By K. Zapotek. University of Oklahoma.

On the other hand discount periactin 4 mg visa, in an incomplete fac- torial design generic periactin 4 mg free shipping, not all levels of the two factors are combined generic 4 mg periactin free shipping. For example, if we had not collected scores from 20-year-olds given one pill, we would have an incomplete factorial design. Television commer- cials are often much louder than the programs themselves because advertisers believe that increased volume makes the commercial more persuasive. To test this, we will play a recording of an advertising message to participants at one of three volumes. Volume is measured in decibels, but to simplify things we’ll call the three volumes soft, medium, and loud. Say that we’re also interested in the differences between how males and females are persuaded, so our other factor is the gender of the listener. The dependent variable indicates how persuasive the message is, on a scale of 0 (not at all) to 25 (totally convincing). Each column represents a level of the volume factor (factor A), and each row represents a level of the gender factor (factor B). For simplicity we have the unpowerful N of 18: Nine men and nine women were tested, with three men and three women hearing the message at each volume, so we have three persuasiveness scores per cell. As usual in any experiment, we want to conclude that if we tested the entire population under our different conditions of volume or gender, we’d find differ- ent populations of scores located at different s. But, there is the usual problem: Our sample data may reflect sampling error, so we might actually find the same population and for all conditions. We want to determine the effect on per- suasiveness when we change (1) the levels of the volume, (2) the levels of gender, and (3) the interaction of volume and gender. The Main Effect of Factor A The main effect of a factor is the effect that changing the levels of that factor has on dependent scores, while we ignore all other factors in the study. Literally erase the horizontal line that separates the rows of males and females back in Table 14. Therefore, for example, we started with three males and three females who heard the soft message, so ignoring gender, we have six people in that level. Thus, when we look at the main effect of A, our entire experiment consists of one factor, with three levels of volume. So, for example, the mean for people (male and female) tested under the soft condition is 6. By averaging together the scores in a column, we produce the main effect means for the column factor. A main effect mean is the overall mean of one level of a factor while ignoring the influence of the other factor. Collapsing across a factor means averaging together all scores from all levels of that factor. To see the main effect of volume, look at the overall pattern in the three main effect means to see how persuasiveness scores change as volume increases: Scores go up from around 6 (at soft) to around 11. The H0 says that no difference exists between the levels of factor A in the population, so H0: A 5 A 5 A 1 2 3 In our study, this says that changing volume has no effect, so the three levels of volume represent the same population of persuasiveness scores. Then we describe this relationship by graphing the main effect means, performing post hoc comparisons to determine which means differ significantly, and determining the proportion of variance that is accounted for by this factor. The Main Effect of Factor B After analyzing the main effect of factor A, we move on to the main effect of factor B. Therefore, we collapse across factor A (volume), so erase the vertical lines separating the levels of volume back in Table 14. Thus, when we look at the main effect of B, now our entire experiment consists of one factor with two levels. For example, we started with three males in soft, three in medium, and three in loud. Averaging the scores in each row yields the mean persuasiveness score for each gen- der, which are the main effect means for factor B. To see the main effect of this factor, again look at the pattern of the means: Apparently, changing from males to females leads to a drop in scores from around 11. Our H0 says that no difference exists in the population, so H0: B 5 B 1 2 In our study, this says that our males and females represent the same population. The alternative hypothesis is Ha: not all B are equal In our study, this says that our males and females represent different populations. Then we graph these means, perform post hoc comparisons, and compute the proportion of vari- ance accounted for. Interaction Effects After examining the main effects, we examine the effect of the interaction.

