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General principles of counseling Many patients are not satisfied with the counseling they receive for exposure to poten- tial teratogens during pregnancy buy 500 mg actoplus met amex signs ng diabetes. Dissatisfaction stems largely from two major issues that both cause patient anxiety purchase actoplus met 500 mg with visa diabetes symptoms men over 50. First order actoplus met 500 mg line diabetes insipidus jelentése, the physician is frequently unable to obtain ade- quate information to make meaningful statements regarding the medical risks of whether the pregnancy was adversely affected by the drug exposure purchase actoplus met 500 mg free shipping diabetes key symptoms. Second, most patients do not understand the difference between an embryo and a fetus. Consequently, patients may not be able to grasp the importance of the concept of ‘critical periods’ unless they have been given a proper briefing during the consultation. It is our policy to explain that there are two distinct phases involved in the growth of a baby, as shown in Fig. The first phase is the embryonic development, and it is dur- ing this period that the structure or architecture for the baby is laid down. Embryonic age should be differentiated from menstrual age, which is 2 weeks greater than embryonic age. Briefly, we explain to our patients that organs take shape and the body assumes the form it will have thereafter by day 58 postconception. All major structures, such as the heart, brain, liver, kidneys, and limbs, have formed by this time. Fetal development dur- ing the remainder of pregnancy, the second phase of development, is primarily devoted to the growth of these organs and structures, and to augmenting their function. It is through this heuristic approach to counseling that the patient understands that most congenital anomalies are caused by early exposures, often before the pregnancy was recognized. This component is included early in the consultation; patients then understand why certain questions are important and having such knowledge increases their cooperation and rapport. Preconceptional counseling Ideally, all counseling regarding drug or medication use during pregnancy should occur before conception, because the opportunity to prevent possible adverse effects is then optimal. Preconceptional counseling should include all the components of a consultation during the pregnancy, with one exception. Recommendations regarding medication or drug use during pregnancy will be prospective for a preventive purpose, and only med- ically indicated drugs and medications known to be safe will be recommended for con- tinued use while attempting to conceive. The concept of background risk for major congenital anom- alies should be explained in a manner tailored to the patient’s level of understanding. This concept is especially important because it conveys to the patient that, even if the drug exposure is harmless, no guarantee can be given that the fetus she carries will not have a congenital anomaly. Notwithstanding other risk factors, the risk for major con- genital anomalies is approximately 3. Other identified risks are generally considered to be additive to background risk. A usual component of counseling is the determination of exactly what drugs were taken, the dosage, the timing and duration of the exposure(s), the patient’s health history and present state of health. A thorough physical examination should be used to deter- mined the present state of health. No No further action although Yes ultrasound may reassure Confirm gestational age by ultrasound Drug taken Drug taken during critical outside of period of organogenesis embryogenesis Rule out Refer for Other possible targeted prenatal adverse fetal ultrasound and tests as effects advice indicated Counseling and evaluation of the drug-exposed pregnant patient 17 parents as well as the baby’s father’s parents, brothers and sisters, and nieces and nephews, should be constructed. The current state of health of all people in the pedigree should also be elicited. For those individuals in the pedigree who are no longer living, whether death was due to a birth defect or to a heritable disorder should be determined. It is also important to ask whether the patient’s family or the baby’s father’s family has any member who was mentally retarded, or has a chromosomal abnormality, Down syn- drome, congenital heart disease, spina bifida or another neural tube defect, or any other inherited disease. When such risk factors are discovered, it is important to explore these avenues further. It is desirable to refer the patient for a medical genetic consultation and evaluation when a risk increase above background is other than zero. The next step in the consultation is to determine