This is based on the fact that 35 discount carbidopa online mastercard translational medicine, 36 most prostanoid receptor ligands are direct derivatives of the endogenous ligands discount 125 mg carbidopa symptoms melanoma, the so-called eicosanoids order carbidopa 125mg fast delivery medicine of the future. These ligands are highly similar, all consisting of large aliphatic, lipophilic alkyl chains. The presence of the leukotriene and cannabinoid receptors in this lipid cluster may seem strange at first. Leukotrienes are however also eicosanoids, which clarifies the position of the leukotriene B4 and cysteinyl-leukotriene 37, 38 receptors in this cluster. In addition, arachidonic acid is the common precursor for eicosanoids and two derivatives of arachidonic acid, anandamide and 2- arachidonylglycerol, both of which are endogenous ligands (‘endocannabinoids’) of the cannabinoid receptors. The relationship between target clustering in the substructure tree (Figure 2) and ligand promiscuity suggests that the substructure tree may be used to identify possible side effects on receptors that are close neighbors in this tree. If inspection reveals a ligand to bind to receptor(s) that are phylogenetically related to the target of interest, a more detailed experimental follow-up with respect to receptor selectivity would be worthwhile. For instance, with the exclusion of the glycoprotein, P2Y, angiotensin, and bradykinin receptors, all other receptors represented by two subtypes occur in pairs in both the ligand tree and the sequence tree. In addition, the prostanoid receptors largely group together in both trees, as do most of the aminergic receptors. D1 and D5 (D1-like) versus D2, D3, and D4 (D2-like), exists both in the sequence-based classification and 39 ligand-based classification. This is in agreement with a previous study and also known from drugs on the market such as the benzazepines that favor D1–like over D2-like dopamine receptors. Similarly, antipsychotics such as chlorpromazine have a higher 40 affinity for the D2-like subtypes than D1-like receptors. The fact that many clusters arise in both trees indicates that the receptors in these clusters have similar sequences and similar ligands, that is, ligands with substantially overlapping substructure sets. The (qualitative) similarities and differences among sequence and substructure trees are discussed in the following. This plot, provided in Figure 3 (and described in detail in the Materials and Methods section), visualizes how receptor distances deviate between the sequence-based tree and the ligand-based classification of receptors. In sequence space, receptor distances indicate the (dis)similarly between protein sequences, while in ligand space, receptor distances reflect the overlap in structural features found in ligands for these receptors. From the delta-delta plot, it becomes apparent that the prostanoid receptors and P2Y1 receptor are on average the most distant receptors from the rest of the classes. This may be a reflection of the evolutionary relationship between sequences, which results in coverage of a small region of the overall sequence space. The ligands for these targets do not have such a direct relationship and thus cover a broader range in overall substructure space. The difference between ligand-based and target-based classifications may be due to 43 convergent evolution. Functional convergence denotes how proteins that differ in sequence may fulfill the same protein function. These may therefore have a different selectivity profile compared to the endogenous ligand. Delta-delta plot visualization of receptor distances in sequence and substructure space. The average distance towards the other targets is plotted for sequence and substructure space. Targets that are, on average, more distant from the rest are plotted further away from the origin; targets plotted above the diagonal are more distant in sequence space, while targets plotted below the diagonal are more distant in substructure space. This indicates that this receptor is, in general, more distant from the other receptors, most prominent in sequence space. Example plots expressing the performance of the simulated receptor de-orphanization. The full set of plotted scores is provided in Additional file 2 – Plotted scores for the leave-one-out validation. For each plot, receptors are ordered along the x-axis (labeled “Number of included receptors”) in order of increasing distance in sequence space to the receptor under study. On the y-axis (labeled “Ligands identified”), the cumulative number of retrieved ligands is depicted, normalized linearly to the interval [0;1]. The red curve indicates the number of active ligands that are retrieved when including all (closest) receptors that are listed along the x-axis up to that point. The blue diagonal illustrates recovery of ligands when performance is equal to random prediction. For each receptor in the dataset, we pretended not to know any of its ligands by excluding them from the datasets (we ‘orphanized’ the receptor in this particular run of the protocol). We next predicted its ligands by considering a model derived from the closest neighbors of the receptor in sequence space (we attempted to ‘de-orphanize’ the receptor whose ligands we omitted from the study in the previous step). The cumulative number of correctly identified ligands of every receptor is plotted against the number of closest neighbors (sequences) included to find these ligands. Curves of the second category display a gradual rise that is approximately equal to the diagonal of the plot. The steep rises are caused by a few receptors identifying the majority of ligands. The poor performance concerning the P2Y1 receptor is probably due to the nature of its ligands: this set consists of a small number of highly similar ligands that all possess a phosphate group, a feature not found in other ligands in the database. The number of features (substructures) shared with ligands of this receptor and other receptors is therefore small. Interestingly, the adenosine A1 and A3 receptors, which are also purinergic, identify most (28 out of 42) of the P2Y1 ligands. However, in sequence space these receptors are at great distance (at positions 91 and 92, respectively). The absence of a receptor may influence the order of other receptors in the trees. Scarcity of ligand data is reflected in the substructure profiles, thereby influencing the correlations among receptors. The issue of data (in) completeness and its effect on interaction networks was recently discussed by Mestres 44 et al. Using three datasets of increasing complexity (more connections) that linked ligands to targets based on full chemical identity, the authors showed that an increase 129 Chapter 4 in the number of connections rapidly leads to shifts in connection patterns. However, our study linked targets based on overlap in substructures; as a consequence sharing of substructures rather than of ligands is sufficient for targets to be identified as related. In addition, our method employs an exhaustive approach to analyze the structural features of ligands. Frequent substructure mining considers all possible substructures that occur in the ligands and is therefore unbiased, i. However, in the present study less ‘obvious’ substructures such as ethyl or isobutyl are also considered [Chapter 3; ref 21]. For a complete discussion on substructure generation and evaluation, see chapter 2 or ref. For instance, it can be applied to the realm of enzymes to complement other 47 chemogenomics analyses. Targets were analyzed based on the substructure profiles of their ligands using an unbiased approach.
