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By C. Hjalte. University of North Florida.

Dissolution tests require more training than colorim- etry and disintegration testing but may help predict the bioavailability of drugs buy super cialis 80mg fast delivery impotence over 70, an important aspect of their effcacy order genuine super cialis erectile dysfunction doctor maryland. If a drug has poor dissolution discount super cialis 80mg free shipping erectile dysfunction differential diagnosis, then the target dose of active ingredient may not be available to the patient purchase genuine super cialis on-line erectile dysfunction normal age. Incorrect excipient formulation, poor-quality manufacturing, and improper storage conditions can all lead to poor dissolution (Kaur et al. Even if the drug contains the correct dose of active ingredient, disintegration and dissolution tests may be able to identify an illegitimate drug (Deisingh, 2005). Disintegration tests are fairly simple and can be done in the feld, but dissolution tests require sophisticated equipment (Kaur et al. Chromatography Chromatography separates mixtures into their constituent parts based on a variety of chemical and physical properties. It can be used to separate drug ingredients for further testing and, when used with appropriate detec- tors, provides both qualitative and quantitative information about active ingredients and impurities (Kaale et al. Chromatography is there- fore the most common analytical method used in drug evaluations (Martino et al. The distance the sample travels is associated with its identity; the intensity of the spot correlates with the amount of the drug present. The plates are only used once, preventing contamination and limiting maintenance requirements (Kaale et al. The systems also require reliable electrical power, which can be an obstacle in develop- ing countries. Although the drugs are chemically similar (see Figure 6-3b), mefoquine is signif- cantly more expensive, and the cheaper drugs are sometimes sold labeled as mefoquine (Gaudiano et al. Gas chromatography, the most powerful chromatographic technol- ogy, provides similar information as the other chromatography systems. However, it may only be used for separation of volatile materials, such as residual solvents, undeclared ingredients, and any volatile impurities. This technique can only be used when the compounds of interest are gaseous in the analytical temperature range and do not degrade at or before the assay’s minimum temperature. For example, artemisinin derivatives for treating malaria are too unstable for gas chromatography (Martino et al. Investigators can use gas chromatography to develop profles of drugs’ volatile impurities and use those profles to link batches of drugs from the same source. The great deal of natural variation in impurities allows this; even batches of genuine product from different sources are distinguishable, and the same is true among different falsifed and substandard versions. In a review of the forensic applications of impurity profles, Mulligan and colleagues concluded that drugs with very similar impurity profles may be from the same place. Statistical analysis of impurity data can determine the probability that different samples have a common source (Mulligan et al. These tests can only be done in central laboratories, Copyright © National Academy of Sciences. The return on the time investment is mixed, as chro- matography separates a minimum number of components present in a sample. Spectroscopy Spectroscopy is a class of analytical techniques that measures the in- teraction of matter and radiation, thereby giving insight into chemical structure and contents. These techniques all provide qualitative data, 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.

Prolonged therapy should be avoided since the risk to the mother increases afer 48 h and the response of the myometrium is reduced cheap super cialis 80mg otc erectile dysfunction what is it. Dose Oral Adult and adolescent-Secondary postpartum haemorrhage: 400 µg 3 tmes daily for 3 days discount super cialis express erectile dysfunction treatment kerala. Slow intravenous injecton Adult and adolescent- Excessive uterine bleeding: 250 to 500 µg when the anterior shoulder is delivered or immediately afer birth order generic super cialis erectile dysfunction causes std. Contraindicatons Inducton of labour order cheap super cialis on line erectile dysfunction diabetes medication, frst and second stages of labour; vascular disease, severe cardiac disease especially angina pectoris; severe hypertension; hepatc impairment (Appendix 7a) and renal impairment; sepsis; eclampsia. Precautons Cardiac disease, hypertension; multple pregnancy (Appendix 7c); porphyria. Adverse Efects Nausea, vomitng; headache; dizziness; tnnitus, abdominal pain; chest pain; palpitatons; dyspnoea; bradycardia, transient hypertension, vasoconstricton; stroke, myocardial infarcton and pulmonary oedema also reported. Injecton: Store protected from light in a single dose container at a temperature not exceeding 30⁰C. Oxytocin* Pregnancy Category-C Schedule H Indicatons Routne preventon and treatment of postpartum and post-aborton haemorrhage; inducton of labour. Slow intravenous injecton Adult and