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By I. Arokkh. Hesston College.

There- fore generic diarex 30caps mastercard, patent-protected medicines are expensive; the cost of these drugs puts them out of the reach of many patients buy 30 caps diarex with mastercard. In developed countries order diarex 30caps with amex, govern- ments or large private insurers can mitigate this problem (Rai diarex 30 caps on-line, 2001). But in poor countries, health insurance is limited and noncompetitive pricing can exclude entire countries from the medicines market (Yadav and Smith, 2012). Explain how these technologies can be best used and implemented in a system to stop the circulation of harmful drugs. This includes rec- ommending defnitions for the products in question that would be sensitive to the needs of drug regulators around the world and focuses on the public health. It also includes recommending how various regulators could collaborate on a global and regional level to best address the problem. The expense of the patent-protected drugs put them out of reach for all but 2 percent of the approximately 2. Tensions over patent protection came to a head in 2001 when the Pharmaceutical Copyright © National Academy of Sciences. After 2001, innovator drug companies began issuing more voluntary licenses at lower prices (Flynn, 2008). More recently, regulators and innovator pharmaceutical companies have devised other ways to make patent-protected drugs available in de- veloping countries. Drugs granted tentative ap- proval “[meet] all safety, effcacy, and manufacturing quality standards for marketing in the U. Patent and Trademark Infringement Patents, not trademark or trade dress, are the main source of ten- sion between intellectual property and public health. But both patent and trademark questions surfaced in 2008 and 2009 when European customs offcials seized consignments of generic medicines in transit from India to Latin American and sub-Saharan Africa (Brant and Malpani, 2011). Dutch courts interpreted this to mean that cus- toms authorities are allowed to treat in-transit goods as if they had been made in Holland (Ho, 2011). French and German customs offcials also seized drug shipments in the same period (Taylor, 2009). When con- tacted, GlaxoSmithKline denied any suspicion of trademark infringement, by which time the shipment had been delayed for 4 weeks (Mara, 2009; Singh, 2009). Drug trademarks can be contentious when companies register trademark names similar to the nonproprietary name (as in the case of Amoxil and amoxicillin) and when drug manufacturers attempt to trademark characteristics such as color. This kind of crime may be different from the civil offense of trademark infringement, if the willfulness of the crime is un- clear, for example, or if the trademark is not identically copied (Clift, 2010). The inability of the consumer to evaluate drug quality is the reason why medicines quality is monitored by an independent, gov- ernment regulatory agency. The courts enforce trademark and patent laws; drugs regulators enforce quality standards. Such was the logic of the International Negotiating Body on a Protocol on Illicit Trade in Tobacco Products, which recently removed all references to counterfeits from its treaty, noting that decisions about trademark infringement in tobacco products was not within their purview (New, 2012). The committee recognizes that many poor-quality medicines also in- fringe on registered trademarks. At times, trademark infringement can become a public health problem, but it is not a public health problem in itself, even insomuch as it pertains to medicines. Competing Meanings of the Term Counterfeit The contentious history of drug patent and trademark enforcement col- ors discussions of drug quality, particularly the use of the term counterfeit. Nevertheless, the word counterfeit, like material and harmless, means one thing to lawyers and judges and something else in common discourse. Its proponents rightly observe that this is what most people understand the word to mean anyway. This defnition has at its center the effort to distinguish between deliberate and accidental problems. The manufacturer is not to blame if a drug is sold after the expiry date or if it has been kept in conditions that encourage rapid degradation. The 2008 contamination of Baxter heparin was a reminder that even expert companies sometimes pro- duce bad products, but the failure was not intentional (Attaran and Bate, 2010). The regulatory system typically punishes such mistakes, whereas the law enforcement system punishes intentional crimes. In practice, however, it is extremely diffcult to distinguish accidental Copyright © National Academy of Sciences. Making the distinction, like determining trademark infringement, is a matter for the courts. Further- more, competing meanings of the word counterfeit—one narrow, meaning infringement on a registered