whether or not the agent(s) has known teratogenic potential. This is the most difficult part of the evaluation because there is insufficient information to make such a determination for more than 60 percent of medications. The Effects of Neurologic and Psychiatric Drugs on the Fetus and Nursing Infant: A Handbook for Health Care Professionals. If it can be documented that the agent has no terato- genic risks or adverse fetal effects associated with its use during pregnancy, then no fur- ther action is required except to document this in the medical record and counsel the patient accordingly. Some patients may benefit from reassurance offered by high-resolu- tion ultrasound to confirm fetal well-being, and this procedure should be offered if the patient’s anxiety is not relieved through counseling. The limitations of diagnostic ultra- sound should also be included in the consultation. If the drug is known not to be safe for use during pregnancy, or if there are reasons to suspect that a drug with unknown risks is associated with congenital anomalies, then gestational age should be confirmed by ultrasound. It is of utmost importance to base the risk assessment and counseling upon embryonic age, not menstrual age. If the expo- sure occurred during embryogenesis, then it is necessary to undertake high-resolution ultrasound in an attempt to detect damage to specific organ systems or structures that were being formed during the time of the exposure. If the ultrasound scan is normal, then it is reasonable to reassure the patient of normal fetal structure within the limits of the sensitivity and specificity of ultrasound, which range from 40 to 90 percent for gross structural abnormalities when the procedure is performed by an experienced sonogra- pher. If the exposure occurred during the fetal period, it is likewise important to evalu- ate the possible fetal effects of the medication. If defects are detected, it is necessary to describe them in detail to the patient and to give a prognosis, as far as available medical knowledge will allow, regarding the out- come of pregnancy and postnatal development. To assist the patient in making a deci- sion on the disposition of the pregnancy, prognostication should include medically doc- umented risk figures. Ethically, pregnancy termination should not be a recommendation made to the patient and her family and significant others. This option should be dis- cussed, but the ultimate decision of whether to continue the pregnancy should be left to the patient and her family and significant others. The role of teratogen counseling is ulti- mately to provide the patient with as much information as possible and encourage her to make her own decision regarding whether to continue the pregnancy. Drug- or chemical-related causes of maternal complications, congenital anomalies, and fetal toxicity are almost unique among adverse pregnancy outcomes because they are potentially preventable, given the window of opportunity to do so. These problems are also exceptional among obstetric complications in that they are often the focus of malpractice litigation. Attorneys recognize that such adverse outcomes could have been prevented, and litigation ensues despite the fact that the window of opportunity to inter- vene prudently may not have existed for the physician and, more importantly, the drug exposure may not be teratogenic at any time during the pregnancy. The major drawback with such disclaimers was that there existed little to no information upon Informed consent and post-exposure counseling 19 which to ‘weigh the possible hazards’. Such disclaimers would make defense of a litiga- tion case involving a drug or medication extremely difficult for the physician because benefits are not easily weighed against unknown possible hazards. With no scientific data relating a specific malformation to a given drug, it is nearly impossible to ‘prove’ in the courtroom that a drug is not a teratogen and is safe for use during pregnancy. Thus a jury may be asked to consider the important question of why a physician would utilize a medication that carried the warning ‘safe use in pregnancy has not been estab- lished’. The disclaimer itself implies that a medication may indeed be a teratogen, although the warning is actually little more than legally formulated rhetoric designed to protect the pharmaceutical company (Brent, 1982). Five risk categories that addressed potential adverse fetal effects, including congenital anomalies, were developed. Although an improvement over the previous labeling disclaimers, this classification is less than perfect (Brent, 1982). These authors pointed out that ‘any classification of agents according to teratogenic risk is incomplete because the risk to a given patient is determined by all of the conditions of exposure’.

