Fluvoxamine-theophylline interaction: gap between in vitro and in vivo inhibition constants toward cytochrome P4501A2 cheap dapoxetine 60 mg free shipping. Fluvoxamine impairs single- dose caffeine clearance without altering caffeine pharmacodynamics cheap 90 mg dapoxetine mastercard. Urinary excretion of 6 beta-hydrox- ycortisol and the time course measurement of enzyme induction in man 30 mg dapoxetine. Receptor-dependent transcriptional activa- tion of cytochrome P4503A genes: induction mechanisms discount 60 mg dapoxetine otc, species differences and interindividual variation in man. Molecular mechanisms of cytochrome P-450 induction by xenobiotics: an expanded role for nuclear hormone receptors. Primary human hepatocytes as a tool for the evaluation of structure-activity relationship in cytochrome P450 induction potential of xenobiotics: evaluation of rifampin, rifapentine and rifabutin. Expression and regulation of cytochrome P450 enzymes in primary cultures of human hepatocytes. The use of adult human hepatocytes in primary culture and other in vitro systems to investigate drug metabolism in man. Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. Evaluation of time-dependent cytochrome P450 inhibition using cultured human hepatocytes. Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir. Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: comparison with rito- navir. Drug interactions in primary care: impact of a new algorithm on risk determination. Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: effect of ketoconazole. Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors, and clinical con- firmation of a predicted interaction with ketoconazole. Ketoconazole inhibition of tri- azolam and alprazolam clearance: differential kinetic and dynamic consequences. Inhibition of triazolam clearance by macrolide antimicrobial agents: in vitro correlates and dynamic consequences. Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Time-course of recovery of cytochrome P450 3A function after single doses of grapefruit juice. A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction. Variation in furanocoumarin content and new furanocoumarin dimers in commercial grapefruit (Citrus paradisi Macf. Identification of 6 ,7 -dihydrox-0 0 ybergamottin, a cytochrome P450 inhibitor, in grapefruit juice. Pomegranate juice does not impair clearance of oral or intravenous midazolam, a probe for cytochrome P450-3A activity: compar- ison with grapefruit juice. Comparative kinetics and response to the benzodiazepine agonists triazolam and zolpidem: evaluation of sex-dependent differences. Kinetics and dynamics of lorazepam during and after continuous intravenous infusion. Age and gender effects on the pharmacokinetics and pharmacodynamics of triazolam, a cytochrome P450 3A substrate. Kinetics and dynamics of single-dose triazolam: electroencephalography compared to the digit-symbol substitution test. Dynamics and kinetics of a modified-release formulation of zolpidem: comparison with immediate-release standard zolpidem and placebo. This increased interest has arisen in part because of many documented adverse clinical consequences of drug-drug interactions, coupled with improved understanding as to their cause. Interest in drug-drug interactions has also increased because of the rise in polypharmacy, where patients may take many drugs in the course of a day. Depending on various short- term conditions, an antibiotic or antifungal might be used. To avoid serious harm, health care practitioners must be aware of and manage potential important interactions. To provide optimum information in product labeling for practitioners and patients, drug development and regulatory 665 666 Huang et al. Further, product labeling for older drugs should be updated as additional information about their potential for being a part of important drug-drug interactions becomes available. Pharmacokinetic drug-drug interactions result from alteration in the dose/ systemic exposure relationship, as reflected in a blood or plasma concentration– time curve, when an interacting drug induces or inhibits one or more routes of elimination or transport of a substrate drug. Inhibition of metabolism may be associated with increased blood levels and pharmacological activity of the sub- strate, but if the substrate is a prodrug, pharmacological activity may be reduced; in some cases, when the parent drug and its metabolite have equal effects, there may be no change in pharmacological activity despite large changes in blood levels of parent and metabolite (Chaps. The magnitude of clinical effect of an inhibitor depends on the magnitude of the effect of the inhibitor on clearance of the substrate, which in turn depends on the extent of inhibition and the extent to which the substrate is cleared by the affected pathway. Drugs that induce meta- bolic pathways and reduce systemic exposure may result in loss of effectiveness (Chaps. Examples include the inhibition of the renal tubular secretion of penicillins by probenecid, which results in major increases in penicillin blood levels (6) or the increase in digoxin blood levels by the coadministration of quinidine, presumably by the inhibition of digoxin renal tubular secretion through inhibition of the P-glycoprotein (P-gp) transporter (7). Less commonly recognized than pharmacokinetic interactions—perhaps because fewer studies have been performed to detect them—are pharmacody- namic drug-drug interactions, changes in response to a drug caused by alteration in exposure/response relationships. This type of drug-drug interaction may arise when the substrate and interacting drug affect the same physiological system or An Integrated Approach to Assessing Drug-Drug Interactions 667 when one drug prevents an appropriate response to the other. As an example of the latter, marked hypotension was observed in patients switched from the calcium channel blocker mibefradil to a dihydropyridine calcium channel blocker, apparently because residual mibefradil inhibited the usual compensatory tachy- cardia caused by the dihydropyridine. Both pharmacokinetic and pharmaco- dynamic drug-drug interactions should be considered when two or more drugs are administered concurrently. The critical question in considering drug interactions is: Does the dose of a substrate drug need to be adjusted in the presence of the interacting drug? More specifically, is the pharmacokinetic and/or pharmacodynamic change in the substrate drug in the presence of the interacting drug of sufficient magnitude require adjustment of the substrate dose (or avoidance of the interacting drug)? Finally, how confident we need to be in the answer depends on the nature of interaction and the consequences of error. On the basis of this information, the potential importance of one or more routes of elimination in contributing to a clinically important drug- drug interaction can be estimated. Even when a metabolic route is important for the elimination of a substrate and is affected by an interacting drug, additional studies may be needed to understand whether a metabolic drug-drug interaction has clinical impact. Various methods may be used to develop the requisite information, including in vitro studies, in vivo pharmacokinetic and pharmaco- dynamic studies, population pharmacokinetic studies, clinical safety and efficacy studies, and postmarketing observational studies. All of these approaches can generate useful information about potentially important drug-drug interactions 668 Huang et al. Interactions in the liver may have only a small effect on single-dose Cmax, but may alter half-life and accumulation index. Interpretation of drug-drug interaction data is sometimes complicated when a substrate drug is actively transported from the serosal to the mucosal side of the gastrointestinal tract by transporters such as P-gp. The early elucidation of drug metabolism, for example, permits in vitro investigations of drug-drug interaction that in turn provide information useful in guiding the clinical program and possibly avoiding some clinical studies. Metabolism data can also provide information on the relevance of preclinical metabolism and toxicological data and permit early identification of drugs that are likely to have large interindividual pharmacokinetic variability due to genetically determined polymorphisms in drug-metabolizing enzymes or drug-drug interactions. An integrated approach is most useful, one in which evidence for and against a drug-drug interaction is examined at all stages of drug development, including (1) preclinical in vitro human tissue studies of drug metabolism and drug-drug interactions to determine which in vivo studies should be conducted, (2) early-phase in vivo studies to assess the most important potential drug-drug interactions suggested by in vitro data, (3) late-phase drug development population pharmacokinetic studies to expand the range of poten- tial interactions studied, including unexpected ones, and to allow examination of pharmacodynamic drug-drug interactions. The further sections of this chapter provide more specific information about these approaches. The utility of these studies has been enhanced by the availability of specific enzyme preparations, microsomal preparations, and liver cell preparations, together with An Integrated Approach to Assessing Drug-Drug Interactions 669 standard substrates and inhibitors/inducers. Information from in vitro metabolic studies can suggest not only that a substrate drug is or is not likely to be a candidate for certain metabolic drug-drug interactions but also whether a drug’s metabolism will be affected by genetic polymorphisms. This guidance emphasizes the value of in vitro studies in human bio- materials in ruling out important metabolic pathways in a drug’s metabolism or the possibility of the drug’s ability to affect certain enzyme systems. Previous chapters have detailed the relative advantages and disadvantages of various in vitro techniques in providing information pertinent to drug-drug interactions. Cellular-based in vitro models, such as isolated hepatocytes and precision- cut liver preparations 2. Expressed human drug-metabolizing enzymes These systems can be used to define a drug’s metabolic pathway, to assess its potential to inhibit the metabolism of other drugs, and to determine whether other drugs influence its metabolism. It is abundantly present in the intestinal epithelium and serves as an efflux pump for a variety of drugs and xenobiotics. In vitro models currently available allow investigation of transporter-mediated drug-drug interactions, including a human colon carcinoma cell line, Caco-2 (10). In Vitro–ln Vivo Correlation A complete understanding of the relationship between in vitro findings and in vivo results of metabolism/drug-drug interaction studies is still emerging. Quantitative prediction of the magnitude of clinical drug-drug interactions based on in vitro methodologies has been the topic of numerous publications and is described in earlier chapters (Chaps. Although excellent quantitative concordance of in vitro and in vivo results has been shown, in some cases in vitro data may also under- or overestimate the clinical effect (13), and at present an observed in vitro effect needs further elucidation in in vivo studies. The bases for in vitro/in vivo disassociations have been described and include (1) irrelevant substrate concentrations and inappropriate in vitro model systems, (2) mechanism-based inhibition, (3) activation/induction phenomena, (4) physical- chemical effects on absorption, (5) parallel elimination pathways that decrease the importance of the in vitro–assessed pathway, and (6) modulation of an important cellular transport mechanism. Specific Clinical Investigations If metabolism is an important mechanism of clearance and in vitro studies suggest that metabolic routes can be inhibited or that the drug may inhibit important clearance pathways of other drugs, in vivo studies are needed to evaluate the extent of these potential interactions. As with in vitro studies, in vivo studies can often use a screening approach involving probe drugs. Where interactions are found, the studies of probe drugs and other drugs will provide a basis for specific recommendations on product labeling as to what An Integrated Approach to Assessing Drug-Drug Interactions 671 concomitant uses should be avoided or what dosage adjustments to make. A critical determination for substrate effects is the size of the effect, measured in the in vivo interaction study, and the importance of the effect. Thus, a 50% increase in blood levels of a well-tolerated drug with little dose-related toxicity may require no dosage adjustment. The same degree of increase for a drug with a narrow therapeutic range might require careful adjustment in dose or avoidance of coadministration. The issues in the areas of study design and data analysis are discussed in more detail in the following section. If in vitro studies and other information suggest a need for in vivo meta- bolic drug-drug interaction studies, the following general issues and approaches should be considered. Depending on the study objectives, the substrate and interacting drug may be investigational agents or approved products. Study Design In general, interaction studies compare substrate levels with and without the interacting drug.

