By H. Curtis. Slippery Rock University. 2019.
However buy cheap dapsone 100mg, only 60–65 % respond to any one drug and response to treatment usually takes 4–8 weeks purchase dapsone 100 mg mastercard, if the drug works cheap dapsone 100 mg line. A failed ﬁrst treatment is the best predictor of treatment dropout and treatment dropout is the best predictor of suicide. Although antidepressant response takes weeks, the effects of antidepressants on monoamine systems is very rapid. Therefore, it is possible that the therapeutic effects of all antidepressants are due to common expression of genes after chronic treatment. The ﬁrst step toward answering this question is ﬁnding out which transcripts are increased or decreased by antidepressant treatment. If a particular system is found to be responsible Universal Free E-Book Store 468 13 Personalized Management of Psychiatric Disorders Table 13. A pharmacogenomic approach to individualize antidepressant drug treatment is based on three levels: 1. Biomarkers of Response to Antidepressant Treatment The most promising biomarkers for response to antidepressant therapy include genetic variants and gene expression proﬁles, proteomic and metabolomic markers, neuroendocrine function tests, electrophysiology and brain imaging. This study is the ﬁrst to link brain function and medication side effects, and to Universal Free E-Book Store Psychopharmacogenetics/Psychopharmacodynamics 469 Table 13. The ﬁndings show the prom- ise of new ways for assessing susceptibility to antidepressant side effects. The ability to identify individuals who are at greatest risk of side effects would greatly improve the success rate of antidepressant treatment. For example, physicians might select a medication with a lower side-effect proﬁle, start medication at a lower dose or choose psychotherapy alone when treating patients susceptible to antidepressant side effects. Having a biological marker of likely treatment effectiveness to predict and guide clinicians’ decisions would reduce the likelihood of unsuccessful treatments with antidepressants. Nevertheless, despite these advantages, not all patients beneﬁt from treatment; some do not respond adequately, while others may Universal Free E-Book Store 470 13 Personalized Management of Psychiatric Disorders react adversely. This necessitates a review of the initial treatment choice, often involving extended periods of illness while a more suitable therapy is sought. Such a scenario could be avoided were it possible to determine the most suitable drug prior to treatment. Current evidence emerging from the ﬁeld suggests that gene variants within the serotonin transporter and cytochrome P450 drug- metabolizing enzymes are of particular importance. It also appears likely that further key partici- pating genes remain to be identiﬁed. The most important areas for future research are explora- tion of known candidate systems and the discovery of new targets for antidepressants, as well as prediction of clinical outcomes. These medications include ﬂuoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa) and escitalopram (Lexapro). It provides unique information relating to drug response: side effect and compliance. Universal Free E-Book Store Psychopharmacogenetics/Psychopharmacodynamics 471 Usually genetic proﬁles cannot predict a large percentage of variation in response to citalopram. Data available through the Sequenced Treatment Alternatives to Relieve Depression database was used to create three boosted Classiﬁcation and Regression Trees to identify 16 subgroups of patients, among whom anticipation of positive or negative response to citalopram was signiﬁcantly different from 0. In a 10-fold cross-validation, this ensemble of trees made no predictions in 33 % of cases. In the remaining 67 % of cases, it accurately classiﬁed response to citalopram in 78 % of cases. The authors concluded that for the majority of the patients, genetic biomarkers can be used to guide selection of citalopram. The rules identiﬁed in this study can help personalize prescription of antidepressants. In addition, these experiments raise the possibility of predicting individual’s response to antidepressant therapy, and adjusting treatment accordingly. Moreover, giving antidepressants to the modiﬁed mice did not further change their behavior. In order to correlate the ﬁndings in mice to what happens in the human brain, the researchers next analyzed genetic information from patients with depression and Universal Free E-Book Store 472 13 Personalized Management of Psychiatric Disorders tracked their response to a course of antidepressant drugs. Search of a database that correlates gene sequences to gene activity in the