trademark, and one broad, meaning intention- ally deceptive—frustrate many. Generics companies may be vulnerable to accusations of trademark infringement or even deception. When a generic and an innovator drug company market bioequivalent medicines under similar-sounding names or with similar-looking pills, it is debatable whether or not these characteristics are copied or made with an intention to deceive the consumer. Counterfeit is a word that almost everyone uses to talk about bad medicines, but as Tables 1-1 and 1-2 indicate, often with widely divergent meanings. The use of the word counterfeit to describe any poor-quality drug does not serve the cause of intellectual precision or pro- ductive discussion. The committee accepts the narrow, legal meaning of a counterfeit drug as one that infringes on a registered trademark. Trademark infringement is not a problem of public health concern, nor, in most cases, is it even readily identifable. Drug companies, both innovator and generic, have the legal right to challenge counterfeiting; sorting out the nuances of trademark infringement should be left to the courts. This report is about drug quality as a public health problem; it is not concerned with trademark infringement. Therefore, this report does not discuss the problem or solutions to the problem of drug counterfeiting, or make mention to counterfeit drugs, except in cases where to do otherwise would be a misrepresentation of someone else’s work. Scientifc literature and public health campaigns, especially those more than 2 or 3 years old, often describe poor-quality drugs as counterfeit. The committee hopes that all parties will break this habit but believes that most speakers who use the term use it broadly with no ulterior motives or ill will toward generics. There is consensus among most organizations that substandard drugs are those that fail to meet established quality specifcations. When regu- lators approve a drug, they approve a quality standard, outlined in the accepted pharmacopeia or in the manufacturer’s approved dossier. As Table 1-3 indicates, the emphasis on national standards is a rela- tively recent change to the defnition of a substandard drug. Before 2009, the emphasis was on an offcial pharmacopeia, not the national standard. Critics of the addition point out that the regulatory authority is responsible for approving national drug standards, a job that exceeds its capacity in many low- and middle-income countries (Ravinetto et al. Accept- ing the national standard might appear to endorse multiple, possibly inad- equate standards (Ravinetto et al. On the other hand, an emphasis on national standards improves the precision of the defnition. There are many internationally accepted phar- macopeias; some give, for example, different acceptable ranges for drug concentration.

Previously used equations can be combined to describe the plasma concentration resulting from a bolus injection with continuous infusion purchase diarex 30caps overnight delivery. With a continuous infusion generic diarex 30 caps on-line, the plasma concentrations are described by: where: t′ = time after beginning infusion discount 30 caps diarex amex, K0 = rate of drug infusion diarex 30caps fast delivery, V = volume of distribution, and K = elimination rate constant. When both the injection and infusion are administered together, the plasma concentration after beginning the regimen is calculated by adding the two equations: -1 For example, an adult patient is estimated to have a theophylline half-life of 8 hours (K = 0. These estimates are obtained from known information about this patient or from published reports of similar patients. If the patient is given a loading dose of 400 mg of theophylline, and a continuous infusion of 60 mg/hour is begun at the same time, what will the plasma concentration be 24 hours later? Taking this procedure into account, we can further modify the above equations to predict plasma concentrations. Plasma drug concentrations over time resulting from a continuous intravenous infusion. Plasma drug concentrations resulting from an intravenous loading dose given with a continuous infusion. This model combines the approaches just presented for multiple-dose injections and continuous infusions. The peak (or maximum) plasma concentration after the first infusion (Cmax1) is estimated by: where: C = concentration in plasma, K0 = rate of drug infusion (dose/time of infusion), V = volume of distribution, K = elimination rate constant, and t = time (duration) of infusion. This equation was used above to describe plasma drug concentrations with continuous infusion before steady state. The trough concentration after the first dose (Cmin1) occurs at the end of the dosing interval (τ) directly before the next dose. A practical example for this equation is shown below to determine the Cpmin or trough concentration of a drug given by intermittent