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Cisplatin causes a Alcoholism Gitelman-like syndrome discount sildalist 120 mg mastercard, which often can be permanent [1 generic 120mg sildalist with amex,2 order 120 mg sildalist,8–12]. Hormonal changes Hyperaldosteronism Primary hyperparathyroidism Hyperthyroidism Uncontrolled diabetes mellitus FIGURE 4-15 SIGNS AND SYM PTOM S OF HYPOM AGNESEM IA Signs and sym ptom s of hypom agnesem ia. Sym ptom s of hypom ag- nesem ia can develop when the serum m agnesium (M g) level falls below 1. M g is a critical cation in nerves and m uscles and is intim ately involved with potassium and calcium. Therefore, neu- Cardiovascular Muscular rom uscular sym ptom s predom inate and are sim ilar to those seen in Electrocardiographic results Cramps hypocalcem ia and hypokalem ia. Electrocardiographic changes of Prolonged P-R and Q-T intervals, W eakness hypom agnesem ia include an increased P-R interval, increased Q -T U waves Carpopedal spasm duration, and developm ent of U waves. M g depletion hastens atherogenesis by increasing Atrial and ventricular arrhythmias Fasciculations total cholesterol and triglyceride levels and by decreasing high-den-? Hypertension Tremulous sity lipoprotein cholesterol levels. H ypom agnesem ia also increases Digoxin toxicity Hyperactive reflexes hypertensive tendencies and im pairs insulin release, which favor Atherogenesis Myoclonus atherogenesis. Low levels of M g im pair parathyroid horm one Neuromuscular Dysphagia (PTH ) release, block PTH action on bone, and decrease the activity Central nervous system Skeletal of renal 1- -hydroxylase, which converts 25-hydroxy-vitam in D 3 Seizures Osteoporosis into 1,25-dihydroxy-vitam in D3, all of which contribute to Obtundation Osteomalacia hypocalcem ia. M g is an integral cofactor in cellular sodium -potas- Depression sium -adenosine triphosphatase activity, and a deficiency of M g Psychosis im pairs the intracellular transport of K and contributes to renal Coma wasting of K, causing hypokalem ia [6,8–12]. Ataxia Nystagmus Choreiform and athetoid movements 4. M g deficiency does the following: increases Mg retention retention angiotensin II (AII) action, decreases levels of vasodilatory prostaglandins (PGs), increases levels of vasoconstrictive PGs and growth factors, increases vascular sm ooth m uscle cytosolic No Mg Mg deficiency deficiency present calcium , im pairs insulin release, produces insulin resistance, and Normal Check for alters lipid profile. All of these results of M g deficiency favor the nonrenal causes developm ent of hypertension and atherosclerosis [10,11]. N a+— ionized sodium ; 12-H ETE— hydroxy-eicosatetraenoic [acid]; TXA — throm boxane A2. Serum M g levels may not always indicate total body stores. M ore refined tools used to assess the status of M g in erythrocytes, muscle, lymphocytes, bone, isotope studies, and indicators of intracellular M g, are not routinely available. Screening for M g deficiency relies on the fact that urinary M g decreases rapidly in the face of M g depletion in the presence of normal renal function [2,6,8–15,18]. All such tests are predicated on the fact that patients with normal M g status rapidly excrete over 50% of an acute M g load; whereas patients with depleted M g retain M g in an Time Action effort to replenish M g stores. FIGURE 4-19 M agnesium (M g) salts that m ay be used in M g replacem ent therapy. FIGURE 4-20 GUIDELINES FOR M AGNESIUM (M g) REPLACEM ENT Acute M g replacem ent for life-threatening events such as seizures or potentially lethal cardiac arrhythm ias has been described [8–12,19]. Acute increases in the level of serum M g can cause nausea, vom it- Life-threatening event, eg, seizures and cardiac arrhythmia ing, cutaneous flushing, m uscular weakness, and hyporeflexia. IV drip over first 24 h graphic changes are followed, in sequence, by hyporeflexia, respira- (2–4 vials [2 mL each] of 50% MgSO4) to provide no more tory paralysis, and cardiac arrest. M g should be adm inistered with Provides 200–400 mg of Mg (8. In the event of an em ergency Closely monitor: the acute M g load should be followed by an intravenous (IV) infu- Deep tendon reflexes sion, providing no m ore than 1200 m g (50 m m ol) of M g on the Heart rate first day. This treatm ent can be followed by another 2 to 5 days of Blood pressure M g repletion in the sam e dosage, which is used in less urgent situa- Respiratory rate tions. Continuous IV infusion of M g is preferred to both intram us- Serum Mg (<2. A continuous infusion avoids the higher urinary fractional excretion of M g seen with interm ittent adm inistration of M g. Subacute