Half-life is determined from the log plasma drug concentration versus time profile for drugs fit- ting a one-compartment model or from the elimination phase for drugs fitting the two-com- partment model periactin 4mg with amex. As long as the dose administered does not exceed the capacity of the elimination systems (i order periactin 4mg amex. The half-life is related to the elimination rate constant (k) by the equation t1/2 ¼ 0 periactin 4 mg sale. For all doses in which first-order elimination occurs, >95% of the drug will be eliminated in a time interval equal to five half-lives. If a drug that is eliminated by first-order kinetics is administered repeatedly (e. Levels will be at the high point of the steady state range shortly after a dose is administered; levels will be at the low point immediately before administration of the next dose. Hence, steady state designates an average plasma concentration and the range of fluctuations above and below that level. A shorter dosing interval decreases fluctuations, and a longer dosing interval increases them. On cessation of multidose administration, >95% of the drug will be eliminated in a time interval equal to five half-lives if first-order kinetics applies. Maintenance dose rate is the dose of a drug required per unit time to maintain a desired steady-state level in the plasma to sustain a specific therapeutic effect. One may understand this fundamental relationship in the following way: To remain at steady state, the dose rate must equal the elimination rate; that is, the rate at which the drug is added to the body must equal the rate at which it is eliminated. If one administers a drug at the maintenance dose rate, a steady state plasma concentration of drug will be reached in four to five half-lives. A large loading dose may be needed initially when the therapeutic concentration of a drug in the plasma must be achieved rapidly (e. To calculate the loading dose, select the desired plasma concentration of drug and multiply by the Vd: Loading dose = Desired [drug]plasma×Vd (amount or mass)=(mass/volume)×(volume) c. After administration of the loading dose (which rapidly achieves the desired plasma con- centration of drug), one administers the drug at the maintenance dose rate to maintain the drug concentration at the desired steady-state level. Review Test for Chapter 1 Directions: Each of the numbered items or incomplete statements in this section is followed by answers or by completions of the statement. Cortisol is capable of targeting intranuclear receptors secondary to its ability to 6. Which of the following is the term used to (A) Recruit intracellular kinases describe the elimination rate via metabolism (B) Undergo autophosphorylation catalyzed by alcohol dehydrogenase when the (C) Diffuse through lipid membranes enzyme is saturated? Which of the following parameters is used to (D) Biotransformation indicate the ability of a drug to produce the (E) Redistribution desired therapeutic effect relative to a toxic effect? A 69-year-old woman is being treated in (A) Potency the intensive care unit for presumed staphylo- (B) Intrinsic activity coccal sepsis. What specific disease presents to the emergency room with considerations will have to be made with obstipation and feculent emesis. A diagnosis of regard to adjustments of the prescribed small bowel obstruction is made, and she is medication? Postoperatively, the patient is noted to preparation have elevated blood pressure, and oral meto- (B) The patient will need to be water restricted prolol is administered; however, no improve- to decrease the volume of distribution ment of hypertension is observed. Glucuronidation reactions (D) It enhances drug metabolism (A) Are considered phase I reactions (E) It decreases untoward side effects (B) Require an active center as the site of conjugation 11. Erythromycin is prescribed ‘‘qid,’’ or four (C) Include the enzymatic activity of alcohol times daily, because of its short half-life. A 38-year-old woman presents to her psychi- drug atrist with a request to try a different antidepres- (E) To ensure that the drug concentration sant medication, since she doesn’t feel her remains constant over time current medication is helping. He is diagnosed with try imipramine; however, since this drug is epilepsy, and phenytoin therapy is started. To known to undergo an extensive first-pass effect, achieve proper drug concentrations in plasma, he orders a hepatic function panel before pre- the patient is first given a loading dose, followed scribing it, given the patient’s recent history of by maintenance doses. What is the rationale for the doc- nytoin is frequently monitored to adjust the tor’s decision? What is the ra- (A) In the presence of hepatic dysfunction, tionale behind such a regimen? A 43-year-old man who was recently fired from a well-paying job decides to commit sui- 13. The C0, obtained by extrap- at home sleeping, but notices that he has olation of the elimination phase, is determined diminished breathing, low body temperature, to be 0. A drug has a volume of distribution of 50 L (B) It decreases proximal tubular secretion and undergoes zero-order elimination at a rate (C) It decreases distal tubular reabsorption of 2 mg/hour at plasma concentrations greater Chapter 1 General Principles of Drug Action 21 than 2 mg/L. In most patients, an antibiotic is eliminated with a plasma concentration of 4 mg/L of the 25% by hepatic metabolism, 50% by renal filtra- drug, how long will it take (in hours) for the tion, and 25% by biliary excretion. If the oral dosing rate of a drug is held con- one 50 mg tablet every 12 hours, what will be stant, what willbethe effectof increasing thebio- the resulting average plasma concentration (in availability of the preparation? You administer to a patient an oral mainte- (A) Blood flow to the tissues nance dose of drug calculated to achieve a (B) Fat content of the tissues steady-state plasma concentration of 5 mcg/L. A decrease in which cell types of the following parameters explains this higher (E) Specific organ clearances than anticipated plasma drug concentration?

