By V. Osko. Western Carolina University.

Spectroscopy Spectroscopy is a class of analytical techniques that measures the in- teraction of matter and radiation purchase sildalist in india, thereby giving insight into chemical structure and contents cheap sildalist 120mg with visa. These techniques all provide qualitative data order sildalist with visa, and some provide signifcant quantitative data as well. Often referred to as the chemical fngerprints of drugs, the various spectra produced using these techniques elucidate different aspects of drug composition; characteristic absorption or emission peaks correspond to aspects of chemical composi- tion and molecular structure. A chemist can extract detailed chemical and structural information from a spectrum, and an inspector with minimal training can also identify falsifed and substandard medicines by comparing the drug spectra to reference materials in drug spectra databases (Kaur et al. Molecular vibration and rotation energies occur in the infrared regions of the electromagnetic spectrum, and these movements may be observed with infrared, near-infrared, or Raman spectrometers. These techniques are relatively straightforward to use and moderately expensive, and routine comparative applications do not require extensive training. Chemists ana- lyze the absorption peaks in these spectra primarily to identify molecular functional groups; most active pharmaceutical ingredients and some or- ganic excipients and impurities have characteristic spectral peaks or spectral fngerprints that can be used to help identify them. Infrared spectroscopy The infrared range of the electromagnetic spectrum can be divided into three subregions: the near-infrared, mid-infrared, and far-infrared. The mid-infrared range is the more discerning and commonly used region (Deisingh, 2005). Figure 6-4 shows the different infrared spec- tra of the antimalarial artemisinin and its derivative, artemether. This comparison can identify the common substitution of artemisinin for more effective and expensive antimalarials (Kaur et al. There are several ways to collect infrared spectra, each having ad- Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs 266 Copyright © National Academy of Sciences. Some manufacturers label their packaging to take advantage of the fact that only inks that absorb in the infrared range will be visible under infrared radiation. Near-infrared and Raman spectroscopy Recent developments of portable near-infrared and Raman spectrometers have led to an increase in the use of these techniques for drug quality analysis (Fernandez et al. Both techniques are nondestructive, fast, and require no sample preparation; radiation can pass through samples in blister packs (Kaur et al. Near-infrared is better suited than mid-infrared to quantitative analysis of drug contents. Near-infrared can identify active ingredients and is particularly useful for detecting incorrect concentrations of excipients, a common inconsistency in falsifed and substandard drugs (Deisingh, 2005). When used with imaging techniques, near-infrared can yield information about a tablet’s composi- tion. Koehler and colleagues demonstrated this by comparing images of a pain relief tablet, one captured using near-infrared imaging and the other Copyright © National Academy of Sciences. The red spots indicate active ingredient and other colors indicate other ingredients. Near-infrared spectra of two different compounds are often only subtly different, and accurately interpreting results may require signifcant training (Martino et al. Portable, battery-powered near-infrared spectrom- eters are a more accessible alternative to traditional spectrometers (Dowell et al. The model they used weighed 4 pounds and contained a battery that could operate for 10 hours after a full charge, making it a powerful feld tool (Bate et al. Raman spectroscopy can readily identify many active ingredients and give further information about excipients, as well as the relative concen- tration of active ingredients to excipients (Deisingh, 2005). These ratios can be key to detecting falsifed and substandard drugs, because criminal manufacturers often take care to use the correct amount of active ingredi- ent but may not be as exacting about the excipients, which may vary even among genuine manufacturers (Deisingh, 2005; Nyadong et al. For example, artesunate tablets may contain either of the highly similar sugars lactose or sucrose, depending on the manufacturer (Nyadong et al. Raman can distinguish between these, and a Raman spectrum of Cialis identifes both the active ingredient, tadalafl, and the primary excipient, lactose (Lim, 2012). Raman spectroscopy is particularly useful for detecting Copyright © National Academy of Sciences. On the other hand, some blister packs, capsule materials, and tablet coatings can interfere with Raman scattering and make readings diffcult (Martino et al. If the materials used produce fuorescence, they interfere with Raman signals, especially those read with handheld Raman spectrometers. Though far more widely available and useful for feld in- spections, these portable devices have less tolerance for fuorescence than their full-sized counterparts. This is especially problematic in screening antimalarials, as artesunate is somewhat