and other potential side effects can alleviate these issues (Stuyver et al. 2002).

Physiological Factors that Influence Drug Delivery for HCV Drugs

Storch et al. 2007) and CYP3A 4 metabolism (Sagir et al. 2003 Zhou et al. 2005). The HIV protease inhibitors ritonavir and atazanavir are potent inhibitors of both P-gp and CYP3A4. Therefore pharmacokinetic boosting has been used as a strategy in HIV therapy and may be feasible for HCV protease inhibitors for increasing peak plasma concentrations (Cmax), reducing the rate of elimination (longer t1 2), increasing exposure (AUC), and lowering the frequency of dosing needed to maintain sufficient drug levels (Cooper et al. 2003 King et al. 2004 Moyle and Back 2001). However, administration of other drugs with protease boosting regimens can result in complex drug interactions, which may require dose modification or drug replacement of either the protease inhibitor or the other drug. Various studies demonstrated the value of developing reliable assays for in vivo pharmacokinetic phenotyping of drug metabolic profiles when using drug combinations (Gerber et al. 2007). Furthermore, the...

Specialist advice and education

A major specific role of clinical pharmacists in infection management is to provide specialist advice on aspects of antimicrobial use such as appropriate initial dose of antimicrobial and dose alterations according to renal or hepatic function, therapeutic drug monitoring, and information on drug interactions and side effects. This information can be supplied directly at the point of prescribing, on review of drug charts or antimicrobial order forms, within a formulary, via computer-assisted support programmes, or as a telephonic service. Formal pharmacokinetic consultation services are commonly established in teaching hospitals and tertiary referral facilities and could be further expanded in smaller community hospitals (Bedard and McLean, 1994).

Miscellaneous Approaches

A recent US patent describes derivatives of amiodarone (27) for the treatment of ventricular fibrillation in patients with heart failure 46 . In the past, amiodarone has been reported to reduce arrhythmias in patients with congestive heart failure undergoing antihypertensive therapy. However, amiodarone has long-term toxicity related to its long half-life, drug-drug interactions and cardiac side effects. Therefore, analogs that are less lipophilic and contain a metabolically labile group should result in a Class III antiarrhythmic agent with significantly lower toxicity. Simple modification of the n-butyl group of amiodarone to incorporate an ester gave 28, which was speculated to be quickly metabolized to a water-soluble compound resulting in a safer antiarrhythmic agent.

Table 1 Examples of Potentially Serious Medication Errors and Possible Prevention Strategies

Wrong Appropriate use of supportive personnel and technology (e.g., bar drug, dose, coding, drug interactions software, alerts for high-risk problems) time, or as much consistency as possible in dosage formulations (e.g., patient lack standard concentrations for IV solutions) appropriate labeling and of sterility packaging, particularly for medications compounded or packaged in-house use of special labeling packaging for high-risk antimicrobial agents procedures in place to minimize medication turn-around time, particularly for first doses of antimicrobials limiting of compounding, particularly of sterile products, to pharmacy

Recommending uses of antifungal agents the limitations

Agents undergoing major clinical trials but not yet licensed in the United States or Europe have not been included among the recommendations that follow. It is likely highly that posaconazole and ravuconazole will have many properties in common with the licensed triazoles, itraconazole and voricona-zole, and that anidulafungin and micafungin will closely match caspofungin. However, their place in clinical practice will depend on the details of their formulations and their adverse event and drug interaction profiles, so it is too early to guess their final place in the antifungal armoury.

Antifungal combinations and therapy changes

Broad-spectrum triazole to another would require strong evidence in vitro of superior antifungal potency at achievable blood levels of the second azole. Outwith straightforward pharmacological considerations (formulation, route of administration, potential for toxicity, or drug interactions in a given patient), there is no particular reason not to switch from one appropriate antifungal class to another. The advent of the echinocandins into clinical use expands the possibilities for class switching in treatment failure, and may in time generate a database that can offer predictive clues to optimize treatment switches.

Management Of Recurrent

For endogenously recurring CDI, where spores may be the source of the problem (110,112), we favor a regimen of vancomycin administered in a pulsed fashion, 125 to 500 mg given as a single dose every 3 days for 2 to 3 weeks as described by McFarland (110). It is theorized that persistent spores revert to their vegetative state in the absence of a hostile environment (e.g., one that contains antimicrobials) where they regain susceptibility to the killing effects of the drug. Although higher-dose vancomycin (500 mg 4 times daily) is effective when given for 10 days to patients with recurrent CDI, it associated with higher recurrence rates than standard therapy followed by a pulsed or tapered vancomycin regimen (110). Higher-dose metronidazole was not effective at reducing future recurrences (and if used for longer periods of time may be associated with increased neurological adverse events) (110). The addition of rifampin to vanco-mycin has been reported to be effective in a small study...

