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When any drug is used by a nursing mother, it is desirable to have the least amount of active drug available in the maternal circulation to diffuse into the breast milk. Category A and to some extent category B drugs have been shown to be safest in pregnancy. The definition of polycystic ovarian syndrome includes hyperandrogenism and hyperinsulinemia. Insulin resistance is common and diabetes can result, but these conditions are not part of the diagnosis. Imipramine is helpful to paralyze the bladder, leading to decreased contractility. Tamsulosin is helpful in some cases of overflow incontinence and this agent can certainly worsen stress incontinence. Bladder retraining and behavioral therapy is helpful for all types of incontinence. The type of bladder retraining depends on the type of incontinence although the concepts are similar between stress and urge incontinence. Overflow incontinence bladder also involves voiding at regular intervals, but they are typically not as frequent as those involved with the other types of incontinence. High-molecular-weight substances are less likely to pass into breast milk because of their size. Drugs that are highly plasma protein bound may reach the breast milk only in small amounts, because a large portion of the drug is bound to the maternal plasma proteins and, therefore, only a small amount is free to diffuse into breast milk. A low molecular weight, moderately lipophilic drug passes easily into breast milk. A drug that has a low degree of plasma protein binding has a significant amount of drug free to diffuse into breast milk. A weakly basic drug may ionize after reaching the breast milk and therefore remain trapped in the milk. Any exposure during this time will have either no effect or the embryo will be destroyed. During the remaining weeks of the pregnancy, teratogens may exert effects on the fetus. Teratogenic effects are not always structural in nature; they can be functional or behavioral. Laboratory tests are performed for multiple purposes, including to discover a disease, confirm or differentiate a diagnosis, stage or classify a disease, and monitor effectiveness of therapy. Diagnostic tests are done in patients with signs and symptoms of disease or with an abnormal screening test. These tests can be expensive, and requests for them must be balanced against potential benefits for patients and how the laboratory test will affect your decision regarding therapy. Generally, lab tests should be ordered only if the results will affect the decisions about the management of the patient. Normal laboratory test results fall within a predetermined range of values, and abnormal values fall outside that range. The normal range of a laboratory test is usually determined by applying statistical methods to results from a representative sample of the general population. Normal limits may be defined somewhat arbitrarily; thus, values outside the normal range may not necessarily indicate disease or the need for treatment. Normal values also vary among institutions and may depend on the method used to perform the test. The goal is not to make all laboratory values normal; resist urges to do something in a clinically stable patient. Controversy surrounds this issue in the United States, and resistance to adopt this system continues. The mole is not influenced by the addition of excess weight of salt or ester formulations. Technically and pharmacologically, the mole is more meaningful than the gram because each physiological reaction occurs on a molecular level. It is still controversial which method should be used to report clinical laboratory values.

To infuse the antibiotic as a solution containing 10-g drug in 500 mL 5% dextrose, how many milliliters per hour of the solution would be infused into the patient The earliest evidence that a drug is stored in tissue is (A) an increase in plasma protein binding. The intensity of the pharmacologic action of a drug is most dependent on the (A) concentration of the drug at the receptor site. The principle of superposition in designing multipledose regimens assumes that (A) each dose affects the next subsequent dose, causing nonlinear elimination. The renal clearance of inulin is used as a measurement of (A) effective renal blood flow. All of the following statements about plasma protein binding of a drug are true except which one The onset time for a drug given orally is the time for the drug to (A) reach the peak plasma drug concentration. The initial distribution of a drug into tissue is determined chiefly by the (A) rate of blood flow to tissue. If digoxin has a half-life of 35 hrs how long will it take for a toxic plasma concentration of 8 ng/mL to decline to a therapeutic plasma concentration of 2 ng/mL However, creatinine formation depends on muscle mass and muscle metabolism, which may change with age and various disease conditions. The equation for the plasma concentration at steady state (Css) provides the formula for calculating the rate of an intravenous infusion (R). Because the half-life in the current case is 1 hr, the time to reach 95% of the Css is 4. Therefore, if a drug solution containing 10 g in 500 mL is used, the required infusion rate is 936 mg 1 hr 500 mL 10000 mg 46. The initial distribution of a drug is chiefly determined by blood flow, whereas the affinity of the drug for tissue determines whether the drug concentrates at that site. The gastric emptying time and degree of plasma protein binding affect drug distribution but are less important than the rate of blood flow to tissue. The kidney, lung, skin, and intestine all have some capacity to biotransform, or metabolize, drugs; but the brain has little capacity for drug metabolism. The superposition principle, which underlies the design of multiple-dose regimens, assumes that earlier drug doses do not affect subsequent doses. If the elimination rate constant or total body clearance of the drug changes during multiple dosing, then the superposition principle is no longer valid. Changes in the total body clearance (ClT) may be caused by enzyme induction, enzyme inhibition, or saturation of an elimination pathway. An increase in plasma protein binding suggests that the drug is located in the plasma rather than in tissue. A decrease in hepatic metabolism, an increase in side effects, or a decrease in urinary excretion of free drug is caused by a decrease in drug elimination. As more drug is concentrated at the receptor site, more receptors interact with the drug to produce a pharmacologic effect. When all of the available receptors are occupied by drug molecules, additional drug does not produce a more intense response. Nonlinear pharmacokinetics is a term used to indicate that first-order elimination of a drug does not occur at all drug concentrations. With some drugs, such as phenytoin, as the plasma drug concentration increases, the elimination pathway for metabolism of the drug becomes saturated and the half-life increases. When the maintenance dose is given at a dosage frequency equal to the half-life, then the loading dose is equal to twice the maintenance dose, in this case 540 g, or 0. For cardiac glycosides, the peak (Cmax) and trough (Cmin) concentrations are calculated, and plasma drug concentrations are monitored after dosing.