Limit Test for Arsenate Acetarsol : An organic arsenic compound carbidopa 110mg without prescription symptoms 5dpo, being therapeutically active when administered orally buy 300mg carbidopa with mastercard treatment 8th february, that might be of value in the treatment of spirochaetal or protozoal diseases carbidopa 125mg with mastercard symptoms of anxiety, for instance : syphilis, yaws, relapsing fever, sleeping sickness and amoebic dysentry. It is made from p-hydroxyphenylarsonic acid, which may be prepared either by straight forward meth- ods from phenol or from p-aminophenylarsonic acid. The resulting compound obtained from either of these reactions is nitrated, reduced and the base is finally acetylated to afford acetarsol. Examples of a few official compounds subject to this test from the Pharmacopoeia are given below : S. Purified Talc When preparing solution A in the test for Calcium, No effervescence produced. Limit Test for Nitrate Basic nitrate is usually found as an impurity in bismuth salts (e. However, this test has a serious disadvantage of correctly matching the yellow colours with great difficulty. Limit Test for Oxalate Oxalate is found to be a frequent impurity in pharmaceutical substances belonging to the category of either organic acids e. The presence of this impurity is due to the following two prime factors, namely : (a) The use of oxalic acid to get rid of Ca2+ during various manufacturing processes. Allow to not more intense than that pro- stand for 2 minutes, decant the liquid into a test- duced by treating 4 ml of a tube containing 0. Sodium Acid Citrate -do- Any red colour produced is not more intense than that pro- duced by treating in the same manner 4 ml of a 0. Com- bine the ethereal layers, evaporate the filtrate to 5 ml and add 1 ml of 2 M acetic acid and l. Limit Test for Phosphate The limit test for phosphate is based upon the formation of a yellow colour reaction with molybdovanadic reagent (combination of ammonium vanadate and ammonium molybdate) in an acidic medium. However, the exact composition of the molybdovanadophosphoric acid complex is yet to be established. Calculate the content of Phosphate from a calibration curve prepared by treating suitable vols. A few typical examples are described below which essentially contains the above cited nonmetallic impurities : 1. The estimation depends upon the conversion of boron to borate and the organic matter is subsequently destroyed by ignition with anhydrous sodium carbonate. Ignite the residue rapidly until the organic matter has been destroyed, allow to cool and add 0. Add sufficient ethanol (96%) to produce 100 ml, filter and measure the absorbance of the filtrate at the maximum of 555 nm. Calculate the content of boron from a reference curve prepared from the absorbance obtained by treating suit- able aliquots of a solution of boric acid in the same manner. Free Halogens A few typical examples of pharmaceutical chemicals in which free halogens like Iodine, Bromine, Fluo- rine and Chlorine are present as non-metallic impurities are given below. Prescribed Limits : Any colour in the chloroform layer is discharged on the addition of 0. Doxycycline Hydrochloride : (Free Fluorine) Materials Required : Doxycyline Hydrochloride : 0. Prescribed Limit : The colour of the resulting solution is greater than that obtained by repeating the operation with no substance enclosed in the successive portions of filter paper burnt in the method for oxygen flask combustion, but adding 3. Tetrachloroethylene (Free Chlorine) Perform the limit test as stated under chloroform. Selenium Sulphide Theory : Selenium is very toxic and its contamination is usually controlled by an absorptiometric method after destruction of the organic compound with fuming nitric acid. The latter converts selenium (Se) as selenous acid (H2SeO3), which on subsequent treatment with 3,3′-diaminobenzidine under controlled experimental pa- rameters, results into the formation of a highly coloured compound known as 3,4-diaminophenylpiazselenol. The latter is consequently extracted with toluene after making the aqueous solution alkaline, and the colour compared with a standard prepared likewise from a known amount of selenium. Prescribed Limit : The measured absorbance at 420 nm is not greater than that of a solution prepared by treating 5 ml of selenium standard solution (1 ppm Se) in the same manner (5 ppm, calculated as Se). What is the importance of ‘Purity’ in pharmaceutical chemicals for manufacturing drugs? Give a comprehensive account on the following aspects : (a) Biological response Vs chemical purity. Elaborate with specific examples the various sampling procedures and errors commonly encountered in a quality control laboratory. Why do the chemical purity and bioavailability of a ‘drug’ equally important to determine the efficiency of a ‘dosage form’? What are the various ‘physical parameters’ that ultimately establish the purity of a drug substance? Discuss the ‘miscellaneous characteristic features’ included in ‘official compendia’ to establish the purity, authenticity and identification of drugs. Give a detailed account on the ‘Limit Tests’ Vs ‘Quantitative Determinations’ by providing suitable examples. Describe the theory, apparatus and procedure involved in the ‘limit tests’ for metallic impurities e. Elaborate the various ‘limit tests’ recommended for the ‘Non-metallic Impurities’ in official compendia e. How will you determine the limit test for ‘Iron’ in Calcium Lactate and Zinc Oxide? Volumetric analysis essentially comprises of the most precise and accurate measurement of interacting solutions or reagents. It makes use of a number of graduated apparatus, such as : graduated (volumetric) flasks, burettes, pipettes and measuring cylinder of different capacities (volumes). However, it is pertinent to mention here that quite a few techniques related to measurement of pharmaceutical substances and reagents involved is more or less common to both gravimetric and volumetric analysis. Besides, in gravimetric