Recent Developments in Antiretroviral Therapies

Introduction - Clinical use of novel potent inhibitors of human immunodeficiency virus (HIV) in the last few years marked a new era in the treatment of HIV infection and for the first time in the history of the disease reverted the AIDS-related death rate. To date, fourteen antiretroviral agents belonging to three distinct classes (nucleoside and non-nucleoside reverse transcriptase inhibitors, and protease inhibitors) have been licensed in the U.S. Combination therapy of at least three potent drugs became the standard of care. The treatments, however, suffer from limitations such as resistance development, frequent cross-resistance within classes, long-term toxicity, difficult dosing regimens, and adverse drug-drug interactions, which all may lead to long-term treatment failure. This chapter reviews the most recent progress in the discovery and development of new antiretroviral agents. Because of an enormous effort occurring both in the academia and pharmaceutical industry, this...

General anaesthesia

The additional risks of general anaesthesia for Caesarean section are compounded in the pre-eclamptic woman by the potential for a significantly compromised airway and the hypertensive response to intubation and extubation. There may also be potential drug interactions, especially between magnesium sulphate and neuromuscular blocking agents.

Computer Assisted Decision Support Programs

Support programs have been designed to provide real-time integrated patient and institutional data including culture and susceptibility results, laboratory measures of organ function, allergy history, drug interactions, as well as cumulative or customized location-specific antibiogram data, and cost information. They provide therapeutic choices for clinicians and allow for the incorporation of clinical judgment by overriding suggestions. Autonomy is preserved while insuring that important variables in the choice of antimicrobial therapy are considered. This topic is covered in depth by Pestotnik in this book.

Historical Barriers to System Adoption

The hallmark of these systems is the capability to address patient-specific problems while accounting for institutional and individual variances. CDSS that target infectious diseases and antimicrobial drug use must adhere to the eight aforementioned design features as well as domain-specific specifications. The infectious diseases domain-specific components include organism and drug name hierarchy lexicons, intrinsic and cross-resistance rules, automated antibiograms, antibiotic selection rules, mitigating factor rules, equivalent and alternative agent rules, contraindication rules, drug interaction rules, formulary matching rules, dosing rules, duration of use rules, explicit logic and caveat statements, literature references and structured feedback tailored at the syndrome, and disease and recommendation levels. Some of these components are technically trivial, whereas others require sophisticated architectures and design.

Combination Drug Therapy

Other mechanisms of neuronal injury exist in addition to the variety that were discussed above. Because there are multiple mechanisms of injury, it is reasonable to consider that there are also multiple mechanisms of neuroprotection. Therefore, although many single agents have been demonstrated to be protective in animal models, a rational approach to therapy is to consider using multiple pharmacologic agents, which affect, or target, more than one potential mechanism or act at several steps in the ischemic cascade (54). It is possible that combined use of an excitatory amino acid antagonist plus a free-radical scavenger may provide greater neuroprotection than either agent alone. The potential synergistic effect of multiple neuroprotective agents has merit. Although some investigators have demonstrated promising results with this technique (55-57), much additional work is required in both small and large animals using various combinations of agents to determine if this approach will...

Enzyme Induction Mechanisms Assays and Relevance to Drug Discovery and Development

Introduction - Clinically important pharmacokinetic drug interactions can occur when one drug alters the metabolism of a co-medication. Such interactions can be due to enzyme inhibition or induction (1). This review focuses on enzyme induction, which is an undesirable drug interaction, since this can result in reduced efficacy of the administered or co-administered drug and can have associated safety implications (2, 3, 4). While reference is made to enzyme induction in animal species, the main focus of this review is on enzyme induction in humans.

Impact of transporters on drug disposition

In recent years there has been an explosion in the knowledge related to drug transporters and their impact on drug disposition, tissue distribution, and PK. Going forward it may be possible to evaluate species differences in the transporter activity and incorporate such information in target exposure and dose projections 72,73 . Hepatic and renal transporters play a key role in DM and distribution. Currently, P-glycoprotein (P-gp) is the most common transporter considered in designing and optimizing a new series. Understanding what hepatic and renal transporters interact with a compound can help predict its uptake, metabolism, clearance, PK profile, and potential drug-drug interactions 74 . For example, integrating transporter information for

Advances in Technologies for the Discovery and Characterization of Ion Channel Modulators Focus on Potassium Channels