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It is very difficult for us to imagine the impact of plague on these small rural communities generic actoplus met 500 mg amex diabetes test in toddlers, where a village might have no more than 400 or 500 inhabitants actoplus met 500 mg lowest price diabetes mellitus glaucoma. Few settlements were totally depopulated generic 500mg actoplus met with amex diabetes test without blood, but in most others whole families must have been wiped out buy generic actoplus met 500mg online diabetes test cats, and few can have been spared some loss, since the plague killed indiscriminately, striking at rich and poor alike. This price seems very high, since even as far away as England, 11 pence could buy you a full pound, by then. Important Facts about the Black Death Interesting information and important facts and history of the disease:  Key Dates relating to the event: Dextrose sugar becomes cheap and plentiful in about 1310. This terrible plague started in Europe in 1328 and lasted until 1351 although there were outbreaks for the next sixty years  Why was the disease called the Black Death? The disease was called the Black Death because one of the symptoms produced a blackening of the skin around the swellings. People became disillusioned with the church and its power and influence went into decline. This ultimately resulted in the English reformation Black Death Symptoms The symptoms of the Black Death were terrible and swift:  Painful swellings (buboes) of the lymph nodes  These swellings, or buboes, would appear in the armpits, legs, neck, or groin  A bubo was at first a red color. The bubo then turned a dark purple color, or black  Other symptoms of the Black Death included:  a very high fever  delirium  the victim begins to vomit  muscular pains  bleeding in the lungs  mental disorientation  The plague also produced in the victim an intense desire to sleep, which, if yielded to, quickly proved fatal  A victim would die quickly - victims only lived between 2 -4 days after contracting the deadly disease Black Death Victims in the Middle Ages - Treatments The Black Death victims in the Middle Ages were terrified of the deadly disease. The most that could be done was that various concoctions of herbs might be administered to relieve the symptoms - there was no known cure. Vinegar was used as a cleansing agent as it was believed that it would kill disease. But bloodletting was commonly thought to be one of the best ways to treat the plague. The blood that exuded was black, thick and vile smelling with a greenish scum mixed in it. Various other remedies were tried including arsenic, lily root and even dried toad. Bristol was an important European port and city in England during the Medieval era. It is widely believed that Bristol was the place where the Black Death first reached England. The River Thames brought more ships and infection to London which spread to the rest of England. The crowded, dirty living conditions of the English cities led to the rapid spread of the disease. Between 1348 and 1350, killed about 30 - 40% of the population of England which at the time was estimated to be about five to six million. Black Death during the Elizabethan Era The Black Death Victims in the Middle Ages - The daughter of the King of England The Black Death struck people and took its victims from all walks of society. Joan (sometimes referred to as Joanna ) left England with the blessing of her parents. The Black Death had not yet taken its hold in England and its first victims had only been claimed in France in August 1348. The Black Death and Religion During the Middle Ages it was essential that people were given the last rites and had the chance to confess their sins before they died. The spread of the deadly plague in England was swift and the death rate was almost 50% in isolated populations such as monasteries. There were not enough clergy to offer the last rites or give support and help to the victims. The church could offer no reason for the deadly disease and beliefs were sorely tested. This had such a devastating effect that people started to question religion and such doubts ultimately led to the English reformation. Consequences and Effects of the Black Death plague The Consequences and effects of the Black Death plague were far reaching in England:  Prices and Wages rose  Greater value was placed on labor  Farming land was given over to pasturing, which was much less labor-intensive  This change in farming led to a boost in the cloth and woolen industry  Peasants moved from the country to the towns  The Black Death