Advise patients with risk factors for osteonecrosis of the jaw (see Pre-treatment checks) not to undergo invasive dental procedures during treatment discount 60 mg dapoxetine otc. This assessment is based on the full range of preparation and administration options described in the monograph order 60mg dapoxetine free shipping. Iloprost 100 micrograms/mL solution in 1-mL ampoules Iloprost must not be confused with its analogue epoprostenol (both names are sometimes erroneously used interchangeably) purchase 30mg dapoxetine visa. Iloprost | 443 * Many centres have their own protocols for dosing and handling iloprost by infusion and these should be followed where available cheap 60mg dapoxetine otc. Pre-treatment checks * Caution in concomitant anticoagulant therapy or drugs that "risk of bleeding. Primary pulmonary hypertension (unlicensed): 1--8 nanograms/kg/minute for 6 hours daily. Alternatively, iloprost may be given via nebuliser (licensed product) at a dose of 2. Dose in renal or hepatic impairment: in liver cirrhosis or in renal impairment requiring dialysis the dose may need to be halved. Calculation of infusion rate (see also Table I3): Dose ðnanograms=kg=minuteÞÂbodyweight ðkgÞÂ60 Infusion rate ðmL=hourÞ¼ Concentration of infusion ðnanograms=mLÞ Table I3 Iloprost rate of infusion using a 2000 nanograms/mL solution Infusion rate (nanograms/kg/minute) 0. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. If adverse effects occur stop the infusion and review; may be recommenced after 1 hour at half the previous rate if appropriate. Technical information Incompatible with No information, but do not mix with any other drug. Significant * The following may "iloprost levels or effect (or "side-effects): interactions other anticoagulants or antiplatelet agents, antihypertensives and vasodilators. Action in case of Reduce the dose or discontinue the infusion and initiate appropriate supportive overdose measures as necessary, e. This assessment is based on the full range of preparation and administration options described in the monograph. Im ipenem w ith cilastatin 500-mg dry powder vials * Imipenem is a semisynthetic carbapenem beta-lactam antibacterial that is always given with cilastatin (which inhibits the renal metabolism of imipenem) in a ratio of 1:1 by weight. Pre-treatment checks * Do not give if there is known hypersensitivity to any carbapenem antibacterial agent or cilastatin, or previous immediate hypersensitivity reaction to penicillins or cephalosporins. Severe and/or life-threatening infections due to less sensitive organisms (primarily some strains of P. Dose in renal impairment: adjusted according to creatinine clearance: * CrCl 31--70mL/minute: 500mg every 6--8 hours. Intermittent intravenous infusion Preparation and administration Imipenem with cilastatin should not be directly mixed with Hartmann’s (incompatible with lactate) but may be co-administered via Y-site. Inspect visually for particulate matter or discoloration prior to administration and discard if present. The infusion rate should be slowed if the patient develops nausea during the infusion. Technical information Incompatible with Imipenem with cilastatin should not be directly mixed with Hartmann’s (incompatible with lactate) but may be co-administered via Y-site. Amiodarone, amphotericin, drotrecogin alfa (activated), fluconazole, lorazepam, midazolam, sodium bicarbonate. Displacement value Negligible Stability after From a microbiological point of view, should be used immediately; however, preparation prepared infusions may be stored at 2--8 C and infused (at room temperature) within 24 hours. Monitoring Measure Frequency Rationale Renal function Periodically if on * Transient "Cr and "U may occur. Development of Throughout treatment * Development of severe, persistent diarrhoea may diarrhoea be suggestive of Clostridium difficile-associated diarrhoea and colitis (pseudomembranous colitis). Additional information Common and serious Immediate: Anaphylaxis and other hypersensitivity reactions have been undesirable effects reported. Other: Nausea, vomiting, diarrhoea, taste disturbances, tooth or tongue discoloration, hearing loss, blood disorders, positive Coombs’ test, rash, pruritus,urticaria,Stevens--Johnsonsyndrome,rarelytoxicepidermalnecrolysis, exfoliative dermatitis, myoclonic activity, convulsions, confusion, mental disturbances. This assessment is based on the full range of preparation and administration options described in the monograph. Inflixim ab 100-mg dry powder vial Infliximab should be used under specialist supervision only. Pre-treatment checks * Screen for tuberculosis, do not give to patients with active tuberculosis or other severe infections. If the condition has responded, maintenance of either 5mg/kg 6 weeks after initial dose, then 5mg/kg every 8 weeks or a further dose of 5mg/kg if signs and symptoms recur. If the condition has responded, consult product literature for guidance on further doses. If there is no response at 6 weeks, no additional treatment with infliximab should be given. If there is no response after 14 weeks, no additional treatment with infliximab should be given. Confirm the patient’s details on the prepared bag, and that the correct dose has been supplied. Inspect visually for particulate matter or discoloration prior to administration and discard if present. Technical information Incompatible with No information Compatible with Flush: NaCl 0. However, prepared infusions are known to be stable if stored at 2--8 C and infused (at room temperature) within 24 hours. Monitoring Measure Frequency Rationale Close observation For 1--2 hours post * Most hypersensitivity reactions are reported for hypersensitivity infusion during this period. Additional information Common and serious Immediate (or with a few hours of administration): Anaphylaxis and other undesirable effects hypersensitivity reactions have been reported. Other: Viral infection, serum sickness-like reaction, headache, vertigo, dizziness, flushing, lower and upper respiratory tract infection, abdominal pain, diarrhoea, nausea, dyspepsia, "transaminases, urticaria, rash, pruritus, hyperhidrosis, dry skin, chest pain, fatigue, fever, blood dyscrasias. This assessment is based on the full range of preparation and administration options described in the monograph. Insulins Insulin 100 units/mL solution in 10-mL vials 3-mL pen cartridges and 3-mL pre-filled pens (see chart below) Restricted use: insulin 500 units/mL solution in 10-mL vials * Insulin is a hormone produced by the pancreas that is crucial in the regulation of carbohydrate, protein and fat metabolism. It is secreted when blood glucose levels start to rise; its action is opposed byglucagon; catecholamines,glucocorticoidsand growth hormone (thecounter-regulatory hormones), and others. Decreased or absent insulin secretion results in the development of diabetes mellitus, although patients with insulin resistance may be markedly hyperinsulinaemic as well as hyperglycaemic. If used it must be kept completely separate from all other insulins, be clearly labelled, and only be administered by staff who have had specific training in its use. Insulin is used in combination with aggressive rehydration, potassium supplementation and many other supportive measures, alongside intensive monitoring. Insulin is used in combination with rehydration, potassium and other supportive measures, alongside intensive monitoring. Once the patient is biochemically stable and able to eat/drink, the usual therapy for diabetes treatment should be resumed or started. Moderate to severe hyperkalaemia (unlicensed): calcium gluconate is given to stabilise the myocardium (see Calcium gluconate monograph) followed by 5--10 units of soluble insulin with Insulins | 453 50mL Gluc 50% over 5--15 minutes. Maintenanceregimens forinsulin-dependentorinsulin-requiringdiabetesmellitus: the regimen chosen depends on the patient’s ability to inject, monitor and adjust doses, patient prefer- enceandthedegree of blood glucosecontrolrequired. Occasionally abiphasic insulin is used, but the dose must then be given in association with a meal. Dose in renal impairment: reduced doses may be required in severe renal impairment. Check that the insulin you have selected is the one specified on the prescription chart. If using an insulin suspension, re-suspend by rolling the vial, cartridge or pen gently between the palms or inverting several times. Withdraw the required dose using an insulin syringe*, or dial up the correct dose according to the manufacturer’s instructions if using an insulin pen. Using an area on the abdomen, outer thigh, upper outer arm or the buttock, pinch up a skin fold between the thumb and forefinger and hold throughout the injection. Avoid overuse of injection sites as this may impair absorption; rotate sites so that individual sites are not reused within 1 month. Continuous intravenous infusion via a syringe pump This method is used for control of blood glucose. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. In use: May be used and stored at room temperature for up to 28 days (some products are stable for 42 days -- see individual product literature). Pens in use should not be stored in the fridge (pens may jam) or with needles attached. Monitoring of Annually (or more frequently * To ensure that complications are treated or diabetic if appropriate) dealt with, and that the patient is counselled complications appropriately. Additional information Common and Injection/infusion-related: serious * Too rapid administration: Hypoglycaemia. Lipoatrophy or lipohypertrophy from overuse of sites (less common with highly purified insulins). Action in case of Symptoms to watch for: Hypoglycaemia: excessive sweating, pallor, palpitations, overdose trembling, feeling cold, impaired vision, irritability, tingling round the lips, inability to concentrate, confusion, personality change, inability to waken. Counselling Correct administration of insulin, insulin storage, disposal of sharps, importance of taking doses regularly as prescribed. Training in use of blood glucose, blood ketone or urine glucose monitoring as appropriate. Patients maintained on insulin should always carry glucose (and glucagon if necessary) and should be able to recognise the symptoms of hypoglycaemia. Relatives or carers should be trained to recognise hypoglycaemia and how to treat it appropriately. This assessment is based on the full range of preparation and administration options described in the monograph. Intralipid 10% emulsion in 100-mL and 500-mL infusion containers 20% emulsion in 100-mL, 250-mL and 500-mL infusion containers 30% in 333-mL infusion container * Intralipid contains fractionated soya oil in the form of a fat emulsion. It is a rich source of linoleic and linolenic acids, which are essential fatty acids. Energy requirements of individuals must be metif aminoacidsaretobeutilisedfor tissuemaintenanceratherthan asanenergy source. Parenteral feeding should be introduced slowly initially, particularly in those patients at risk of refeeding syndrome, e. Treatment of local anaesthetic induced cardiac arrest that is unresponsive to standard therapy: data is still extremely limited; there are no standard methods for lipid emulsion therapy. Intravenous infusion * Intralipidmay be given as a separate infusion or (more commonly now) as an ‘all-in-one’ admixture. Subsequently the dose is usually increased and, when a larger intake is indicated, the dose may be increased to a maximum of 3g/kg/day. Fat emulsions may extract phthalate plasticisers from bags and giving sets and non-phthalate containing equipment should be used wherever possible.