human brain revealed that all three variations caused less gene activity. This ﬁnding could lead to genetic tests that enable physician’s to predict a patient’s response to antidepressants, and it also provides a target for potential new therapies for the disease. The study is using genetic biomarker data to compare standard treatment with that guided by Genomind’s Genecept assay, which combines a pro- prietary panel of genetic tests with an analytical report to clinicians. The primary objective of the study is to improve depressive symptoms from baseline to 6 months. Researchers will focus on pharmacogenetic genotyping of metabolic activity, which can then be used to guide treatment of patients with antidepressants. Also, genome-wide association study analysis will be performed in the future to identify biomarkers that may be predictive of patient response to and tolerance of certain therapeutics. As approximately one-half of depressed patients do not achieve satis- factory results with current ﬁrst-line treatment options, a product that combines a genetic test with vilazodone will assist physicians in matching patients with a drug that is more likely to be effective for each patient in the ﬁrst instance. The primary and supportive secondary efﬁcacy endpoints were met in a randomized, double-blind, placebo-controlled trial. In addition, the study separately identiﬁed candidate bio- markers for a potential companion pharmacogenetic test for response to vilazodone. Further research is needed to determine the mechanisms related to poor response in patients with the 9/9-repeat genotype, and to determine if this group responds differentially to alternative treatments. Future studies should incorporate this endophenotype in clinical trials to investigate further the efﬁcacy of new treatments in this substantial subgroup of patients. Personalized Approach to Addiction Pharmacogenetics of Drug Addiction Pharmacogenetics provides the tools required to identify genetic predictors of prob- able drug response, drug efﬁcacy, and drug-induced adverse events-identiﬁcations that would ideally precede treatment decisions. Drug abuse and addiction genetic data have advanced the ﬁeld of pharmacogenetics in general. Although major ﬁnd- ings have emerged, pharmacotherapy remains hindered by issues such as adverse events, time lag to drug efﬁcacy, and heterogeneity of the disorders being treated. The sequencing of the human genome and high-throughput technologies are enabling pharmacogenetics to have greater inﬂuence on treatment approaches. Genes important in drug abuse pharmacogenetics have been identiﬁed, which pro- vide a basis for better diagnosis and treatment of drug abuse disorders.
Conjugation is the passage of genes from bacteria to bacteria via direct contact through a sex pilus or bridge discount 100mg dapsone visa. Conjugation occurs primarily in gram-negative bacilli generic dapsone 100mg with visa, and it is the prin- cipal mechanism of acquired resistance among enterobacteria order dapsone 100 mg. Structure and mechanism of action (1) Penicillins are analogues of alanine dipeptide (Fig. Modifications of the R-group side- chain (attached to the b-lactam ring) alter the pharmacologic properties and resistance to b-lactamase. Gram-positive bacteria with thick external cell walls are particularly susceptible. The genes for b-lactamases can be transmitted during conjugation or as small plasmids (minus conjugation genes) via transduction. Common organisms capable of producing penicillinase include Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Neisseria gonorrhoeae, and Bacillus, Proteus, and Bacteroides species. Selected drugs and their therapeutic uses (Table 11-1) (1) Penicillin G and penicillin V are mainly used to treat infections with the following organisms (resistant strains of bacteria are being isolated more frequently): (a) Gram-positive cocci (aerobic): Pneumococci, streptococci (except S. This group represents the most common pathogens for which first-generation penicillins are used today. Pro- benicid, a uricosuric agent that blocks renal secretion of penicillin, is used rarely for this purpose. Chapter 11 Drugs Used in Treatment of Infectious Diseases 255 (3) Penicillinase-resistant penicillins (oxacillin, dicloxacillin, and nafcillin) are used pre- dominantly for penicillinase-producing staphylococcal infections. Ampicillin is useful for infections caused by Haemophilus influenzae, Streptococcus pneumonia, Streptococcus pyrogenes, Neisseria meningitides, Pro- teus mirabilis, and Enterococcus faecalis. Amox- icillin is commonly used for endocarditis prophylaxis before major procedures. Piperacillin/tazobactam is effective against most gram-negative