analysis, some more additional techniques play a vital role, namely : precipitation, filtration, washing of the precipitate and ignition of the precipitate. Biomedical analytical chemistry happens to be one of the latest disciplines which essentially embraces the principles and techniques of both analytical chemistry and biochemistry. This particular aspect of analytical chemistry has gained significant cognizance in the recent past by virtue of certain important techniques being included very much within its scope of analysis, namely : colorimetric assays, enzymic assays, radioimmunoassays and automated methods of clinical analysis. It is, however, important to mention here that certain other routine procedures also carried out in a clinical laboratory fall beyond the scope of biomedical analytical chemistry, narnely : microbiological assays, heamatological assays, serum analysis, urine analysis and assays of other body fluids. Titrant is the solution of known strength (or concentration) employed in the assay e. Titration is the process of adding and then actually measuring the volume of titrant consumed in the assay. Indicator is a chemical substance sensitive enough to display an apparent change in colour very close to the point in the ongoing titration process at which equivalent quantities of analyte and titrant have almost virtually reacted with each other.
Figure 14-1 demonstrates the relationship between serum levels achieved with the loading and maintenance doses of theophylline or aminophylline purchase carbidopa 125mg without prescription nature medicine. A theophylline level is ordered immediately and is reported by the laboratory as 22 mcg/mL order carbidopa cheap medicine on time. Now that we have his actual clearance generic carbidopa 300mg mastercard treatment urticaria, we can calculate a new maintenance dose that will give us the desired theophylline serum concentration of 13 mcg/mL: (See Equation 14-4. Next we can determine the time we need to wait by using the following equation: -Kt C = C0e (See Equation 3-2. Clinical Correlate The most significant side effects from theophylline occur at serum concentrations higher than 20 mcg/mL. At concentrations higher than 35 mcg/mL, major adverse effects include hyperglycemia, hypotension, cardiac arrhythmias, seizures, brain damage, and death. Plasma concentrations with a loading dose and continuous infusion of theophylline or aminophylline. She has a history of heavy marijuana and tobacco use but no other medical problems. Suggest an oral dosage regimen that will produce a pss average of approximately 12 mcg/mL, using a sustained released product dosed every 12 hours. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute; 1997. Recent advances in our understanding of the use of theophylline in the treatment of asthma. Theophylline: pooled Michaelis-Menten behavior of theophylline and its parameters (Vmax and Km) among asthmatic children and adults. Cimetidine inhibition of theophylline elimination: influence of adult age and time course. Phenytoin is usually administered either orally or intravenously and exhibits nonlinear or Michaelis-Menten kinetics (see Lesson 10). Unlike drugs undergoing first-order elimination (Figure 15-1), the plot of the natural logarithm of concentration versus time is nonlinear with phenytoin (Figure 15-2). Consequently, as the phenytoin dose increases, a disproportionately greater increase in plasma concentration is achieved. This enzyme saturation process can be characterized with an enzyme-substrate model first developed by the biochemists Michaelis and Menten in 1913. In this metabolic process, drug clearance is constantly changing (in a nonlinear fashion) as dose changes. To describe the relationship between concentration and dose, a differential equation can be written as shown below: (See Equation 10-1. Next, this differential equation can be expressed algebraically by assuming that we are at steady state and dX/dt is held constant. Then dX/dt, the change in the amount of drug (X) over time (t), can be expressed as X0/τ (dose over dosing interval), as shown in the following equation: (See Equation 10-1. The oral bioavailability of phenytoin is considered to be 100%, so an F factor is not needed in these calculations. Other pertinent clinical data include: weight, 75 kg; height, 5 feet, 11 inches; serum creatinine, 1. What intravenous loading dose and oral maintenance dose would you recommend to achieve and maintain a phenytoin concentration of approximately 20 mg/L? Calculation of the loading dose is not affected by the nonlinear pharmacokinetics of multiple-dose phenytoin regimens. Therefore: We could then order a dose of 1000 mg of phenytoin mixed in 100 mL of normal saline given intravenously via controlled infusion. The administration rate should not exceed 50 mg/minute to avoid potential cardiovascular toxicity associated with the propylene glycol diluent of the phenytoin injection. The accuracy of this loading dose estimate can be checked by obtaining a phenytoin plasma drug concentration at approximately 1 hour after the end of the loading dose infusion. Propylene glycol is a cardiotoxic agent and can cause various complications such as bradycardia and hypotension. This dose of 400 mg/day may be divided into 200 mg twice daily if necessary to decrease the likelihood of enzyme saturation and reduce concentration-dependent side effects. Therefore: Note how the units in the equation cancel out, yielding "mg/day" as the final units. It is difficult to calculate when multiple dosing with phenytoin will reach steady state because the time to steady state is concentration dependent. With drugs that undergo first-order elimination, steady state can be reached in three to five drug half-lives because this model assumes that clearance and volume of distribution are constant. However, because of its capacity-limited metabolism, phenytoin clearance decreases with increasing concentration. Therefore, the calculation of time to reach steady state is quite complicated and cannot be based on half-life. In fact, phenytoin does not have a true half-life; its half-life is dependent on drug concentration. The major factor in determining how long it will take to attain steady state is the difference between Vmax and the daily dose. This relationship between Vmax and concentration can be derived mathematically by examining the equations used to calculate dose for first- and zero-order models. We will start by rearranging two definitions in the first-order model: (See Equation 1-1. Examination of this equation shows that when Css is very small compared to Km, Clt will approximate Vmax/Km, a relatively constant value. Therefore, at low concentrations, the metabolism of phenytoin follows a first-order process. However, as Css increases to exceed Km, as is usually seen with therapeutic concentrations