and chronic Mg replacement Patients with m ild M g deficiency m ay be treated with oral M g salts rather than parenteral M g and m ay be equally efficacious. Parenteral M g also is adm inistered (often in a m anner different from that shown here) to patients with preeclam psia, asthm a, acute m yocardial infarction, and congestive heart failure. N adler JL, Rude RK: Disorders of m agnesium m etabolism. Q uam m e GA: M agnesium hom eostasis and renal m agnesium han- 13. Kayne LH , Lee DBN : Intestinal m agnesium absorption. Rom ani A, M arfella C, Scarpa A: Cell m agnesium transport and 14. Roth P, W erner E: Intestinal absorption of m agnesium in m an. Int J hom eostasis: role of intracellular com partm ents. M iner Electrolyte Appl Radiat Isotopes 1979, 30:523–526. Fine KD, Santa Ana CA, Porter JL, Fordtran JS: Intestinal absorption 4. Sm ith DL, M aguire M E: M olecular aspects of M g transport system s. J Clin Invest 1991, M iner Electrolyte M etab 1993, 19:266–276. Roof SK, M aguire M E: M agnesium transport system s: genetics and protein structure (a review). Sutton RAL, Dom rongkitchaiporn S: Abnorm al renal m agnesium han- loop of the m ouse is a voltage-dependent process. W hang R, H am pton EM , W hang DD: M agnesium hom eostasis and H ypertension 1993, 21:1024–1029. Ryzen E, Elbaum N , Singer FR, Rude RK: Parenteral m agnesium tol- 9. M cLean RM : M agnesium and its therapeutic uses: a review. Am J M ed erance testing in the evaluation of m agnesium deficiency. Abbott LG, Rude RK: Clinical m anifestations of m agnesium deficien- 19. O ster JR, Epstein M : M anagem ent of m agnesium depletion. Al-Ghamdi SM G, Cameron EC, Sutton RAL: M agnesium deficiency: 20.

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The fetal effects of nicotine may be (72% versus 28%) order sildalist australia. Genetic factors also appeared important greater during the later stages of pregnancy effective 120mgmg sildalist, a finding sug- for the appearance of alcohol dependence (55% versus gesting the first trimester is the most desirable period for 45%) purchase generic sildalist line, consistent with a common genetic vulnerability and NRT during pregnancy. Based on the rat data, it may be showing that nicotine and alcohol dependence occur to- preferable to introduce NRTs early in pregnancy to try to gether (60). Environmental factors more strongly deter- reduce the fetal exposure to nicotine before the second or mined age of first use of tobacco and alcohol, whereas la- third trimester. In the rat models, episodic nicotine delivery, tency between first use and patterns of regular use were as happens with smoking, is associated with less nicotine more genetically determined (54). A major genetic influence exposure to the fetus than continuous exposure from a nico- accounting for about 70% of the variance in risk in a group tine patch. Of course, fetal exposure to tobacco smoke pre- of Vietnam era twin pairs is consistent with other studies sents a host of other toxins besides nicotine. Cognitive defi- Genetically determined dopamine receptor functional cits, behavioral problems in childhood, particularly atten- differences and genetic variation in hepatic enzyme activity tion-deficit/hyperactivity disorders, conduct disorders, and important in metabolizing nicotine suggest possible mecha- substance abuse in the exposed children are associated with nisms. Individuals with TaqIA alleles (A1 and A2) and maternal smoking. Children whose mothers smoked ten or TaqIB (B1 and B2) of the D2 dopamine receptor gene had more cigarettes daily during pregnancy had a fourfold in- earlier onset of smoking, smoked more, and made fewer creased risk of prepubertal-onset conduct disorder in boys attempts to quit (58). Specific gene mutations, including and a fivefold risk in adolescent-onset drug dependence in those associated with dopamine D2 receptors (23) and do- girls (98). The outcomes are not explained by other risk pamine transporter proteins (95), have been implicated as factors. Maternal prenatal smoking appeared to be related possible determinants for nicotine addiction. People lacking to future criminal behavior in male children, with a a fully functional genetically variable enzyme CYP2A6 im- dose–response relationship between intensity of third portant in the metabolism of nicotine to cotinine are slow trimester smoking and arrest history of 34-year-old men nicotine metabolizers (30). This genotype may be important whose mothers smoked during pregnancy (63). Although in protecting against tobacco dependence because of im- such studies are limited by retrospective maternal reports paired nicotine metabolism