By P. Hogar. Indiana University Northwest.

We start with sponse variable for which a test of the null hypothesis of the most basic steps pertinent to initial studies in humans cheap acticin 30gm overnight delivery. Brasic: Department of Radiology buy 30gm acticin with visa, Johns Hopkins Medical Institution acticin 30gm cheap, Baltimore, Maryland. Potter: Lilly Research Laboratories, Indianapolis, Indiana. Interestingly, before phar- and dog) whereby one does not exceed some predetermined macokinetic (PK) data were routinely used to limit expo- ratio between the exposure (i. Thus, depending on have a viable clinical candidate. Starting with three or more times the lowest stan- a constricted range of exposures and an inability to address dard dose of a selective serotonin reuptake inhibitor (SSRI) the question of whether therapeutic (or biochemical) effects will produce far more marked nausea (and even vomiting) are greater at the MTD until much later in development than after building up to the same dose over several weeks, as (4). If a compound does not produce significant side effects is done for the treatment of obsessive–compulsive disorder within this original range, doses much higher than those (OCD). This may seem simply common sense but the per- used in initial Phase I studies can be tested depending on ceived market advantage of the starting and ultimate thera- the nature of the toxicity observed in animals at the limiting peutic dose being the same discourages exploration of higher exposure. Even if a limiting dose is identified in volunteer doses that require some sort of titration over time in order subjects, a greater dose may be tolerated in patients (5). For instance, even though it was appre- Sramekand colleagues (1997) (6) have defined this transi- ciated early on that an antidepressant, venlafaxine, might tion from dosing in healthy volunteers to patients to be be more efficacious at higher doses that were associated with Chapter 34: Proof of Concept 459 TABLE 34. MEASURES THAT SERVE AS SURROGATES FOR PREDICTED BIOCHEMICAL EFFECT OF DRUGS TARGETED TO MONOAMINE NEUROTRANSMITTERS, TRANSPORTERS, RECEPTORS, AND DEGRADATIVE ENZYMESa Neurotransmitters and Metabolitesb Plasma Hormones Physiologic Drug Class NE and MHPG 5HT, 5HIAA HVA PRL GH ACTH/Cortisol Temperature SWS Serotonergic SSRIs ↓5HT, ↓5HIAA ±↑ Indirect-Ag 5HT1A-Ag ±↑ ↑ ↑ ↓ 5HT1B/D-Ag c 5HT2C-Ag Noradrenergic NERI ↑NE, ↓MHPG ↑ α2-Ag ↓NE ↑ α2-An ↑NE Dopaminergic c D2-An ↑↓ DA-Ag ↓ Mixed Tricyclic ↓MHPG ↓5HIAA antidepressants MAOIs ↓MHPG ↓5HIAA ↓ Atypical ±↑NE =d antipsychotics 5HIAA, 5-hydroxy indoleacetic acid; 5HT, serotonin; ACTH, adrenocorticotropic hormone; Ag, agonist; An, antagonist; GH, growth hormone; HVA, homovanillic acid; MAOI, monoamine oxidase inhibitor; MHPG, 3-methoxy-4-hydroxyphenylglycol; NE, norepinephrine; NERI, norepinephrine re- uptake inhibitor; PRL, prolactin; SSRI, selective serotonin reuptake inhibitor; SWS, slow wave sleep. Although the specified drug classes may affect other measures than those indicated (e. SSRIs also decrease MHPG), only those hypothesized to reflect a primary action are shown. In the over 225 mg per day range (which requires some degree of titration to avoid unacceptable side effects), venlafaxine produces effects PHARMACOKINETICS consistent with norepinephrine (NE) as well as serotonin (5HT) uptake inhibition (8,9) and is reported to be superior Analytical technology, especially that provided by much to SSRIs (10,11). Obviously, it would be beneficial if the simpler to operate equipment, allows for precise quantifica- relevant dose ranges of such compounds could be better tion of very low concentrations in blood so that rapid and understood earlier rather than later in the life of a drug. If a half-life is too short or long or if nonlinear in development as possible, then the doses necessary to pharmacokinetics are marked (e. Similarly, if a compound shows unac- would be 'surrogate' markers for clinical doses, allowing ceptably wide variations in clearance because its metabolism one to test the widely held hypothesis that in a big enough is dependent on a highly polymorphic isozyme of cyto- population of patients with depression, one will find those chrome P-450 (e. Thus, concentrations measured over time Although the ratios established in preclinical studies are in Phase I studies serve, at this most basic level, as a surrogate interpreted as providing a reasonable estimate of any ulti- of whether a compound has the potential to become a suc- mate therapeutic index in humans, they are specific for both cessful drug (12). In other words, the con- Drug interactions