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Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception toprol xl 50 mg fast delivery. Evaluation of the role of multidrug resistance-associated protein (Mrp) 3 and Mrp4 in hepatic basolateral excretion of sulfate and glucuronide metabolites of acetaminophen generic toprol xl 100mg without a prescription, 4-methylumbelliferone purchase toprol xl 100mg on-line, and harmol in Abcc3-/- and Abcc4-/- mice. Multidrug resistance-associated protein 4 is involved in the urinary excretion of hydrochlorothiazide and furosemide. Dominant-negative inhibition of breast cancer resistance protein as drug efflux pump through the inhibition of S-S dependent homodimerization. Subcellular localization and distri- bution of the breast cancer resistance protein transporter in normal human tissues. The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Investigation of efflux transport of dehy- droepiandrosterone sulfate and mitoxantrone at the mouse blood-brain barrier: Drug-Drug Interactions Involving the Membrane Transport Process 197 a minor role of breast cancer resistance protein. Breast cancer resistance protein (Bcrp/abcg2) is a major determinant of sulfasalazine absorption and elimination in the mouse. The breast cancer resistance protein (Bcrp1/Abcg2) restricts exposure to the dietary carcinogen 2-amino-1- methyl-6-phenylimidazo[4,5-b]pyridine. Role of breast cancer resistance protein (Bcrp1/Abcg2) in the extrusion of glucuronide and sulfate conjugates from enter- ocytes to intestinal lumen. Mechanism of the pharmacokinetic inter- action between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions. The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implica- tions for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients. Impaired renal excretion of 6-hydroxy-5,7- dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (e3040) sulfate in breast cancer resistance protein (bcrp1/abcg2) knockout mice. Interactions in the renal and biliary elimination of digoxin: stereoselective difference between quinine and quinidine. Digoxin-verapamil interaction: reduction of biliary but not renal digoxin clearance in humans. Effects of verapamil, diltiazem, and nifedipine on plasma levels and renal excretion of digitoxin. Characterization of the uptake of rocuronium and digoxin in human hepatocytes: carrier specificity and comparison with in vivo data. Stereoselective inhibition by the diastereomers quinidine and quinine of uptake of cardiac glycosides into isolated rat hepatocytes. Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney. Inhibition of P-glycoprotein-mediated drug transport: a unifying mechanism to explain the interaction between digoxin and quinidine [see comments]. Role of P-glycoprotein as a secretory mechanism in quinidine absorption from rat small intestine. Contribution of oatp (organic anion- transporting polypeptide) family transporters to the hepatic uptake of fexofenadine in humans. Inhibition of oat3-mediated renal uptake as a mechanism for drug-drug interaction between fexofenadine and probenecid. P-glycoprotein plays a major role in the efflux of fexofenadine in the small intestine and blood-brain barrier, but only a limited role in its biliary excretion. Lack of dose-dependent effects of itraco- nazole on the pharmacokinetic interaction with fexofenadine. The effect of short- and long-term administration of verapamil on the disposition of cytochrome P450 3A and P-glycoprotein substrates. Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery. Effect of grapefruit juice volume on the reduction of fexofenadine bioavailability: possible role of organic anion transporting poly- peptides. Evaluation of peppermint oil and ascorbyl palmitate as inhibitors of cytochrome P4503A4 activity in vitro and in vivo. Grapefruit juice reduces the oral bioavail- ability of fexofenadine but not desloratadine. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients. Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A. Effects of organic anion transporting polypeptide 1B1 haplotype on pharmacokinetics of pravastatin, valsartan, and temocapril. Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Multiple interactions of cimetidine and pro- benecid with valaciclovir and its metabolite acyclovir. Effects of probenecid on the pharma- cokinetics and elimination of acyclovir in humans. Pharmacokinetics of intravenously admin- istered cefmetazole and cefoxitin and effects of probenecid on cefmetazole elimi- nation. Pharmacokinetic interactions of cefprozil with food, propantheline, metoclopramide, and probenecid in healthy volunteers. Comparison of dose doubling with pro- benecid for sustaining serum cefuroxime levels. Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients. Effect of probenecid on the distribution and elimination of ciprofloxacin in humans. The inhibitory effect of probenecid on renal excretion of famotidine in young, healthy volunteers. Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacoki- netics. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies.