infusion. It also can be used to predict plasma concentrations at any time between Cmax and Cmin, where t′ equals the time between the end of the infusion and the determination of the plasma concentration. Suppose a patient with severe renal dysfunction receives a 1-g dose of vancomycin, and a peak concentration, drawn 2 hours after the end of the infusion, is 40 mg/L. First, K can be calculated using: Knowing K, we can calculate the time (t) required for the concentration to decrease to 10 mg/L: Therefore, it will take approximately 8. For a drug regimen, if the elimination rate (K) of a drug is reduced while V, X0, and τ remain constant, the peak and trough concentrations will: A. An increase in drug dose will result in higher plasma concentrations at steady state but will not change the time to reach steady state. Giving which of the following dosing techniques results in greater fluctuation between peak and trough plasma levels? When the volume of distribution increases (and clearance remains the same), steady-state plasma concentrations will have more peak-to-trough variation. When drug clearance decreases (while volume of distribution remains unchanged), steady-state plasma concentrations will: A. Steady-state plasma concentration is approximately reached when the continuous infusion has been given for at least how many half-lives of the drug? For a continuous infusion, given the equation C = K0(1 - e )/Cl , at steady state the value fort -Kt t approaches infinity and e approaches infinity A. To achieve an immediate effect, a loading dose is to be administered over 30 minutes and then the continuous infusion is to be begun. Assume that none of this drug has been administered in the last month, so the plasma concentration before therapy is 0 mg/L. A patient is to be given 100 mg of gentamicin intravenously over 1 hour every 8 hours. For the patient in the question above, what will the peak plasma concentration be after 20 doses? For the patient in the previous question, calculate the trough plasma concentration after 20 doses. Because the time interval would be relatively short, there would not be as much time for plasma concentrations to decline. A larger volume of distribution will result in the same amount of drug distributing in a greater volume, which would result in a lower peak-to-trough variation. When clearance decreases, plasma concentrations will increase because drug is administered at the same rate (dose and dosing interval) but is being removed at a lower rate. At five half-lives, approximately 97% of the steady-state concentration has been reached. The changes in the infusion rate will directly affect plasma concentrations, if other factors remain constant. If volume of distribution increased, the steady-state plasma concentration would decrease. The steady-state concentration is directly proportional to the drug infusion rate. If K (the elimination rate constant) increased, the steady-state plasma concentration would decrease. To double the steady-state plasma concentration from 10 to 20 mg/L, the infusion rate should be doubled to 50 mg/hour. The loading dose is determined by multiplying the desired concentration (15 mg/L) by the volume of distribution: Css(desired) × V = 15 mg/L × 40 L = 600 mg. By 20 doses, steady state would have been reached, and the equation below would be used: B, C, D. The trough concentration is calculated from the peak value as follows: -K(t -τ) Ctrough = Cpeak × e -0. Explain how changing the dosing interval (τ) influences the time to reach steady state when multiple doses are administered. If clearance is reduced to 25% of the initial rate and all other factors (such as dose, dosing interval, and volume of distribution) remain constant, how will steady-state plasma concentrations change? The following pharmacokinetic parameters are estimated for this patient: Cl = 15 mL/minute,t V = 31. If the infusion is stopped after steady state is reached, what would the concentration be 24 hours later? A loading dose of 1000 mg is infused over 30 minutes and a continuous infusion is begun when the loading infusion is stopped. What will the plasma concentration be 12 hours after beginning the constant infusion? What is the following portion of the multiple-dose equation called, and why is it called that? Explain why, for most drugs, the increase in drug plasma concentrations resulting from a single dose will be the same magnitude whether it is the first or the tenth dose. Calculate alpha (α), beta (β), and intercepts A and B for a drug conforming to a two-compartment model. Calculate Vc, Varea (also known as Vβ), and Vss (using both methods) for a two-compartment model. In this lesson, we briefly discuss multicompartment models and present a few applications. Multicompartment models are not used as frequently as the one-compartment model in therapeutic drug monitoring, partly because they are more difficult to construct and apply.