adolescent- Preventon of postpartum haemorrhage: 5 units when the anterior shoulder is delivered or immediately afer birth. Note: The dose shown above is suitable for use in hospital where equipment to control the infusion rate is available; alternatve recommendatons may be suitable for other setngs. Careful monitoring of fetal heart rate and uterine motlity essental for dose ttraton (never give intravenous bolus injecton during labour); discontnue immediately in uterine hyperactvity or fetal distress. Contraindicatons Hypertonic uterine contractons, mechanical obstructon to delivery, fetal distress; any conditon where spontaneous labour or vaginal delivery inadvisable; avoid prolonged administraton in oxytocin-resistant uterine inerta, in severe pre-eclamptc toxaemia or in severe cardiovascular disease; uterine hyperactvity; major cephalopelvic disproporton, placental previa. Precautons Inducton or enhancement of labour in presence of borderline cephalopelvic disproporton (avoid if signifcant); mild to moderate pregnancy (Appendix 7c)-associated hypertension or cardiac disease; age over 35 years; history of low-uterine segment caesarean secton; avoid tumultuous labour if fetal death or meconium-stained amniotc fuid (risk of amniotc fuid embolism); water intoxicaton and hyponatraemia (avoid large volume infusions and restrict fuid intake); caudal block anaesthesia (risk of severe hypertension due to enhanced vasopressor efect of sympathomimetcs); interactons (Appendix 6a). Adverse Efects Uterine spasm, uterine hyperstmulaton (usually with excessive doses-may cause fetal distress, asphyxia and death, or may lead to hypertonicity, tetanic contractons, sof- tssue damage or uterine rupture); water intoxicaton and hyponatraemia associated with high doses and large-volume infusions; nausea, vomitng, arrhythmias, rashes and anaphylactoid reactons also reported; hypotension; sinus bradycardia; hematoma; fetal asphyxia. Dose Mifepristone 200 mg orally followed 1 to 3 days later by misoprostol 800 µg vaginally. Patents should return for followup visit afer approximately 14 days afer administraton of mifepristone. Contraindicatons Hypersensitvity to Mifepristone, Misoprostol or other prostaglandin; confrmed or suspected ectopic pregnancy (Appendix 7c); chronic adrenal failure; haemorrhagic disorders or concurrent antcoagulant therapy; inherited porphyria. Adverse Efects Abdominal pain, diarrhoea, nausea, vomitng; fever, chills, uterine cramping; vaginal bleeding or spotng; Pelvic infammatory disease. Contraindicatons Anaemia; heart disease, arterial hemorrhage; postpartum; premature detachment of placenta; hypersensitvity. Precautons Blood disorders, bleeding episodes or allergies, pregnancy (Appendix 7c), lactaton. Adverse Efects Dizziness,nausea and vomitng; tachycardia, Irregular heart beat, hypotension, chest pain; fushed skin, rashes. Terbutaline* Pregnancy Category-B Schedule H Indicatons Bronchial spasm in bronchial asthma and chronic bronchits; emphysema; premature labour; lymphoma. Subcutaneous, intramuscular or intravenous injecton Uncomplicated premature labour: Adult- 5 µg/min for 20min, increased every 20min in steps of 2. Contraindicatons Cardiac disease; antepartum haemorrhage; intrauterine infecton; intrauterine fetal death; placenta praevia; abrupto placenta; threatened miscarriage; cord compression; and eclampsia or severe pre-eclampsia; thyrotoxicosis; toxaemia. Precautons Suspected cardiovascular disease (such patents should be assessed by a cardiologist before initatng therapy), hypertension, mild to moderate pre-eclampsia, hyperthyroidism, and hypokalaemia (partcular risk with potassium-depletng diuretcs). It is important to monitor pulse rate (should not exceed 140 beats per min) and the patent’s fuid and electrolyte status (avoid over- hydraton-discontnue drug immediately and initate diuretc therapy if pulmonary oedema occurs). It should also be used with cauton in diabetes-monitor blood glucose (risk of hyperglycaemia and ketoacidosis, especially with intravenous β2 agonist); pregnancy (Appendix 7c). Adverse Efects Nausea, vomitng; pulmonary oedema; palpitaton; tachycardia, arrhythmias, peripheral vasodilaton; headache, tremor, hyperglycaemia, hypokalaemia, muscle cramps and tension and hypersensitvity reactons (including angioedema, urtcaria, rash, bronchospasm, hypotension, and collapse). They also exert a cardiostmulatory efect which may be the result of a direct acton on the heart. Thyroid hormones are used in hypothyroidism (myxoedema) and also in difuse non-toxic goitre, Hashimoto thyroidits (lymphadenoid goitre) and thyroid carcinoma. Levothyroxine Sodium (thyroxine Sodium) is the treatment of choice for maintenance therapy. It is almost completely absorbed from the gastrointestnal tract but the full efects are not seen for up to 1 to 3 weeks afer beginning therapy; there is a slow response to dose change and efects may persist for several weeks afer withdrawal. Dosage of levothy- roxine in infants and children for congenital hypothyroidism and juvenile myxoedema should be ttrated according to clinical response, growth assessment and measurement of plasma thyroxine and thyroid-stmulatng hormone. Antthyroid Drugs: Antthyroid drugs such as propylthiouracil and carbimazole are used in the management of