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Papular dermatitis of pregnancy Papular dermatitis is very rare (< 1 percent) and is limited to pregnancy (Spangler et al buy generic toprol xl 50mg on line. Recurrence in subsequent pregnancies is known and it is associated with an increased frequency of pregnancy loss purchase 50 mg toprol xl visa. Papular dermatitis is characterized by small cheap 100 mg toprol xl amex, ery- thematous papules that usually involve all of the skin. High-dose systemic steroids, such as prednisone, are used to treat this dermatitis. The rash usually starts on the abdomen and spreads to the extremities, with facial spar- ing (Alcalay et al. Treatment consists primarily of topical steroids, although oral prednisone may be required for severe cases. Herpes gestationis Another rare dermatologic disease of unknown etiology is herpes gestationis. Contrary to what might be implied from the name, herpes gestationis is not a viral infection but an autoimmune disease. Erythematous papules and large, tense bullae, usually on the abdomen and extremities characterize this disease. Some investigators have reported that an increased frequency of pregnancy loss is associated with this condition in some studies (Lawley et al. Minor malformations characteristic of the retinoic acid embryopathy and other birth outcomes in children of women exposed to topical tretinoin during early pregnancy. Quinine overdoses are associated with an attempt to induce abortion over 90 percent of the time, but most other over- doses of the drug are also attempted suicide. Successful suicide during pregnancy occurs among one in every 88 000–400 000 live births (Table 14. Among 162 pregnant women who presented with an indication of poisoning, 86 percent were overdoses (78 percent suicide attempts and 8 percent induced abortion attempts (Czeizel et al. Maternal death associated with suicide gestures occurs in approx- imately 1 percent of gravid women and more than 95 percent of suicide gestures involve ingestion of a combination of drugs (Rayburn et al. In New York city, suicide was identified as the cause of 13 percent of maternal deaths (Dannenberg et al. Use of drug megadoses that are potentially lethal in pregnant women involves two patients: mother and fetus. Assessment of the pregnant woman who has potentially toxic (megadoses) amounts of drugs must begin with laboratory evaluation of the sub- stance(s) ingested (i. In Finland in the late 1990s, the pattern was similar with the top three substances used in suicide attempts being benzodiazepines, analgesics, and psychotropics (antipsychotics/antidepressants) (Table 14. The patient will usually recall approximately how much she took of which substances. If family members or signifi- cant others are present, they may be able to provide corroborative information, such as presence of medicine bottles, known prescriptions, etc. Toxicology screens with samples every hour or two (for serial evaluation) should be ordered as soon as possible to deter- mine exactly what substances are involved and whether or not levels are rising or falling, or toxic or approaching toxic. However, a generalized treatment plan may be under- taken before toxicology results are available. If the patient still has a gag reflex, orogastric lavage with normal saline should be begun. Following lavage, administer an activated charcoal slurry regimen (the nonspecific anti- dote regimen). Whole-bowel irrigation has been used successfully in some cases of drug overdose and has a clinically significant effect on lowering serum drug levels. Evaluation of the fetal heart rate should begin as soon as possible, especially in cases in which the fetus is viable. When toxico- logical screens are available to document what drugs and/or chemicals have been ingested and may be in potentially toxic doses, information on antidote regimens for given substances may be obtained from several sources. A general plan for the management of the drug-overdosed gravida includes sta- bilization, monitoring, supportive care, and toxicology screens (Box 14. Specific management plans should be formulated in consultation with the regional certi- fied poison control center, which is available 24 h per day, and handles international calls. Maternal and fetal sequelae for specific antidote regimens are provided below for the 14 drug classes most frequently taken in suicide gestures by pregnant women (Table 14. Sixty-nine cases of acetaminophen overdose in suicide gestures during pregnancy have been reported (Table 14. The salient clini- cal features of these cases are that early administration of the specific antidote (N-acetyl- cysteine) can prevent maternal hepatotoxicity if the antidote is tolerated and fetal hepa- totoxicity is uncommon. In a case series of 60 acetaminophen overdoses during pregnancy from a multicenter study in which 24 mothers had serum acetaminophen levels in the toxic range (Riggs et al. The distribution of these cases across trimesters of pregnancy is given in Table 14. No evidence of teratogenicity of acetylcysteine (or paracetan) was found in one study (Janes and Routledge, 1992). However, the investiga- tors concluded that delays in the administration of the antidotal treatment might increase the risk of spontaneous abortions, fetal death, and serious maternal liver damage. Of the available antidote regimens, N-acetylcysteine is the most effective (Table 14. Acetaminophen overdose during pregnancy should be treated with either oral or intra- venous N-acetylcysteine without delay according to the protocols provided in the man- ufacturer’s insert. Delay in administering the antidote increases the risk of maternal and fetal toxicity, hepatorenal failure, and death (Kozer and Koren, 2001). Measured levels of acetaminophen at time postingestion can broadly predict whether or not hepatotoxicity should be expected (Fig. Acetaminophen’s metabolic pathways (sulfation and glucuronidation) become saturated, causing an increased metabolic load to cytochrome P-450 oxidases. The P-450 system oxidizes the drug and produces a highly reactive intracellular metabolite that complexes with hepatic glutathione. The P-450-produced metabolite binds to hepatocellular macromolecules when glutathione is depleted and hepatotoxicity ensues (Andrews et al. Fetal P-450 has 10 per- cent or less of adult activity and produces negligible amounts of the toxic metabolite.