sometimes can constitute a serious centration necessary to achieve a behavioral or biochemical safety risk(e. The relationship among in vitro genetically susceptible individuals) and, almost always, a biochemical effects, activity in some in vivo model, and marketing disadvantage. The same preclinical approaches undesired effects is poorly understood even at the preclinical referred to in the preceding are used to screen out com- level, particularly when one is investigating novel targets. In vivo PK (and sometimes drug interaction data) based either on activity in an animal model (e. First, for most compounds an oral development of central nervous system (CNS) drugs is noto- form is seen as the ideal (if not only) option and low bio- riously inefficient to identify therapeutic concentrations. For instance, zyme inhibition do not drive the selection of an efficacious 2% to 10% bioavailability means an automatic fivefold concentration. In other words, the basic preclinical work range before individual variations seen in metabolic clear- that underlies any test of a specific hypothesis such as 'X% ance after intravenous (IV) administration are taken into of inhibition produces effect Y' is rarely, if ever, done. High variability in exposure per 3 ratios that provide a great deal of flexibility to study a ex- unit dose makes clinical studies more difficult. Second, to tremely wide range of concentrations in humans, especially reach the exposures required to define the concentration at with novel compounds. This is actu- Phase I ally a far more significant issue than is generally appreciated because amounts of material are limited early in develop- Select starting doses for healthy volunteers based on findings ment. It can be very costly to develop efficient synthetic from the preceding toxicokinetic studies, which is often one- schemes; one does not want to invest too much in syntheses tenth of the dose that produces a no-adverse-event level in until one is fairly sure that a compound is safe at pharmaco- the most sensitive species studied (4). Most marketed central logically active concentrations. Multiple dose studies, administering var- This introduces the critical role of toxicokinetics, the goal ious fixed doses over a 2- to 4-weekperiod are also part of of which is to establish in animals (usually rats and dogs) the Phase I protocols to get a general idea of safety and the ratio between the concentration that produces either tolerability under likely clinical conditions (14). There are can be used reliably with a combination of subjective re- instances in which humans ultimately prove tolerant to ports, objective measures of performance (looking for decre- drugs much more than would be predicted by these ratios, ments), and the electroencephalogram (EEG) (15–19). On the other hand, the so- Chapter 34: Proof of Concept 461 called pharmaco-EEG (P-EEG) is sometimes introduced as Cerebrospinal Fluid a surrogate measure of the therapeutic action a compound The monoamine hypotheses of depression and schizophre- is likely to produce (20,21), but is probably more usefully nia, which are, in turn, based on the pharmacology of anti- viewed as a direct measure that a compound has produced depressants and antipsychotics, generated an interest in some change in surface brain electrical activity. The P-EEG measures of norepinephrine (NE), serotonin (5HT), and provides neither evidence of a direct effect in the brain nor dopamine (DA) in humans. In most instances these were proof of a hypothesized causative role of specific pharmaco- initially studied in an attempt to distinguish patients from logic activity of the molecule (22). Side turnover as measured by NE and its metabolites in urine effects are often simply recorded as spontaneous reports on or cerebrospinal fluid (CSF) (28–31) and by increasing a grid of prespecified subjective descriptors; sometimes a plasma NE (32) or, more precisely, its spillover rate (33, formal checklist is used. Another marker of NE reuptake inhibition is based on sures of drug effect are sparse. These latter two procedures have with healthy volunteers and patient populations, before been recently employed to establish the dose at which venla- going on to full Phase II studies. These latter studies are faxine produces NE reuptake inhibition (8,9,36). Because powered to detect a clinically significant improvement, usu- NE metabolism varies according to whether it occurs inside ally over placebo, often utilizing multiple dose arms (each or outside neurons (37), a more definitive and perhaps more with at least 50 or more patients) and multiple clinical sites. However, all