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Your bowel moves food along at a normal pace cheap 60mg dapoxetine amex, in a transit time from ingestion to elimination of twelve to twenty-four hours generic 90mg dapoxetine with amex. Your hair stays on your head quality dapoxetine 60 mg, your skin is moist and your nails aren’t dried out discount 30mg dapoxetine visa, your sex drive is strong, and your memory is crystal clear. The Lowdown on Low Thyroid The symptoms of low thyroid were summarized decades ago on I Love Lucy, when Lucille Ball hilariously peddled a sham energy drink called Vitameatavegemin by asking, “Are you tired, run down, listless? Age, however, does not explain a puffy face, high cholesterol, excessive menstrual bleeding, and many other symptoms of low thyroid function. Mary Shomon, a colleague of mine and impassioned advocate for her patients, calls the triad of fatigue, weight gain, and depression thyropause, because these symptoms are akin to those that can occur with the ovarian sputtering that characterizes menopause. Oprah was famously diagnosed with thyroid issues in 2007, although certainly her thyroid doesn’t explain the entire story of her weight challenges. Oprah isn’t alone in this: if you look at women in this country who are forty- two and older, you’ll find that 24 percent are taking thyroid medication, and 11 percent are on antidepressants. In imaging studies, the hypothyroid brain looks remarkably like the depressed brain: both show subtle changes in blood vessels, myelination (fatty insulation around nerves), and neurogenesis (nerve growth). Why Doctors Underdiagnose Thyroid Issues It’s estimated that about 60 million Americans, both men and women, struggle with thyroid problems. Given the depth of suffering, we can no longer ignore that so many people are burned out, confused, and underfunctioning. The medical profession needs an urgent call to action: increase the diagnosis of hypothyroidism. Conventional physicians often respond with skepticism, derision, and even hostility to women who earnestly ask for thyroid help. Many of their doctors have expressed the belief that “doctors like me” are prescribing thyroid treatment indiscriminately and under the false pretense that it will help with weight problems and fatigue. I’d agree that some alternative medicine providers appear to have a tendency to overdiagnose and overtreat patients. As I’ve emphasized, the best practice is to apply rigorous science, which I’ve distilled for you in this chapter. For women with a thyroid disorder, thyroid treatment will help with weight and fatigue issues because it addresses the root cause of women’s symptoms. Women respond most effectively when the best of both worlds are combined: thyroid symptoms are carefully considered with objective blood testing using the latest scientific guidelines. In general, they may • have an outdated reference range— doctors treat women using the “normal” reference ranges they learned in medical school, years ago. They don’t know that laboratory-based reference ranges are skewed by including patients with hypothyroidism, and are unfamiliar with new national guidelines for a narrower normal range. They haven’t read the latest data, which shows improved outcomes in people treated for borderline thyroid function (referred to by clinicians as subclinical hypothyroidism). As patients, we’re conditioned not to fight, and when you are also hypothyroid, you’ve got little fight left. It’s time to start demanding more from your team of medical professionals, and if they don’t agree, move on to a new team. Who among us wants to end up on antidepressants, sleeping pills, or to purchase “fat” clothes and be sent to a psychiatrist for a biological problem? Fortunately, there is a bottom-up revolution taking place to change the problem of underdiagnosed thyroid problems, led by powerful activists such as Mary Shomon, arguably the most popular thyroid advocate internationally, and Janie Bowthorpe, founder of another popular thyroid patient-to-patient online tribe. Unfortunately, even the most well-read women who come to my medical practice have never heard of either woman. They stare at me, perplexed, when I tell them their thyroid function is low, and further (based on the ten or so years of lab tests they brought in for our first appointment), that it’s been low for a decade but undiagnosed and untreated. Getting someone on your team isn’t as hard as you think: Empower and educate yourself to have the will and tenacity to get the best help. Use the strategies described in Appendix B to identify a doctor who can serve as an informed and compassionate partner for you. Spread the word, so that we can amplify this message and help people struggling unnecessarily due to low thyroid function. It’s Not Just Aging Chances are you have a friend or two, probably female, who has had trouble with her thyroid. That’s because women face a 20 percent chance of developing a thyroid problem at some point in their lives. Unfortunately, too many physicians mistake the symptom for the problem— weight gain and depression, for instance. Or worse: many doctors believe women try to use the low-thyroid diagnosis as an excuse to avoid a nutritional and exercise regimen to manage their weight effectively, but data show that more than 10 percent of the U. When patients complained of blurry vision, doctors used to joke about how we’re all getting older. The Science of Low Thyroid Skip this section if you struggle with brain fog, a key symptom of low thyroid function. Come back and read it when you’ve implemented The Gottfried Protocol and are able to concentrate fully again! One of the largest of the endocrine glands, the thyroid is attached to the front of the trachea, just below the larynx, and consists of two relatively flat ovals connected by a narrow bar in a butterfly shape. The name comes from its resemblance to the thyreos, the shield used by ancient Greek warriors. Unlike a shield, however, the thyroid is asymmetric; the right lobe is normally much larger than the left. For some reason (perhaps fluctuating estrogen levels), the thyroid is larger in women than in men and grows slightly during pregnancy. When the swelling thyroid gland causes the necklace to break, people assume she’s pregnant. Before its release into the bloodstream, thyroglobulin is converted into thyroxine (T4) and other closely related thyroid hormones. Compared with other markers of metabolism, such as glucose, thyroid hormones circulate in the blood in very low concentrations and, in healthy individuals, remain stable over long periods of time. Certain hormones may change how much thyroglobulin you make, for example, synthetic estrogen pills, which raise thyroglobulin by 40 percent, result in 10 percent less free thyroid hormone (thyroxine, T4) available in the blood. In the United States, the cause is most commonly Hashimoto’s thyroiditis, when your immune system attacks your thyroid, and initially leads to high levels of thyroid hormone in the blood plus antibodies. You either keep up with the orders from headquarters, or you don’t—perhaps because your immune system has destroyed your thyroid, or an environmental toxin is disrupting your thyroid function. Thyroid by the Numbers: It’s the Free T4 and T3 That Wreak Havoc Maybe you aren’t a numbers person, but I urge you, when it comes to your thyroid, to pay attention. These are numbers you’ll want to understand, because chances are that if you recognized yourself in the questionnaire, you have a thyroid issue. Essentially, that means you need it, but it’s mostly a precursor of the more important or “active” version, which is T3 (triiodothyronine). T4 is essentially a storage hormone, biologically a lame duck, waiting in the wings to be converted into T3, the catalyst for weight loss, warm limbs, and good mood. T4 makes up more than 90 percent of your thyroid hormones, but it must be converted into T3 before it can be used. Unfortunately, too often women are treated with only T4, with no acknowledgment that T3 should be in the mix. More than 99 percent of your thyroid hormones are linked to specific “binding proteins” found in the nucleus of the cells. Most of the T4 in your blood is attached to a protein called thyroxine-binding globulin. Less than 1 percent of the T4 is unattached, or “free”—but it’s the free-roaming T4 that causes thyroid problems. Despite being present in such small amounts, free T3 has a greater effect on the way you use energy. It is the primary influence on your weight, cholesterol, energy, memory, menstrual cycle, skin, hair, body temperature, muscle strength, and heart rate. About Reverse T3 Reverse T3 (rT3) is an inactive metabolite of T4, and provides a mechanism to slow down metabolism in order to save energy. Generally, if you are healthy, T4 gets made into T3, and a small portion of T4 gets converted into reverse T3. Put another way, reverse T3 provides a feedback system to keep you in balance under normal conditions. But occasionally this plan backfires, and what was designed to be adaptive for your body becomes disadvantageous. Here’s why: if your body is stressed or on a calorie-restricted diet, a signal is sent to change the ratio, and you produce more reverse T3. When faced with stressors such as the flu, extreme cold, a car accident, hospitalization, or a vow to lose weight with calorie restriction, for example, your metabolism will slow down by raising production of reverse T3. Most mainstream doctors claim this is a rare condition, and they often miss it—mostly because they don’t check for it. Furthermore, mainstream doctors believe that high reverse T3 is mostly found in hospitalized patients and chronic disease. Yet I commonly find high reverse T3 in my clients, who are neither sick nor hospitalized but coping with stressful, ordinary lives. One study found that normal reverse T3 predicted survival and physical functioning better than other thyroid blood tests, and that people with low serum T3 and high reverse T3 had worse physical performance associated with aging (such as difficulty arising from bed, dressing, eating, walking, hygiene, grip, and other common activities of daily living) than those with normal levels. After giving birth, about 7 percent of women develop what’s called postpartum thyroiditis, when the immune system attacks the thyroid, causing mood swings, lethargy, thinning hair, and difficulty with weight loss. Women with baseline thyroid antibodies before pregnancy are much more likely to develop postpartum thyroiditis. Of course, lots of women experience postpartum blues, sleep deprivation, and struggles with weight and hair loss. Since many doctors never think to check a woman’s thyroid after she’s given birth, too many new mothers suffer from an unrecognized thyroid condition. Here’s the single most common scenario I hear in my integrative medicine practice among mothers with thyroid problems: “Dr. Yet my doctor kept looking at me with that knowing glance that said, ‘Oh, honey, you just had a baby. When your thyroid gland is not making enough thyroid hormone, your brain senses this. As a result, the hormone factory in the thyroid (if it has the necessary resources and cortisol isn’t interfering) manufactures more thyroid hormones, which are then sensed by the brain. In more than twenty years of practice, I’ve observed gradations of thyroid imbalance. More women than we recognize brave thyroid imbalance because of old reference ranges for thyroid imbalance. Many doctors prefer not to treat subclinical hypothyroidism because they believe treatment hasn’t been shown to be helpful. I like to believe that people are inherently good—your doctor might not be intentionally hiding something from you; he or she just might have completed medical training prior to these new guidelines and may still be using the old reference range when monitoring your medication, symptoms, and lab tests.