Discovery of Katp openers and specific openers of another type of potassium channel, the large-conductance calcium-activated (maxi-K or BK) potassium channel (6,7). Subsequently, it has been found that many K+ channels are potentially 'druggable' targets. Small molecule modulators ( including openers or activators) have now been reported for other K+ channels, such as KCNQ channels (8). These findings have resulted in considerable effort to discover and improve techniques for high throughput screening (HTS) of K+ channels. In addition, drug interactions with certain K+ channels have resulted in undesirable side effects and the recall of approved drugs (9). These K+ channels are involved in regulation of action potential duration in the heart key among these is the hERG channel (10). Regulatory agencies now expect quantification of hERG interaction as part of the safety assessment of any clinical candidate, and pharmaceutical companies need HTS techniques to eliminate hERG and other...

Neuronal activation and energy metabolism

Another important metabolic aspect of neuronal cell function is the storage and timely release of neurotransmitters upon receipt of signals, functions which require intense membrane fatty acid synthesis and turnover. Insulin production exemplifies the importance of neuropeptides in regulating de novo fatty acid synthesis and turnover in differentiating islet beta cells as outlined later in this review. Glucagon-like peptide-l (GLP-1) is a powerful neuropeptide regulating beta cell de novo fatty acid synthesis and turnover with a primary effect of increasing glucose carbon channeling towards fatty acid synthesis, chain elongation and desaturation of the long chains. Further explorations of these unique metabolic effects of hormones acting in the brain, for example, GLP-1, improve the understanding of neuronal response and neurological and psychiatric diseases and lead to the discovery of new target sites for drug interactions with molecular mechanisms responsible for defective...

Human Immunodeficiency Virus HIV 21 HIV Diversity

Several approaches have been developed to increase the genetic barrier of drug regimens. First of all, novel inhibitors with an intrinsic high genetic barrier have been designed. The protease inhibitor darunavir (see chapter by Anderson et al., this volume) is an example of a compound with such an high intrinsic genetic barrier (De Meyer et al. 2005 Dierynck et al. 2007). Second, for some drugs, increasing the drug concentration of the inhibitor, for instance through ritonavir-boosting (see chapter by Anderson et al., this volume), can increase the genetic barrier. Finally, a very successful approach to increase the genetic barrier is to combine two or more inhibitors, which do not share resistance patterns (discussed in more detail in chapter by Hofmann and Zeuzem, this volume). Not all combination therapy regimens were shown to be sufficiently effective. For instance, it was demonstrated that a low genetic barrier could explain early virological failure to a...

Therapy And Prophylaxis

The introduction of the combination antiviral therapy regimens that contain at least one protease inhibitor with two reverse transcriptase inhibitors (see Chapter 4) has had a striking impact on AIDS lethality, with a dramatic decrease in the frequency of opportunistic infections. Though many patients experience improvements in quality of life with this therapy, there are several concerns with it. In particular, difficulties for many patients to adhere to the demanding drug dose schedules, side-effects, toxicities, development of multiresistant viruses and drug interactions. A key issue of intensive antiviral chemotherapy is to what extent the immune abnormalities induced by HIV can be reversed by efficient viral suppression and how long the beneficial effects last until eventual AIDS diagnosis. Guidelines for antiviral chemotherapy of HIV-infected adults, children and pregnant women have been published by the Department of Health and Human Services, USA and the British HIV...

Management of Opioid Adverse Effects

Successful opioid therapy requires that the benefits of analgesia clearly outweigh treatment-related adverse effects. This implies that a detailed understanding of adverse opioid effects and the strategies used to prevent and manage them are essential skills for all involved in postoperative pain management. The pathophysiological mechanisms contributing to adverse opioid effects are incompletely understood. The appearance of these effects depends on a number of factors, including patient age, extent of disease, concurrent organ dysfunction, prior opioid exposure, the route of drug administration, and the adverse drug interactions. The potential for additive side effects and serious toxicity from drug combinations must be recognized. The sedative effect of an opioid may add to that produced by numerous other centrally acting drugs, such as anxiolytics, neuroleptics and antidepressants. Likewise, drugs with anticholinergic effects probably worsen the constipatory effects of opioids. As...

Antimicrobial Therapy

Antimicrobials often fail to cure the infection. Some of the reasons they do not work are the development of bacterial resistance, achievement of insufficient tissue levels, incompatible drug interaction, and the development of an abscess. The environment of an abscess is detrimental for many antimicrobials. The abscess fibrotic capsule interferes with the penetration of antimicrobial agents, and the low pH and the presence of binding proteins or inactivating enzymes (i.e., beta-lactamases) may impair the activity of many antimicrobials. The low pH and the anaerobic environment within the abscess are especially deleterious toward the aminoglycosides (10). It should be remembered that an acidic environment, high osmolarity, and presence of an anaerobic environment can develop in an infection site without the presence of an abscess (11).