of these measures reflect instance, if one had an ampakine such as CX-516 that im- functional changes in the peripheral sympathetic nervous proved learning in rats, then one might show enhancement system; therefore, they are at best surrogates for effects in of some aspects of cognition in healthy volunteers after safe the brain. The improved Some of these same measures have been applied to study performance in healthy subjects would then be a surrogate other compounds, which are predicted to affect NE func- for improvement in AD to identify the appropriate dose. These In the more usual case of a variation on an existing mech- include bupropion, clozapine, alpha 2 antagonists, and anism (e. Interest- produces the desired biochemical effect so as to move as ingly, such studies are not yet available to support or refute quickly as possible into Phase II trials with doses that one claims that the relatively new antidepressant mirtazapine is confident will work(25,26). In this latter instance, the produces alpha 2 antagonism in humans. Some of these studies been used in enough instances over the last two decades to were clearly done prior to Phase II trials so they can be qualify as surrogate markers. There is no available literature inferred to have influenced the selection of dose. Doses of as to the extent to which these measures actually drove deci- SSRIs known to inhibit platelet uptake in humans have also sions about what doses to use in Phase II trials, but one can been shown to reduce the turnover of 5HT in the CNS as assume that they must have been influential in some cases.

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Single-trial analyses are important not only a number of different tasks (much like the approach taken for achieving a closer correspondence between brain activity in neuropsychological testing) generic acticin 30gm with visa. Many of the same interpreta- and behavioral performance but also for ascertaining the tional issues that are of concern with neuropsychological degree of trial-to-trial variability that may characterize dif- testing may become relevant for testing with an ERP bat- ferent clinical syndromes acticin 30 gm fast delivery. All of these techniques will sub- tery purchase 30 gm acticin with visa, together with some that are specific to these physiologic stantially increase the utility of ERP/ERF recordings for measures. Chapter 32: Event-Related Potentials and Magnetic Fields 437 ACKNOWLEDGMENTS 20. Mismatch negativity: differ- ent water in the same river. This work was supported by NIH grants MH-25594, HD- 21. We thank Carole Montejano, Matt Audiology Neuro-Otology 2000;5:140–150. Marlow, and Tom Urbach for assistance with manuscript 22. The mismatch negativity REFERENCES of event-related potentials as a probe of transient auditory mem- ory: a review. Electrical and magnetic brain recordings: contribu- 24. Curr Opin Neurobiol 1993;3: mismatch negativity in neuropsychiatry. Cambridge, distractibility as evaluated with event-related brain potentials. Towards the possible clinical application of´ ric mapping: combining fMRI and MEG for high-resolution the mismatch negativity component of event-related potentials. Intracortical mechanisms of mismatch negativity dys- to the electromagnetic inverse problem. Duration and frequency evoked potential generators by retinotopic and topographic mismatch negativity in schizophrenia. Hillsdale, New Jersey: representation of virtual pitch in the human auditory cortex. Behavioral lifetime of mediating selective attention. The cogni- human auditory sensory memory predicted by physiological tive neurosciences. Neurophysiological junctions: an event-related brain potential study. J Exp Psychol evidence for a defect in neural mechanisms involved in sensory Hum Percept Perform 1994;20:81–94. Neurobiological indices of selective attention and cortical lateralization in schizo- studies of sensory gating in schizophrenia. Spatial atten-¨ ¨ ¨ schizophrenia and normal comparison subjects: a methodologi- tion to central and peripheral auditory stimuli as indexed by cal analysis. Improved auditory¨ ¨ ¨ Gen Psychiatry 2000;57:57–64. Visual attention mediated by biased competition phrenics: a failure to find strong P50 suppression in normals. Philos Trans R Soc Lond B Biol Sci Biol Psychiatry 1990;27:1216–1226. Event-related brain potentials in phrenia in the context of task related effects. Int J Psychophysiol the study of visual selective attention. Sensory gain control (amplifi- a measure of sensory gating in schizophrenia. Biol Psychiatry cation) as a mechanism of selective attention: electrophysiologi- 1998;43:873–878. The