Subsequently purchase dapoxetine 60 mg without prescription, the film is analyzed for the number of full turns of the head made trusted 60mg dapoxetine, usually accompanied by attempted licking and biting of the application sites dapoxetine 30 mg fast delivery. Using this technique dapoxetine 30mg mastercard, it was possible to rank pyrethroids for their ability to produce paresthesia and corresponded to the ranking available from human exposure. Sweat was removed from the nasolabial fold and cheek, then a 5% aqueous solution of lactic acid was briskly rubbed over the area. Those who reported stinging for 3 to 5 min within the first 15 min were designated as stingers and were used for subse- quent tests. Subjects were asked to evaluate the degree of stinging as 0 no stinging; 1 slight stinging; 2 moderate stinging; 3 severe stinging. Skin permeability theory in relation to measurements of percutaneous absorption in toxicology. Cutaneous biotransformations and some pharmacological and toxicological implications. Advances in mechanisms of aller- gic contact dermatitis: In vitro and in vivo research. Multiple-application delayed-onset contact urticaria: possible relation to certain unusual formalin and textile reactions. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membrane. Guinea pig maximization test, open epicutaneous test and chamber test in induction of delayed contact hypersensitivity. Application of the Hill Top Patch Test Cham- ber to dermal irritancy testing in the albino rabbit. The Duhring chamber: An improved technique for epicuta- neous testing of irritant and allergic reactions. Procedures for the appraisal of the toxicity of chemicals in foods, drugs, and cosmetics. Use of graded concentrations in studying skin sensitizers: experimental contact sensitization in man. Comparative studies on the irritancy of oils and synthetic perfumes to the skin of rabbit, guinea pig, rat, miniature swine, and man. Species specificity of non-immunologic contact urticaria: guinea pig, rat and mouse. Pyre- throid mediated skin sensory stimulation characterized by a new behavioral para- digm. Frequency dependent effects of the pyrethroid in- secticide decamethrin in frog myelinated nerve fibers. By the height of the ancient Roman civilization, virtually all types of cosmetics that * Mr. He served as Chief Counsel for the Food and Drug Administration during 1971–1975, is the coauthor of the legal casebook used to teach food and drug law at law schools throughout the United States, and personally teaches a full course on food and drug law at Harvard Law School during Winter Term. Cosmetics have continued to be widely used from these ancient times to the present. During the 19th century, virtually all government regulation of private en- terprise in the United States was conducted at the city, county, and state levels. Because of the Supreme Court’s narrow interpretation of the power of the federal government to regulate interstate commerce, federal laws regulating consumer products did not emerge until the first decade of the 20th century. The earliest known state regulatory law explicitly mentioning cosmetics was enacted by Massachusetts in 1886. That law included all cosmetics within the statutory defi- nition of a drug, thus imposing the same regulatory requirements on both cosmet- ics and drugs (3). From 1879 through 1906, Congress held hearings and debated the enact- ment of a federal food and drug law (4). Although bills introduced in Congress during 1898–1900 explicitly defined the term ‘‘drug’’ to include all cosmetics (5), the inclusion of cosmetics was deleted from the drug definition in 1900 as part of a legislative compromise (6). As a result, cosmetics were not included when the legislation was finally enacted as the Federal Food and Drugs Act of 1906 (7). When the Roosevelt Administration introduced a bill to replace the 1906 Act (11), cosmetics were included (12) through a separate definition and separate regulatory requirements. Out of these deliberations, the following important princi- ples and policies emerged. First, the 1938 Act, like the 1906 Act, classified products according to their intended use. In a paragraph from the 1935 Senate Report on the legislation, Congress established the policy that the representations of the sellers with respect to a product would determine its classification: The use to which the product is to be put will determine the category into which it will fall. If it is to be used only as food it will come within the definition of food and none other. If it contains nutritive ingredients but is sold for drug use only, as clearly shown by the labeling and advertising, it will come within the definition of drug, but not that of food. If it is sold to be used both as a food and for the prevention or treatment of disease it would satisfy both definitions and be subject to the substantive requirements for both. The manufacturer of the article, through his representations in con- nection with its sale, can determine the use to which the article is to be put. For example, the manufacturer of a laxative which is a medicated candy or chewing gum can bring his product within the definition of drug and escape that of food by representing the article fairly and unequivocally as a drug product (15). This principle remains the touchstone for product classification under the 1938 Act. The 1906 Act limited the drug definition to products intended to prevent or treat disease. Accordingly, from the initial bill to the final law, the drug definition was ex- panded to include articles ‘‘intended to affect the structure or any function of the body of man or other animals’’ (16). Because the representations made for the product would determine the proper classification of the product, and thus classi- fication was within the sole control of the seller, Congress concluded that the product should be subject to whatever statutory requirements are established for whatever product classifications applied, based upon those representations: It has not been considered necessary to specify that the definitions of food, drug, and cosmetic shall not be construed, other than to the extent expressly provided, as mutually exclusive. The present law does not have such a clause relating to the definitions of food and drug and there has never been a court decision to the effect that these definitions are mutually exclu- sive, despite the fact that repeated actions have been brought, for example, against filthy foods bearing unwarranted therapeutic claims, alleging these products to be adulterated as food because of their filth, and misbranded as drugs because of their false and fraudulent therapeutic claims (17). Thus, dual and even triple classification of a product as a food, drug, and cosmetic was contemplated by Congress under the 1938 Act. Fourth, Congress realized that there must be one exception to the general rule of nonexclusive definitions. Accordingly, Congress explicitly excluded food from the structure/function prong of the drug definition, but not from the disease prong. In the Senate debate on the legislation in April 1935, the exclusion of food from the structure/function prong of the drug definition was expanded, without discussion, to include cosmetics (18). That bill was not passed by the House of Representatives, however, and no subsequent legislation retained the cosmetic exclusion. Accordingly, any cosmetic represented to affect the structure or func- tion of the human body is classified as a drug as well as a cosmetic and must meet the statutory requirements for both categories of products. Fifth, Congress also included in the 1938 Act, as it had in the 1906 Act, a third prong of the drug definition to include articles recognized in specified pharmacopeias. This was intended, however, to include pharmacopeial articles only when they are in fact represented for disease or structure/function purposes (19). Accordingly, this prong of the definition may be excluded from further consideration in this chapter. Parts of the drug definition not pertinent here have been revised since 1938, but the central core of the definition has not been altered. In short, it is only the very rare cosmetic product that could justify this level of investment. It is therefore essential that cosmetic products be formulated and labeled in such a way as to avoid the drug definition. Second, the agency published pamphlets and other educational materials with examples of product classification. Third, it brought court action to contest the legality of cosmetic products with labeling that contained what the agency concluded to be drug claims. From this body of literature and precedent has emerged, over six decades, a number of well-developed examples: A suntan product is a cosmetic but a sunscreen product is a drug. An antibacterial deodorant soap is a cosmetic but an antibacterial anti-infec- tive soap is a drug. Products that are represented only to change the structure or function of the hair or nails are regarded as cosmetics and not drugs. Products that are repre- sented to affect the hair or nails systemically, on the other hand, are regarded as drugs. Cosmetic products represented as ‘‘hypoallergenic,’’ and thus with reduced allergic potential, remain classified as cosmetics and not as drugs (23). Only if these products are represented to treat specific reactions or diseases would they be classified as drugs. Inclusion of an active ingredient in a cosmetic does not automatically clas- sify it as a drug, unless the active ingredient is so closely identified with therapeu- tic properties that the mere use of the term would connote a drug claim. In many instances, however, ingredients can be used in both cos- metic and drug products. Legal Distinction in the United States Between a Cosmetic and a Drug 229 In many instances, the context of a word or phrase must be considered before a determination can be made about proper classification of the product as a drug or cosmetic. A product represented as a treatment for disease is a drug, but a product represented as a beauty treatment is a cosmetic. A product repre- sented to kill germs that cause infection is a drug but a product tht is represented to kill germs that cause odor is a cosmetic. These examples illustrate the difficulty in drawing a clear and definitive distinction between these two categories of products. The Wrinkle Remover Cases of the 1960s In the early 1960s, the cosmetic industry developed a line of products, broadly characterized as ‘‘wrinkle remover’’ products, containing ingredients intended to smooth, firm, and tighten the skin temporarily and thus to make wrinkles less obvious. Courts of Appeals involving three products: Line Away, Sudden Change, and Magic Secret. The District Court in the Line Away case took the position that, by in- tending to smooth and tighten the skin, Line Away had as its objective affecting the structure of the skin and thus was a drug (26). The Court of Appeals agreed, citing the ‘‘strong therapeutic implications’’ of the promotional material (27). The District Court in the Sudden Change case concluded that the product was represented merely to alter the appearance of the skin and thus was a cosmetic (28). The majority held that the claims that that product would give a ‘‘face lift without surgery’’ and would ‘‘lift out puffs’’ had ‘‘physiological connotations’’ (29). The majority went out of its way, however, to state that all of the traditional cosmetic claims (e. One judge dissented on the ground that the two claims cited by the majority as drug claims were indistinguishable from such cosmetic claims as smooths, firms, tones, and moisturizes the skin. Finally, the District Court in the Magic Secret case determined that the product was a cosmetic, not a drug, based on the conclusion that the claims were less exaggerated than in the other two cases.