and may be important as well of smoking behaviors during pregnancy, there is a consis- in determining dose and response to NRTs. Tobacco and Nicotine Exposure During Pregnancy MANAGEMENT AND THERAPEUTICS OF In the United States, about 25% of pregnant women smoke NICOTINE ADDICTION cigarettes, and so each year about 1 million babies are ex- posed in utero to tobacco smoke (89). Within those countries, smokers Tobacco smoking has long been known to present consider- have the lowest income, are the least educated, and have able fetal risks (59). Less well appreciated is that nicotine the poorest access to health care. Thus, from a world view, itself is a neuroteratogen (89). Nicotine given to rats during cost of therapeutics and access become important considera- gestation or adolescence at levels assumed to be consistent tions. Prevention is obviously an important strategy, but with those in human smokers alters gene expression and strategies to prevent tobacco addiction must deal with a produces long-lasting central nervous system cellular dam- politically powerful and wealthy multinational industry pro- age, by reducing cell number and impairing synaptic activity moting use of tobacco (64). The tobacco industry in the and cell signaling (62). Developing brain cells appear partic- United States alone spent 6 billion dollars in 1998 to market ularly vulnerable. In adult rats, similar exposure stimulates cigarettes, about 18 million dollars each day. More is spent nicotinic cholinergic receptors without lasting cellular promoting tobacco use elsewhere in the world. Individual or group behavioral treatments appear Contemporaneous reviews of tobacco addiction thera- almost equally effective. Intensive treatment programs are peutics (59,70–73) and an extensive report on tobacco ad- effective in assisting even very dependent smokers to stop diction pharmacology and therapeutics from the Royal Col- for a few months. However, as with other addictions, relapse lege of Physicians (49) offered similar conclusions. Initial quitting rates of 50% to 60% summary review from the Cochrane Tobacco Addiction Re- at 1 month typically decrease to 20% to 30% at 1 year. Details of the 20 None has proven clearly effective. Most tobacco addicts re- systematic reviews are available on the Internet in the Coch- peat the quitting process on average every 3. The reviews used a similar strategy and three or four times before finally stopping forever (66). In reviewed much the same literature on tobacco addiction that respect, stopping smoking is similar to overcoming ad- therapeutics as did the Public Health Service review. Tobacco addiction The Cochrane reviews considered the results from ran- treatment programs are cost-effective. Average treatment domized controlled trials having at least 6 months of follow- costs per year of life saved are $1,000 to $2,000 per year up (91). Sustained abstinence or point prevalence quit rates for brief counseling alone and $2,000 to $4,000 per year were used in the metaanalysis as necessary. Simple advice of life saved with more intensive counseling and pharmaco- from physicians presented during routine care was studied therapy to aid in smoking cessation (34,67). Smoking cessa- in 31 trials that included 26,000 smokers in a variety of tion treatments are less costly per year of life saved than are clinical settings. Brief advice increased quit rate more than generally accepted therapies for hypertension, hypercholes- no advice (odds ratio, 1. Individual counseling was better than brief advice or usual care. Group therapy was more effective than self- Therapeutics: Clinical Guidelines help materials alone but not consistently better than inter- ventions with more personal contact. Self-help informa- Guidelines for treating tobacco dependence were published tional material and printed descriptions of behavioral strate- in 2000 by the United States Public Health Service (2,13). The detailed report resulted from critical review of approxi- mately 6,000 peer-reviewed articles on tobacco addiction therapeutics and 50 metaanalyses based on that literature Nicotine Replacement Therapeutics (69). NRT decreases the discomfort of nicotine withdrawal. The The major general conclusions were as follows: relatively stable brain nicotine levels resulting from NRT 1. Tobacco dependence is a chronic condition warranting should facilitate a desensitized state for some nicotinic cho- repeated treatment until abstinence is achieved. All are more desensitized than others, both nicotine agonistic tobacco users should be offered treatment. Clinicians and health care systems must institutionalize NRT.