However, this approach is limited to the 20 amino acids that are normally used in protein synthesis. One way to increase the diversity of the proteins formed after mutagenesis is to introduce synthetic amino acids with unique side chains at specific sites. Thissystemmaybemanipulatedtoinsert a variety of different amino acid analogues into specified sites within proteins in the hope of producing functional proteins with altered activities compared with the native form. While the full potential of these approaches has yet to be realized, it is nevertheless clear that it is now possible to produce proteins containing unusual chemical structures and possibly having unique properties. A major reason why additional enzymes are not used to any great extent in industrial processes is that an activity that has evolved to perform a particular function for a microorganism, animal, or plant under natural conditions usually is not wellsuitedforahighlyspecializedindustrialapplication. Mostenzymes are easily denatured by exposure to the conditions, such as high temperature and the presence of organic solvents, that are used in many industrial processes. Although thermotolerant enzymes can be isolated from thermophilic microorganisms, these organisms often lack the particular enzyme that is required for use in industrial processes. However, with the availability of directed mutagenesis and gene cloning, these constraints are no longer significant. Adding Disulfide Bonds the thermostability of a protein can be increased by creating a molecule that will not readily unfold at elevated temperatures. In addition, these thermostable enzymes are often resistant to denaturation by organic solvents and nonphysiological conditions, such as extremes of pH. The addition of disulfide bonds (through the introduction of specifically placed cysteine residues) can usually significantly increase the stability of a protein. The problem is whether extra disulfide bonds perturb the normal functioning of a protein. The side chains of the amino acid residues that were targeted to become cysteine residues were known to be spatially close to each other in the active enzyme. This proximity ensured that the overall conformation of the molecule would remain essentially unaffected by the formation of the new disulfide linkages. The newly introduced cysteines created disulfidebondsbetweenpositions3and97,9and164,and21and142of the enzyme, where the numbers denote the amino acid positions in the polypeptide, starting from the N terminus. The thermostability of a protein is often defined as the temperature at which the overall structure of the protein is 50% denatured; the state of denaturation can be assessed by monitoring the circular dichroism of the protein in solution. The wild-type (native) form of the enzyme T4 lysozyme has two free cysteine residues that both exist as free sulfhydryl groups, neither of which is involved in a disulfide bond. In the so-called pseudo-wild-type enzyme, these cysteines were changed by oligonucleotide-directed mutagenesis to threonine (Thr) and alanine (Ala) without altering either the activity or the thermostability of the enzyme. Consequently, the pseudo-wild-type sequence provided a standard for comparing variants with potentially thermostabilizing disulfide bonds and also prevented spurious disulfide bonding between the introduced cysteine residues and the naturally occurring ones. The results of this experiment indicate that the thermal stability of the enzyme increases as a result of the presence of disulfide bonds, with the most thermostable variant being the one with the largest number of disulfide bonds, and that some variants (C, E, and F in Table 8. The loss of enzymatic activity in three of the variants probably reflects a distortion of the peptide backbone of the molecule containing a disulfide linkage between residues 21 and 142. Hence, the precise amino acid changes that yield the "best" variant are not always obvious. However, from this experiment, it is clear that increasing disulfide bonds to enhance protein stability is feasible. In a similar study, the development of a temperature-stable mutant of the enzyme xylanase from Bacillus circulans was undertaken. During the making of paper, wood pulp is chemically treated to remove the hemicellulose that would otherwise contribute to the discoloration of the paper product. Unfortunately, this step results in the creation of large amounts of potentially toxic effluent. From an environmental perspective, treatment of wood pulp with xylanase, which degrades hemicellulose, is preferred to pulping. Treatment of wood pulp with this enzyme could lower the amount of bleaching chemical that would otherwise be required as a part of this process. Directed Mutagenesis and Protein Engineering 309 follows the hot-alkali treatment of the pulp. While it is possible to lower the pH of this material by adding acid, current industry practice is directed toward using less water to cool the pulp, so if xylanase were to be used in this process, it must function efficiently at relatively high temperatures. Computer modeling of the three-dimensional structure of xylanase was used to predict sites along the polypeptide chain where one, two, or three disulfide bridges could be introduced in order to stabilize the enzyme without disrupting its catalytic activity.