mismatch negativity: a powerful tool for cog-¨¨ ¨ 41. Mismatch negativity: clinical and other¨¨ ¨ Nature Neurosci 1999:364–369. The time course¨ ¨ ¨ 438 Neuropsychopharmacology: The Fifth Generation of Progress of cortical facilitation during cued shifts of spatial attention. Curr Opin Neurobiol 1998; dent field potentials in human hippocampal formation. Neurochemical sub- potential, pre-motion positivity, and motor potential of the strates and neuroanatomic generators of the event-related P300. A spatio-temporal dipole¨ multiple stages of processing: evidence from human and monkey model of the readiness potential in humans. The new cognitive neu- Electroencephalogr Clin Neurophysiol 1994;91:286–294. Cortico-limbic circuits and novelty: a movement-related brain potentials. Brain Res 1980;202: review of EEG and blood flow data. Mental chro- processing streams in verbal working memory: evidence from nometry and the study of human information processing. Electrophysiology of mind: event- Res 1997;6:95–113. Neural correlates of encoding nary L, Bernston G, eds. Electroencephalogr Clin Neu- bridge: Cambridge University Press, 2000:53–84. Recall and stem-completion priming have different tion and movement-related cortical potentials in Parkinsonism. Bereitschafts- Trans R Soc Lond B Biol Sci 1999;354:1307–1324. Task-related and item- Electroencephalogr Clin Neurophysiol 1993;89:95–103. Performance monitoring in a confus- USA 1999;96:1794–1799. J Exp Psychol Hum Percept Perform In: Tulving E, Craik FIM, eds. Boston: Birkhauser, monitoring: negative affect and emotionality in relation to fron- 1994:149–168. Is the P300 component a manifesta- brain potentials and positron emission tomography. Event-related potentials and cognition: a critique priming vs explicit remembering during the repetition of visual of the context updating hypothesis and an alternative interpreta- word-form.

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Blood pressure control should be initiated immediately upon diagnosis of SAH buy acticin 30 gm with amex. Medical preoperative management includes prophylactic anticonvulsants cheap acticin 30gm overnight delivery, calcium channel blockade purchase 30 gm acticin free shipping, corticosteroids, and antihypertensives as needed. We do not initiate antifibrinolytic therapy unless surgery is not considered within 48 hours of the initial SAH. Medications that can be initiated prior to transfer to interventionist or neurosurgeon include: – dexamethasone, 4 mg IV six hourly – nimodipine, 60 mg orally four hourly – phenytoin, 10 mg/kg IV load, then 100 mg orally/IV three times daily A frequent source of diagnostic difficulty for the interventionist lies in the use of excessive amounts of narcotic analgesics prior to transfer to the neurosurgical service. Clinical 52 | Critical Care in Neurology grading also, obscured by large doses of narcotic analgesics, makes surgical planning more difficult. Basic Hemodynamic Monitoring of Neurocritical Patients | 53 5. Basic Hemodynamic Monitoring of Neurocritical Patients Bassem Zarif, Magdy Khalaf, Nabil Kitchener The importance of basic hemodynamic monitoring of neurocritical patients comes from the goal of maintaining brain autoregulation. Brain autoregulation and other biological signals are the variables to be monitored by using biomedical sensors. Complications that may occur in neurocritical patients (e. The goals of hemodynamic monitoring in neurocritical care units are to assess the magnitude of physiological derangements in critically ill patients and to institute measures to correct the imbalance. The following steps should be taken to reach these goals. Although our review of data may be helpful, the attending physician should decide what to use and when to use it. Pulse oximeter (SpO2) is regarded as one of the most important advances in critical care monitoring. SpO2 provides a continuous non-invasive method to measure arterial oxygen saturation, and should be used on every neurocritical patient. The absorption spectra of both 54 | Critical Care in Neurology oxyhemoglobin and deoxyhemoglobin and the characteristics of pulsatile blood can thus be determined. SpO2 is accurate to within ± 2% for saturations >70%. SpO2 is widely used in monitoring patients who have a variety of neurological conditions (Adams 1997), and calculations made from the processed signals provide estimates of the tissue or venous and arterial blood and provide an estimate of the amount of oxygenated hemoglobin and the percent saturation of hemoglobin by oxygen SaO2, which is not the same as the PaO2 (partial pressure of oxygen) in the blood (Adams 