The population average sleep duration is 7 to 8 hours and people sleeping far more or less than this average are called long and short sleepers buy genuine toprol xl, respectively (Ferrara and De Gennaro buy toprol xl 25 mg on-line, 2001) purchase toprol xl 25 mg. From a population perspective short sleep is more common than long sleep (Luyster et al. Sleep quality and sleep duration are separate even if partly overlapping and correlated characteristics of sleep (Buysse et al. Sleep quality issues are often referred to as insomnia symptoms or insomnia-like symptoms that include difficulties initiating or maintaining sleep, non-restorative sleep or global dissatisfaction with sleep (Ohayon, 2002). Depending on the way to operationalize sleep quality the average population prevalence of poor or disturbed sleep vary between 6% and 30% (Ohayon, 2002). In Finland, epidemiological data from 1972 to 2013 indicate a continuing considerable increase in occasional insomnia-like symptoms in the working-aged population (Kronholm et al. Sleep related problems more often occur in women than in men, and are also more common along with increasing age (Barclay and Gregory, 2013; Kronholm et al. There are also some questionnaires that are being used in population studies to assess both the duration and quality of sleep, as for example the Pittsburgh Sleep Quality 26 Index (Buysse et al. It is also possible to assess times for going to bed and getting up from bed (Kronholm et al. Self-reported measures of sleep in population-based research can be held sufficiently valid when compared to polysomnography (Zinkhan et al. The golden standard method to measure sleep is the polysomnography that simultaneously measures the electrical activity of the brain, heart, and muscles, movements of the eye and respiratory actions while the person is at sleep (Knutson, 2010; Krystal and Edinger, 2008). In large scale studies polysomnography is an inconvenient method due to its practical and economical requirements. Developments in accelerometer technology have enabled the increasing use of accelerometry as a means to assess sleep in large scale settings (Ferrie et al. The agreement between wrist worn accelerometers with polysomnography has shown to be superior to that of hip placement with polysomnography (Zinkhan et al. The validity of wrist worn accelerometers in sleep assessment seem to be accepted in the literature relative to polysomnography, at least in terms of total sleep time and sleep efficiency (Girschik et al. In middle- aged the day-to-day variation in actigraphy is high, whereas the year-to-year variation is not significant, indicating that one multiple day collection will likely be reflecting a true habitual average for that person (Knutson et al. According to differences in the timing of sleep and wake, and differences in preferences for performing physical and mental tasks, different chronotypes can be identified (Adan et al. Those with early bed times and morning awakenings and high morning alertness are called morning types and those with peak alertness later in the afternoon with a preference for later bed times are called evening types (Adan et al. Approximately 60% of people do not belong to either of these two extreme chronotypes, but rather have an intermediate type (Adan et al. The chronotype is affected by individual and environmental factors such as age, gender, daylight and activity (Adan et al. There is some evidence from cross-sectional data that chronotype shifts with age, with young children being morning type and a pronounced tendency to evening type during adolescence where after morning preference again becomes more prevalent with increasing age (Adan et al. Women experience the maximum in eveningness at an earlier age than men, and women also have a shorter intrinsic circadian period than men (Adan et al. However, a different distribution of morning type and evening type by gender is not altogether supported by the literature (Paine et al. In Finland the population prevalence of evening types among men seem to have increased from the 1980’s to the 2000’s (Broms et al. In a large sample of mainly central European participants a significant change in the average chronotype to more evening types from 2002 to 2010 was observed (Roenneberg et al. The risk for social jetlag is often higher in evening types because they are more often forced to follow an earlier social rhythm compared to their intrinsic circadian phase (Roenneberg et al. Different self-report tools have been created to provide non- invasive, more practical ways to assess chronotypes, particularly in large- scale studies (Di Milia et al. Since then several other questionnaires and ways to assess this trait have been developed (Adan et al. One discussed limitation with self-report questionnaires of chronotype is the cutoff values that are being used to distinguish between different chronotypes (Di Milia et al. More evidence is needed regarding the modifying effect of