fuorescent (Martino et al. But some investigators maintain that the fuorescence of genuine artesunate can serve as a tool to distinguish between good- and poor-quality samples, as those without suffcient active ingredient will not produce as much fuorescence (Ricci et al. Ricci and colleagues found that fuores- cence interfered more with their readings on the handheld scanner, but it ultimately produced as reliable results as the Fourier-transformed Raman scanner (Ricci et al. Like Raman and near-infrared spectrometry, it is a nondestructive, reliable technique, applicable to nuclei that have a non- zero spin, such as those in hydrogen and carbon-13, that yields quantitative data with little sample preparation. Integrating the area under each absorption peak can provide detailed information about molecular composition and structure; the area under each peak corresponds to the number of nuclei (in protons or carbon-13 atoms) contributing to that particular signal. Many common chemical con- taminants produce characteristic absorption peaks (Gottlieb et al. Using these methods, sci- entists have successfully differentiated between many authentic and falsifed versions of antimalarials, erectile dysfunction drugs, and antidepressants (Martino et al. X-ray diffraction and X-ray fuorescence are other techniques that can give substantial information about drug contents. X-ray diffraction can be used to analyze active ingredients and excipients, while X-ray fuorescence is used for elemental analyses that can often distinguish real from falsifed drugs (Kaur et al. Mass Spectrometry Mass spectrometry, generally called mass spec, is a sophisticated ana- lytical technique that requires extensive training and expertise to use. It provides abundant structural information and the precise molecular weight of the compound under investigation. Mass spec can identify many ac- tive ingredients and excipients, as well as some impurities (Kaur et al. This technique successfully detected falsifed halofantrine syrup, an antimalarial, in West Africa that instead contained a sulphonamide antibiotic (Wolff et al. When mass spectrometers were the size of a dishwasher (Stroh, 2007), their value in the poorest countries was hard to realize, but newer, portable machines can take this sophisticated technology into the feld (Yang et al. However, mass spectrometers require a stable electrical power source, which may be dif- fcult to obtain in some developing countries. An isotope ratio mass spectrometer provides detailed information about the abundance of various elemental isotopes. Many elements have naturally occurring isotopes that are present in minute quantities in any sample. The exact ratio of isotopes varies over time and space and with dif- ferent production techniques.

The expense of required assays cheap sildalist 120 mg on-line, discussed further in Chapter 6 order sildalist canada, is one barrier buy sildalist 120mgmg online, but a large part of the problem is logistical. The frst step in drawing a systematic random sample of drugs is identifying the sampling frame, the list of every drug vendor in a given area. In developed coun- tries, registered pharmacies and dispensaries are the only place most of the population gets medicine. In low- and middle-income countries, however, there is often an extensive pharmaceutical gray market. Identifying all the vendors is diffcult and can be further complicated by the blurry lines be- tween licit and illicit commerce (Seear et al. Health workers may supplement their incomes by selling medicine informally (Peters and Bloom, 2012); peddlers may trade medicines occasionally, along with any number of dry goods, at bazaars and fea markets. Without formative research to catalogue the sampling frame, research on medicines quality is vulnerable to bias. Samples should be bought by patient actors, local study staff posing as shoppers who conceal from the vendor that they are working on an epidemiological investigation. Without taking steps to protect study validity, the researchers risk wast- ing time and money on a study that does not produce reliable estimates. For example, in 2009 the Indian government conducted a massive survey of drug quality across the country, estimating that only 0. Questions about the methodological rigor of the survey, particularly the choice of sampling frame and methods for sample collection, have called these results into question both within India and internationally (Bate, 2009, 2010; Pandeya, 2009). The committee supports the guidelines on feld surveys of medicine quality that Newton and colleagues proposed in March 2009 (Newton et al. They provide a standard protocol for collecting medicines samples and concrete advice on sampling techniques (Newton et al. More research adhering to the checklist in Table 3-8 would allow for a better understanding of the burden of falsifed and substandard drugs, and it would facilitate valid comparisons of the problem among countries and over time. There is no substitute, however, for pharmacovigilance and postmarket surveillance. It is not a coincidence that falsifed and substandard medicines circulate Copyright © National Academy of Sciences. National surveillance systems should work to detect signals of substandard and falsi- fed drugs. Incorporating