Rarely, however, a reciprocal translocation may alter the expression or structure of an oncogene or a tumor suppressor gene, conferring an abnormal growth advantage to the cell. A classic example is a reciprocal translocation of the long arms of chromosomes 9 and 22, termed the Philadelphia chromosome. This translocation alters the activity of the abl proto-oncogene (protooncogenes can lead to cancer; see Chapter 5). They occur only in the acrocentric chromosomes (13, 14, 15,21, and 22) and involve the loss of the short arms of two of the chromosomes and subsequent fusion of the long arms. If alternate segregation occurs, the offspring will inherit either a normal chromosome complement or will be a normal carrier like the. If adjacent segregation occurs, the offspring will have an unbalanced chromosome complement (an extra or missing copy of the long arm of chromosome 21 or 14). Consequences of a Robertsonian, Translocaton in One Parent (illustrated with a male) I Robertsonian Translocation and Down Syndrome. Approximately 5% of Down syndrome cases are the result of a Robertsonian translocation affecting chromosome 14 and chromosome 21. When a translocation carrier produces gametes, the translocation chromosome can, segregate with the normal 14 or with the normal 21. A diagram can be drawn to represent the six possible gametes that could be produced. The key difference is 47 versus 46 chromosomes in the individual with Note Robertsonian Translocations When one parent is a Robertsonian translocation carner: Adjacent segregation produces unbalanced genetic material and most likely loss of pregnancy. The recurrence risk (determined empirically) for female translocation carriers is 10-15%, and that for male translocation carriers is 1-2%. The elevated recurrence risk for translocation carriers versus noncarri~rs underscores the importance of ordering a chromosom~ study when Down syndrome is suspected in a newborn. Examples include: Prader-Willi syndrome Angelman syndrome If a micro deletion includes several contiguous genes, a variety of phenotypic outcomes may be part of the genetic syndrome. Inversions thatinclude the centromere are termed pericentric, whereas those that do not include the centromere are termed paracentric. The karyotype of the inversion shown in Figure 11-3-8, extending from 3p21 to 3q13 is 46,xy,inv(3)(p21;q13)~ Inversion carriers still retain all of their genetic material, so they are usually unaffecte (although an in~ersion may interrupt or otherwise affect a specific gene and thus cause disease) Because homologous chromosomes must line up during meiosis, inverted chromosomes. Pericentric Inversion of Chromosome 16 A male infant, the product of a full-term pregnancy, was born with hypospadias and ambiguo genitalia. His brother had two childre " " both healthy, and the father assumed that he would also have normal children. A Pericentric Inversion of Chromosome 3 I t Ring Chromosome A ring chromosome can form when a deletion occurs on both tips of a chromosome and the remaining chromosome ends fuse together. The karyotype of an isochromosome for the long arm of the X chromosome would be 46;X,i(Xq); this karyotype results in an individual with Turner syndrome, indicating that most of the critical genes responsible for the Turner phenotype are on Xp. Isochromosome Xq Uniparental Disomy Uniparental disomy is a rare condition in which both copies of a particular chromosome are contributed by one parent. This may cause problems if the chromosome contains an imprinted region or a mutation. For example, 25-30% of Prader- Willi cases are caused by maternal uniparental disomy of chromosome 15. A smaller percentage of Angelman syndrome is caused by paternal uniparental disomy of chromosome 15. For example, a probe that is specific for chromosome 21 will hybridize in three places in the cells of a trisomy 21 patient, providing a diagnosis of Down syndrome. In combination with special cameras and imageprocessing software, this technique produces a karyotype in,which every chromosome is "painted" a different color. This allows the ready visualization of chromosome rearrangements, such as small translocations. Karyotypes of the mother, the father, and the most recently aborted fetus are represented schematically below. A woman brings her 16-year-old daughter to a physician because she has not yet begun menstruating.