thyrotoxicosis. They are usually well- tolerated, with mild leukopenia or rashes developing in a few percent of cases, usually during the frst 6-8 weeks of therapy. During this tme the blood count should be checked every 2 weeks or if a sore throat or other signs of infecton develop. The drugs are generally given in a high dose in the frst instance untl the patent becomes euthyroid, the dose may then be gradually reduced to a maintenance dose which is contnued for 12-18 months, followed by monitoring to identfy relapse. There is a lag tme of some 2 weeks between the achievement of biochemical euthyroidism and clinical euthyroidism. Beta- adrenoceptor antagonists (beta-blockers) (usually propranolol) may be used as a short-term adjunct to antthyroid drugs to control symptoms but their use in heart failure associated with thyrotoxicosis is controversial. Treatment can be given, if neces- sary, in pregnancy but antthyroid drugs cross the placenta and in high doses may cause fetal goitre and hypothyroidism. The lowest dose that will control the hyperthyroid state should be used (requirements in Graves disease tend to fall during preg- nancy). If surgery (partal thyroidectomy) is contemplated, it may be necessary to give iodine for 10 to 14 days in additon to antthyroid drugs to assist control and reduce vascularity of the thyroid. Iodine should not be used for long-term treat- ment since its antthyroid acton tends to diminish. In patents in whom drug therapy fails to achieve long-term remissions defnitve treatment with surgery or (increasingly) radioactve iodine is preferable. Carbimazole* Pregnancy Category-D Schedule H Indicatons Thyrotoxicosis; Grave’s disease. Contraindicatons Nodular goitre; subacute thyroidits, postpartum painless thyroidits. Adverse Efects Nausea, mild gastro-intestnal disturbances; headache; rashes and pruritus, arthralgia; rarely, myopathy, alopecia, bone marrow suppression (including pancytopenia and agranulocytosis); vasculits; cholestatc jaundice, hepatc necrosis. Storage Store protected from light and moisture at a temperature not exceeding 30⁰C. Contraindicatons Lactaton (Appendix 7b), tuberculosis, bron- chits, asthma, hyperkalaemia, acne vulgaris. Adverse Efects Hypersensitvity reactons including coryza- like symptoms; headache; lacrimaton; conjunctvits, pain in salivary glands; laryngits, bronchits, rashes; on prolonged treatment depression, insomnia, impotence; goitre in infants of mothers taking iodides; eosinophilia, hypothyroidism, abdominal pain, arrhythmia. Storage Store in ground glass stoppered container or earthenware container with waxed bungs. Dose Oral Adult- Hypothyroidism: Initally 50 to 100 µg daily (25 to 50 µg for those over 50 years) before breakfast, increased by 25 to 50 µg every 3 to 4 weeks untl normal metabolism maintained (usual maintenance dose, 100 to 200 µg daily); where there is cardiac disease, initally 25 µg daily or 50 µg on alternate days, adjusted in steps of 25 µg every 4 weeks. Child- Congenital hypothyroidism and juvenile myxoedema; Up to 1 month: initally 5 to 10 µg/kg daily. Over 1 month: initally 5 µg/kg daily, adjusted in steps of 25 µg every 2 to 4 weeks, untl mild toxic symptoms appear, then reduce dose slightly. Immunologicals Actve Immunity: Actve immunity may be induced by the administraton of micro-organisms or their products which act as antgens to induce antbodies to confer a protectve immune response in the host. Vaccinaton may consist of (a) a live atenuated form of a virus or bacteria, (b) inactvated preparatons of the virus or bacteria, or (c) extracts of or detoxifed exotoxins. Live atenuated vaccines usually confer immunity with a single dose which is of long duraton. Inactvated vaccines may require a series of injectons in the frst instance to produce an adequate antbody response and in most cases, require reinforcing (booster) doses. Extracts of or detoxifed exotoxins require a primary series of injectons followed by reinforcing doses. Passive Immunity: Passive immunity is conferred by injectng preparatons made from the plasma of immune individuals with adequate levels of antbody to the disease for which protecton is sought. This immunity lasts only a few weeks but passive immunizaton can be repeated where necessary. Sera and Immunoglobulins Antbodies of human origin are usually termed immunoglob- ulins. Because of serum sickness and other allergic-type reactons that may follow injectons of antsera, this therapy has been replaced wherever possible by the use of immunoglobulins. Contraindicatons and Precautons Anaphylaxis, although rare, can occur and epinephrine (adrenaline) must always be immediately available during immunizaton. Immunoglobulins may interfere with the immune response to live virus vaccines which should normally be given either at least 3 weeks before or at least 3 months afer the administra- ton of the immunoglobulin. Intravenous injecton; Systemic reactons including fever, chills, facial fushing, headache and nausea may occur, partc- ularly following high rates of infusion. Ant-D Immunoglobulin (Human): Ant-D immunoglobulin is prepared from plasma with a high ttre of ant-D antbody. It is available to prevent a rhesus- negatve mother from forming antbodies to fetal rhesus- positve cells which may pass into the maternal circulaton.