organisms, including Pseudomonas spp. Adverse effects (1) Penicillins cause hypersensitivity reactions in nearly 10% of patients. All types of reac- tions, from a simple rash to anaphylaxis, can be observed within 2 minutes or up to 3 days following administration. Endocarditis prophylaxis (1) Endocarditis prophylaxis is indicated for patients with prosthetic heart valves; those who have previously been diagnosed with endocarditis; patients born with cyanotic heart disease; and patients with surgically constructed systemic pulmonary shunts. Patients with intermediate risk for endocarditis are those who were born with other con- genital cardiac abnormalities; those with acquired valvular dysfunction; and patients with hypertrophic cardiomyopathy. Structure and mechanism of action (1) Cephalosporins consist of a 7-aminocephalosporanic acid nucleus and a b-lactam ring linked to a dihydrothiazine ring (see Fig. Third-generation cephalosporins are sensitive to another class of b-lactamase, the cephalosporinases (genes are generally located on chromosomes as opposed to plasmids). They are used in treatment of streptococcal infections as well as infections Chapter 11 Drugs Used in Treatment of Infectious Diseases 257 caused by E. Ceftriaxone is used for sexually trans- mitted infections caused by gonorrhea, as well as in empiric therapy for commu- nity-acquired meningitis. Adverse effects and drug interactions (1) Cephalosporins most commonly cause hypersensitivity reactions (2%–5%); 5%–10% of penicillin-sensitive persons are also hypersensitive to cephalosporins. Aztreonam (Azactam) (1) Aztreonam is a naturally occurring monobactam lacking the thiazolidine ring that is highly resistant to b-lactamases. Vancomycin (Vancocin, Vancoled) (1) Vancomycin is a tricyclic glycopeptide that binds to the terminal end of growing pepti- doglycan to prevent further elongation and cross-linking; this results in decreased cell membrane activity and increased cell lysis. Rapid infusion may cause anaphylactoid reactions and ‘‘red neck’’ syndrome (flushing caused by release of histamine). Bacitracin (1) Bacitracin inhibits dephosphorylation and reuse of the phospholipid required for accep- tance of N-acetylmuramic acid pentapeptide, the building block of the peptidoglycan complex. Cycloserine (Seromycin) (1) Cycloserine is an amino acid analogue that inhibits alanine racemase and the incorpo- ration of alanine into the peptidoglycan pentapeptide. Daptomycin (Cubicin) (1) Daptomycin is a bactericidal agent that binds to and depolarizes the cell membrane resulting in loss of membrane potential and rapid cell death. Fosfomycin (Monural) (1) Fosfomycin inhibits the enzyme enolpyruvate transferase and therby interferes down- stream with the formation of bacterial cell wall specific N-acetylmuramic acid. Structure and mechanism of action (1) Aminoglycosides are amino sugars in glycosidic linkage to a hexoseaminocyclitol. Transport across the inner membrane requires active uptake that is dependent on electron transport (gram- negative aerobes only), the so-called energy dependent phase I transport. This ‘‘freezes’’ the initiation complex and leads to a buildup of monosomes; it also causes translation errors. Selected drugs and their therapeutic uses (1) The role for aminoglycosides has decreased substantially due to their narrow spectrum of activity and toxicity, and the availability of other agents. Adverse effects (1) Aminoglycosides have a narrow therapeutic index; it may be necessary to monitor se- rum concentrations and individualize the dose. Tetracyclines (tetracycline [Sumycin], oxytetracycline [Terramycin], demeclocycline [Declo- mycin], doxycycline [Vibramycin], minocycline [Minocin], tigecycline [Tygacil]) a. Structure and mechanism of action (1) Tetracyclines are derivatives of naphthacene carboxamide. Resistance to one tetracycline confers resistance to some, but not all, congeners. Doxycycline is excreted almost entirely via bile into the feces and hence is the safest tetracycline to administer to individuals with impaired renal function. Spectrum and therapeutic uses (1) Tetracyclines are active against both gram-negative and gram-positive organisms, but the use of these agents is declining because of increased resistance and the develop- ment of safer drugs. They are also used in combination regimens for elimination of infections caused by Helicobacter pylori. Chapter 11 Drugs Used in Treatment of Infectious Diseases 261 (4) Tigecycline, a derivative of minocycline, has a broad spectrum of activity and has activ- ity against many tetracycline-resistant organisms. Children age 6 months to 5 years receiving tetracycline therapy can develop tooth discolorations.