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To date purchase dapoxetine 30mg on line, this methodology has been applied primarily to investigating nicotine’s metabolism within the context of cigarette smoking and addiction (116 order 60mg dapoxetine with mastercard,117) generic 30 mg dapoxetine with amex. Despite the need for stable-labeled drugs and the associated sophisticated instrumentation for their measurement order dapoxetine 90mg without a prescription, such an approach would provide a gold-standard against which alternative trait measures such as the coumarin index or others could be evaluated and validated. Possibly, a simpler, single-point plasma- or urine-based measure could be developed using nicotine/cotinine. Accordingly, these two isoforms have received the most attention with regard to the development and application of in vivo probes. Such drugs for which the isoform catalyzes the formation of a principal metabolite include phenytoin, tolbutamide, fluoxetine, losartan, S-warfarin, torsemide, valproic acid, and many nonsteroidal anti-inflammatory agents (diclofenac, ibuprofen, naproxen, piroxicam, suprofen, and tenoxicam). Furthermore, this difference has also been noted to be present in patients receiving warfarin therapy, where a gene-dose effect leads to reduced clearance of the anticoagulant’s S-enantiomer (120–122). However, for safety and analytical reasons, it is unlikely that the anticoagulant could be used as an in vivo probe in healthy subjects. Tolbutamide The metabolism of tolbutamide (l-butyl-3-p-tolysulfonylurea) in humans in- volves a single pathway, with the initial and rate-limiting step being tolyl methyl-hydroxylation to form hydroxytolbutamide, which is further oxidized to carboxy-tolbutamide by alcohol and aldehyde dehydrogenases. Since the drug’s half-life ranges between 4 and 12 hours, this approach requires not only multiple blood samples but collection over a considerable time period (24–36 hr). However, such use is not without problems, in par- ticular, the safety issue associated with the hypoglycemic response produced by tolbutamide administration. However, in fasted individuals, blood glucose levels may be sig- nificantly reduced by tolbutamide and require reversal using glucose supple- mentation (130); use of a lower dose (250 mg) may obviate this problem. Unfortunately, validation of neither of these putative trait measures using diclofenac has been reported. Such preliminary information will obviously require appropriate substantiation before the descri- bed trait measures will be widely accepted. Although, its substrate specificity was originally thought to be limited to related anticonvulsant agents, the in vivo metabolism of an increasing number of structurally unrelated drugs appear to be mediated by this isoform. These include R-mephobarbital (4 -hydroxylation)0 (135), hexobarbital (3 -hydroxylation) (136),proguanil (ring cyclization)(137),omeprazole, and related0 proton pump inhibitors (5 -methylhydroxylation)0 (138–140), diazepam (N-demethylation) (141), certain tricyclic antidepressants (N-demethylation) (142–144), carisoprodil (N-dealkylation) (145), citalopram (N-demethylation) (146), moclobemide (C-hydroxylation) (147), propranolol (side-chain oxidation) (148), and nelfinavir (methylhydroxylation) (149). A similar low prevalence rate is also present in Africans and African Americans (161–163). By contrast, a much higher frequency (13–23%) is found in indigenous populations living in Southeast Asia, such as Chinese, Japanese, and Koreans (138,164–168). These factors have led to the development of in vivo probes to classify individuals according to phenotype. Subsequently, two alternative phenotyping procedures were developed that have been widely used throughout the world by numerous investigators. The 4 -hydroxylation0 of S-mephenytoin is not only extensive but also rapid, and this is in contrast to metabolism of the R-enantiomer, which involves mainly N-demethylation (150). The pharmacokinetic basis of the trait measure has been described, and studies have confirmed that the urinary S:R ratio is the same as the comparable ratio of the areas under the plasma concentration–time profiles of the enantiomers during the collection period, which in turn reflects the relative 604 Wilkinson intrinsic clearances of the two isomers (169). Also, this trait value has been found to be reproducible in individuals over a long period of time (170). For this reason, there is some merit in using the R:S ratio, which is linearly related to such activity, so the smaller its value, the lower the 4 -hydroxylating0 activity (21,171). A minor route of metabolism of S-mephenytoin results in the formation and urinary excretion of an acid-labile conjugate that is probably a cysteinyl derivative (172). The significance of this urinary metabolite is that it is easily hydrolyzed back to S-mephenytoin, and this can occur to an unpre- dictable extent during sample storage, even at À208C (173). The resulting artifactual S:R ratio value may, therefore, misclassify an individual’s phenotype. The most widely used procedure is to obtain a repeat S:R value but following acid hydrolysis of the urine sample prior to analysis. Another approach (176) includes measurement of the S:R ratio in a urine sample collected 24 to 32 hours after drug administration, since little or no acid-labile metabolite is present at this time. Also, it is possible to extract the collected urine immediately after collection and store the dried extract at À208C until subsequent analysis (176). For this reason, an alternative phe- notypic trait measure based on the formation and urinary elimination of 4 -0 hydroxymephenytoin has also been frequently used. After its formation, 4 -hydroxymephenytoin0 is glucuronidated and excreted in this form into the urine. Thus, an antimodal value that discriminates between the two phenotypes cannot be defined with absolute precision and varies between laboratories. As a result, phenotypic mis- classification may occur when the zero- to eight-hour urinary recovery is in the range of about 15 to 25 mmol. A further interpretive difficulty is the trait’s dependency on a complete zero- to eight-hour urine collection, since a low recovery of the 4 -hydroxy0 metabolite can also reflect poor subject compliance. Alternatively, the phenotype is determined by combining the information provided by both the excretion of 4 -hydroxymephenytoin0 and the urinary S:R ratio. Despite the described approaches and precautions, the trait values of a small number of individuals may not be consistent with genotypic information or are uninterpretable based on the assumption that only two phenotypes are present. It is possible that the urinary S:R ratio measured at 24 to 32 hours may also identify such individuals, since occasional subjects have been noted to have values between 0. Mephenytoin has been extensively used for phenotyping purposes; how- ever, such use is not without practical problems. Accordingly, a dose of 50-mg mephenytoin is often used to phenotype such individuals. A further complicating factor is that racemic 1 mephenytoin (Mesantoin , Sandoz/Novartis, Basal, Switzerland) is not avail- able in many parts of the world. In addition, the drug has a short elimination half-life (1–2 hour) and has a far wider therapeutic ratio than mephenytoin, resulting in better tolerability by subjects. However, different sampling times and trait values have been used by different investigators. A third trait value, using a single four-hour blood sample, has also been used: (omeprazole þ omeprazole sulfone):5 -hydroxyomeprazole0 (187). For example, analytical sensitivity issues may limit omeprazole’s wider application, since in one population study 23 of 100 subjects could not be phenotyped because of unmeasurable concentration of omeprazole and/or its 5 -hydroxy0 metabolite (185,186). Proguanil The antimalarial effects of proguanil (chloroguanide) are dependent on its metabolic activation to cycloguanil. However, in other studies this value did not necessarily separate the two phenotypes (191,193), and a better antimode was suggested to be 15 (196). Accordingly, a plethora of reports and reviews addressing various aspects of the enzyme have been published (202,203). The genetic polymorphism was discovered independently by three groups of investigators, two studying the metabolism of debrisoquine (204,205) and another interested in sparteine (206). Currently, some 48 mutations resulting in 53 alleles are known and additional rare ones continue to be identified (203,207,209). However, the five most common alleles represent over 95% of the variants (209), and a formal nomenclature scheme has been adopted (210). Considerable heterogeneity is present in the frequencies of these various alleles in different worldwide populations, dependent on racial/geographic factors (203,207). However, consid- erable heterogeneity also appears to be present among various African pop- ulations (sec. These include, for example, b-adrenoceptor blockers (metoprolol, propranolol, timolol), antiarrhythmic agents (sparteine, prop- afenone, mexilitene, encainide, flecainide), antidepressants (tricyclics, selective serotonin reuptake inhibitors), neuroleptics (haloperidol, perphenazine, thio- ridazine, zuclopenthixol), opioids (codeine, dihydrocodeine, dextromethorphan), amphetamines (methamphetamine, methylenedioxymethylamphetamine— ‘‘ectasy,’’ fenfluramine), and various other drugs (202). Such a pheno- typing approach is robust and has been applied to several thousand individuals. However, formation of 4-hydroxydebrisoquine is quantita- tively the most important of these pathways, accounting for between 1% and 30% of an administered dose, depending on genotype, and the metabolite is almost exclusively of the S-enantiomer configuration (19). An alternative ‘‘urinary recovery ratio’’ [4-hydroxydebrisoquine: (debrisoquine þ 4-hydroxy-debrisoquine)] has also been used, but to a far lesser extent (21,35). However, a significant practical problem 1 associated with debrisoquine (Declinax , Hoffman La-Roche, Nutley, New Jersey, U. Metoprolol Over 95% of an administered dose of metoprolol is metabolized in humans to a number of metabolites, including a-hydroxymetoprolol, which accounts for up to 10% of the eliminated dose (218). Although metoprolol’s urinary excretion may be affected by urinary pH (218) and the drug’s metabolism exhibits stereoselectivity (223), neither of these factors appears to be an important variable in the trait measure, which has been shown to be reproducible with respect to phenotypic assignment (220). A single-point, 3-hr postdose metabolic ratio approach has also been suggested based on its good agreement with the equivalent urinary trait measure (224); however, its use has been limited. One reason for this limited use has been the application of an even safer and more widely used drug for phenotyping pur- poses, namely, dextromethorphan. Dextromethorphan Dextromethorphan (3-methoxy-17-methylmorphinan) is a widely used and effec- tive non-narcotic antitussive. After oral administration, it is rapidly and exten- sively metabolized in humans by O- and N-demethylation to form dextrorphan and 3-methoxymorphinan; a small amount of secondary metabolite, 3-hydroxymorphinan, is also formed. Moreover, its high safety profile and global availability would permit its universal application, even in subjects where use of unapproved drugs like sparteine and debrisoquine was not possible (e. A 0–8-hr urinary metabolic ratio (dextromethorphan:dextrorphan) is usu- ally used as the trait measure following an oral dose of 15-40 mg dextro- methorphan hydrobromide in a solid dosage form or as cough syrup. Because dextrorphan is conjugated prior to excretion, hydrolysis of the urine by pretreatment with (b-glucuronidase is usually performed, although some inves- tigators have suggested that this may not be necessary (226). Pharmacokinetic studies have substantiated that the urinary meta- bolic ratio reflects the plasma levels of the unchanged drug to its metabolite (227), and possible factors affecting the trait measure have been investigated (228). It is also possible to determine a single time-point, dextromethorphan metabolic ratio in plasma within 2–5 hr after an oral dose or in a 6-hr saliva sample (229,230); however, neither of these alternative approaches has been widely used. Accordingly, it is not possible to identify ultrarapid or inter- mediate metabolizers. Moreover, no polymorphism was apparent in the population distribution curve in Nigerians using either debrisoquine or sparteine (212,242), and no significant relationship (r = 0. It has been speculated that such dissociations might reflect poor patient compliance with the clinical protocol or that the antimode value established in populations of European descent does not always apply to other populations. This variant allele, which expresses a protein with reduced catalytic activity compared with the wild-type gene (248,249), is not present in Europeans but is common among black African populations (203,207,248). The choice of probe depends mainly on the local regulatory situation and the availability of the particular drug and its metabolites. However, in neither case does it appear possible to identify an individual’s genotype on the basis of the subphenotypic trait value. Likewise, modulation of such activity requires the use of an in vivo probe, and all three of the widely used approaches appear to be sufficiently sensitive for this purpose. This has led to considerable speculation regarding their possible involvement as risk factors in, for example, alcoholic liver disease and cancer. Efforts to address such issues are complicated by the fact that the frequencies of the polymorphisms vary substantially according to the racial/geographic char- acteristics of the study population. As a result, such molecular epidemiological findings have become controversial, since the resulting data are often conflicting and suffer from low statistical power. The latter problem also applies to popu- lation studies attempting to relate genotype to phenotype. Chlorzoxazone [5-chloro-2(3H)-benzoxazolone] is a skeletal muscle relaxant that has been approved for clinical use for over 40 years.

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Reducing the carbonyl group in the resulting compound with aluminum isopropoxide in isopropyl alcohol gives D discount dapoxetine 90 mg otc,L-threo-2-acetamido- 1-(4-nitrophenyl)-1 30mg dapoxetine free shipping,3-propandiol (32 buy dapoxetine 30mg fast delivery. The acetyl group is hydrolyzed in hydrochloric acid to form D cheap 90 mg dapoxetine,L-threo-2-amino-1(4-nitrophenyl)-1,3-propandiol. The resulting racemic mixture of amines is treated with camphor-D-sulfonic acid, and the resulting enantiomeric salts are separated. After alkaline hydrolysis of the selected salt, the product D,(−)-threo-2- amino-1-(4-nitrophenyl)-1,3-propandiol (32. Acylating the aminogroup of this compound with the methyl ester of dichloroacetic acid gives the desired chloram- phenicol (32. Reacting the resulting bromide with ammonia gives an isomeric mixture of D,L-threo-5-amino-2,2-dimethyl-4-phenyl-1,3-dioxane, which upon treatment with D-tartaric acid, separation of the resulting salts, and subsequent alkaline hydrolysis of the selected salt gives D-(−)-5-amino-2,2-dimethyl-4-phenyl-1,3-dioxane (32. Acylating this with the methyl ester of dichloroacetic acid gives D-(−)-threo-5-dichloroac- etamido-2,2-dimethyl-4-phenyl-1,3-dioxane (32. The phenyl ring is then nitrated, during which the 1,3-dioxane ring is cleaved off, giving dinitrate of D-(−)-threo-2- dichloroacetamido-1-(4-nitrophenyl)-1,3-propandiol (32. Reducing the nitro group in this compound with bivalent iron sulfate gives the desired chloramphenicol (32. It easily diffuses into the bacterial cell, where it reversibly binds with the 50 S ribo- somal subunit. However, this drug inhibits synthesis of mitochondiral proteins in mammalian cells, possibly because of the similarty between mitochondrial and bacterial ribosomes. Chloramphenicol has a broad spectrum of antimicrobial activity, including Gram-posi- tive, Gram-negative, aerobic, and anaerobic bacteria, spirochaeta, mycoplasma, chlamy- dia, and so on; however, it can cause pronounced suppression of blood flow, which is accompanied by reticulocytopenia, granulocytopenia, and in severe cases, aplastic anemia. This enzyme acetylates the drug, giving it unable to bind with 50 S subunits of bacterial ribosomes. It is the drug of choice for treating typhoid fever, and it is used for treating brain abscesses. Until recently, it was the drug of choice for therapy of bacterial meningitis in children (in com- bination with ampicillin). However, third-generation cephalosporins are currently pre- ferred for such purposes. Chloramphenicol is an effective alternative for a number of infections in situations, where drugs of choice cannot be used for one reason or another. However, it should never be used for infections that can readily be treated with other antimicrobial drugs. Synonyms of this drug are levomycetin, amindan, aquamycetin, chloromycetin, ophthoclor, opulets, leukomycin, and many others. Despite the broad spectrum of activity, spectinomycin is used only for gonococci infections. It is effective with respect to most strains of gonococci, as well as a number of other Gram-negative microorganisms. It is used for treating severe gonorrheal urethritis and proctitis in men, and severe gon- orrheal proctitis in women, which is caused by strains of gonococci that are sensitive to the drug. Based on its chemical structure and contents, vancomycin is classified as a glycopeptide antibiotic. Its molecular mass is significantly more than practically any other used antibi- otics [325–330]. Unlike beta-lactam antibiotics, which inhibit the third stage of peptidoglycan synthesis, vancomycin affects the second stage of creating bacterial cell membranes. Vancomycin inhibits the reaction in which the repeating unit of the cell membrane is separated from the cytoplasmic membrane-bound phospholipids, and binds with the already existing peptidoglycan. Resistance of Gram-negative organisms (such as mycobacteria), fungi, virii, and prota- zoans to vancomycin occurs because the barrier is impermeable to the drug, which is ensured by the outer membrane. Vancomycin is used for serious bacterial infections caused by microorganisms