pharmacovigilance into the broader public health surveillance system will help ensure the system’s survival. Recommendation 3-1: Governments should establish or strengthen systems to detect substandard, falsifed, and unregistered medicines. This surveillance should be integrated with established public health surveillance systems. Analysis and reporting should precisely describe the product’s quality, packing, and registration. As Chapter 4 explains, governments can be slow to act against falsi- fed and substandard medicines. It is also diffcult to promote international effort against a threat as amorphous as fake medicines. Concrete data spur politicians and policy makers to action—information such as the number of doctor’s appointments repeated because of falsifed and substandard drugs, the number of hospital beds taken by victims of pharmaceutical crimes, premature deaths from untreated disease, and productive years lost to society from medicine poisoning. When pharmacovigilance systems indicate lack of medicines’ effcacy, these signals should be followed. In-depth investiga- tions can eventually produce data on the specifc consequences of falsifed and substandard medicines. Statistical methods 8 Describe the data analysis techniques used Ethical issues 9 Whether ethical approval was sought and whether the study encountered any ethical issues Packaging 10 Packaging examination and reference standards Chemical analysis 11 Chemical analysis and dissolution testing procedures and location(s) of laboratory. Possibly, validation against a reference method or inter-laboratory study continued Copyright © National Academy of Sciences. Packaging and chemical 16 • Packaging and chemistry results and their results relationship • Details of products sampled—how many, in what drug classes, countries of origin, batch numbers, manufacture and expiry dates • Results for each analysis—packaging, % active ingredient, dissolution • Additional information could be included in supplementary material Category of poor-quality 17 A clear statement for each medicine sample medicine detected, whether the investigators class it as genuine, counterfeit, substandard, or degraded, with an explanation as to why and whether the medicine was registered with the government in the location(s) sampled State company and 18 If the names of companies and addresses are not address as given on given, give a reason as to why this information is packaging not provided. Sharing data with the 19 Whether the data shared with the appropriate regulatory authority regulatory agency Dissemination 20 Description of any noncovert packaging features that would allow others to detect counterfeit medicines. If publication is not possible, consider disseminating via web-based supplementary material. Discussion Key Results 21 Summarize key results with reference to study objectives Limitations 22 Discussion of limitations of study, especially how robust the estimates of prevalence are and how applicable they may be to wider geographical areas. There is some reason to suspect problems with unregistered medicines in developing countries, but these problems resist detection (Amin et al. Postmarket surveillance systems, by defnition, follow only those products registered and granted market authorization in a given country. The committee believes that unregistered medicines are as important a sur- veillance target as falsifed and substandard ones. Research on the quality of unregistered medicines indicates that they are often of poor quality (Bate et al. Furthermore, drugs for sale in a country where they are not registered have often been traffcked. Chapter 5 will explain why any product that has left the licit chain of custody is suspect. A complete picture of the magnitude of the problem of poor-quality medicines depends on thorough and novel surveillance. This surveillance should advance systematic investigation of drug quality failures to build evidence for changing policy. Evidence suggests, however, that the problem is most common in low- and middle-income countries. Unscrupulous manufactur- ers and criminal cartels take advantage of the comparatively weak drug regulatory systems in these countries, knowing that the regulators are Copyright © National Academy of Sciences. The committee believes this project is promising for the 10 countries5 participating in the pilot program and, eventually, for the world. The investigator 5 Cambodia, Croatia, Georgia, Indonesia, Kyrgyzstan, Malaysia, the Philippines, Russia, Ukraine, and Vietnam. Regulators from the 10 pilot countries testing the rapid alert form and incident investigation system had training on the system in September 2012. Already the system has allowed investigators to link incidents in multiple countries. The lack of consensus on how to defne falsifed and substandard medicines has held back all public action on the topic, even surveillance. This depends on motivated and knowledgeable patients, and a longer-term improvement to the project might aim to increase reporting from health workers. The committee recognizes that building surveillance systems will be challenging in many countries. Nevertheless, taking steps to establish a system or to strengthen the existing system is a reasonable frst step in most of the world.