of phenytoin, Cl will decrease and metabolism will convert tot zero order. We can calculate an estimate of the time it takes to get to 90% of steady state using the following equation: (See Equation 10-4. This equation is derived from a complex integration of the differential equation describing the difference between the rate of drug coming in (i. This equation gives us an estimate of when to draw steady-state plasma concentrations and is based on the assumption that the beginning phenytoin concentration is zero. Clinical Correlate The t90% equation is a very rough estimate of time to 90% of steady state and should be used only as a general guide. The clinician should check nonsteady-state phenytoin concentrations before this time to avoid serious subtherapeutic or supratherapeutic concentrations. Therefore: Note how the units cancel out in this equation, leaving the answer expressed in days, not hours. Close inspection of this calculation illustrates the impact that the denominatorthe difference of Vmax and daily dosehas on the time it takes to reach steady state. A phenytoin plasma concentration of 6 mg/L is drawn 18 days after the beginning of therapy.
One of the major 140 mm Hg and diastolic blood pressure public health recommendations rel- below 90 mm Hg cheapest carbidopa treatment lower back pain. Sodium is specified ative to high blood pressure is to de- here as the chemical entity or electro- crease consumption of salt buy cheap carbidopa 300 mg online medicine 0552. On a popu- lyte "sodium" and is distinguished lation-wide basis purchase carbidopa once a day medications memory loss, reducing the average from sodium chloride, or salt, which is sodium intake would have a small but 39 percent sodium by weight. A health claim associating marily because it is a major risk factor diets low in sodium with reduced risk for mortality from coronary heart dis- of high blood pressure may be made on ease and stroke. Early management of the label or labeling of a food described high blood pressure is a major public in paragraph (c)(2)(ii) of this section, health goal that can assist in reducing provided that: mortality associated with coronary (A) The claim states that diets low in heart disease and stroke. There is a sodium "may" or "might" reduce the continuum of mortality risk that in- risk of high blood pressure; creases as blood pressures rise. Individ- (B) In specifying the disease, the uals with high blood pressure are at claim uses the term "high blood pres- greatest risk, and individuals with sure"; moderately high, high normal, and nor- (C) In specifying the nutrient, the mal blood pressure are at steadily de- claim uses the term "sodium"; creasing risk. The scientific evidence (D) The claim does not attribute any indicates that reducing sodium intake degree of reduction in risk of high lowers blood pressure and associated blood pressure to diets low in sodium; risks in many but not all hypertensive and individuals. There is also evidence that (E) The claim indicates that develop- reducing sodium intake lowers blood ment of high blood pressure depends on pressure and associated risks in many many factors. The food shall (1) Diets low in sodium may reduce meet all of the nutrient content re- the risk of high blood pressure, a dis- quirements of §101. Coronary heart United States who have high blood disease is the most common and seri- pressure. The sources of this informa- ous form of cardiovascular disease and tion must be identified, and it must be refers to diseases of the heart muscle current information from the National and supporting blood vessels. Dietary lipids (fats) in- (6) In specifying the disease, the clude fatty acids and cholesterol. Total claim may include the term "hyper- fat, commonly referred to as fat, is tension" in addition to the term "high composed of saturated fat (fatty acids blood pressure. I (4–1–10 Edition) (b) Significance of the relationship be- or labeling of a food described in para- tween dietary saturated fat and choles- graph (c)(2)(ii) of this section provided terol and risk of coronary heart disease. Early manage- (B) In specifying the disease, the ment of risk factors for coronary heart claim uses the terms "heart disease" disease is a major public health goal or "coronary heart disease;" that can assist in reducing risk of coro- (C) In specifying the nutrient, the nary heart disease. A larg- saturated fat and cholesterol; and er number of individuals with more (E) The claim states that coronary moderately elevated cholesterol also heart disease risk depends on many have increased risk of coronary events; such individuals comprise a substantial factors. The scientific evidence indi- meet all of the nutrient content re- cates that reducing saturated fat and quirements of §101. Recommended daily tion from paragraphs (a) and (b) of this cholesterol intakes are 300 mg or less section, which summarize the relation- per day. A health claim associating (4) In specifying the nutrients, the diets low in saturated fat and choles- claim may include the term "total fat" terol with reduced risk of coronary in addition to the terms "saturated heart disease may be made on the label fat" and "cholesterol". A diet low in United States who have coronary heart saturated fat, cholesterol, and total fat disease. The sources of this informa- may help reduce the risk of heart dis- tion shall be identified, and it shall be ease; and current information from the National (5) Diets low in saturated fat, choles- Center for Health Statistics, the Na- terol, and total fat may reduce the risk tional Institutes of Health, or "Nutri- of heart disease. Heart disease is de- tion and Your Health: Dietary Guide- pendent upon many factors, including lines for Americans," U. Risk factors include: are model health claims that may be A family history of a specific type of used in food labeling to describe the re- cancer, cigarette smoking, overweight lationship between dietary saturated and obesity, alcohol consumption, ul- fat and cholesterol and risk of heart traviolet or ionizing radiation, expo- disease: sure to cancer-causing chemicals, and (1) While many factors affect heart dietary factors. A healthful (b) Significance of the relationship be- diet low in saturated fat, total fat, and tween consumption of diets low in fat and cholesterol, as part of a healthy life- high in fiber-containing grain products, style, may lower blood cholesterol lev- fruits, and vegetables and risk of cancer. Current dietary guidelines from graphs (a) and (b) of this section, which summarize the relationship between Federal government agencies and na- diets low in fat and high in fiber-con- tionally recognized health professional taining grain products, fruits, and organizations recommend decreased vegetables, and some types of cancer consumption of fats (less than 30 per- and