Indisetron Antiemetic [5862

Indisetron, a 5-HT3 5-HT4 antagonist, has, therefore, been launched in Japan as an anti-emetic. Since 5-HT4 is implicated in intestinal motility, dual antagonism should improve the anti-emetic effect, although this remains to be demonstrated. The diazabicycloamine portion of indisetron is prepared in four steps starting with methylamine and bromoacetaldehyde dimethylacetal. Coupling to the indazole core is accomplished via the acid chloride of lH-indazole-3-carboxylic acid. In vitro, indisetron displaced 3H GR-65630 binding to the 5-HT3 receptor in rat brain membranes in a concentration-dependent manner with a pK value of 8.77, which is comparable to the activities of other 5-HT3 antagonists such as granisetron and on-dansetron. In animal models (ferrets and dogs), indisetron reduced the number and duration of cisplatin-induced emetic episodes when administered orally at O.l-l mg kg prior to cisplatin treatment. Compared to granisetron and ondansetron, there were...

Sorafenib Anticancer [8892

Evaluating the tumor response, 2 of sorafenib-treated patients had a confirmed partial response while no patients in the placebo group experienced a partial response, suggesting that the gain in PFS for the drug-treated group is primarily a reflection of stable disease. In this Phase III study, 30 of sorafenib-treated patients reported adverse events compared to 22 for placebo with the primary complaints in both groups including rash, diarrhea, hand-foot skin reaction, fatigue, and hypertension. Most of the observed laboratory abnormalities were comparable for sorafenib and placebo with the exception of hypophosphatemia (45 versus 11 with placebo). Regarding drug-drug interactions, caution should be exercised in coadministering drugs that inhibit CYP3A4 and UGT1A9 although limited data suggests that concomitant use of ketoconazole, an inhibitor of both CYP3A4 and UGT1A9, did not lead to an increase in the mean AUC of a 50 mg dose of sorafenib. Conversely, since sorafenib has been...

Pregabalin Antiepileptic [7881

As a follow-up to its g-aminobutyric acid (GABA) agonist gabapentin, Pfizer has developed and launched pregabalin for the treatment of epilepsy and neuropathic pain. Although pregabalin is a structural analog of GABA, it does not interact with GABA-A or GABA-B receptors or influence GABA uptake. The exact mechanism of action is unclear, but pregabalin may reduce excitatory neurotransmitter release by binding to the a2-8 protein subunit of voltage-gated calcium channels. The resulting inhibition of excess neuronal activity is believed to be the basis for pregabalin's efficacy in epilepsy and neuropathic pain alleviation. Since the activity is attributed to the (S)-enantiomer alone, an efficient asymmetric synthesis is employed for commercial production. The key step is the asymmetric hydrogenation of 3-cyano-5-methyl-3-hexenoic acid using a chiral rhodium catalyst to afford an intermediate that is enriched in the (S)-enantiomer. The cyano group is ultimately reduced by routine...

Tigecycline Antibiotic [97103

No potential drug-drug interactions are anticipated since tigecycline is not extensively metabolized nor does it inhibit any of the major P450 isoforms. It is recommended, however, that prothrombin time or other suitable anticoagulation tests should be monitored if tigecycline is co-administered with warfarin. Finally, as with all antibiotics, concurrent use with oral contraceptives may render the oral contraceptives less effective.

Pharmacological Management

Leukotrienes are chemical mediators that are synthesized via the arachidonic acid pathway and have a wide range of biological activities, including airway edema, mucus secretion, eosinophil migration into the airways, and smooth muscle bronchoconstriction. Leukotriene modifiers are daily, oral, long-term controller medications that are designed to counteract these biological effects in the airways. There are two classes of leukotriene modifiers, defined based on their site of action cysteinyl leukotriene receptor antagonist (e.g., montelukast and zafirlukast) and leukotriene synthesis inhibitor (e.g., zileuton). Montelukast is dosed once daily at night as 4-mg granules or a 4-mg chewable tablet for children aged 12 mo to 5 yr as a 5-mg chewable tablet for children aged 6-14 yr and as a 10-mg tablet for adolescents older than 15 yr. Zafirlukast has been approved for use in children older than 7 yr of age and is dosed twice daily. Zileuton, a 5-lipoxygenase...

