By Z. Konrad. Wilkes University.

Am ino acid losses can be esti- Stimulation of protein catabolism? Amino acid and protein W ith the large molecular size cut-off of membranes used in hemofil- metabolism are altered not only by substrate losses but also by activa- tration discount 200 mg modafinil, small proteins such as peptide hormones are filtered discount modafinil 100mg. In view tion of protein breakdown mediated by release of leukocyte-derived of their short plasma half-life hormone losses are minimal and proba- proteases, of inflammatory mediators (interleukins and tumor necro- bly not of pathophysiologic importance. Quantitatively relevant elimi- sis factor) induced by blood-membrane interactions or endotoxin. On the other Dialysis can also induce inhibition of muscle protein synthesis. Nutrition, Renal Function, and Recovery FIGURE 18-25 A, B, Im pact of nutritional interventions on renal function and Infusion of amino acids raised renal cortical protein synthesis as course of acute renal failure (ARF). Starvation accelerates protein evaluated by 14C-leucine incorporation and depressed protein breakdown breakdown and im pairs protein synthesis in the kidney, whereas in rats with mercuric chloride–induced ARF. On the other hand, in a refeeding exerts the opposite effects. In experim ental anim als, similar model of ARF, infusions of varying quantities of essential amino provision of am ino acids or total parenteral nutrition accelerates acids (EAA) and nonessential amino acids (NEAA) did not provide any tissue repair and recovery of renal function. In patients, protection of renal function and in fact increased mortality. However, however, this has been m uch m ore difficult to prove, and only one in balance available evidence suggests that provision of substrates may study has reported on a positive effect of TPN on the resolution enhance tissue regeneration and wound healing, and potentially, also of ARF. Am ino acid infused before or during ischem ia or nephrotoxicity m ay enhance tubule dam age and accelerate loss of renal function in rat m odels of ARF. In part, this therapeutic para- dox from am ino acid alim entation in ARF is related to the increase in m etabolic work for transport processes when oxygen supply is lim ited, which m ay aggravate ischem ic injury. Sim ilar observations have been m ade with excess glucose infusion during renal ischem ia. Am ino acids m ay as well exert a protective effect on renal function. Glycine, and to a lesser degree alanine, lim it tubular injury in ischem ic and nephrotoxic m odels of ARF. Arginine (possibly by producing nitric oxide) reportedly acts to preserve renal perfusion and tubular function in both nephro- toxic and ischem ic m odels of ARF, whereas inhibitors of nitric oxide synthase exert an opposite effect [56,57]. In m yoglobin- induced ARF the drop in renal blood flow (black circles, ARF con- trols) is prevented by L-arginine infusion (black triangles). Various other endocrine-m eta- im proves nitrogen balance, B,. In a rat m odel of postischem ic ARF, treatm ent with IGF-1 ly confirm ed in clinical studies [59, 60]. In any patient with evidence of m al- nourishm ent, nutritional therapy should be instituted regardless of DECISIONS FOR NUTRITION IN PATIENTS whether the patient will be likely to eat. If a well-nourished patient W ITH ACUTE RENAL FAILURE can resum e a norm al diet within 5 days, no specific nutritional sup- port is necessary. The degree of accom panying catabolism is also a factor. For patients with underlying diseases associated with excess Decisions dependent on protein catabolism , nutritional support should be initiated early. Patients ability to resume oral diet (within 5 days? M odern nutritional strategies should be aimed at 1.