the significance of the relation- cent of calories), maintenance of desir- ship. The following ment of cancer depends on many fac- model health claims may be used in tors; food labeling to characterize the rela- (E) The claim does not attribute any tionship between diets low in fat and degree of cancer risk reduction to diets high in fiber-containing grain products, low in fat and high in fiber-containing fruits, and vegetables and cancer risk: grain products, fruits, and vegetables; (1) Low fat diets rich in fiber-con- (F) In specifying the dietary fiber taining grain products, fruits, and component of the labeled food, the vegetables may reduce the risk of some claim uses the term "fiber", "dietary types of cancer, a disease associated fiber" or "total dietary fiber"; and with many factors. These studies correlate bles, and grain products that con- diets rich in fruits, vegetables, and tain fiber, particularly soluble fiber, grain products and nutrients from and risk of coronary heart disease. Persons consuming these diets fruits, vegetables, and grain products that frequently have high intakes of dietary contain fiber, particularly soluble fiber, fiber, particularly soluble fibers. High coronary heart disease plex carbohydrate content of these rates occur among people with high foods, other nutrients in these foods, or blood cholesterol levels of 240 milli- displacement of saturated fat and cho- grams per deciliter (mg/dL) (6. Borderline high risk blood lesterol, and high in fruits, vegetables, cholesterol levels range from 200 to 239 and grain products that contain fiber, mg/dL (5. Dietary lipids (fats) in- disease is a major public health con- clude fatty acids and cholesterol. Total cern in the United States, primarily fat, commonly referred to as fat, is because it accounts for more deaths composed of saturated fat (fatty acids than any other disease or group of dis- containing no double bonds), and eases. Early management of risk fac- monounsaturated and polyunsaturated tors for coronary heart disease is a fat (fatty acids containing one or more major public health goal that can as- double bonds). Although the specific roles of ally, consuming diets high in fruits, these plant foods are not yet fully un- vegetables, and grain products, foods derstood, many studies have shown that contain soluble fiber, may be a that diets high in plant foods are asso- useful adjunct to a low saturated fat ciated with reduced risk of coronary and low cholesterol diet. I (4–1–10 Edition) (2) Other risk factors for coronary (C) The claim is limited to those heart disease include a family history fruits, vegetables, and grains that con- of heart disease, high blood pressure, tain fiber; diabetes, cigarette smoking, obesity (D) In specifying the dietary fiber, (body weight 30 percent greater than the claim uses the term "fiber," "die- ideal body weight), and lack of regular tary fiber," "some types of dietary physical exercise. Intakes of choles- (E) In specifying the fat component, terol are, on average, at or above rec- the claim uses the terms "saturated ommended levels. Intakes of fiber-con- fat" and "cholesterol;" and (F) The claim indicates that develop- taining fruits, vegetables, and grain ment of heart disease depends on many products are about half of rec- factors; and ommended intake levels. One of the (G) The claim does not attribute any major public health recommendations degree of risk reduction for coronary relative to coronary heart disease risk heart disease to diets low in saturated is to consume less than 10 percent of fat and cholesterol and high in fruits, calories from saturated fat, and an av- vegetables, and grain products that erage of 30 percent or less of total cal- contain fiber. Results of numerous studies be declared in the nutrition informa- have shown that fiber-containing tion panel, consistent with fruits, vegetables, and grain products §101. Cancer has many consistent with "Nutrition and Your causes and stages in its development. Health: Dietary Guidelines for Ameri- Both genetic and environmental risk cans," U. Persons con- The sources of this information shall suming these diets frequently have be identified, and it shall be current in- high intakes of these nutrients. The following diets rich in fruits and vegetables, in- model health claims may be used in cluding but not necessarily limited to food labeling to characterize the rela- dietary fiber, vitamin A (as beta-caro- tionship between diets low in saturated tene) and vitamin C, to displacement of fat and cholesterol and high in fruits, fat from such diets, or to intakes of vegetables, and grain products that other substances in these foods which contain soluble fiber: are not nutrients but may be protec- (1) Diets low in saturated fat and tive against cancer risk. The overall economic costs of cancer, (2) Development of heart disease de- including direct health care costs and pends on many factors. Eating a diet losses due to morbidity and mortality, low in saturated fat and cholesterol are very high. Stud- grain products that contain fiber may ies in various parts of the world indi- lower blood cholesterol levels and re- cate that populations who habitually duce your risk of heart disease. I (4–1–10 Edition) diets generally are low in fat and rich (J) The claim indicates that develop- in many nutrients, including, but not ment of cancer depends on many fac- limited to, dietary fiber, vitamin A (as tors. A health claim associating diets low in fat and high in fruits and substances in diets low in fat and high vegetables and some types of cancer in fruits and vegetables with reduced and the significance of the relation- risk of cancer may be made on the ship.
The construction of laboratory knowledge is not a function of the scientifc context alone order carbidopa 110 mg with mastercard treatment zinc toxicity. It is harnessed discount 300mg carbidopa with mastercard treatment works, changed cheap carbidopa online master card medications 230, transmitted, distorted, used, and conjured away in response to variations in economic, clinical, technological, and cultural circumstances. Indeed, these preliminary results reveal the presence in the laboratories of what Knorr Cétina and Latour call “plural knowledge,” which might just as well be called “multidimensional knowledge. They highlight the diversity of institutions concerned, disciplines the researchers belong to and types of knowledge present. Time amplifes this diversifcation and the increase in collaborations that can fuctuate as circumstances change over the course of a career, since the way knowledge is subdivided is a result of differential principles of action. Finally, in the chronology of the substances, the circulation of knowledge may seem chaotic. In fact, depending on the type of substance, its pathway may well be marked by both uncertainty