sensitive to this drug when penicillins and cephalosporins are ineffective for diseases such as sepsis, endocarditis, pneumonia, pulmonary abscess, osteomyelitis, meningitis, and enterocolitis, or when penicillins and cephalosporins cannot be tolerated by patients. Vancomycin is the drug of choice for infections caused by methicillin-resistant forms of S. Rifampicin: Rifampicin, 5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22-hep- tamethyl-8-[N-(4-methyl-1-piperazinyl)-formimidoyl]-2,7-(epoxypentadeca-1,11,13-trien- imino)-naphtho-[2,1-b] furan-1,11(2H)dion-21-acetate (32. Rifampicin is a semisynthetic derivative of rifamicin B, a macrolactam antibiotic and one of more than five antibiotics from a mixture of rifamicins A, B, C, D, and E, which is called a rifamicin complex, which is produced by actinomycetes Streptomyces mediteranei (Nocardia mediteranei). Synthesis of rifampicin begins with an aqueous solution of rifamicin, which under the reaction conditions is oxidized to a new derivative of rifamicin S (32. Besides mycobacteria, rifampicin also exhibits activity with respect to a large number of organisms. Anaerobic cocci, forms of Clostridium, and Bacteroids are frequently sensitive to rifampicin. Rifampicin is the most effective drug for treating pulmonary and non-pulmonary forms of tuberculosis, including tuberculosis meningitis. Polymyxines: Polymyxines are a group of related polypeptide antibiotics that are pro- duced by sporo-forming soil bacteria Bacillus polymyxa and B. Five different polymyxines have been identified—polymyxines A, B, C, D, and E, which differ in the amino acid content and are differentiated by additional letter notations and names—polymyxine B (aerosporin) and polymyxine E (colistin). Threonine and α,γ-diaminobutyric acid are present within the structure of these antibi- otics. The distinguishing feature of the polymyxine group is in that they contain 4–5 free γ-amine groups of α,γ-diaminobutyric acid, which gives them the property of a cationic detergent able to form complexes with phospholipids of cellular membranes. Polymyxine B is N-[3-amino-1-[[1-[[3-amino-1-[[6,9,18-tris-(2-aminoethyl)-15-benzyl- 3-(1-hydroxyethyl)-12-isobutyl-2,5,8,11,14,17,20-hyptaoxo-1,4,7,10,13,16,19-heptaazacy- clotris-21-yl]-carbamoyl]-propyl]-carbamoyl]-2-hydroxypropyl]-carbamoyl]-propyl]-6-me thyloctanamide (32. Practically all polymyxines are active exclu- sively against aerobic Gram-negative microorganisms. They do not affect coccal aerobic (staphylo-, strepto-, pneumo-, gono-, and meningococci) and anaerobic microorganisms, as well as most strains of Proteus bacterias causing tuberculosis and diphtheria. These drugs are used for gastrointestinal diseases (colitis, enterocolitis, severe and chronic dysentery, sepsis, meningitis, pneumonia, infections of the urinary tract, and oth- ers caused by P. They are effectively used in the form of ointments for treating a few forms of eczema, boils, hidradenitis, and other skin diseases. Parenteral use of polymyxines is limited due to their neuro- and nephrotoxic effects. However, they are used for seri- ous, life-threatening infections such as bacteremia, which are caused by some strains of P. Bacitracin: Bacitracins are polypeptide antibiotics that are isolated from a culture fluid of B. Ten individual bacitracins have been isolated: bacitracins A, A1,B,C,D, E, F1,F,F,2 3 and G. However, the drug itself, named bacitracin, that is used in medicine is a mixture of polypeptide antibiotics. However, bacitracin A, N-[[2-(1-amino-2-methylbutyl)-4,5-dihydro-4-thiazolyl] carbonyl]bacitracin F (32. It is used most often externally for local treat- ment of purulent infections of the eyes and skin. Indications for intramuscular introduction are extremely limited because of its nephrotoxicity. It can be used as a drug for extreme cases of staphylococcus pneumonia in children with emphyemic resistance to all other antibiotics. They were introduced into medical practice even before the discovery of penicillins. This is the difference between bacterial and animal cells, and it is the reason behind the selective toxicity of sulfonamides. Sulfanilamide, whose structure is similar to the structure of p-aminobenzoic acid, com- petes with p-aminobenzoic acid for inclusion in the folic acid molecule. In short, by tak- ing the place of p-aminobenzoic acid, it “interferes” with the biosynthesis of folic acid. As a result, the “misled” enzymes construct a “false” molecule of folic acid, which is not able to carry out the vital function of true folic acid. Antimicrobial Drugs Thus sulfonamides are bacteriostatic drugs that inhibit bacterial growth by interfering with the microbial synthesis of folic acid. More specifically, sulfonamides block the biosyn- thetic pathway of folic acid synthesis, thus competitively inhibiting the transformation of p-aminobenzoic acid to folic acid (mediated by the enzyme dihydropteroate synthetase), which allows them to be considered as antimetabolites. Currently, various sulfanilamide drugs are used in medicine, the choice of which depends on various factors, but above all on the type of stimulant, course of the disease, speed in which the drug is absorbed from the gastrointestinal tract, the speed in which it is excreted, and its ability to diffuse into different organs and tissues. Sulfonamides have a broad spectrum of antimicrobial activity, including Staphylococcus aureus, nonenterococcal types of Streptococcus, Listeria monocytogenes, Nocardia, Neisseria, Haemophilius influenzae, enteric Gram-negative types of E. Above all, sulfonamides are used for treating uncom- plicated infections of the urinary tract, infections caused by Nocardia asteroids, streptococcal pharyngitis, menigococcal diseases, toxoplasmosis, and others. Bacterial resistance to sul- fonamides can develop as a result of mutations expressed either in the overproduction of p-aminobenzoic acid, or in changes in dehydroproteorate synthetase itself, which becomes more sensitive to the drugs. Resistance can also be mediated by plasmids that code for dehydroproteorate synthetase, or by reduced diffusion of the drug through bacterial cell membranes. They are subdivided into short-lasting (sulfacytine, sulfadiazin, sulfamerazine, sulfametazine, sulfametizole, sulfisoxazole); mod- erate-lasting (sulfamethoxazole, sulfapyridine); and long-lasting (sulfamethoxypiridazine, sulfamter), which, however, are no longer used as independent drugs because of extremely rare, yet nonetheless occurring, hypersensitivity reactions. Drugs for local use include those for ophthalmological use (sulfacetamide, sulfozoxazol); vaginal use (sulfabenzamide, sul- facetamide, sulfathiazole, sulfizoxazol); and external use (maphenid, silver sulfadiazine). Finally, this group includes sulfasalazine and phthalylsulfathiazole, a drug that acts in the lumen of the intestines, but which is poorly absorbed from the gastrointestinal tract. In terms of determining a correlation between structure and activity, it was shown that the free p-amino group in the benzene ring is necessary for the exhibition of antibacterial activity, and it can only be replaced by those groups that permit its transformation to a free 33. The presence of an additional substituent in the o- and m-positions of the ben- zene ring reduces the activity of the given series of compounds as antibacterial agents. Replacing one of the hydrogen atoms on the nitrogen atom in the sulfonamide region of the molecule leads to a significant change in the activity and solubility of the compounds. Moreover, the nature of the substituent in the sulfonyl radical determines the antimicrobial activity and the pharmacokinetic features of each of the individual compound. Thus the pres- ence of this easily obtained and high volume product, 4-acetylaminobenzenesulfonyl chloride, which is made by reacting acetylaniline with chlorosulfonic acid, or the presence of 4-aminobenzenesulfonamide, which is made from a further reaction of 4-acetylaminoben- zenesulfonyl chloride with ammonia and subsequent hydrolysis, the task of synthesizing new, potential sulfonamides has practically resorted to making new heteroaromatic amines. This easily cyclizes to 1-ethyl-5,6-dihydrocyto- sine in the presence of sodium methoxide, and is isolated in the form of a hydrobromide (33. Bromine turns out to be the optimal oxidant for this purpose, and using nitrobenzene as the solvent gives a hetero- aromatic amine, 1-ethylcytosine (33. Sulfacytine is used for pneumonia, cerebral meningitis, staphylococcal and streptococcal sepsis, and other infectious diseases. The subsequent hydrolysis of this product with a base leads to the formation of the desired sulfadiazine [5–8]. Sulfadiazine is used for pneumonia, cerebral meningitis, staphylococcal and streptococcal sepsis, and other infectious diseases, although it is the drug of choice for nocardiosis. This drug is not recommended for urinary tract infections because of its low solubility and certain nephrotoxicity. It is used in the form of silver salts (sulfadiazine silver) as an external antibacterial agent, primarily for treating burns. It is believed that the presence of the silver ion in the molecule facilitates increased antimicrobial and wound-healing action.