Performance Parameters of Gamma Cameras window or adjusts the pulse height to compensate for the variations buy generic dapsone 100mg line. This is performed in real-time during the data collection in patient studies and should be carried out for each radionuclide 100 mg dapsone mastercard. Nonlinearity The spatial nonlinearities are systematic errors in the positioning of X- buy 100 mg dapsone amex, Y-coordinates of pulses in the image and result from local count compres- sion or expansion. The spatial distortions due to nonlinearity are corrected by micro- processors built into modern cameras that use correction matrices. Nonlin- earity correction factors are generated by calculating the spatial shift of the observed position of an event from its actual position. The test pattern is placed directly on the detector, and an image is stored in a 128 × 128 matrix. The actual location (X, Y) of each pixel is known and the corresponding location on the image is measured. These variations in X, Y for all pixels are calculated as correction factors and are normally supplied by the manufacturer in the form of a look-up table. These correction factors are subsequently applied in real-time to each detected event to move it to the actual position during patient imaging. As stated above, modern cameras include two look-up matrices, the pulse-height correction and the linearity correction, to compensate for vari- ations in the overall uniformity of images. As the camera slowly drifts over time, the correction tables have to be updated for proper correction of the patient scan. The exact frequency of reacquiring the correction tables depends on stability of the camera and varies with the manufacturer. The pulse-height correction tables require more frequent acquisitions, whereas the linearity correction tables are typically performed by a service engineer. Different manufacturers recommend monthly to quarterly acquisition of these correction factor maps. Even though the uni- formity corrections at times can correct for large nonuniformities, frequent retuning of the gamma camera is essential as these corrections affect lin- earity, resolution, and overall sensitivity of the camera. Gamma Camera Tuning 131 Edge Packing Edge packing is seen around the edge of an image as a bright ring and results in nonuniformity of the image. Normally a 5-cm wide lead ring is attached around the edge of the colli- mator to mask this effect. The source of radiation can be either the radi- ation from the patient or an external radioactive source, for example, 99mTc. Performance Parameters of Gamma Cameras Effects of High Counting Rates As discussed in Chapter 8, the scintillation cameras suffer count losses at high counting rates due to pulse pileup. Pulse pileup results from the detec- tion by the camera of two events simultaneously as one event with ampli- tude different from that of either original event. If one or both of the events are photopeaks, then the amplitude of the new event will be outside the pulse-height window setting and so the event will be rejected resulting in a loss of counts. If, however, two Compton scattered photons are processed together to produce an event equivalent to the photopeak in amplitude, then the event will be counted within the window setting. But the X, Y posi- tion of the event will be misplaced on the image somewhere between the locations of the two events. Both count rate loss and image distortion at high count rates must be taken into consider- ation in evaluating the performance of different cameras. Several techniques are employed to improve the high count rate performance of a gamma camera. In modern cameras, buffers (or deran- domizers) are used in which pulses are processed one at a time, and over- lapping events are kept on “hold” until the processing of the preceding event is completed. Other cameras use pulse pileup rejection circuits to minimize the count loss and image dis- tortion and thus to improve images, although they tend to increase the dead time of the camera. Recent developments include high-speed electronics that reduce the number of misplaced events and improve the image quality signiﬁcantly. Contrast Contrast of an image is the relative variations in count densities between adjacent areas in the image of an object. Contrast (C) gives a measure of detectability of an abnormality relative to normal tissue and is expressed as A − C = (10. Lesions on the image are seen as either “hot” or “cold” spots indicating increased or decreased uptakes of radioactivity in the corresponding areas in the object. Several factors affect the contrast of the image, namely, count density, scattered radiation, pulse pileup, size of the lesion, and patient motion, and each contributes to the contrast to a varying degree. Quality Control Tests for Gamma Cameras 133 Statistical variations of the count rates give rise to noise that increases with decreasing information density or count density (counts/cm2) and is given by (1/ N ) × 100, where N is the count density. For a given imaging setting, a minimum number of counts need to be collected for rea- sonable image contrast. Even with adequate spatial resolution from the imaging device, lack of sufﬁcient counts may give rise to poor contrast due to increased noise, so much so that lesions may be missed. This count density depends on the amount of activity administered and the uptake in the organ of interest. Contrast is improved with increasing administered activity and also with the differential uptake between the normal and abnormal tissues. However, due consideration should be given to the radiation dose to the patient from a large amount of administered activity. Sometimes, high count density is achieved by counting for a longer period of time in the case of low administered activity. It should be emphasized that spatial resolution is not affected by the increased count density from increased administered activity or longer counting. Background in the image increases with scattered radiations and thus degrades the image contrast. As discussed above, at high count rates, pulse pileup can degrade the image contrast. Image contrast to distinguish a lesion depends on its size relative to system resolution and its surrounding background. Unless a minimum size of a lesion larger than system resolution develops, contrast may not be suf- ﬁcient to appreciate the lesion, even at higher count density. The lesion size factor depends on the background activity surrounding it and on whether it is a “cold” or “hot” lesion. A relatively small-size “hot” lesion can be well contrasted against a lower background, whereas a small “cold” lesion may be missed against surrounding tissues of increased activities. This primar- ily results from the overlapping of normal and abnormal areas by the move- ment of the organ.