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The orbitofrontal cortex was also activated by cues in the (three) studies of cocaine subjects in recent cessation buy 100 mg modafinil amex. The hippocampus was not regularly activated by cocaine Cerebellum cues generic modafinil 100mg line, which suggests that the cue-induced state does not The cerebellum, important in motor coordination and re- depend on declarative memory/factual recall. The dorsolat- tention of simple motor schemas, was not activated in our eral prefrontal cortex was not activated in most of the cue PET study with 15O bolus in which videos were used to studies but was activated by cocaine cues that were intermit- induce craving for cocaine (47). Similarly, it was not acti- tent or repeated; this activation may be relatively indepen- vated by the cues of Maas et al. The cerebellum was differentially acti- cerebellum was not activated in most cue studies, although vated in the study of Wang et al. The The brain regions activated by cocaine cue paradigms (highly ritualized and overlearned) handling of cocaine para- (amygdala, anterior cingulate, nucleus accumbens, insula) phernalia may have triggered motor memories and schemas, do substantially overlap those activated by cocaine itself in a cerebellar function. In support of this notion, the study the fMRI study of Breiter et al. Most cue paradigms, even tween craving and cerebellar activation. This correlation those in which fMRI is used, have not yet described the would occur if handling of paraphernalia acted both as a temporal pattern of the signals from these regions during potent conditioned cue for drug craving and as a trigger for cues; such information would permit a more detailed com- motor memories/highly practiced motor schemas related to parison of cue effects with the multiple effects of cocaine cocaine preparation. No studies have yet examined the ventral tegmental area or basal forebrain in Sensory/Association Cortex response to cues. In addition to the regions discussed, one imaging study The orbitofrontal cortex deserves special mention in the has shown differential activation of visual association areas discussion of craving and drug motivation. Orbitofrontal (peristriate) by cocaine cues (83), and two studies have dysfunction in other disorders has been associated with diffi- shown differential activation of the inferior parietal lobe culties in modulating rewarded or punished behavior (e. As additional neuroimaging studies accrue, it will be contingencies) (93), impaired somatic/emotional response easier to determine whether less common activations such in anticipation of the consequences of a decision ('future as these reflect a feature of the paradigms used or a feature insensitivity') (94), and perseverative, compulsive behaviors of the target state. Clinically, some of these same difficulties have been 1586 Neuropsychopharmacology: The Fifth Generation of Progress noted in substance abusers, which raises the possibility of little support for the notion of a 'sensitized' substrate, a core deficit in some patients (95). Long-term users of sometimes proposed as a potential mechanism for stimulant amphetamine are impaired on a decision-making task that drug craving/incentive motivation. Beyond the first week places demands on ventromedial prefrontal (orbital) func- of cessation, cocaine patients often exhibit resting hypoac- tion (96), and long-term administration of stimulants tivity in limbic and frontal regions in comparison with con- clearly erodes orbitostriatal inhibitory function in primates trols. Exposure to cocaine cues or to a stimulant can produce (93). Whether such orbitofrontal cortex deficits predate a significant activation in these affected brain regions, but drug use in humans, predispose to it, or are a consequence the absolute level of brain response is often no greater than of it, the news for long-term cocaine users is not good; in controls, and may even be less. Of course, the appropriate they may be at a particular disadvantage in managing their test for sensitization would require comparing the current craving for the drug. Interestingly, the reviewed studies link responses of cocaine patients with their own initial responses increases in orbitofrontal cortex activity to craving in all to the drug. It three paradigms: (early) cessation, stimulant administration, does, however, highlight a limitation of all our neuroimag- and response to cues (during early cessation from cocaine). Theoretic Implications Treatment Implications The neuroimaging of craving states is at a very early stage, and most findings should be replicated before they are taken Imaging data from the stimulant administration and cue as either a confirmation or a challenge to theories of addic- paradigms suggest that craving is often associated with rela- tion and drug motivation. With this caveat kept in mind, tive increases in the activity of the same brain DA systems some findings from the paradigms reviewed may have impli- that may otherwise be hypoactive in cocaine users. Classic DA antagonists (typified by the systems of cocaine patients do differ from those of controls, older antipsychotics) are poor candidates for this modula- craving did not show a good relationship to these changes tory role because they could worsen symptoms related to beyond the first week of cessation. These compounds act as agonists ing ('substrates for craving are the same as the substrates under conditions of low DA tone (as may occur in cessa- for high') nor a simple opponent process ('substrates for tion), but as antagonists when the DA concentration in- craving are the opposite of the substrates for high') view. The 'chame- Studies of craving during methylphenidate administration leon-like' nature of partial agonists may possibly offer the indicate the possible contribution of non-DA (in addition cocaine patient a moment-to-moment regulation of the DA to DA) systems. Unfortunately, for now, no partial agonists (D1, The cue paradigms suggest that the regions activated dur- D2, or D3) are approved for humans, although considerable ing cue-induced craving often overlap the regions activated animal research has been done and preliminary safety trials by cocaine itself (i.