and the absence of data. For prescription medications, in contrast to other types, these problems assume greater prominence. As the analyses of the chronologies show, once out of the laboratory, the circulation of knowledge is somewhat hampered. Laboratories operate in a context of scientifc verifcation, while the production and approval of medications are based on partial forms of risk-beneft assessments, upon which civil society constructs the most fantastic hopes and despair. Further analyses of other laboratories, should help enhance this preliminary exploration. Request reprint permission for this book Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs Committee on Understanding the Global Public Health Implications of Substandard, Falsifed, and Counterfeit Medical Products Board on Global Health Gillian J. The members of the committee responsible for the report were chosen for their special competences and with regard for appropri- ate balance. Any opinions, fndings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily refect the view of the organizations or agencies that provided support for this project. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent ad- opted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Cover image from 1900 calendar produced by the Antikamnia (“Opposed to Pain”) Chemical Company of St. Countering the Problem of Falsified and Substandard Drugs “Knowing is not enough; we must apply. Countering the Problem of Falsified and Substandard Drugs The National Academy of Sciences is a private, nonproft, self-perpetuating society of distinguished scholars engaged in scientifc and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Acad- emy has a mandate that requires it to advise the federal government on scientifc and technical matters. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engi- neers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineer- ing programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Insti- tute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. The National Research Council was organized by the National Academy of Sci- ences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientifc and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Countering the Problem of Falsified and Substandard Drugs Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confdential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Georges Benjamin, American Public Health Association Martha Brumfeld, Martha A. The review of this report was overseen by Harold Fallon, Medical University of South Carolina, and Elaine Larson, School of Nursing and Mailman School of Public Health, Columbia University. Appointed by the National Research Council and the Institute of Medicine, they were respon- sible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the fnal content of this report rests entirely with the authoring committee and the institution. Countering the Problem of Falsified and Substandard Drugs Acknowledgments This report is a product of the cooperation and contributions of many people. The committee and staff are especially grateful to Danielle Turnipseed and Livia Navon for their work on the manuscript, and to Deepali Patel and Susan McCutchen for their fast and accurate refer- ence review. The project ran smoothly because of the contributions of Jim Banihashemi, Sarah Ziegenhorn, Laura Harbold DeStefano, Anne Claiborne, and Vilija Teel of the Institute of Medicine. Janice Mehler of the Report Review Committee oversaw a careful peer review of the manuscript. Many experts outside of the Academies helped the committee and staff with this project. Bryan Liang of the University of California, San Diego, was not able to serve on the committee but contributed to the frst meeting. Members of the committee and staff traveled to Brasília, Delhi, Ge- neva, Hyderabad, London, and São Paulo, during this project. The committee is grateful to the following participants who spoke at meetings and helped staff plan agendas: Martin Harvey Allchurch Laurie Garrett P. Gaugh Amir Attaran Debora Germano Martin Auton Raj Shankar Ghosh Sunil Bahl Ashif Gogo Roger Bate Antony Raj Gomes Ilisa Bernstein Subhash Gouda Katherine Bond L. Goyal Regina Brown Wendy Greenall Gian Luca Burci Jeffery Gren Claudio Henrique Cabral Catherine Hill-Herndon Nicholas Cappuccino Meghana Inamdar Ranjan Chakrabarti Mariaou Tala Jallow Ranjit Chaudhury Kees de Joncheere Lim Chin Chin Connie Jung John Clark Mohga Kamal-Yanni Charles Clift Harparkash Kaur David Cockburn Sabine Kopp Emer Cooke Alan Leather Ediná Alves Costa Jamie Love Alan Coukell Rohit Malpani Elize Massard da Fonseca Paola Manchisini Filipe Soares Quirino da Silva Linda Marks Ashok Dang Sylvia Meek Joelle Daviaud Mayira Milano Leandro Teixeira de Morais Bejon Misra Jenifer Devine Archna Mudgal Pritu Dhalaria Koduru Surendra Nath Albinus D’Sa Paul Newton Douglas Duarte Fernando Nogueira Paul Ellis Doroteia Koparanova Ollivier Frederico Benite Filho Arun Panda Michele Forzley Sharon Peacock Odile Frank Patrícia Oliveira Pereira Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs Copyright © National Academy of Sciences.
Precautons Avoid exposure to sunlight or sunlamps- photosensitvity reported; renal impairment; hepatc impairment (Appendix 7a); lactaton (Appendix 7b); interactons (Appendix 6c) purchase carbidopa 125 mg without a prescription treatment juvenile rheumatoid arthritis. Storage Store protected from light and moisture at a temperature not exceeding 30⁰C purchase carbidopa visa medicine plus. Dose Radical treatment Adult- 15 mg daily for 14 days 125mg carbidopa with amex treatment resistant anxiety, may be increased to higher dose. Contraindicatons Hypersensitvity, granulocytopenia, pregnancy, lactaton, children below 1 year. Proguanil Pregnancy Category-B Schedule H Indicatons With chloroquine, prophylaxis of malaria in areas of low resistance. Dose Oral Prophylaxis Adult- Preferably 200 mg once daily, start 1 to 2 days before entering endemic area and contnue for 4 weeks afer leaving. Child- (11-20 kg) - 25 mg once daily; (21-30 kg)- 50 mg once daily; (31-40 kg)- 75 mg once daily; more than 40 kg- 100 mg once daily. Child- Up to 1 year: 25 mg; 1 to 4 years; 50 mg; 5 to 8 years: 100 mg; 9 to 14 years: 150 mg; above 14 years: 200 mg. Contraindicatons Use in areas of known resistance to either proguanil or pyrimethamine. Precautons Renal impairment; pregnancy (folate supplements required, Appendix 7c); lactaton. Adverse Efects Mild gastric intolerance, diarrhoea; occasional mouth ulcers and stomatts; skin reactons and hair loss reported; rarely, hypersensitvity reactons such as urtcaria and angioedema. Dose Oral Adult- Prophylaxis: 300 mg once weekly, start one week before entering endemic area and contnue for 4 weeks afer leaving. Patents and their caretakers should be told how to