factors such as light exposure, body composition and diet (Chennaoui et al. Also in Finland, adults with mid-range sleep are more often physically active than short or long sleepers (Kronholm et al. Furthermore, physically active adults less often report having self-estimated insufficient sleep than physically inactive adults (Hublin et al. However, in highly active groups such as athletes, the actual sleep duration is often lower than the mid-range defined in a general population (Lastella et al. Recent findings in physically active preindustrialized societies suggest that these people have shorter habitual sleep duration than populations from less physically active, industrialized societies (Yetish et al. In many cross-sectional epidemiological studies have associations between physical inactivity and more sleep complaints or poorer sleep quality been reported (Kim et al. Particularly in older persons, sleep quality is often reported being not so good among the physically inactive than the physically active persons (Brassington and Hicks, 1995; Foley et al. Similarly has an extended time in bed found to be related with a future poor physical functioning in a sample of older (≥65 years) adults (Stenholm et al. A recent study including a multinational sample of European adults, show that even if long sleepers spend 3. There is some support from intervention studies that exercise is an as effective treatment for poor sleep or sleep disturbances as hypnotic drugs in middle-aged and older persons with chronic sleep disturbances (Passos et al. Previous sleep habits seem to impact the magnitude of the effect (Chennaoui et al. Sedentary behaviors can cause alterations in lipid and glucose uptake and some evidence also exist of vascular changes as a consequence of sedentary behavior (Dempsey et al. However, this relationship is partly mediated by eating behaviors (Heinonen et al. However, so far the evidence regarding the healthiness of breaking up prolonged sitting suffers from many shortcomings (Chastin et al. Short sleep duration has been associated with increased coronary heart disease and stroke mortality (Cappuccio et al. Men and women with a high Framingham Risk Score have been reported more likely to have short sleep (Matthews et al.

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This integrated approach should be based on good under- standing and utilization of the primary question discount toprol xl online, our willingness to rely on in vitro and in vivo pharmacokinetic and pharmacodynamic data 100 mg toprol xl mastercard, and our understanding of the degree to which an observed change in substrate mea- sures caused by an interacting drug is or is not clinically important buy toprol xl 100mg without a prescription. In recent years, understanding the metabolic disposition and identifying the potential for metabolic drug-drug interactions such as inhibition and induction of enzymes has become an integral part of the drug development process. Improved understanding of the mechanistic basis of metabolic drug-drug interactions has enabled standardized and focused approaches to evaluating interactions with generalizable conclusions. The recently published guidance (10) reflects the agency’s current view in the evaluation of drug- drug interactions during drug development and includes the following prin- ciples. Future efforts in assessing, managing, and communicating the risks of drug-drug interactions may focus on (1) improved uses of in vitro tests to evaluate transporter-based interactions, (2) better use of in vitro data as a surrogate for in vivo findings, e. Lesko, Patrick Marroum, Srikanth Nallani, Janet Norden, Wei Qiu, Atik Rahman, Kellie Reynolds, Soloman Sobel, Toni Stifano, John Strong, Robert Temple, Kenneth Thummel, Douglas C. Drug interaction studies—study design, data analysis and implications for dosing and labeling. Inhibition of P-glycoprotein-mediated drug transport: a unifying mechanism to explain the interaction between digoxin and quinidine. Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Life-threatening interaction of mibefradil and beta-blockers with dihydropyridine calcium channel blockers. Draft guidance for industry: Drug-Drug interactions— study design, data analysis and implications for dosing and labeling. Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant admin- istrations of erythromycin. Assessment of single- and multiple-dose interactions between ritonavir and saquinavir. Drug-drug, drug-dietary supplement, and drug- citrus fruit and other food interactions—labeling implications. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. The safety of newly approved medicines: do recent market removals mean there is a problem? What have we learned from the recent market withdrawal of terfenadine and mibefradil? Presentation at the 101st Annual Meeting of American Society of Clinical Pharmacology and Therapeutics, March 15–17, 2000, Beverly Hills, California. Guidance for Industry: Exposure-Response Rela- tionship, Study Design, Data Analysis, and Regulatory Applications, April 2003 (posted May 2003). Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the ‘‘Cocktail’’ Approach. Nelson Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington, U. Most adverse drug reactions occur in only a small percentage of patients and are termed idiosyncratic, and many of these reactions are caused by reactive metabolites formed from drugs (2–4). Reactions of reactive metabolites with tissue macromolecules can lead to direct or intrinsic toxic effects and/or cause toxicity by forming haptens that lead to immunotoxic effects. Although new animal models are being developed that provide insights into factors that play a role in these idiosyncratic toxicities (5–7), no generally useful models are yet available. In some cases a new drug may be the precipitator or perpetrator of toxicity of another drug by altering its metabolism and/or disposition, or the new drug may be the object or victim of altered metabolism and/or disposition caused by a drug already on the market. In many instances, the object or victim is a drug with a narrow therapeutic index, window, or ratio (for a discussion, see Ref. Several definitions have been applied to this terminology, including the qual- itatively simple one of a drug ‘‘for which relatively small changes in systemic 687 688 Nelson concentrations lead to marked changes in pharmacodynamic response’’ (9). This chapter will focus on those metabolic drug-drug interactions that have led or can lead to serious toxicological consequences in humans. Most of the chapter will describe examples of metabolic drug-drug interactions that have caused serious toxicities. As discussed in chapter 15, the majority of drug-drug inter- actions of clinical significance have occurred through interactions at the level of cytochromes P450. Since substantial information is now either available or readily obtainable about induction and inhibition of these enzymes as well as the kinetic parameters associated with the metabolism of drugs and other probe substrates, many metabolic drug-drug interactions can be predicted prior to clinical trials. However, because the situation in vivo is complicated by a variety of genetic and environmental factors that affect drug absorption, distribution, and metabolism and because the physiological response to a toxic insult may vary from one individual to another, it is often difficult to predict that a particular drug-drug interaction will lead to a toxic insult. Nonetheless, the results of preclinical studies should provide the basis for more informed planning of clinical studies. Warfarin Because of its narrow therapeutic window and extensive oxidation to inactive metabolites by cytochromes P450, warfarin (and the closely related drug ace- nocoumarol) is subject to many metabolic drug-drug interactions that can place patients at severe risk of either hyper- or hypocoagulability. Several inducers of cytochromes P450, including rifampin, several barbi- turates, aminoglutethimide, primidone, phenytoin, and carbamazepine increase requirements for warfarin dosing, although mechanisms for most of these interactions have not been thoroughly investigated (11–13). Clinically, this effect becomes manifest either when a patient stabilized on warfarin adds one or more of these drugs to his or her therapy or, more commonly, when the patient removes one of these drugs from his or her therapy after stabilization on the combination therapy. Several inhibitors of cytochromes P450 can substantially decrease require- ments for warfarin dosage that, if not attended to, can lead to life-threatening bleeding episodes. Cimetidine contains an imidazole moiety, but it is a much better inhibitor of the metabolism of (R)-warfarin (17), the least potent enantiomer, so that an effect on warfarin therapy is observed only at high doses of cimetidine (18). Although many case reports have appeared of interactions between warfarin and a variety of other drugs with many different drug structures (19), only a few of these have resulted in serious toxic effects, and mechanisms are largely unknown. Because of their increased use, further investigations with some of these drugs, such as tamoxifen (20,21), seems warranted. Theophylline General aspects of the drug-drug interactions involving theophylline are similar to those described for warfarin, because it too is a drug with a narrow therapeutic index. Increases in its rate of metabolism, either by some inducers of cyto- chromes P450 or by removal of an inhibitor of those P450s given concomitantly with theophylline, lead to diminution of therapeutic effect, resulting in increased dyspnea. Conversely, decreases in its rate of metabolism either by inhibitors of P450s involved in the metabolism of theophylline or by removal of an inducer given concomitantly can lead to serious toxicities, including convulsions and heart arrhythmias that can be serious enough to cause death.