These routes are also being studied for the local delivery of drugs directly to the site of action buy super cialis 80mg line erectile dysfunction treatment in the philippines, thereby reducing the dose needed to produce a pharmacological effect and also possibly minimizing systemic side-effects purchase super cialis 80 mg otc erectile dysfunction in middle age. Drug delivery technology is becoming increasingly sophisticated and current approaches take into account such factors as the influence of pharmacokinetic processes on drug efficacy 80 mg super cialis with amex erectile dysfunction in the military, as well as the importance of drug timing and of drug targeting to the site of action discount super cialis amex erectile dysfunction doctor calgary. Emerging technologies are addressing a variety of issues, including bio-responsive drug release and the delivery of nucleic acid therapeutic entities. This book is concerned with the various routes of delivery under investigation, and these new and 3 emerging delivery technologies. However, a full appreciation of these concerns cannot be gained without first understanding: • the concept of bioavailability; • the process of drug absorption; • the pharmacokinetic processes; • the importance of timing for optimal drug therapy; • delivery considerations for the “new biotherapeutics”; • the limitations of conventional therapy. This chapter provides an overview of these considerations and highlights the necessity for advanced drug delivery systems, in order to optimize drug efficacy. In terms of drug efficacy, the bioavailability of a drug is almost as important as the potency of the active agent itself. Measuring a drug’s bioavailability thus involves measuring the rate and extent of drug absorption. This is ideally measured in terms of the clinical response of a patient; however, only a minority of clinical responses, such as blood pressure, can provide accurate quantitative data for analysis. A further method of assessment is the measurement of the drug concentration at the site of action; however, this cannot be achieved practically. For clinical purposes, it is generally accepted that a dynamic equilibrium exists between the concentration of drug at the site of action (C ) and the concentration of drug in blood plasma (C ). Thus Cs p p is generally used as an indirect indicator of the concentration of drug at its site of action and the most# commonly used method of assessing the bioavailability of a drug involves the construction of a Cp versus “Time” curve (Cp vs T curve). A typical Cp vs T curve following the administration of an oral tablet is given in Figure 1. At zero time (when the drug is first administered), the concentration of drug in the plasma is zero. As time proceeds, more and more of the drug starts to appear in the plasma, as the drug is gradually absorbed from the gut. Following peak levels, the concentration of drug in the plasma starts to decline, as the processes of drug distribution and drug elimination predomi-nate. Thus a profile of the rate and extent of drug absorption from the formulation over time is obtained. Formulation B has a slower onset of therapeutic action, but the therapeutic effect is sustained longer than that obtained with formulation A. Formulation C demonstrates both a slow rate and extent of absorption, in comparison to the other two formulations. Relative Bioavailability is the comparison of the rate and extent of absorption of two formulations given by the same route of administration. A study of relative bioavailability generally involves the comparison of a 4 Figure 1. For example, the bioavailability of a new tablet formulation of a drug for oral administration can be compared with the oral bioavailability of the brand leader tablet formulation. The relative bioavailabilities may be calculated from the corresponding Cp vs T curves as follows: (Equation 1. In contrast, Absolute Bioavailability involves comparison of the drug’s bioavailability with respect to the corresponding bioavailability after iv administration. Absolute bioavailability may be calculated by comparing the total area under the Cp vs T curve obtained from the absorption route in question (often the oral route, although the approach can be used for other routes, such as the nasal, buccal, transdermal routes etc. In contrast, a drug administered via any other route (intramuscular, subcutaneous, intestinal, rectal, buccal, sublingual, nasal, pulmonary and vaginal) will have to circumvent various physical and chemical barriers (discussed below), so that the bioavailability will be lower in comparison to that obtained after iv administration. For example, to achieve 100% bioavailability via the oral route requires the drug to: • be completely released from the dosage form into solution in the gastrointestinal fluids; # Using C as an indicator of C is obviously a simplification that is not always valid and the relationship cannot be used p s without first estabkishing that C and c are consistently related. As many drugs bind in a reversible manner to plasmap s protenis, a more accurate index of C is the concentration of the drug in protein-free plasma Cs pfp. However, this measurement is more difficult to carry out practically than measuring the totle concentration of both unbound drug in total plasma, thus C is often used in preference to Cp pfp as an index of Cs 5 • be completely stable in solution in the gastrointestinal fluids; • pass through the