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For example order sildalist 120 mg on-line, the rCBF of cocaine- dependent subjects administered intravenous cocaine exhib- ited increases in the nucleus accumbens 120mg sildalist with visa, subcallosal cortex discount sildalist online american express, MAGNETIC RESONANCE SPECTROSCOPY and hippocampus and decreases in rCBF in the amygdala, temporal pole, and medial frontal cortex (137). Future stud- Magnetic resonance spectroscopy (MRS) provides surrogate ies utilizing this paradigm could additionally assess whether markers to determine clinical endpoints to evaluate new another compound administered before cocaine can antago- therapeutic interventions for specific diseases. Additionally, [19F]MRS has been explicitly employed to examine the pharmacokinetics of BIOMARKERS OF ALCOHOL ABUSE psychotropic medications containing a fluorine group such as fluvoxamine (130). This allows direct comparison of The synergistic combination of carbohydrate-deficient brain and plasma concentrations, and brain elimination transferrin (CDT), gamma-glutamyl transferase (GGT), 468 Neuropsychopharmacology: The Fifth Generation of Progress and mean red cell volume (MCV) functions as a possible the CNS could be administered as therapeutic agents to biomarker for alcohol abuse (138). CSF from treated patients and bioluminescent compounds responsive to the presence of the enzyme that should be NEWER MARKERS FOR DRUG absent could then be injected into experimental animals. DEVELOPMENT Detection of the bioluminescence in the experimental ani- mal would then indicate failure of the new drug to prevent Several techniques recently have been developed to provide the growth of the tumor or infection. Thus, this technique the means to assess the efficacy of newly developed potential offers the potential of surrogate markers to monitor the drugs. These procedures assist clinicians in both the (a) diag- presence of CNS tumors and infections. The appli- Simultaneous Optical and Magnetic cation of the following novel procedures to drug develop- Resonance Microscopy ment is the result of a collaborative effort jointly of the Simultaneous optical and magnetic resonance imaging National Institutes of Health (NIH), the United States (MRI) is being developed in experimental animals. MRI Food and Drug Administration (FDA), the Health Care contrast agents (143), such as fluorescently detectable mag- Financing Administration (HCFA), and private industry netic resonance imaging agents, are utilized to permit light (139). The protocols described in this section are likely to and magnetic resonance imaging microscopy at the same be instrumental in drug development for neuropsychiatric time (144). These compounds can be detected deep in tis- disorders in the future. Although External Imaging of Internal light microscopy can penetrate only 100 to 300 m beneath Bioluminescent and Fluorescent Signals the surface of organisms, MRI microscopy can penetrate 1 to 6 mm into an organism (144). For example, agents that Biological processes, such as the propagation of cancer cells, can be simultaneously recognized by MRI microscopy and are studied in animal models by the detection of biolumi- by fluorescent optical microscopy permit visualization of nescent (140) and fluorescent signals recorded externally structures 1 to 6 mm below the surface of an organism by means of sensitive photon detection systems (141). Other examples in- Diffusion-Based Optical Imaging clude the evaluation of potential agents to treat human can- cer and infection by assessing the behavior of cells from Procedures to measure light emitted into opaque structures patients in animals utilizing bioluminescent markers. The have been termed medical optical imaging (MOI), medical technique utilizes bioluminescent compounds bound to optical spectroscopy (MOS), near-infrared imaging (NIRI), specific enzymes that signal the proliferation of cancers and and near-infrared optical spectroscopy (NIOS) (146). Human subjects with cancer or infection are example, three-dimensional optical coherence tomography