Because tumor cells are hypoxic periactin 4mg mastercard, treatment of tumors with radiation under high-oxygen pressure has been advocated discount 4 mg periactin with mastercard. It has been found experimentally that the proportion of hypoxic cells in a tumor remains the same before and after fractionated radiation therapy buy cheap periactin 4 mg on line. Logically, radiotherapy should have killed more oxygenated cells and thus raised the proportion of hypoxic cells. Instead, it remains the same and has brought in the argument of reoxygenation of the tumor cells during frac- tional radiation therapy, provided sufficient time is allowed for this to happen. This phenomenon has an important implication in radiation therapy in that even though the proportion of hypoxic cells remains the same, the total number of hypoxic tumor cells will be killed by radiation over time, thus leading to a successful treatment. The mechanism of reoxygenation has been attributed to the fact that as the tumor shrinks in size, surviving cells that were previously deprived of oxygen diffusion due to distal location 244 15. Radiation Biology of the blood vessels find themselves closer to the blood supply and so reoxygenate. When cells are treated with these drugs for several days before irradiation with x- or g-rays, cells become highly sensitive to radia- tion. For optimal therapeutic gain in radiotherapy, patients should be treated for a period of time extending over several cell cycles to maximize drug incorporation into the cells. Others Radiosensitizers such as actinomycin D, puromycin, methotrexate, and 5- fluorouracil have been successfully used in combination with radiation to treat cancer. Whether these agents truly increase radiosensitivity or are simply toxic to the cells is still not clear. Investigators have been trying to explore radiosensitizing chemicals to substitute for oxygen that requires the use of a high-pressure technique. Metronidazole (Flagyl), having a structure with high electron affnity, is a good radiosensitizer for hypoxic cells. Another useful radiosensitizer for hypoxic cells is misonidazole, which also has high electron affnity. Mis- onidazole is almost ten times more effective than metronidazole in sensi- tizing hypoxic cells. Another radiosensitizer of this kind is etanidazole, which is less toxic than misonidazole, and has great potential in radio- therapy. These agents protect normal cells from radia- tion damage by combining with free radicals that are produced by radia- tion and would be toxic to normal cells. However, these compounds cause severe adverse reactions such as nausea and vomiting. Experimental evidence showed that Classification of Radiation Damage 245 these products concentrate more in normal cells and less in tumor cells. As a result, normal cells are protected better than tumor cells if these agents are administered immediately before the radiation dose is given. Expo- sure of cells to 100 to 1000rad (100 to 1000cGy) causes delay in the G2 phase to M phase transition. An exposure of 1000rad (1000cGy) inhibits the progression of the S phase cells by 30%, whereas the S phase to G2 phase transition is not affected by such an exposure (Prasad, 1995). Classification of Radiation Damage Cell death is a measure of extreme radiation damage. All these damages are relevant in clinical radiation therapy as to the effective- ness of treatment. Sublethal damage occurs in mammalian cells, when a radiation dose is given in fractions at different time intervals rather than a single dose. Repair involves the healing of the radiation-induced damage in the time interval between the two fractions of the dose. If the second dose is applied too soon after the first application, the damage does not have enough time to repair and the cell will die. In the redistribution process, the cells are desynchronized and sensitized to show increased damage. Following irradiation, the radiosensitive cells will die, and one would expect the proportion of radioresistant cells and hence the surviving fraction to increase. Regeneration is a mechanism of response to depopulation of a cell cohort due to radiation damage, and depends on the types of tissue and their proliferating capacity. Protracting a fractionated dose should be beneficial to normal tissues and somewhat harmful to regenerating tumor cells. Reoxygenation discussed earlier is an effect that makes the hypoxic cells more radiosensitive in the presence of oxygen in fractionated radiotherapy. Sublethal damage repair depends very much on the dose rate and in which stage of the cell cycles the cells are. For example, the testis of male rats is most radiosensitive, whereas the small intestine seems to be less affected by radiation. The repair is significant with x-rays and g-rays and almost nonex- istent for neutrons and a-particles. For example, the survival of the HeLa cells increased after irradiation, when the cells were treated with excess thymidine or hydro- xyurea for a period of 4hr.