epithelium of the gastrointestinal tract; • undergo no first-pass metabolism in the gut wall or liver, prior to reaching the systemic circulation. The bioavailable dose (F) is the fraction of the administered dose that reaches the systemic circulation. For example, if a drug is given orally and 90% of the administered dose is present in the systemic circulation, F=0. Similarly, drugs administered by alternative routes, such as the buccal, sublingual, nasal, pulmonary and vaginal routes, must all cross the appropriate epithelial interfaces to reach the general circulation. The types of epithelial interfaces, the barriers they pose to drug absorption, and the routes and mechanisms of drug absorption across these interfaces, are described below. They consist of one or more layers of cells, separated by a minute quantity of intercellular material. All epithelia are supported by a basement membrane of variable thickness, which separates the epithelium from underlying connective tissues. Epithelial interfaces are involved in a wide range of activities such as absorption, secretion and protection; all these major functions may be exhibited at a single epithelial surface. For example, the epithelial lining of the small intestine is primarily involved in absorption of the products of digestion, but the epithelium also protects itself from potentially harmful substances by the secretion of a surface coating of mucus. Epithelia are classified according to three morphological characteristics: • the number of cell layers; • the cell shape; • the presence of surface specializations. A single layer of epithelial cells is termed simple epithelium, whereas those composed of more than one layer are termed stratified epithelia. Stratified epithelia are found in areas which have to withstand large amounts of wear and tear, for example the inside of the mouth, or the skin. Epithelial cells may be, for example, squamous (flattened), columnar (tall), cuboidal (intermediate between squamous and columnar) and may contain surface specializations, such as cilia in the nasal epithelium and keratin in the skin. Detailed descriptions of the epithelia present in the various routes of drug delivery are given in the relevant chapters; a generalized summary is given here in Table 1. In man, goblet cells are scattered amongst cells of many simple epithelial linings, particularly of the respiratory and gastrointestinal tracts. Mucus is mainly composed of long, entangled glycoprotein molecules known as mucins, which vary in length from 0. Each monomer consists of a protein backbone, approximately 800 amino acids long, rich in serine, proline and threonine. Oligosaccharide side chains, generally up to 18 residues in length, composed of N- acetylgalactosamine, N-acetylglucosamine, galactose, fucose and N-acetylneuraminic acid are attached to the protein monomers. Its most important property is its viscoelasticity, which enables it to act as a mechanical barrier, but also allows it to flow. Mucus acts as a physical barrier through which drug molecules must diffuse, prior to reaching the absorbing surface. The rate of diffusion through the mucus will be dependent upon such factors as the thickness of the mucus layer, mucus viscosity and any interactions which may occur between the drug and mucus. In the respiratory tract, mucus is also involved in the process of mucociliary clearance, which contributes to the epithelial barrier properties by entrapping potentially hazardous substances, such as dust and microorganisms, within a viscoelastic mucus blanket. The mucus is then propelled by the claw-like tips of “hair-like” cilia towards the throat (movement occurs in a downwards direction from the nasal epithelium, or 7 in an upwards direction from the lungs), where the mucus and any entrapped particulates are either swallowed or expectorated. Although this process is beneficial if inhaled particles are hazardous, drug particles may also be cleared by this mechanism. Hydrophobic membranes and cell junctions Membranes surround all living cells and cell organelles. In the fluid mosaic model of the plasma membrane, the surfaces of the membrane are composed of tightly packed lipoidal molecules (including phospholipids, sphingolipids and sterols), interspersed with proteins. The proteins were originally thought to float in a sea of lipid, resulting in a rather ill-defined mixed membrane. Proteins in specific conformations act as structural elements, transporters of nutrients and environmental monitors. The plasma membrane of epithelial cells, in common with other cell types, is selectively permeable, allowing the penetration of some substances but not others. The construction of the membrane from amphipathic lipid molecules forms a highly impermeable barrier to most polar and charged molecules, thereby preventing the loss of most water-soluble contents of the cell. This selective permeability presents a physical barrier to drug absorption, limiting absorption to specific routes and mechanisms, as described below (see Section 1. A further important feature of epithelia for drug delivery is that the epithelial cells are bound together by several types of plasma membrane specializations, including desmosomes, gap junctions and junctional complexes (Figure 1. Desmosomes (macula adherens) are the commonest type of cell junction and are found at many intercellular sites, including cardiac muscle, skin epithelium and the neck of the uterus. At the desmosome, the