Because of the usefulness of epoprostenol purchase diarex 30caps on-line, a variety of prostacyclin formulations have been developed that allow oral (beraprost) discount diarex 30 caps overnight delivery, inhaled (iloprost) order 30caps diarex otc, or subcutaneous (treprostinil) administration 30 caps diarex mastercard. Prostacyclin seems to have somewhat more selectivity for the pulmo- nary circulation, but, at high doses, can precipitate a hypotensive crisis in unstable postoperative patients with refractory pulmonary hypertension. Admin- istration of aerosolized iloprost requires multiple doses during 24 hours in critically ill patients. The pharmacokinetics, when iloprost is administered by this route, are not well worked out for adults or children. Promising therapy is offered by inhaling the more stable and longer-acting analog of prostacyclin, ilo- prost. Sildenafil has been thought beneficial to children with pulmonary hypertensive disease, including structural heart disease. The intravenous form, as with all vasodilators, runs the risk of increasing any intrapulmonary shunt and inducing systemic vasodilation. Sildenafil has crept into common practice as adjunctive therapy in the intensive care unit without benefit of properly controlled clinical trials. Undoubtedly, because the cause of pulmonary hypertension in the intensive care setting is frequently multifactorial, our “best” therapy will be multiply 10. There is a predominance of cases in girls/women, with a female-to-male ratio of 1. As recently as the 1980s, pulmonary hypertension carried a grave prognosis in children, with a median life expectancy of less than 1 year. Indeed, recent data suggest median survival well in excess of 5 years in patients with access to vasodilator therapy, such as prostacyclin and calcium channel blocker treatment. This find- ing places a premium on the correct classification of patients as responders/ nonresponders to acute vasodilator testing. There are several unique challenges when interpreting the treatment lit- erature for pulmonary hypertension. First, pulmonary hypertension is a het- erogeneous disorder, arising from many different etiological factors, not all of which are known. This diversity complicates the understanding of the treat- ment and expected outcomes for patients. Second, pulmonary hypertension, particularly in the pediatric population, is a relatively rare disorder. Thus, treatment principles for children are often derived from observations in adults, without large clinical experiences in younger people to confirm independently the same observations. There are reasons why data from adults may not be easily extrapolated to children, including the different natural life expectancy, different etiologies for pulmonary hypertension, different intrinsic pulmonary vascular reactivity, and the historically worse natural history of the disease in children. Many trials have reported on mean changes in 6-minute walking distance or changes in hemodynamic function. Beyond these technical challenges, relatively few studies have reported on long-term clinical outcomes, such as survival, or on quality of life or functional status, which may be crucial measures for children and their families. For all of these reasons, treatment of pediatric patients with pulmonary hypertension remains individualized. Although many algorithms have been promulgated to guide treatment choices, the exact sequence, duration, combination, and timing of treatments have not been characterized. The therapeutic approach to the pediatric patient with pulmonary hyper- tension begins with a thorough identification of underlying causes and with 238 M. Anticoagulation In adults with primary pulmonary hypertension, warfarin therapy is associated with improved survival. Because microvessel thrombosis may contribute to the ongoing pathogenesis of pulmonary hypertension, anticoagulation may help minimize damage to the vasculature even in the absence of overt hypercoagulable states or proven thromboembolism. Patients with documented thromboembolism or hypercoagulable states, such as positive cardiolipin or lupus anticoagulant tests, or known inherited thrombotic disorders, merit higher levels of anticoagulation. Oxygen Supplemental oxygen therapy can be valuable in certain patients with pulmonary hypertension to alleviate chronic hypoxemia. Such patients include those with sleep apnea or other hypoventilation syndromes, patients with intrinsic lung disease or acute respiratory infection, and patients with exercise- induced hypoxia. Patients with advanced right