recognize the signs of blood disorders and advised to seek medical atenton as soon as possible if symptoms such as fever, sore throat, rash, mouth ulcers, purpura, bruising or bleeding develop. They should also be told how to recognize signs of hepatts and advised to seek medical atenton if symptoms such as anorexia, abnormal weight loss, asthenia, abdominal pains, fever, nausea or vomitng develop. Adverse Efects Blood disorders including leukopenia and agranulocytosis; hepatts; gastrointestnal disturbances, visual disturbances (retnopathy associated with long-term, high-dose therapy); rarely, rash, pruritus, skin pigmentaton, neuromyopathy. Arteether Pregnancy Category-C Schedule H Indicatons Complicated falciparum malaria;chloroquine resistant malaria; cerebral malaria. Contraindicatons Hypersensitvity to artemisinin derivatves; preganacy (Appendix 7c). Adverse reactons It is clinically very well tolerated without any signifcant side efects; neurological or biochemical. Storage Store protected from light in tamper evident container so as to avoid contaminaton by micro-organisms. Dose Oral Adult- 160 mg in two divided doses on frst day followed by 80 mg once a day for next four days. Dizziness may impair ability to perform skilled tasks, for example operatng machinery, driving. Artesunate* Pregnancy Category-C Schedule H Indicatons Treatment of uncomplicated P. Dose Oral Adult- total oral dose 600 mg can be divided into two 50 mg tablets twice a day on frst day thereafer 50 mg twice a day for next 4 days. Precautons Risk of recurrence if used alone in non- immune patents; hepatc/renal insufciency, pregnancy (Appendix 7c), lactaton, paediatrics. Dizziness may impair ability to perform skilled tasks, for example operatng machinery, driving. Intravenous infusion for patents unable to swallow tablets Loading dose 900 mg to 1. Sulfadoxine + Pyrimethamine* Pregnancy Category-C Schedule H Indicatons Treatment of malaria due to susceptble P. Contraindicatons Hypersensitvity to sulfonamides or pyrimethamine; severe hepatc or renal impairment (except where no alternatve treatment available); blood dyscrasias, neonates, megaloblastc anaemia and folate defciency. Adverse Efects Rashes, pruritus, slight hair loss; rarely, erythema multforme (Stevens-Johnson syndrome) and toxic epidermal necrolysis; gastrointestnal disturbances including nausea, vomitng, stomatts; rarely, hepatts, leukopenia, thrombocytopenia, megaloblastc anaemia and purpura- withdraw treatment; fatgue, headache, fever, polyneurits, also reported; pulmonary infltrates such as eosinophilic or allergic alveolits-if symptoms of cough or shortness of breath-withdraw treatment. The incubaton period between infecton and appear- ance of leprosy is normally between 2 to 10 years, but may be up to 20 years. It is transmited from person-to-person when bacilli are shed from the nose; most individuals have natural immunity and symptoms are suppressed. The 2 forms may be distn- guished by skin smears, but facilites are not always available to process them and their reliability is ofen doubtul. Drugs used in the treatment of leprosy should always be used in combinaton; this is essental to prevent the emergence of resistance. Lepra reactons are episodes of sudden increase in the actvity of leprosy and are ofen accompanied by neurits; reactons must always be treated promptly to prevent permanent nerve damage and disability. Leprosy multdrug therapy should contnue during a lepra reacton without interrupton. If there is no nerve damage, type 1 reactons may be treated with analgesics such as acetylsalicylic acid or para- cetamol. If there is nerve involvement cortcosteroids, such as oral prednisolone should be used in additon to analgesics. Therapy for type 2 reactons may include analgesics, such as acetylsalicylic acid or paracetamol and a cortcosteroid, such as oral prednisolone. Severe type 2 lepra reactons should be treated under medical supervision in hospital. If a patent does not respond to lepra reacton treatment within 6 weeks or seems to become worse, the patent must be sent immediately to the nearest specialist centre. It can be successfully treated with a 12-week course of oral pred- nisolone; if patents do not respond, specialist centre treat- ment is required. Treatment Regimens: The recommended regimen for paucibacillary leprosy in adults (50-70 kg) is rifampicin 600 mg once monthly and dapsone 100 mg daily. Children aged 10-14 years may be given rifampicin 450 mg once monthly and dapsone 50 mg daily. Children aged 10-14 years may be given rifampicin 450 mg and clofazimine 150 mg, both once a month together with clofazimine 50 mg every other day and dapsone 50 mg daily. For example, dapsone 25 mg daily, clofazimine 50 mg twice a week and clofazimine 100 mg and rifampicin 300 mg once a month. Precautons Pre-existing gastrointestinal symptoms (reduce dose, increase dose interval or discontinue if symptoms develop during treatment); liver and renal impairment; may discolour soft contact lenses; paediatrics, elderly, interactions (Appendix 6d). Adverse Efects Reversible discolouraton of skin, hair, cornea, conjunctva, tears, sweat, sputum, faeces and urine; dose-related gastrointestnal symptoms including pain, nausea, vomitng and diarrhoea; severe mucosal and submucosal oedema, with prolonged treatment with high doses-may be severe enough to cause subacute small-bowel obstructon (see also Precautons); pruritus, ichthyosis, elevated blood sugar, diminished vision, dizziness, eosinophillic enteropathy. Dermatts herpetformis: start with 50 mg daily and increase up to 400 mg tll full response is obtained; dose reduced to minimum maintenance level as soon as possible. Child- 1 to 2 mg/kg body weight as minimum dose to start with, increased weekly so that at the end of 7th week patent is receiving max.
Cytogenetic changes were measured in pregnant mice given a single intraperitoneal injection of 1 order carbidopa 125 mg with amex treatment e coli. Injection on day 7 increased the frequency of embryonic cells with structural aberrations buy discount carbidopa on-line treatment norovirus, one-third of which were stable safe 110mg carbidopa medications versed, consisting of chromosomes with metacentric or submeta- centric markers. Injection on day 6 or 8 increased the percentage of embryonic cells with numerical aberrations, most of which were hypoploidy (monosomy) (Sieber et al. It does not inhibit bacterial topoisomerases and may not mutate bacterial cells by the same mechanism as mammalian cells. It possesses readily oxidizable functions: Some of the etoposide-induced effects have been ascribed to the formation of free radicals by oxidation of its 4′-phenolic hydroxy group to a semiquinone free radical (Sakurai et al. The first is that etoposide itself causes the translocations, perhaps through a cytotoxic action. The second possibility