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Thus generic modafinil 100 mg with amex, the intensity of these symp- report suggested that olanzapine administration was associ- toms is less after recovery but the content of these concerns ated with weight gain and maintenance as well as reduced remains unchanged purchase 200mg modafinil otc. The persistence of these symptoms agitation and resistance to treatment in 2 women with AN after recovery raise the possibility that the disturbances are (30). Several drugs have been tested because of anecdotal premorbid traits that contribute to the pathogenesis of AN reports of their effects on stimulating appetite. Clonidine was also found to have no therapeu- PHARMACOLOGIC TREATMENT OF tic effect on increasing weight restoration as compared to ANOREXIA NERVOSA placebo (32), even with doses that affected hemodynamic parameters. Most medication trials in AN have been conducted with When underweight, patients with anorexia nervosa have inpatients in an attempt to accelerate restoration of weight. Still, delayed gastric emptying could perpetuate the mood or anorectic attitudes. A wide variety of psychoactive disorder in some patients by limiting the quantity of food medications, such as L-dopa (18), phenoxybenzamine (19), that may be comfortably eaten. Most studies of prokinetic diphenylhydantoin (20,21), stimulants (22), and naloxone drugs in AN have been limited to parenteral preparations (23), have been administered to people with anorexia ner- or experiments with small uncontrolled groups of patients vosa in open, uncontrolled trials. In a controlled trial, cisapride (37) was no better medications have been claimed to be beneficial, but none than placebo in improving gastric emptying, although some of these observations has been confirmed under double- subjective measures of distress during meals and measures blind, controlled conditions. Few studies of medication using rigorous double-blind In summary, these medication trials have been of short placebo-controlled trials have been reported in patients with duration and focused on whether medication produces ad- AN. In contrast to the positive claims from open trials, ditive benefit to an established treatment program. Few fol- results from double-blind trials have been limited, for the low-up studies have examined whether medication treat- most part. Double-blind studies, at most, report marginal ment produces lasting benefit. A new generation of studies success in treatment of specific problems such as improving has begun to focus on whether medication can prevent re- the rate of weight gain during refeeding, and disturbed atti- lapse after patients leave to a structured treatment setting. Use of Antidepressants in AN One problem with determining the efficacy of pharma- cotherapy in AN is that often medications have been given There has been controversy as to whether AN and major in association with other therapies. Thus, it may be unclear depressive disorders share a common diathesis; however, whether it was the medication or therapy that resulted in critical examination of clinical phenomenology, family his- improvement. Furthermore, the primary criterion for im- tory, antidepressant response, biological correlates, course provement has often been weight gain, not a normalization and outcome, and epidemiology yield limited support for of thinking and reduction in fears of being fat. Still, the high frequency of mood tant to emphasize that treatment in structured settings, such disturbances associated with this disorder resulted in trials as inpatient units, even without medication, succeeds in of drugs such as amitriptyline (41–43), and lithium (44). Thus, it may be difficult to prove that an active medi- compared with the effects of placebo. However, relapse within For more that 50 years (45), investigators have suggested 1 year after successful inpatient weight restoration is very that AN shares similarities with obsessive-compulsive disor- common (25). In fact, patients with AN have a high prevalence ported that only 23% of the patients had a good outcome of obsessive-compulsive symptoms or disorders (46–48), as at 1 year after discharge despite intensive outpatient individ- well other anxiety disorders (49). Controlled trials of the neuroleptics pimozide (27) and Individuals with a past history of AN display evidence of sulpiride (28) have suggested limited effects in accelerating increased serotonin (51) activity that persists after long-term weight gain or altering anorectic attitudes for some patients weight recovery. In addition, women who recover from AN for part of the study, but overall drug effect was marginal. Similarly (10), personality characteris- a good outcome on placebo (P. Aside tics associated with AN, such as introversion, self-denial, from improved outcome, fluoxetine administration was as- limited spontaneity, and a stereotyped thinking style, may sociated with a significant reduction in obsessions and com- also persist after weight recovery. Studies in humans and pulsions and a trend toward a reduction in depression. Together, these data raise the possibility in some patients with AN.

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Low levels of M g im pair parathyroid horm one Neuromuscular Dysphagia (PTH ) release generic 200 mg modafinil with mastercard, block PTH action on bone modafinil 200 mg low cost, 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.

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