Systemic Glucocorticoid Therapy Pharmacokinetics

Once absorbed, GCs bind to serum proteins with prednisolone binding to transcortin, albumin, and a1-acid glycoprotein, while methylprednisolone binds primarily to albumin. GCs are metabolized in the liver into inactive compounds. The rate of metabolism or clearance of GCs can be altered by drug interactions and disease states. Hyperthyroid patients require higher GC doses because of enhanced clearance and metabolism. With hypothyroid patients, slowed elimination is a concern however, this has not been well studied. Cystic fibrosis results in enhanced clearance of prednisolone. GC elimination may also be altered by numerous concomitant medications (Table 2). Drug interactions may result in either reduced or enhanced clearance and consequently an increased risk for adverse effects or a diminished therapeutic response, respectively. The anticonvulsants phenytoin, phenobarbital, and carbamazepine cause an increased rate of elimination for dexamethasone, prednisolone, and...

Assays To Monitor For Enzyme Induction In Vitro

The technology of cDNA microarrays allows the investigator to monitor for changes of gene expression on a relatively massive scale typically 25 - 50 K oligonucleotide probes or cDNA fragments at one time (50, 51). Such experiments are likely to be undertaken in the context of attempting to understand a drug-drug interaction or a specific toxicology. In the context of a drug-drug interaction, once potential associations between selected gene sets and proteins involved in the disposition of the co-administered drugs have been identified, then assays to quantify induction of specific genes is undertaken and will typically be performed using a technique such as quantitative RT-PCR (e.g. TaqMan, Applied Biosystems).

Prototypic Victims Of Enzyme Induction

Since the degree and duration of suppression of HIV replication is significantly correlated with plasma concentrations, this co-medication has been contraindicated because of the potential for drug interactions which could result in clinically significant adverse events (93).

Toxicity Definitions [54

Drug-drug interaction is the fact that a pharmaceutical or dietary agent affects the metabolism, clearance, or safety of another molecule. Off-target activities can be beneficial or detrimental and involve interactions with a target that was not expected. Antitargets are targets that are detrimental to the progression of a compound. Off-target toxicity such as binding to CYP or hERG is related to pharmacophore-induced toxicity. Drug-drug interaction can occur when patients receive several medications, at the same time potentially leading to a competition for the same metabolizing enzyme such as CYP3A4. Consumption of grapefruit or grapefruit juice inhibits the metabolism of statins, which increases the risk of dose-related adverse effects including myopathy rhabdomyolysis. Furano-coumarins in grapefruit inhibit the cytochrome P450 enzyme CYP3A4, which is involved in the metabolism of most statins.

Clinically Studied Inhibitors 31 5LO and FLAP inhibitors

Reduce Corneum

Zileuton (1) is the only marketed 5-LO inhibitor and is approved for the treatment of asthma 44 . The treatment of mild asthmatics with zileuton (600 mg qid, 2 weeks) resulted in a 96 increase in plasma thromboxane B2 from baseline levels and a corresponding 62 increase in spontaneous platelet aggregation, suggesting a shunting of arachidonic acid metabolism to the cyclooxygenase pathway 45 . In a small clinical trial, zileuton provided a magnitude of prophylaxis in exercise-induced asthma (as measured by FEV1) equivalent in magnitude but considerably shorter in duration than salmeterol, montelukast and zafirlukast 46 . Zileuton inhibited bronchoalveolar lavage (BAL) fluid eosinophil counts by 68 upon antigen challenge in a sub-population of allergic asthmatics who exhibited a significant increase in BAL leukotrienes and inflammatory cytokines, but not in those patients where leukotriene levels were unchanged upon antigen challenge 47 . Zileuton provided minimal efficacy 48 or no...

Kathleen Steger Craven

Identify the site of infection, pathogen, and the antibiotic sensitivity pattern Evaluate host factors age, pregnancy, drug allergies, renal, hepatic, and immune status Assess antibiotic dose, route, synergy, antagonism, pharmacokinetics, drug interactions, and adverse events

Therapy

In addition to selecting the most appropriate antimicrobial agents for the treatment of serious infections, clinicians must insure that antibiotic administration follows certain minimal requirements. These minimal requirements include proper dosing, interval administration, optimal duration of treatment, monitoring of drug levels when appropriate, and avoidance of unwanted drug interactions (30). Lack of adherence to these minimal requirements may result in unforeseen administration of suboptimal or excessive antibiotic tissue concentrations, which increases the likelihood for antibioticresistance, patient toxicity, and lack of effectiveness, despite selecting an appropriate antimicrobial regimen (31).