generic 120mg sildalist visa

purchase sildalist 120mgmg otc

When the recommendation relates to a specific population buy 120mgmg sildalist with amex, the key issues for that population may be briefly summarized purchase 120mg sildalist with visa. The new evidence on which the recommendation is based and other key operational and programmatic considerations that informed the development of the recommendation are summarized purchase sildalist 120mg with amex. In some cases, key clinical implementation issues specific to the recommendation are listed. For several key recommendations, discussion of implementation considerations relevant to programme managers is presented in Chapter 10. In some cases, critical issues requiring further research are briefly described or listed, where these are integral to the recommendations. The references relating to each section are listed at the end of the guidelines by chapter number. In general, these are presented in the following format: Background; Source(s) for recommendation(s); Additional guidance (where appropriate); and Existing recommendation(s). The population relevant to each recommendation is clearly specifed and also marked by an appropriate symbol for quick reference. The tables highlight selected topics that are particularly relevant to the respective populations. However, the topics listed are not exhaustive and many of the recommendations and other guidance are relevant across different populations. Algorithms for the 2013 recommendations for pregnant and breastfeeding women Annex 6. Adolescents may access care in a variety of settings, including paediatric and antenatal care clinics, as well as adult clinics. Since few health systems provide adolescent-specific services it can be challenging for adolescents to access health care and maintain adherence to treatment regimens. In general, in these guidelines, clinical and general care recommendations for adults apply to adolescents. Where guidance for adolescents is addressed in recommendations for children, this is clearly indicated. There are four specific recommendations on testing and counselling taken from additional recent adolescent-specific guidance. Most-at-risk populations include men who have sex with men, transgender people, people who inject drugs and sex workers. The location of the most important guidance and recommendations specific to key populations is summarized in Table 4. The topics Guidance for listed here are indicative of some of the specifc issues programme managers Socioeconomic, policy and legal context Section 10. The people tested who are not infected should be linked to appropriate prevention services, such as voluntary male medical circumcision in the priority countries in sub-Saharan Africa, or harm reduction services for those who use drugs, and encouraged to retest at a later time. Strategies should be able to reach the people who are most vulnerable, most-at-risk and marginalized (Box 5. Quality assurance systems should be put in place to minimize false-positive and false-negative results. Failure to do this will lead to people being given incorrect test results, with potential serious adverse long-term consequences. Mandatory or coerced testing is never appropriate, whether that coercion comes from a health care provider or from a partner or family member. Although confdentiality should be respected, it should not be allowed to reinforce secrecy, stigma or shame. Counsellors should raise, among other issues, whom else the person may wish to inform and how they would like this to be done. Shared confdentiality with a partner or family members and trusted others and with health care providers is often highly benefcial. Quality assurance mechanisms and supportive supervision and mentoring systems should be in place to ensure the provision of high-quality counselling. Quality assurance may include both internal and external measures and should include support from the national reference laboratory as needed. Connections to prevention, care and treatment services should include the provision of effective referral to appropriate follow-up services as indicated, including long- term prevention and treatment support. Quality assurance of both testing and counselling is essential in all approaches used. Rationale and supporting evidence The recommendations are based on evidence and on operational and programmatic considerations. The systematic review identified four randomized studies (3,4) and eight observational studies (5–10) comparing community-based testing to facility-based testing in generalized epidemics (Web Annex: www. However, the frequency of positive test results was higher in health facility–based testing than in many community settings. An additional review covering key populations identified three studies comparing community-based testing to facility-based testing in key populations (11–13). Fifteen studies examined potential negative consequences of community-based testing (10,14–25). These studies discussed both the clients’ positive testing experiences and their fears. The studies New did not demonstrate that community-based approaches either reduced stigma or fear or increased them or other harms. The few studies comparing the cost per person tested using facility- and community-based testing found that the cost per person tested was similar in both approaches (Web Annex: www. Community-based testing should be implemented in addition to provider-initiated testing and counselling. Multiple approaches are needed, which may include stand- alone sites, home-based testing, mobile outreach (including in workplaces, schools, universities, special testing campaigns and events) and multi-disease campaigns tailored to epidemiological and social contexts. It can identify seroconcordant positive couples who can be linked to treatment and receive treatment adherence support. Services should be offered to married and cohabiting couples, premarital couples, polygamous unions and any other partnerships. Health providers must be aware of the potential for intimate partner–based violence and should support individuals when they do not want to test with their partners. Existing recommendations (2) Generalized epidemics Provider-initiated testing and counselling is recommended for women as a routine component of the package of care in all antenatal, childbirth, postpartum and paediatric care settings. Low-level and concentrated epidemics Provider-initiated testing and counselling should be considered for pregnant women. While early testing is increasing, there are ongoing challenges of access, return of results and initiation of early treatment in infants testing positive. Point-of-care virological testing, in development, is expected to greatly improve early diagnosis and treatment. Final diagnosis (or definitive diagnosis) at the end of the risk period for mother- to-child transmission (breastfeeding period) should be ensured. For the most part, published evidence for adolescent-specifc recommendations is lacking; for these guidelines, considerable weight is given to expert opinion, values and preferences of adolescents and their health care providers, and to the feld experience of practitioners.