heart failure and resting oxygen desaturation may also benefit from oxygen therapy. Drugs for Treatment of Right Heart Failure Patients with pulmonary hypertension and right heart failure may benefit from cardiac glycosides, such as digoxin, and from diuretic therapy. Because pulmonary hypertension patients are vulnerable to reductions in cardiac preload, the initiation of diuretic therapy needs to be performed cautiously to avoid excessive volume depletion and hypotension. Pharmacological Treatment 239 Calcium Channel Blockers Historic experience with use of calcium channel blockers as vasodilator therapy suggested that these drugs can prolong survival in patients with response to therapy. Because of the potential for severe hemodynamic collapse during initial challenge with calcium channel blockers, these drugs are not appropriate as first-line treat- ment during diagnostic challenge. Patients who tolerate ini- tiation of calcium channel blockers and who have sustained hemodynamic benefit are continued on standing oral therapy. Patients without sustained benefit during initiation of therapy should have treatment with calcium channel blockers discontinued. The literature regarding treatment of adults with pulmonary hypertension suggests that fewer than 20% have clinical response to calcium channel blocker treatment; in children, a greater pro- portion—nearly 40%—seem to respond to such therapy. Bosentan has been shown in randomized clinical trials to improve functional capacity and hemodynamics in adults with pulmonary hypertension. Careful monitoring of transaminases and hemoglobin levels is warranted in patients receiving treat- ment. Young patients need to be counseled regarding these effects and use effective forms of contraception. Sildenafil is most readily available in oral forms and has been shown to have somewhat selective 240 M. Wessel pulmonary vasodilating capacity while lowering the left atrial pressure and providing a modest degree of afterload reduction. Chronic oral administra- tion of sildenafil to adults with primary pulmonary hypertension improves the exercise capacity and reduces pulmonary artery pressure. Endothelin 1: mitogenic activity on pulmonary artery smooth muscle cells and release from hypoxic endothelial cells. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Endothelium-derived relax- ing factor produced and released from artery and vein is nitric oxide. The pathology of hypertensive pulmonary vascular disease: a description of six grades of structural changes in the pulmonary arteries with special attention to congenital cardiac septal defects. Impairment of endothelium-dependent pul- monary artery relaxation in children with congenital heart disease and abnormal pulmonary hemodynamics. Normal pulmonary vascular development and its disturbance in con- genital heart disease. Thromboxane A2 and prostacyclin biosynthesis in children and adolescents with pulmonary vascular disease. Effect of intracardiac repair on thromboxane A2 and prostaglandin biosynthesis in children with left to right shunt.

The primary site of sequestration is the membrane oxygenator 30caps diarex amex, and the binding seems to be irreversible (Rosen generic 30 caps diarex amex, 198639; Koren cheap diarex 30 caps amex, 198440; Hynynen cheap diarex 30 caps on line, 198741). The increasing concentrations with time would be observed if circuit _binding sites became saturated. Lorazepam Lorazepam, an agent commonly used for sedation in this patient population, was demonstrated to have 30 to 50% lower concentrations at 3 hours in an in vitro circuit. Drug levels were significantly below expected for the first 24 hours, but by 48 hours, they exceeded the expected concentration. His findings suggested an increased volume of distribution and circuit sequestration in the first 24 hours. However, by 48 hours, dosing could be reduced because of an increased half-life, probably because of reversible circuit binding. The authors further suggested that midazolam be administered directly to the patient rather than to the circuit (Mulla, 2003a44; Mulla, 2003b45). Propofol levels can fall to 45% of their expected level after the initiation of cardiopulmonary bypass, and to 37% after 10 minutes. In an in vitro preparation, 75 to 98% of the drug was bound by the circuit (Hynynen, 199446; Mulla, 20006). Phenobarbital Phenobarbital, which is used to treat seizures, has also been studied. As noted earlier, Dagan observed a 17% loss of phenobarbital in an in vitro circuit (Dagan, 199438). As with many of the other drugs, there is a greater