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Displacement value Negligible Stability after From a microbiological point of view buy dapoxetine 30 mg mastercard, should be used immediately; however: preparation Reconstitutedvials and prepared infusionsmay be storedat 2--8 Cand given(at room temperature) within 24 hours order dapoxetine 90mg on line. Monitoring Measure Frequency Rationale In treatment of myocardial infarction Heart rate Continuously * #Pulse may result from reperfusion purchase 90mg dapoxetine mastercard. Additional information Common and serious Immediate: Anaphylaxis and other hypersensitivity reactions have been undesirable effects reported rarely purchase 30 mg dapoxetine with amex. Significant * The following may "risk of haemorrhage with alteplase: anticoagulants, interactions heparins, antiplatelet agents, e. Stop administration and give supportive therapy as appropriate including fresh frozen plasma, fresh blood and tranexamic acid if necessary. Risk-reduction strategies are recommended This assessment is based on the full range of preparation and administration options described in the monograph. Am ikacin 100mg/2mL, 500mg/2mL solution in vials * Amikacin sulfate is a semi-synthetic aminoglycoside antibiotic derived from kanamycin A. Life-threatening infections and/or those caused by Pseudomonas: up to 500mg every 8 hours and for no more than 10 days (maximum total treatment dose should not exceed 15 g). If this is not possible then flush the line thoroughly with a compatible solution between drugs. Inspect visually for particulate matter or discoloration prior to administration and discard if present. Intermittent intravenous infusion Preparation and administration If used in combination with a penicillin or cephalosporin, administer at a different site. If this is not possible then flush the line thoroughly with a compatible solution between drugs. Withdraw the required dose and add to a suitable volume of compatible infusion fluid (usually 100mL NaCl 0. Inspect visually for particulate matter or discoloration prior to administration and discard if present. Aminophylline, amphotericin B, ampicillin, benzylpenicillin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, gentamicin, heparin sodium, Pabrinex, pantoprazole, phenytoin sodium, propofol, tobramycin. Stability after From a microbiological point of view should be used immediately; however, reconstitution prepared infusions may be stored at 2--8 C and infused (at room temperature) within 24 hours. Amikacin | 29 Monitoring Measure Frequency Rationale Vestibular and Daily * Ototoxicity is a potential effect of over exposure to auditory amikacin. Amikacin serum See right-hand * For meaningful interpretation of results the concentration column for details of laboratory request form must state: first measurement. Additional information Common and serious Common vestibular and auditory damage, nephrotoxicity. Significant * Amikacin may "risk of nephrotoxicity with the following drugs: ciclosporin, interactions platinum compounds, tacrolimus. This assessment is based on the full range of preparation and administration options described in the monograph. Am inophylline 25mg/mL solution in 10-mL ampoules; 250mg/mL solution in 2-mL ampoules * Aminophylline is a soluble complex of theophylline and rapidly liberates theophylline after injection or infusion. It relaxes bronchial smooth muscle, relieves bronchospasm, and has a stimulant effect on respiration. Serum levels should be monitored regularly, particularly during initiation of therapy. The pharmacokinetics of theophylline are affected by several factors includ- ing age, smoking, disease, diet, and drug interactions. Pre-treatment checks * Do not use in patients hypersensitive to ethylenediamine or those allergic to xanthine derivatives, e. Knowledge of the time, route of administration and dosage form of the patient’s last theophylline dose may inform this decision. Loading dose for patients already on oral theophylline/aminophylline: * Defer treatment until serum theophylline level is available. Intravenous injection via a syringe pump This method is used for the loading dose only -- the infusion rate must be reduced after the initial 20-minute loading infusion. Preparation of a 10mg/mL solution (other strengths may be used according to local policies) 1. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. If patients experience acute adverse effects while the loading dose is being infused, either stop the infusion for 5--10 minutes or give at a slower rate. Fluid restriction: the maximum concentration that can be given is 25mg/mL via a central line. Withdraw 500mg aminophylline (20mL of 25mg/mL solution) and add to the prepared infusion bag. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Fluid restriction: the maximum concentration that can be given is 25g/mL via a central line. Aminophylline | 33 Table A4 Aminophylline maintenance dose: rate of infusion using a 1mg/mL solution Ideal 300 500 800 bodyweight micrograms/kg/hour micrograms/kg/hour micrograms/kg/hour (kg) (mL/hour) (mL/hour) (mL/hour) 40 12 20 32 45 13. Amiodarone, ciprofloxacin, cisatracurium, clarithromycin, dobutamine, hydralazine, ondansetron. If therapy is resumed, decrease subsequentinfusionrate byabout 50% and recheck serum concentration after 24 hours. Serum K Daily * During regular therapy serum K levels must be monitored as #K may occur rapidly. Additional information Common and serious Immediate: Anaphylaxis has been reported rarely. Pharmacokinetics Elimination half-life is about 8 hours in non-smoking adults; about 10--12 hours in elderly patients; about 32 hours in liver cirrhosis; about 3--5 hours in smokers. Action in case of Symptoms to watch for: "Pulse, nausea, vomiting, arrhythmias and seizures overdose (may occur even without preceding symptoms of toxicity and often result in death). Consider charcoal haemoperfusion if plasma theophylline concentration >80mg/L (acute) or >60mg/L (chronic), or if >40mg/L in elderly patients. This assessment is based on the full range of preparation and administration options described in the monograph. As soon as an adequate response has been obtained oral therapy should be initiated concomitantly at the usual loading dose (e. Intravenous infusion Preparation and administration Amiodarone is incompatible with NaCl 0. Very irritant: repeated or continuous infusions should be given via a central line. Withdraw the required dose and add to a suitable volume of Gluc 5% (use 250mL for the initial infusion; use up to 500mL for the subsequent infusion). Inspect visually for particulate matter or discoloration prior to administration and discard if present. Intravenous injection (cardiopulmonary resuscitation only) Preparation and administration 1. Alternatively withdraw 3--6mL of 50mg/mL solution from an ampoule, dilute to 10--20mL with Gluc 5% and mix well. Inspect visually for particulate matter or discoloration prior to administration and discard if present. Amiodarone hydrochloride | 37 Technical information Incompatible with Amiodarone is incompatible with NaCl 0. Aminophylline, bivalirudin, ceftazidime, digoxin, drotrecogin alfa (activated), furosemide, heparin sodium, imipenem with cilastatin, magnesium sulfate, micafungin, pantoprazole, piperacillin with tazobactam, sodium bicarbonate. Stability after From a microbiological point of view should be used immediately; however, preparation prepared infusions may be stored at 2--8 C and infused (at room temperature) within 24 hours. Injection site reactions are common (pain, erythema, oedema, necrosis, thrombophlebitis, phlebitis). Long-term use: pulmonary toxicity (pneumonitis, fibrosis, pleuritis), changes in thyroid function, corneal micro deposits, photosensitivity Pharmacokinetics Elimination half-life: (single dose) 25 days; (chronic dose) 14--107 days (mean 52 days). Significant * The following may "risk of ventricular arrhythmias with amiodarone (avoid interactions combination): amisulpride, antidepressants-tricyclic, arsenic trioxide, artemether with lumefantrine, atomoxetine, benperidol, chloroquine, co-trimoxazole, disopyramide, droperidol, erythromycin-parenteral, fosamprenavir, haloperidol, hydroxychloroquine, ivabradine, levofloxacin, lithium, mefloquine, mizolastine, moxifloxacin, nelfinavir, pentamidine isetionate, phenothiazines, pimozide, quinine, ritonavir, sertindole, sotalol, sulfamethoxazole, sulpiride, tolterodine, zuclopenthixol. Action in case of Besides supportive measures, prolonged surveillance of the patient is required overdose because of the long biological half of amiodarone. Advise of the need for regular blood tests and for an annual ophthalmic examination. This assessment is based on the full range of preparation and administration options described in the monograph. Am oxicillin (am oxycillin) 250-mg, 500-mg, 1-g dry powder vials * Amoxicillin sodium is a penicillin. Haemophilus influenzae, Escherichia coli, Proteus mirabilis, Salmonella) and also for susceptible Gram-positive bacteria (e. Pre-treatment checks * Do not give if there is known hypersensitivity to penicillins. Dose in renal impairment: adjusted according to creatinine clearance:1 * CrCl >20--50mL/minute: Dose as in normal renal function. If this is not possible then flush the line thoroughly with a compatible solution between drugs. The solution should be clear and a pale straw colour (a transient pink colour or slight opalescence mayappearduringreconstitution). Inspectvisually for particulate matterordiscolorationpriorto administration and discard if present. Intermittent intravenous infusion Preparation and administration See Special handling below. If this is not possible then flush the line thoroughly with a compatible solution between drugs. The solution should be clear and colourless to pale straw in colour (a transient pink colour or slight opalescence may appear during reconstitution). Inspect visually for particulate matter or discoloration prior to administration and discard if present. Intramuscular injection Preparation and administration See Special handling below. If pain occurs, 1% lidocaine may be used for reconstitution (see the monograph Lidocaine for cautions and monitoring). Monitoring Measure Frequency Rationale Renal function Periodically, * Impaired renal function may occur: consider dose especially if for adjustment. Prothrombin time * Possible prolongation of bleeding time and defective platelet function (monitor closely if anticoagulated). Signs of supra- Throughout treatment * May result in the overgrowth of non-susceptible infection or organisms: appropriate therapy should be superinfection commenced; treatment may need to be interrupted. Development of Throughout and up to * Development of severe, persistent diarrhoea may diarrhoea 2 months after be suggestive of Clostridium difficile-associated treatment diarrhoea and colitis (pseudomembranous colitis).