opposing plasma membranes are separated by a gap in which many fine, transverse filaments are present. Desmosomes provide strong points of cohesion between cells and act as anchorage points for the cytoskeleton of each cell. Gap junctions (nexus) are broad areas of closely opposed plasma membranes, but there is no fusion of the plasma membranes and a narrow gap, of about 2 to 3 nm wide, remains. The “gap” is crossed by cytoplasmic filaments, which allow intracellular cytoplasm to transfer between cells. This type of cell junction not only functions as an adherent zone, but also permits the passage of ions and other small molecules (sugars, amino acids, nucleotides and vitamins). Junctional complexes comprise intercellular membrane specializations which encircle the cells, preventing access of luminal contents to the intercellular spaces. They are found between the cells of simple cuboidal (for example in the lungs) and simple columnar (for example in the gastrointestinal tract) epithelia, and lie immediately below the luminal surface. They are made up of three components: (i) tight junctions (zonula occludentes), which consist of small areas where the outer lamina of opposing plasma membranes are fused with one another, via specific proteins which make direct contact across the intercellular space. A fine mat of filamentous material is present on the cytoplasmic aspect of these junctions. Biochemical barriers 9 In addition to a physical barrier, the epithelia also present a biochemical barrier to drug absorption, in the form of degradative enzymes. For example, the gastrointestinal tract contains a wide array of enzymes, which are present in a variety of locations: • the lumen; • adsorbed to the mucus layer; • the brush-border (microvilli) of the enterocytes; • intra-cellular (free within the cell cytoplasm and within cellular lysosomes); • the colon (colonic microflora).

Te reasons for not giving further considera- text on non-infuential issues in the section on tion to an individual study also are indicated in exposure purchase line super cialis erectile dysfunction high cholesterol, such as a general description of data the square brackets super cialis 80mg generic erectile dysfunction treatment germany. Meeting participants or subgroup chair cheap super cialis 80 mg without prescription erectile dysfunction on prozac, draf text that pertains to the description or interpretation of cancer data purchase discount super cialis on line diabetic with erectile dysfunction icd 9 code, or Five categories of participant can be present participate in the evaluations. Te declarations are updated and reviewed again at the opening of Representatives of national and interna- the meeting. Interests related to the subject of tional health agencies ofen attend meetings the meeting are disclosed to the meeting par- because their agencies sponsor the programme ticipants and in the published volume (Cogliano or are interested in the subject of a meeting. Representatives do not serve as meeting chair or Te names and principal afliations of par- subgroup chair, draf any part of a Monograph, ticipants are available on the Monographs pro- or participate in the evaluations. Observers do not serve as meeting chair or Group serves as an individual scientist and not as subgroup chair, draf any part of a Monograph, a representative of any organization, government or participate in the evaluations. Subsequently, relevant the meeting chair or subgroup chair, they may biological and epidemiological data are collected also draf text or prepare tables and analyses. Te chair may elect other knowledgeable organizations may be to poll Working Group Members to determine asked to provide input to the sections on produc- the diversity of scientifc opinion on issues where tion and use, although this involvement is not consensus is not readily apparent. Information on pro- Afer the meeting, the master copy is verifed duction and trade is obtained from governmen- by consulting the original literature, edited and tal, trade and market research publications and, prepared for publication. Information on uses may be obtained from published sources but is ofen complemented by direct contact with man- B. Te available studies are summarized by the Six months before the meeting, the mate- Working Group, with particular regard to the rial obtained is sent to meeting participants to qualitative aspects discussed below. Care is taken to ensure that each study include complex mixtures, occupational expo- summary is written or reviewed by someone sures, physical and biological agents, lifestyle not associated with the study being considered. Over time, the structure of a Monograph meets in plenary session to review the subgroup has evolved to include the following sections: drafs and develop the evaluations. As a result, Exposure data the entire volume is the joint product of the Studies of cancer in humans Working Group, and there are no individually Studies of cancer in experimental animals authored sections. Consensus refects broad Evaluation and rationale agreement among Working Group Members, but 12 Preamble In addition, a section of General Remarks at response and clinical disease other than cancer the front of the volume discusses the reasons the are also presented. For foreign bodies, fbres and respir- Tis part of the Preamble discusses the types able particles, size range and relative dimensions of evidence considered and summarized in each are