buy sildalist 120 mg with amex

purchase sildalist 120 mg

Verapamil may increase serum concentrations of digoxin order sildalist 120 mg with mastercard, quinidine cyclosporine purchase sildalist 120 mg fast delivery, and carbamazepine order genuine sildalist on-line. Confusion, stu- por, nausea, vomiting, metabolic acidosis, and hyperglycemia may also be observed. Continu- ous infusion, initiate infusion of 10mg/h and increase by 5mg/h to 15 mg/h. When increasing the infusion dose, administer for less than 24 hours at a rate of less than 15 mg/h Conversion from I. Contraindications Severe hypotension, second- or third-degree heart block or sinus node dys- function, and acute myocardial infarction with pulmonary congestion are con- traindications for diltiazem use. Dubin Precautions/Warnings Use of diltiazem with β-blockers or digoxin can result in conduction abnor- malities. Drug-Drug Interactions Cimetidine use may increase diltiazem serum concentrations. The risk of bradycardia or heart block is increased with β-blocker or digoxin use. Diltiazem may decrease metabolism of cyclosporine, carbamazepine, digoxin, lovastatin, midazolam, and quinidine. Noncardiac symptoms include confusion, stupor, nausea, vomiting, metabolic acidosis, and hyperglycemia. Compatible Diluents/Administration The final concentration for infusion of diltiazem should be 1 mg/mL. Antiarrhythmic Medications 183 Mechanism of Action Adenosine is an endogenous purinergic agent. Contraindications Second- or third-degree heart block or sinus node dysfunction, unless a pace- maker is in place, are contraindications for adenosine use. The initial dose of adenosine should be decreased in patients receiving dipyridamole. Atropine has a half-life in children younger than 2 years of 7 hours; in children older than 2 years, of 2. Precautions/Warnings Psychosis can occur with atropine use in sensitive individuals. Drug-Drug Interactions Atropine has additive effects when administered with other anticholinergic drugs. Dubin Mechanism of Action Magnesium sulfate suppresses early after-depolarizations that can trigger tor- sade de pointes. Contraindications Heart block, serious renal impairment, and coma are contraindications for magnesium sulfate use. Precautions/Warnings Use magnesium sulfate with caution in patients with renal dysfunction and those receiving digoxin. Compatible Diluents/Administration Magnesium sulfate is incompatible when mixed with fat emulsions, calcium gluceptate, clindamycin, dobutamine, hydrocortisone, polymyxin B, procaine hydrochloride, nafcillin, tetracyclines, and thiopental. Effect of acetyla- tor phenotype on the rate at which procainamide induces antinuclear antibodies and the lupus syndrome. Mexiletine: an effective antiarrhythmic drug for treatment of ventricular arrhythmias in congenital heart disease. Control of late post- operative ventricular arrhythmias with phenytoin in young patients. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. Proarrhythmia, cardiac arrest and death in young patients receiving encainide and flecainide. Usefulness of propafenone for supraven- tricular arrhythmias in infants and children. Intravenous esmolol for the treatment of supraventricular tachyarrhythmia: results of a multicenter, baseline-controlled safety and efficacy study in 160 patients. Double-blind titrated-dose comparison of metoprolol and pro- pranolol in the treatment of angina pectoris. Efficacy and safety of intravenous and oral nadolol for supraventricular tachycardia in children. Intravenous amiodarone for life-threatening tachyarrhythmias in children and young adults. Amiodarone in the treatment of cardiac arrhythmias in children: one hundred thirty-five cases. Pediatric use of intravenous amiodarone: efficacy and safety in critically ill patients from a multicenter protocol. Bretylium tosylate: a newly available antiarrhythmic drug for ventricular arrhythmias. Cardiac decompensation following verapamil ther- apy in infants with supraventricular tachycardia. Acute conversion of paroxysmal supraventricular tachycardia with intravenous diltiazem. The addition of these agents reduces early acute rejection events and may improve long-term graft and patient outcomes. The most controversial issue is whether corticos- teroids should be routinely added to form a “triple therapy. Finally, there is no agreement on whether intravenous anti- body induction therapy should be routinely used. A summary of the options for induction and maintenance therapy is shown in Table 8-1. It should be noted that there have been no large-scale randomized controlled tri- als of any immunosuppressive therapy in pediatric thoracic transplantation. Corticosteroids (Methylprednisolone and Prednisone) Indication Corticosteroids have broad immunosuppressive and anti-inflammatory effects. Many pediatric heart transplant centers are using steroid-avoidance regimens or early steroid withdrawal to avoid the many side effects and complications associated with long-term steroid use in children. High-dose steroids remain the standard therapy for treatment of acute rejection episodes. Mechanism of Action Corticosteroids decrease inflammation through the suppression of the migration of polymorphonuclear leukocytes and the reversal of increased 8. Corticosteroids prevent immune activation by inhibiting antigen presentation, cytokine production, and proliferation of lymphocytes. Some centers use moderate-dose oral steroids for less severe episodes of acute rejection (e. Maintenance Therapy Those centers that use long-term maintenance therapy typically use prednisone in doses of 0. Webber prednisone indefinitely, whereas others wean to discontinuation in the first few months if the rejection history is benign.