for the role of etoposide in causing translocations is that it selects for cells that already have translocations. Chemotherapy has profound effects on the kinetics of the marrow: it causes cell death, forcing many marrow stem cells to divide, which might select for the rare stem cells with a translocation (Knudson, 1992). In the patients with Langerhans cell histiocytosis, a strongly increased risk for acute myeloid leukaemia of the promyelocytic type was found after treatment with etoposide alone; however, the possibility could not be ruled out that such patients have an inherently increased risk for acute promyelocytic leukaemia. In several cohort studies of germ-cell tumours in men, treatment with etoposide, cisplatin and bleomycin was associated with an increased risk for acute myeloid leukaemia. On the basis of the combined data from six studies, the relative risk for acute myeloid leukaemia was 40 times greater than that of the general population; substantially higher relative risks have been found with high cumulative doses of eto- poside. Although the other two agents (cisplatin and bleomycin) in etoposide-containing chemotherapy regimens for germ-cell tumours may have contributed to the positive association seen in the cohort studies, use of these agents in a similar regimen without etoposide has not been associated with acute myeloid leukaemia. As the background risk for acute myeloid leukaemia is low, the absolute risk for this disease in men treated for germ-cell tumours with etoposide-containing regimens is low. A strongly increased risk for acute myeloid leukaemia was also found in one cohort study of lung cancer patients treated with etoposide, cisplatin and vindesine. The possibility cannot be excluded that etoposide exerts its effects only in the presence of other cytotoxic agents. Several other cohort studies reported strongly increased risks for acute myeloid leukaemia following treatment of various primary malignancies with etoposide- containing regimens that also included alkylating agents, or etoposide-containing regimens in combination with teniposide. In these studies, the possibility cannot be excluded that the excess leukaemia risk was partly or wholly due to the other agents. Its bioavailability is around 50%, but this decreases with oral doses of > 200 mg. About 50% of an intra- venous dose of etoposide is recovered in urine; up to 17% is excreted as a glucuronide metabolite and less than 2% as a catechol metabolite. Preliminary studies suggest that the remainder of the dose is excreted in the faeces. The catechol metabolite has also been detected in plasma at concentrations around 2. In rhesus monkeys, 60% of a radiolabelled dose of etoposide was excreted in urine and 30% in faeces. These oxidation products have cytotoxic activity, but it is unclear how much they contribute to the activity of etoposide. The major dose-limiting toxic effect of etoposide in humans is myelosuppression, manifest principally as leukopenia. Cases of hypotension were reported in early trials in which short infusions were given, but this effect is rarely seen with infusions of longer than 30 min. Hypersensitivity reactions have been reported but are seen much less frequently than with teniposide. Myelosuppression was the main toxic effect of intravenously administered eto- poside in a number of the animal species studied. Other effects included changes in the lung in rats and renal and hepatic toxicity, electrocardiographic changes, decreased testis weight and disorders of spermatogenesis in rats and dogs. After intrapleural and intraperitoneal administration to mice and rats, delayed chronic pleuritis and peri- tonitis, with liver and spleen inflammation, were reported. Teratogenic effects espe- cially on the central nervous system have been observed. Etoposide-containing regimens have been associated with the development, after a short latency, of leukaemia which is characterized by chromosomal translocations. Etoposide is often used in combination chemo- therapy with alkylating agents, which are themselves associated with leukaemia with specific chromosomal aberrations after a longer latency. These chromosomal aberrations are unbalanced chromosomal losses and deletions, especially monosomy 7, 7q and 5q deletions. There is sufficient evidence in humans for the carcinogenicity of etoposide given in combination with cisplatin and bleomycin. There is inadequate evidence in experimental animals for the carcinogenicity of etoposide. In reaching this conclusion, the Working Group noted that etoposide causes distinc- tive cytogenetic lesions in leukaemic cells that can be readily distinguished from those induced by alkylating agents. The short latency of these leukaemias contrasts with that of leukaemia induced by alkylating agents. Etoposide in combination with cisplatin and bleomycin is carcinogenic to humans (Group 1). Blood, 90, 535–541 Royal Pharmaceutical Society of Great Britain (1999) Martindale, The Extra Pharmacopoeia, 13th Ed. Intra- venous administration to rats prior to and in the early stages of pregnancy. It is poorly soluble, and the 50-mg intravenous preparation typically also contains benzyl alcohol (0. Trade names for teniposide include Vehem, Vehem-Sandoz, Vumon and Vumon Parenteral (Royal Pharmaceutical Society of Great Britain, 1999; Swiss Pharmaceu- tical Society, 1999). The methods for the analysis of teniposide in various matrices include high-performance liquid chromatography, thin-layer and paper chromatography and radioimmunoassay (Kettenes-van den Bosch et al. During early clinical trials for cancer chemotherapeutic use, podophyllotoxin itself proved to be too toxic, and, in the 1960s, two epipodophyllotoxins, teniposide and etoposide (see monograph, this volume), were described (Keller-Juslén et al. Teniposide is used in the treatment of adult and childhood leukaemia, typically at doses of 30–50 mg/m2 per day for five days or three doses of about 200 mg/m2 over seven days. The drug is also used in the treatment of brain tumours in adults and neuroblastoma in children. Teniposide is active against a number of other tumour types, including small-cell and non-small-cell lung cancer, lymphomas and bladder cancer. It is used much less commonly than the related drug etoposide (Giaccone, 1992; Giaccone et al. Studies of Cancer in Humans This section summarizes only studies in which tepinoside was given without agents with known or suspected leukaemogenic properties. In studies in which patients were treated with both tepinoside and etoposide, the authors used various conversion factors to derive an ‘equivalent dose’ of etoposide from that of teniposide. The conversions were based, however, on the therapeutic effects rather than on meta- bolic considerations. Of 60 patients in whom complete remission was achieved, 14 suffered a bone-marrow relapse.