Conclusions

Accordingly, many lessons have been learned and extensive knowledge has been built from these failures. Newer protease and polymerase inhibitors have emerged as potent, specifically targeted therapies against HCV infection, but will need to be used in combination with interferon and probably ribavirin to minimize resistance and increase the sustained virological response. Their introduction into practice will add complexity to the treatment of HCV infection because of the potential development of resistance and drug-drug interactions with other medications. The proper timing for the introduction of these drugs relative to interferon and ribavirin therapy are factors that will need to be individualized according to patient's needs and viral kinetics, requiring specialized infectious disease physicians and gastroenterologists with intimate knowledge of how these compounds act in inhibiting viral replication to maximize their efficacy. In 2007, it became clear that add-on therapy to...

Other interventions

The practice of using combination therapy is an extension of effective antituberculous and antihuman immunodeficiency virus therapy, that is, the administration of two or more antibiotics reduces the likelihood of the emergence of resistant strains. However, while some investigators outside of the setting of tuberculosis have demonstrated a trend towards less frequent emergence of resistance in patients given combinations of drugs, and others have reported higher clinical and bacteriological cure rates (the latter, in principle, helping to reduce transmission of antibiotic-resistant strains), most of those who have compared the efficacy of combination therapy with that of monotherapy (usually a p-lactam aminoglycoside combination and a p-lactam alone respectively) have failed to show that the former is superior to the latter in terms of preventing the emergence of resistant strains. The combination approach also leads to considerable hidden costs and may be associated with drug...

Mechanisms

Drug interactions can generally be classified as either pharmacokinetic or pharmacodynamic. Pharmacokinetic interactions result from processes that lead to a change in the disposition of one or more drugs and result in a change in clinical response. The most common form of a pharmacokinetic interaction occurs when one drug induces or inhibits the metabolism and or elimination of another, and the steady-state concentration of a drug is lowered or raised. Alcohol can affect many medications through competition for the same microsomal oxidase system, involved in the metabolism of various drugs 22 , Pharmacodynamic interactions result when drugs have separate actions that are either augmented or antagonized when the drugs are used together. Alcohol appears to enhance aspirin-induced gastric mucosal damage and aspirin-induced prolongation of the bleeding time. Alcohol-drug interaction varies greatly in the range between social drinkers and heavy chronic drinkers. This phenomenon is also...

Biotransformation

Tegaserod inhibited CYP1A2 and CYP2D6 with Ki values of 0.84 and 0.85 mM, respectively. These Ki values are approximately 140-fold greater than the maximal plasma concentrations following administration of the recommended clinical dose of tegaserod (i.e., 6mg). The metabolite 7 (R Gluc), the main circulating metabolite, did not demonstrate any inhibitory potential toward cytochrome P450 enzymes in vitro. The data indicate that cytochrome P450-mediated metabolism plays an insignificant role in the elimination of tegaserod. No clinically relevant drug-drug interactions with tegaserod have been identified.

Integrase Inhibitors

A second clinical development compound named GS-9137 JTK-313 (elvite-gravir) belongs to the structurally related class of 4-oxoquinoline integrase inhibitors (Satoh et al. 2005 Shimura et al. 2008). Elvitegravir, which needs to be boosted with ritonavir, was recently shown to be as effective as a boosted protease inhibitor regimen at cutting viral load in heavily pre-treated HIV-positive patients, according to phase II results. The drug-drug interaction studies are already completed and showed no interactions. Among the observed IN mutations, T66I and E92Q substitutions mainly contributed to elvitegravir resistance. Some resistance mutations conferred reduced in vitro-susceptibility to other IN inhibitors, including raltegravir, suggesting that a common mechanism is involved in resistance and potential cross-resistance. Based on the currently still limited data set, resistance to INSTI appears to develop faster than with protease inhibitors, but not quite as fast as with some of the...

Patient Safety

Life-threatening arrhythmias (e.g., macrolides, ketolides, azole antifungals, fluoroquinolones), metabolic liability in the form of cytochrome P450 3A4 inhibition leading to serious drug interactions that may result in rhabdomyolysis or other serious adverse events (e.g., azoles, macrolides, ketolides), Stevens-Johnson syndrome (e.g., trimethaprim sulfamethoxazole), nephrotoxicity (e.g., aminoglycosides, amphotericin b), and life-threatening hypersensitivity reactions (e.g., beta-lactams) (5-7) all antimicrobials are associated with CDI (8). Disturbingly, the rate and severity of CDI is increasing and the emergence of a new toxin gene variant strain of C. difficile appears to be responsible for epidemics (9,42-44). A recent study showed that one in five patients admitted to the intensive care unit (ICU) with CDI were receiving antimicrobials without any evidence of infection (45). Unnecessary antimicrobial use has been shown to be responsible for some of these life-threatening adverse...