was therefore also responsible for the decline of the Feudal system  People became disillusioned with the church and its power and influence went into decline This resulted in the English reformation The End of the Plague and the spread of sugar Nostradamus was a healer of sort and he said for people to clean their houses, open the windows and let in good sunshine and clean air. In the recipe listings of "Le Menagier de Paris", 1393, sugar in many various forms is listed 72 separate times. Honey by comparison is only mentioned 24 times, and the price for candied orange peel, made with honey, is precisely the same as that for sugared almonds (10 sous/lb). So, in a quick survey of Europe in the 13th and 14th centuries, sugar was widely available in England, France, Spain, and Italy in powdered form as well as block, in cooking as well as medicinally, and more widely used than honey! Special traffic regulations had been needed for the transport of firewood and cane. So valuable was sugar for the economy that the law allowed compulsory purchase of land for it, and water could be taken from whatever source; workers were also bound to the industry by law and were free from arrest during the season when the refineries were working. During the 42 years following the accession of Alfonso in 1416, "On one occasion Alfonso personally seems to have cornered the market in sugar exports to Flanders," Smith tells us. Kilns for boiling the liquid and ceramic molds to crystallize the sugar into loaves/cones. The perception that all medieval sugar consisted of burnt black cones is a common misapprehension brought on by the experience of those of us who have been part of the Early American historical groups. Do-it-yourself pioneers in America produced some really bad sugars in an effort to be self sufficient, but that should not be projected to our thoughts about Medieval times where industrial production and transport was common. Though some bought the cheaper loaf and saved money by grinding it themselves, powdered sugar was common, and the quality was high. In 1492 Christopher Columbus stopped at the Canary Islands on his famous journey, for rest and provisions for a few days, but ended up staying a month. When he finally left he was given cuttings of sugar cane which became the first to reach the New World. Therefore much later Sugar Cane came to be cultivated in the New World, and as a side effect became multi-sourced particularly due to British Colonial policies (you see how this all links up now) and influence throughout the geographical coverage of the empire in the mid 1600s to mid 1700s. This is really the key point along the timeline where sugar, outside Asia, became commonly available and no longer a rare indulgence of the wealthy. Notably, this was also closely linked to the international slave trade - African slaves became the dominant plantation workers in North America, partly because they turned out to be naturally resistant to Yellow Fever and Malaria, and as a result the British imported over 4 million slaves to the West Indies. At this point (the mid to late 1700s) the Caribbean was the world’s largest producer of sugar, and due to high death rates anyway on sugar plantations, there were only 400,000 African people left alive in the West Indies by the time slavery ended. In 1772 Slavery was declared illegal in England, including overseas slaves not living in England. Poor Blacks are grossly mistreated and paid almost nothing to harvest a dealy product. Later Barbados and the British Leewards were extremely successful in the production of sugar because it counted for 93% and 97% respectively of each island’s exports, largely due to changes in the eating habits of many Europeans. Whereby we may see the sequel of things not always, but very seldom, to be such as is pretended in the beginning. As we can see from the above, when sugar was half a crown for a pound, cinnamon was fourpence the ounce. Imported goods rose and fell with various import laws, but were eminently reasonable in price at all times. Also, we can see that in relationship to other commodities, sugar has come down dramatically in price as well. This would perhaps account for all those description from foreign ambassadors about the English having bad teeth! By the Elizabethian period, the best sugar was considered to be that of Madiera, with those of Barbary (Morocco) or the Canaries a close second. When he saw they were English he ran off , and going ashore, they discovered, "many sorts of sweetmeats and conserves, with great store of sugar, being provided to serve the fleet returning to Spain.