apparent volume of distribution with variable clearance (Elliot, 199948). Drugs with small volumes of distribution are more greatly affected than those with large volumes of distribution. The increased volume of distribution and decreased clearance results in prolonged drug half-life. These alterations in drug pharmacokinetics are clearly most acute when the circuit is new, and they diminish over time. The binding process may be irreversible or reversible and may contribute to drug tachyphylaxis, dependency, and prolonged action after discontinuation. Extracellular fluid and total body water changes in neonates undergoing extracorporeal membrane oxygenation. Effect of extracorporeal membrane oxygena- tion on body water content and distribution in lambs. Preliminary studies of the effects of extracorpor- eal membrane oxygenator on the disposition of common pediatric drugs. In vitro evaluation of sedative drug losses dur- ing extracorporeal membrane oxygenation. Effects of injection site and flow rate on the distribution of injected solutions in an extracorporeal membrane oxygenation circuit. Pro: pulsatile flow is preferable to nonpulsatile flow during cardiopulmonary bypass. Thiopentone pharmacokinetics during car- diopulmonary bypass with a nonpulsatile or pulsatile flow. Pharmacokinetics of gentamicin in neonates on extracorporeal membrane oxygenation. Gentamicin pharmacokinetics in neonates under- going extracorporeal membrane oxygenation. Population pharmacokinetic models: effect of explicit versus assumed constant serum concentration assay error patterns upon parameter values of gentamicin in infants on and off extracorporeal membrane oxygenation. Gentamicin pharmacokinetics in term neonates receiving extracorporeal membrane oxygenation. Pharmacokinetics of gentamicin in neonatal patients supported with extracorporeal membrane oxygenation. Pharmacokinetic changes during extracorporeal membrane oxy- genation: implications for drug therapy in neonates. Vancomycin pharmacokinetics in patients undergoing extracorporeal membrane oxygenation. Pharmacokinetics in critically ill infants undergo- ing extracorporeal membrane oxygenation. Vancomycin pharmacokinetics in neonates receiving extracorporeal membrane oxygenation. Population pharmacokinetics of vancomycin in patients receiving extracorporeal membrane oxygenation. Pharmacokinetics and pharmacodynamics of bumetanide in neonates treated with extracorporeal membrane oxygenation. Pharmacokinetics and pharmacodynamics of ranitidine in neonates treated with extracorporeal membrane oxygenation. Amrinone loading during cardiopulmo- nary bypass in neonates, infants and children. Pharmacokinetics of alcuro- nium in children with acyanotic and cyanotic cardiac disease undergoing cardiopul- monary bypass surgery. Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation. Changes in pharmacodynamic response to fentanyl in neonates during continuous infusion. Issues of pharmacology in pediatric cardiac extracorpor- eal membrane oxygenation with special reference to analgesia and sedation. Opioid withdrawal in neonates after continu- ous infusions of morphine or fentanyl during extracorporeal membrane oxygena- tion. Effects of extracorporeal membrane oxygenation on morphine pharmacokinetics in infants. Plasma fentanyl levels in infants under- going extracorporeal membrane oxygenation. Plasma concentrations of midazolam in neonates receiving extracorporeal membrane oxygenation. Pharmacokinetics of midazolam in neonates undergoing extracorporeal membrane oxygenation. Phenobarbital dosing and pharmacokinetics in a neonate receiving extracorporeal membrane oxygenation. Wessel Pathophysiology of Pulmonary Hypertension Elevated pulmonary arterial pressure arises from three well-characterized vascular changes: vasoconstriction, thrombus formation, or proliferation of smooth muscle and/or endothelial cells in the pulmonary vessels. Recent advances in molecular biology have allowed for the identification of several key mediators of vascular function in the pulmonary vasculature. This, in turn, has enabled development of specific pharmacological therapies for the disease. Arachidonic acid metabolites, such as prostacyclin and thromboxane A2, are active in the pulmonary vessels, associated with vasodilation and vaso- constriction, respectively. In addition, prostacyclin is a platelet inhibitor and is capable of inhibiting endothelial cell proliferation, whereas thromboxane A2 is a platelet activator. Endothelin-1 is a vasoconstrictor that causes smooth- muscle proliferation in pulmonary vessels.