Quinolones

Gatifloxacin, 5, is another methoxyfluoroquinolone that is actually furthest along in clinical development for tuberculosis treatment. Like moxifloxacin, it is used to treat a variety of bacterial infections, has been used globally for many years, and has no interactions with ARV drugs. Gatifloxacin is a structurally similar to moxifloxacin and likely to have the same mechanism of action against bacterial DNA gyrase. This means cross-resistance is possible between these two drugs. Gati-floxacin's toxicity and drug-drug interaction profile is similar to moxifloxacin's.

Allylamines

Allylamines are antifungal agents targeted to squalene epoxidase, an enzyme necessary for ergosterol biosynthesis. Naftifine (12) was the first allylamine agent introduced in therapy in the early 1980s as 1 cream or gel for topical use. It has fungicidal activity against dermatophytes and fungistatic activity against Candida species. Its sensitizing capacity seems to be greater than in the commonly used azoles 58 . Terbinafine (13) was approved in 1990s in the UK and USA for the treatment of onychomycosis. It is the most frequently prescribed oral antifungal agent in North America, for onychomycosis. Eighteen randomized controlled trials have shown terbinafine to be highly effective with mycological cure of 76 . 13 has an established safety profile and very low occurrence of drug interactions 59 . An improved antifungal composition for topical application to the skin and nails has been developed for allylamines (naftifine or terbinafine) 60 . A formulation to provide a product having...

Other Ion Channels

Dmg Action at Ion Channels and The Impact of Molecular Biology - Two major classes of drugs acting at ion channels have been distinguished according to their sites of action. Drugs acting at classically defined receptor sites of ligand-gated channels and for which physiologically based llgands exist fall within the first category. The second category includes drugs which interact at sites associated with the channel proper physiologically equivalent ligands likely do not exist (but see 118). This second class of agents interacts at sites associated with the permeation and gating processes of the channel and their activity both determines and is determined by the functional state of the ligand- or voltage-gated channel - resting, open or inactivated. Formal treatments of these drug-channel interactions are available in the modulated- and guarded-receptor mechanisms according to which the affinity or the access respectively of the receptor varies according to channel state (137,138)....

Impact on liver

An important function of the liver is the metabolism of xenobiotics. Both Pgp and cytochrome P450 3A enzyme (CYP3A) are expressed in hepatocytes and their substrate specificities overlap considerably unlike CYP2C another isoform with more limited substrate specificity for these drugs. Expression of CYP3A and Pgp in the liver and the intestine are co-ordinately regulated by the pregnane (steroid) xenobiotic receptor to eliminate xenobiotics, i.e., Pgp effluxes the drug out of the cell while CYP3A further removes the substance by metabolism within the cell 106,107 . Thus, therapeutics that are inhibitors or substrates of both could be expected to lead to drug-drug interactions, resulting in increased levels of the co-administered drugs circulating in plasma.

Absorption

Clovir) or as high as almost 100 per cent (doxycycline). There are four main factors that affect gastrointestinal (GI) absorption. These are GI motility and blood flow, GI pH, particle size, and the formulation of the drug and various physiochemical factors (e.g. drug interactions). The fraction of the drug that is absorbed into the systemic circulation and is available at its site of action is known as the bioavailability.

Elimination

Drug metabolism occurs primarily in the liver, by the cytochrome P450 (CYP450) enzyme system. When a drug is absorbed through the GI tract, it often undergoes first-pass metabolism. This is where the absorbed drug passes through the liver before being distributed throughout the rest of the body and whilst in the liver, it is metabolised. This process can either activate a drug, as is the case with valaciclovir, or form an inactive metabolite, as with the opioid analgesics. Some metabolites may be toxic and lead to adverse effects. If a drug is heavily metabolised in the liver, it can lead to poor oral bioavailablity, resulting in higher doses being required. Some drugs can inhibit or induce CYP450 enzymes, leading to drug-drug interactions. For example, ritonavir is a potent inhibitor of cytochrome isoenzyme 3A4 thus it can greatly affect the bioavail-ability of other drugs, such as sildenafil.