1997). The PaO2 and SaO2 measurements of oxygenation are related through the oxyhemoglobin dissociation curve. Importantly, SpO2 is a measure of arterial oxygenation saturation, not arterial oxygen tension (PaO2). Given the characteristics of the oxygen dissociation curve, large fluctuations in PaO2 can occur despite minimal changes in SpO2. In addition to its inability to measure PaO2, SpO2 provides no measure of ventilation or acid-base status. Therefore, it cannot be used to determine pH or arterial carbon dioxide tension. Significant increases in arterial carbon dioxide can occur with normal readings in SpO2. Although useful for arterial oxygen saturation, SpO2 should not be assumed to provide information about ventilation. Studies have shown that to assure a saturation of 60 torr (8. Oxygenation is considered adequate if the arterial oxygen saturation is above 95%. The majority of these patients are placed on positive end expiratory pressure (PEEP) at 5cm H2O (Curley 1990). Also, for patients with manifestations consistent with hypoxemia (e. Again in hypothermia, low CO2, and vasoconstriction secondary to drugs or peripheral hypoxia Basic Hemodynamic Monitoring of Neurocritical Patients | 55 all increase bias, imprecision, and response time for hypoxic episodes, so we proceed to the next step. Arterial blood gas analysis is widely available in hospitals and offers direct measurements of many critical parameters (pH, PaO2, PaCO2). Arterial blood gas analysis is among the most precise measurements of oxygen tension and pressure that will reflect tissue oxygenation (García 2011). Non-invasive automated blood pressure devices are frequently used to obtain non-invasive, intermittent blood pressure measurements. Measurements of systolic and diastolic pressure to calculate the mean arterial pressure (MAP) is mandatory to calculate the cerebral perfusion pressure. These devices are less accurate in critically ill patients as well as in those with secondary brain injury. These less accurate readings can distract the attention of the caregiver. The evaluation of blood pressure will be significantly affected by the use of vasopressors. Therefore, the numeric reading may reflect vasoconstriction in spite of decreasing perfusion with adequate blood pressure. Invasive blood pressure monitoring for continuous monitoring and recording of the arterial pressure via an arterial catheter is preferable to the use of an automated blood pressure device in hemodynamically unstable patients (García 2011). The radial artery is most commonly cannulated because of its superficial location, relative ease of cannulation, and in most patients, adequate collateral flow from the ulnar artery. Other potential sites for percutaneous arterial cannulation include the femoral, brachial, axillary, ulnar, dorsalis pedis, and posterior tibial arteries. Possible complications of intra-arterial monitoring include hematoma, neurologic injury, arterial embolization, limb ischemia, infection, and inadvertent intra-arterial injection of drugs. Intra-arterial catheters are not placed in extremities with potential vascular insufficiency. However, with proper selection, the 56 | Critical Care in Neurology complication rate associated with intra-arterial cannulation is low and the benefits can be important. A Foley catheter, for monitoring of urine output on an hourly basis or for 24 hours, is a simple and important tool to monitor volume status of the patient besides renal perfusion and function. The hourly urine output is a cheap, simple and indirect method of assessing adequacy of cardiac output and tissue perfusion. A temperature probe is also indicated for purposes of monitoring core temperature. Subsequent fluid management should be based upon urine output and maintaining central venous pressure between 5 and 10 mmHg. Monitor potassium, sodium, glucose and arterial blood gases every 4 hours. Especially if there is respiratory embarrassment at initial evaluation, measurement of hematocrit, magnesium, blood urea nitrogen, creatinine, calcium, liver function tests, urine analysis, prothrombin, partial thromboplastin times and phosphate levels are mandatory. If hematocrit is below 30%, transfuse cross-matched blood (Amin 1993). Common indications for central venous cannulation: measurement of mean central venous pressure, large bore venous access, administration of irritating drugs and or parenteral nutrition, hemodialysis, placement of a pulmonary artery catheter. Placement of a pulmonary artery catheter is indicated to obtain direct and calculated hemodynamic data that cannot be obtained through less invasive means (Sakr 2005).