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Under such conditions buy actoplus met 500 mg mastercard diabetes insipidus hyponatremia, enzyme 2 generic actoplus met 500 mg on-line diabetes diet wiki, the high-Km enzyme actoplus met 500mg free shipping diabetes in dogs for dummies, contributes negligibly to vtotal at low substrate concentrations buy cheap actoplus met 500mg on-line blood sugar elevated in the morning, and the range of substrate concentrations where this is largely true can be identified by visual inspection of the Eadie-Hofstee plot; (Fig. These “enzyme 1” data are plotted on an Eadie-Hofstee plot to obtain Km1 and Vmax1. Subsequently, v2 (which equals vtotal À v1) is calculated, and the data are plotted on an Eadie-Hofstee plot to obtain Km2 and Vmax2. When Km1 and Km2 differ by less than an order of magnitude, or when the range of substrate concentrations does not bracket both Km1 and Km2, it may not be possible to determine the kinetic constants of the individual enzymes. Two enzymes with similar Km values toward the same substrate have frequently been observed, and these will result in an Eadie-Hofstee plot consistent with single-enzyme kinetics. Applying the dual-enzyme model for such situations will not help; instead, reaction-phenotyping data must be used to tease out the role of the two enzymes. These result in an S-shaped curve on a (substrate) versus rate graph and a “hook”- shaped line graph on an Eadie-Hofstee plot. When allosteric interactions are In Vitro Study of Drug-Metabolizing Enzymes 323 Figure 23 Depictions of a reaction catalyzed by two kinetically distinct enzymes. The- oretical data illustrate the method used to determine the kinetic constants when two enzymes are involved in the same reaction. Note that the direct plot (left) does not effectively indicate that two enzymes might be involved in a given reaction. However, this is readily achieved by a concave-appearing Eadie-Hofstee plot (middle graph). The kinetic constants (Km and Vmax) of the high-affinity (low-Km) enzyme are determined using the initial rates observed at low substrate concentrations (solid line in the middle graph). Then, the contribution of the low-Km enzyme is subtracted and the kinetic constants for the high- Km enzyme are determined (dotted line in the middle graph). It is evident that the relative contribution of the high-Km enzyme increases (and that of the low-Km enzymes decreases) as the substrate concentration is increased. The Hill equation is: n Vmax Á ½ŠS v ¼ n ð9Þ S50 þ ½ŠS where S50 is analogous to (but not identical to) Km (i. When n is greater than 1, it indicates positive cooperativity (substrate activation); when n is less than 1, it indicates negative cooperativity (substrate inhibition) (109). A Hill coefficient of 2 implies the presence of two discrete (nonoverlapping) substrate-binding sites on the enzyme, whereas a Hill coefficient of, say, 1. Correlation Analysis: Sample-to-Sample Variation in the Metabolism of the Drug Candidate Correlation analysis is one of the four basic approaches to reaction phenotyping. The experimental conditions for examining the in vitro metabolism of the drug candidate by a bank of human liver microsomes are based on the results of experiments described in Steps 2 and 3 (i. In order to obtain clinically relevant results, the metabolism of the drug candidate by human liver microsomes must be examined at pharmacologically relevant concentrations of the drug candidate, as illustrated for lansoprazole 5-hydroxylation in Figure 20. In our laboratory, reaction phenotyping is carried out with a bank of human liver microsomal samples (e. Banks of human liver microsomes intended for correlation analysis are commercially available as kits (e. The latter determination also provides a measure of the statistical significance of any correlations. Correlation analysis provides valuable information on the extent to which the metabolism of a drug candidate will potentially vary from one subject to the next (i. However, when two or more enzymes contribute to metabolite formation, corre- lation analysis may lack the statistical power to establish the identity of each enzyme. Statistically significant correlations should always be confirmed with a visual inspection of the graph because there are two situations that can produce a misleadingly high correlation coefficient: (1) the regression line does not pass through or near the origin and (2) there is an outlying data point that skews the correlation analysis, as illustrated in Figure 25. Correlation analysis works particularly well when a single enzyme dominates the formation of a particular metabolite. This approach success- fully identifies the enzymes involved when each enzyme contributes 25% or more to metabolite formation, but it will likely not identify an enzyme that contributes only approximately 10%. A graphical representation of the application of multivariate analysis to the results of a reaction phenotyping experiment is shown in Figure 26, on the basis of an examination of the sample-to-sample variation in the 1-hydroxylation of bufuralol (12 mM) by a panel of human liver microsomes. The sample-to-sample variation in bufuralol 1-hydroxylation correlates reasonably well