Pregnane X Receptor

2.2 Biological models to assess PXR-mediated drug interactions The assessment of CYP induction and drug-drug interaction potential is most often conducted with primary cultures of human hepatocytes. This cell-based model has the ability to respond to a variety of CYP inducers and isoforms, such as CYP1A, 2B, and 3A due to the presence and function of multiple nuclear hormone receptor systems and transcription factors. Although the primary human hepatocyte assay replicates a broad array of induction responses, it suffers from limited availability, random access, and low-moderate throughput. Newer cell-based models using immortalized hepatocytes have demonstrated the ability to respond to CYP-isoform induction similar to primary human hepatocytes. The most common immortalized hepatocyte cell lines reported to date are the Fa2N-4 and HepaRG cell lines 17,18 . A drawback of the immortalized hepatocyte model is the inability to replicate all CYP induction pathways similar to primary human...

Interactions

Erythromycin was the first macrolide to be developed, and has been a mainstay of treatment for many infections for the last forty years. More recently clarithromycin and azithromycin have become available in the UK. Their main benefits are that they offer easier dosing, are more tolerable to take and do not have as many drug interactions.

Possession Of Skill

Emergence of chemical genomics 67,68 has brought additional dimensions to the information available to chemists, requiring further changes in the optimization philosophy. Traditionally, the structure-centric thinking has been natural for medicinal chemists trying to hit a specific molecular target. Most of the properties requiring optimization could be directly or indirectly related to the structure, and after all, it is the structure that chemists have control over and can change. In chemogenomics space, drug interactions with all components of the biological system are taken into account in order to understand the mechanism of drug's

Ch3so3h

And in combination with data from in vitro inhibition of the CYP isozymes, lisdexamfetamine should possess a low potential for drug-drug interactions. Approximately 96 of the radioactivity was recovered in the urine with only 0.3 found in the feces. Regarding the efficacy of lisdexamfetamine, a doubleblind, randomized, placebo-controlled study was conducted in 290 children aged 6-12 years who met DSM-IV criteria for ADHD. Over the course of 4 weeks, patients were randomized to a fixed dose of lisdexamfetamine (30, 50, or 70 mg) or placebo once daily in the morning. Employing the ADHD rating scale, significant improvements in patient behavior were observed at endpoint for all doses compared to placebo. While the mean effects were similar for all doses, the 70-mg dose was superior to the lower two doses. Furthermore, as assessed by the Connor's Parent rating scale, the effects were maintained throughout the day with culmination at the 6 p.m. evaluation. The most common adverse events,...

Alglucosidase Alfa

And launched as the ERT for Pompe disease. As a recombinant human enzyme, it is produced by transfected CHO cells as a 110-kDa precursor that targets lysosomes via the mannose-6-phosphate (M6P) receptor. Following endocytosis, the enzyme is transformed to its mature 76-kDa form that restores glycogen processing and reverses accumulation. The dosing regimen of alglucosidase alfa is 20mg kg infused over a period of 4h every two weeks. The pharmaco-kinetic properties are dose-proportional between 20 and 40 mg kg. Following a single infusion of 20mg kg, a Cmax of 162 + 31 mg mL, a clearance of 25 + 4mL h kg, a volume of distribution of 96 + 16L, and a half-life of 2.3 +0.4 h are observed. Two separate clinical trials evaluated the safety and efficacy of alglucosidase alfa. The first study restricted inclusion to patients less than seven months of age with demonstrated cardiac hypertrophy but no ventilatory support at first infusion. Efficacy was determined by decreased mortality and...

Lubiprostone

Chronic constipation is an affliction affecting 4-5 million Americans alone. When no specific cause is identified, it is classified as idiopathic. Dietary and lifestyle modifications are the first-line conventional approaches followed by the administration of laxatives. Unfortunately, chronic idiopathic constipation is frequently refractory to traditional therapy thus, the need for novel agents exists. Lubiprostone is a bicyclic fatty acid with a novel mechanism of action. Without affecting sodium and potassium ion concentrations, lubiprostone activates intestinal chloride ion channels, thereby, increasing intestinal water secretion and intestinal fluid chloride ion concentration. In basolateral membrane-permeabilized T84 gastrointestinal epithelial cells under chloride gradient conditions, lubiprostone concentration-dependently increased short-circuit current with an EC5o of approximately 20 nM. Lubiprostone may be prepared in 10 steps starting from the commercially available Corey's...

The Kidneys

Since tubular secretion is an active process, it may be subject to saturation and drug interactions. The clearance of penicillin G 41 in normal individuals occurs predominantly via the kidney. It is extremely rapid and is the result of glomerular filtration and active tubular transport, with the latter route predominating 42 . Urinary recovery is reported to be 58-85 of the administered dose. Coadminis-tration of probenecid, a drug normally administered to treat gout, competes with the same acid transporter and blocks the renal tubular secretion of penicillin resulting in slower rate of excretion of penicillin G and increased serum concentrations. It has been shown that probenecid also alters the distribution of penicillins to various