indicated. Exposure data such as historical perspectives or the description Each Monograph includes general informa- of an industry or habit, may be included. Also included is information on An overview of methods of analysis and production and use (when appropriate), meth- detection of the agent is presented, including ods of analysis and detection, occurrence, and their sensitivity, specifcity and reproducibility. Methods for monitoring human agent, regulations and guidelines for use may be exposure are also given. Information tion may allow a reasonable estimate to be made on chemical and physical properties that are rel- of the date before which no human exposure to evant to identifcation, occurrence and biologi- the agent could have occurred. A description of technical reported occurrence of an exposure are also pro- products of chemicals includes trade names, rel- vided when available. In addition, methods of evant specifcations and available information synthesis used in past and present commercial on composition and impurities. Some of the production and diferent methods of production, trade names given may be those of mixtures in which may give rise to diferent impurities, are which the agent being evaluated is only one of described. Te countries where companies report pro- For biological agents, taxonomy, struc- duction of the agent, and the number of compa- ture and biology are described, and the degree nies in each country, are identifed. It should not, (e) Regulations and guidelines however, be inferred that those areas or nations Statements concerning regulations and are necessarily the sole or major sources or users guidelines (e. Some identifed uses may not be maximal levels permitted in foods and water, current or major applications, and the coverage pesticide registrations) are included, but they is not necessarily comprehensive. In the case of may not refect the most recent situation, since drugs, mention of their therapeutic uses does not such limits are continuously reviewed and modi- necessarily represent current practice nor does it fed. Te absence of information on regulatory imply judgement as to their therapeutic efcacy. For biological agents, leg- Information on the occurrence of an agent in islation and control, including vaccination and the environment is obtained from data derived therapy, are described. When available, data on the generation, per- Tis section includes all pertinent epidemio- sistence and bioaccumulation of the agent are logical studies (see Part A, Section 4). Such data may be available from biomarkers are included when they are relevant national databases. Data that indicate the extent of past and pre- sent human exposure, the sources of exposure, (a) Types of study considered the people most likely to be exposed and the fac- tors that contribute to the exposure are reported. Several types of epidemiological study con- Information is presented on the range of human tribute to the assessment of carcinogenicity in exposure, including occupational and environ- humans — cohort studies, case–control studies, mental exposures. Tis includes relevant fndings correlation (or ecological) studies and interven- from both developed and developing countries. Rarely, results from randomized tri- Some of these data are not distributed widely and als may be available. Case reports and case series may be available from government reports and of cancer in humans may also be reviewed. In the case of mixtures, indus- Cohort and case–control studies relate indi- tries, occupations or processes, information is vidual exposures under study to the occurrence of given about all agents known to be present. For cancer in individuals and provide an estimate of processes, industries and occupations, a histori- efect (such as relative risk) as the main measure cal description is also given, noting variations in of association. Intervention studies may provide chemical composition, physical properties and strong evidence for making causal inferences, as levels of occupational exposure with date and exemplifed by cessation of smoking and the sub- place. For biological agents, the epidemiology of sequent decrease in risk for lung cancer. In correlation studies, the units of inves- tigation are usually whole populations (e. Confounding is a form of bias individual exposure is not documented, which that occurs when the relationship with disease is renders this kind of study more prone to con- made to appear stronger or weaker than it truly is founding. Tese types of study tors have been minimized in an individual study, generally arise from a suspicion, based on clinical consideration is given to several aspects of design experience, that the concurrence of two events — and analysis as described in the report of the that is, a particular exposure and occurrence of study. For example, when suspicion of carcino- a cancer — has happened rather more frequently genicity arises largely from a single small study, than would be expected by chance. Case reports careful consideration is given when interpreting and case series usually lack complete ascertain- subsequent studies that included these data in an ment of cases in any population, defnition or enlarged population. Most of these considera- enumeration of the population at risk and esti- tions apply equally to case–control, cohort and mation of the expected number of cases in the correlation studies. Cases of disease in the case–control and cohort