treated with agents to alter the expression of genes that (OCT) is a technique to image nontransparent biologic tis- produce the enzymes needed for the growth of the cancer sue by recording and analyzing light emitted into scattering or bacteria. Then animals are injected with (a) cells from media. OCT has been employed to visualize nerve fascicles the previously cancerous or infected tissue of treated hu- in experimental animals for the microsurgical anastomoses mans, and (b) bioluminescent markers that respond to the of vessels and nerves (147). An example of diffusion-based presence of the enzyme that was hopefully blocked in optical imaging is the use of optical tomography to detect the humans. Detection of the bioluminescent markers in intraventricular hemorrhage in premature infants by exter- the animals indicates the proliferation of the enzyme to be nal transmission of light emitted through the skull (146). This technique, which provides a human disease, including infections and malignancies surrogate for the clinical effects, is being applied to a variety (146). Hopefully, in the future they will be applied to CNS of human diseases including cancer and infection (http:// tumors and malignancies. By analogy, this procedure could be ap- plied to assess drugs developed to treat malignancy and in- Magnetic Resonance Microscopy fection of the CNS. For example, novel agents to alter the expression of the genes that code for the control of the Microscopic visualization of magnetic resonance images has production of enzymes required by cancer and infection of detected transgene expression in experimental animals. Chapter 34: Proof of Concept 469 Identification of pathologic processes, including the prolif- Biomarkers and surrogate endpoints: advancing clinical research eration of tumor cells in clinical settings (148), may be and applications program book. Bethesda, Maryland: National Institutes of Health, 1999;15–16. Surrogate endpoints in clinical trials: definition means to both detect the occurrence of malignancies and and operational criteria. Bioassay design and MTD setting: old methods cedure to human CNS malignancy is a goal to be attained and new approaches. Regul Toxicol Pharmacol 1995;21:44–51; in the future. Determination of appropriate dosage in clinical development guidance. In: Balant LP, Benitez J, Dahl Electron Paramagnetic Resonance SG, et al. Clinical pharmacology in psychiatry: finding the right dose of psychotropic drugs. Brussels: European Commission, Electron paramagnetic resonance (EPR) (149) imaging and 1998:307–322. Prog Neuro-Psychopharmacol Biol Psychiatr labels into the system of interest (150). Phase I clinical develop- of experimental animals (150) and to measure oxygen free ment and finding the dose: the role of the bridging study. In: radical generation in human endothelial cells exposed to SramekJJ, Cutler NR, Kurtz NM, et al. New York: John Wiley and anoxia and reoxygenation (151). Recent dose-effect studies regarding antidepres- (152), a process vital to the measurement of the progression sants. Clinical of pathologic processes (153), including cerebral ischemia pharmacology in psychiatry: finding the right dose of psychotropic (154) and malignancies. Debate resolved: there are differential effects of serotonin selective reuptake inhibitors on cytochrome P450 en- zymes. Comparison of the effects of low and high doses of venlafaxine on serotonin and Biomarkers and surrogate markers are tools currently uti- norepinephrine reuptake processes in patients with major depression and healthy volunteers. Int J Neuropsychopharmacol lized to develop new drugs. Currently drugs are being developed treatment-resistant unipolar depression. J Clin Psychopharmacol by the use of neuroendocrine markers including CSF, pro- 1994;14:419–423. Venlafaxine: measuring the lactin, GH, ACTH, and cortisol. Imaging studies provide onset of antidepressant action. Psychopharmacol Bull 1995;31: the means to estimate therapeutic dosages of new drugs. Surrogate markers include a variety of neuroimaging tech- 12.

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