with In Vitro Study of Drug-Metabolizing Enzymes 327 Figure 25 Common pitfalls in correlation analysis. Correlation analysis is suspected when the regression line is unduly affected by a single outlying data point, or when the regression line does not pass near the origin. When two enzymes contribute significantly to metabolite formation, their identity and relative con- tribution can be established by performing correlation analysis in the presence and absence of an inhibitor of one of the participating enzymes (preferably the major contributor). This approach works even when one of the enzymes contributes substantially less than 25% to metabolite formation, as was demonstrated by 328 Ogilvie et al. Chemical and Antibody Inhibition Chemical and antibody inhibition represent the second and third approaches to reaction phenotyping. As in the case of correlation analysis, chemical and antibody inhibition experiments must be conducted with pharmacologically relevant concentrations of the drug candidate in order to obtain clinically relevant results. Therefore, appropriate solvent and preincubation controls should be included in all chemical inhibition experiments. The lack of specificity can complicate the interpretation of chemical inhibition experiments. If a drug candidate is metabolized by a high-affinity enzyme, the con- centration of a competitive chemical inhibitor must be increased with increasing concentration of the drug candidate in order to achieve a high degree of inhi- bition. A good rule of thumb is to use multiples (generally up to 10-fold) of the lowest inhibitor concentration, which is calculated from the following equation: ½DrugŠÁKiðinhibitorÞ Lowest½InhibitorŠ¼ ð10Þ KmðDrugÞ where [Drug] is the intended final concentration of the drug candidate added to the microsomal incubation, Ki is the inhibition constant of the inhibitor for a given enzyme, and Km is the Michaelis constant of the drug candidate (as determined in Step 3). This method of calculating of the lowest concentration of inhibitor is applicable to competitive inhibitors but not to noncompetitive or metabolism-dependent inhibitors. A range of inhibitor concentrations is rec- ommended to demonstrate concentration dependence. For example, if the lowest concentration of the chemical inhibitor were calculated to be 1 mM (from the above equation), then the range of inhibitor concentration should span at least 10-fold (e. If both enzymes contribute to metabolite formation, the inhibitory effect of the chemical on one enzyme may be offset by its activating effect on the other enzyme. When chemical inhibition experiments are conducted with a relatively metabolically stable drug candidate (one that must be incubated with relatively high concentrations of human liver microsomes for a relatively long time in order to generate quantifiable levels of metabolite), it is important to take into account the metabolic stability of the inhibitors themselves. Lack of metabolic stability makes some compounds poor choices as chemical inhibitors despite their selectivity. Finally, appropriate controls should be included in each chemical inhibi- tion experiment to evaluate whether any of the chemical inhibitors interfere with the chromatographic analysis of the metabolites of interest and whether metabolite formation is inhibited by any of the organic solvents used to dissolve the chemical inhibitors. Unfortu- nately, the utility of this method is limited by the availability of specific inhibitory antibodies and by nonspecific effects associated with the addition of antiserum and ascites fluid to the microsomal incubation. The use of antiserum (for polyclonal antibodies) and ascites fluid (for monoclonal antibodies) rather than purified antibodies often necessitates adding a large amount of albumin and other proteins to the micro- somal incubation. For this reason, control (preimmune) serum and ascites fluid should be included as negative controls in antibody inhibition experiments. These issues are lessened when purified antibodies are used instead of antisera and ascites fluid. As in the case of chemical inhibition, a lack of specificity can complicate the interpretation of antibody inhibition experiments. A lack of specificity and the nonspecific effects outlined above likely account for the majority of cases where the sum of the inhibitory effects of a panel of inhibitory antibodies adds up to greater than 100%. If an antibody inhibits the metabolism of a marker substrate by 80%, and if the same antibody inhibits the metabolism of drug candidate by 80%, there is uncertainty as to whether the inhibited enzyme contributes 80% or 100% to the metabolism of the drug candidate. Genetic or drug- mediated loss of an enzyme that accounts for 80% of a drug’s clearance will cause a fivefold increase in systemic exposure, whereas loss of an enzyme that accounts for 99% of a drug’s clearance will cause a 100-fold increase in exposure. In both cases, cytochrome b5 increases Vmax/Km, which is a measure of in vitro intrinsic clearance. The kinetic constants are only determined for those enzymes that were shown in preliminary experiments to be capable of metabolizing the drug candidate.

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