studies, however, these study population should have been identifed in types of study may add materially to the judge- a way that was independent of the exposure of ment that a causal relationship exists. Tey may, in some instances, other variables that can infuence the risk of dis- strengthen inferences drawn from studies of ease and may have been related to the exposure cancer itself. Potential confounding by such vari- ables should have been dealt with either in the (b) Quality of studies considered design of the study, such as by matching, or in the analysis, by statistical adjustment. In cohort It is necessary to take into account the pos- studies, comparisons with local rates of disease sible roles of bias, confounding and chance in may or may not be more appropriate than those the interpretation of epidemiological studies. At the very least, they should have ured co-variates that may difer among studies. In a cohort study, data on all pooled analysis that is pertinent to a particular cancer sites and all causes of death should have Monograph (see Part A, Section 4). Additionally, been given, to reveal the possibility of reporting as a means of gaining insight from the results of bias. In a case–control study, the efects of inves- multiple individual studies, ad hoc calculations tigated factors other than the exposure of interest that combine data from diferent studies may should have been reported. Te results estimates of relative risk, absolute rates of can- of such original calculations, which would be cer, confdence intervals and signifcance tests, specifed in the text by presentation in square and to adjust for confounding should have been brackets, might involve updates of previously clearly stated by the authors. Tese methods have conducted analyses that incorporate the results been reviewed for case–control studies (Breslow of more recent studies or de-novo analyses. Combined analyses of data from (d) Temporal efects multiple studies are a means of resolving this ambiguity, and well conducted analyses can be Detailed analyses of both relative and abso- considered. Tere are two types of combined lute risks in relation to temporal variables, such analysis. Te frst involves combining summary as age at frst exposure, time since frst exposure, statistics such as relative risks from individual duration of exposure, cumulative exposure, peak studies (meta-analysis) and the second involves a exposure (when appropriate) and time since pooled analysis of the raw data from the individ- cessation of exposure, are reviewed and sum- ual studies (pooled analysis) (Greenland, 1998). Analyses of temporal Te advantages of combined analyses are relationships may be useful in making causal increased precision due to increased sample size inferences. In addition, such analyses may sug- and the opportunity to explore potential con- gest whether a carcinogen acts early or late in the founders, interactions and modifying efects process of carcinogenesis, although, at best, they 16 Preamble allow only indirect inferences about mechanisms (f) Criteria for causality of carcinogenesis. Afer the quality of individual epidemiologi- cal studies of cancer has been summarized and (e) Use of biomarkers in epidemiological assessed, a judgement is made concerning the studies strength of evidence that the agent in question Biomarkers indicate molecular, cellular or is carcinogenic to humans. In making its judge- other biological changes and are increasingly ment, the Working Group considers several crite- used in epidemiological studies for various pur- ria for causality (Hill, 1965). Tis is a rapidly evolving feld that encom- of the same design or that use diferent epidemi- passes developments in genomics, epigenomics ological approaches or under diferent circum- and other emerging technologies. If there are inconsistent and interindividual diferences in susceptibility results among investigations, possible reasons to the agent(s) being evaluated may contribute are sought (such as diferences in exposure), and to the identifcation of carcinogenic hazards to results of studies that are judged to be of high humans. If the polymorphism has been demon- quality are given more weight than those of stud- strated experimentally to modify the functional ies that are judged to be methodologically less activity of the gene product in a manner that is sound. Te demonstration of a decline in risk afer ity may provide evidence that reinforces biologi- cessation of or reduction in exposure in indi- cal plausibility. It should be noted, however, that viduals or in whole populations also supports a when data on genetic susceptibility originate causal interpretation of the fndings. On the one hand, an agent results and inconsistencies across studies, and may be specifc in causing tumours at one site or such data therefore require careful evaluation. On the other, carci- If the known phenotype of a genetic polymor- nogenicity may be evident through the causation phism can explain the carcinogenic mechanism of multiple tumour types. Temporality, precision of the agent being evaluated, data on this pheno- of estimates of efect, biological plausibility and type may be useful in making causal inferences. Such a judgement requires tal animals was established or highly suspected frst that the studies meet, to a sufcient degree, before epidemiological studies confrmed their the standards of design and analysis described carcinogenicity in humans (Vainio et al.