Certainly completion of the CALAA-01 phase I clinical trial, incl

Certainly completion of the CALAA-01 phase I clinical trial, including establishment of a maximum tolerated dose (MTD) and recommended dose level for subsequent trials, is a near-term priority. Thorough evaluation of all of the safety and preliminary efficacy indications from this study will greatly inform the design of a phase II investigation of CALAA-01. Beyond CALAA-01, investigation

of additional therapeutic candidates Inhibitors,research,lifescience,medical employing the RONDEL system, such as those targeting hypoxia-inducible factor-2α (HIF-2α), has been undertaken. The relatively fast clearance of these nanoparticles that has been observed, as has been described above, suggests that strategies to prolong circulation in an effort to enhance tumor accumulation may warrant investigation. The transient elevations in some cytokine Inhibitors,research,lifescience,medical levels seen in interim CALAA-01 clinical data imply that exploration of chemical modifications to the siRNA payload may yield nucleic acids that enhance the nanoparticles therapeutic index. With encouraging interim clinical data in hand, avenues for continued development and improvement of nanoparticles identified, and the emergence of alternative siRNA-containing

nanoparticles in the clinic from which all in this field Inhibitors,research,lifescience,medical will learn, the future for siRNA-containing nanoparticles based on cyclodextrin-containing polycations appears

bright. 9. Conclusions CDP-based nanoparticles have made the transition from the laboratory to the Inhibitors,research,lifescience,medical clinic within the last several years. Two technology platforms have been developed, Cyclosert for small molecule delivery and RONDEL for nucleic acid delivery. Both programs have Inhibitors,research,lifescience,medical produced a clinical candidate for oncology, CRLX101 (formerly IT-101), a camptothecin analog, and CALAA-01, an siRNA therapeutic targeting RRM2. While clinical development is still in the early phases, proof of concept was achieved for both technologies. Clinical development is ongoing and it will be interesting to see what patient benefits these innovative drugs can provide.
The (-)-p-Bromotetramisole Oxalate design and development of simple systems with the aim of delivery and controlled release of hydrophilic drugs administered through oral route are still a challenge. Compared to classical dosage forms, the goals for the development of such systems include maintaining of blood levels for the drug in a therapeutic window for a desired period. Such controlled drug-delivery systems present considerable advantage over conventional dosage forms, but they PR-957 molecular weight involve carrying out specific and complex technologies [1–12]. The most widespread systems giving modified releases are hydrophilic matrix carriers or hydrophilic coating matrix (e.g., on tablets).

Following the spread of the ideas of the French Revolution and th

Following the spread of the ideas of the French Revolution and their implementation by Napoleonic

conquests, the first half of the nineteenth century saw, especially in the German states, the growing emancipation of the Jews. The struggle for equality was accompanied by an increasing number of young Jews seeking secular education in the gymnasia and universities, achieving Inhibitors,research,lifescience,medical high positions in culture, science, and medicine. In the history of Medicine, the mid-nineteenth century is marked by the emergence of methodological experimental physiology, led by figures like Magendie in France and Müller in Germany who incorporated the achievements in physics and chemistry into physiology and employed instrumentation enabling the measurement and recording of the physiological data. The planned controlled experiment became the cornerstone of the budding scientific medicine. Inhibitors,research,lifescience,medical These processes are personified

by the eminent experimental physiologist, Moritz Schiff (1823–1896). His scientific achievements were hailed all over Europe and the US, but he was forced to live in exile, first because of his involvement in the German liberal movement and, later, because of his dedication to science clashing with prejudice and ignorance tainted by chauvinism. Inhibitors,research,lifescience,medical In recent decades, new facets of his activities have been revealed. The aim of this paper is to contribute to the renewed interest by reporting on a rather ignored line of research that only nowadays is being appreciated as one of the roots of modern functional imaging of Inhibitors,research,lifescience,medical the brain. GERMANY Moritz Schiff was born on January 28, 1823 to a prosperous Jewish merchant family in Frankfurt-am-Main. After matriculating from a German gymnasium and failing in commerce, he became an apprentice in the prestigious Schankenbergische Institute of Natural

History and, in 1844, received his M.D. in Göttingen after studying physiology with the clinical trial famous Johan Müller in Berlin. His love of the natural sciences took him to Paris where he studied under one of the founders of modern physiology, François Magendie (1783–1855), Inhibitors,research,lifescience,medical and with his pupils, ADP ribosylation factor François A. Longet (1811–1871) and Carlo Matteucci (1811–1868). Concomitantly, he worked at the Museum of Zoology in the famous Jardin des Plantes. In the summer of 1845, he returned to Frankfurt and, in 1846, obtained the position of the director of the ornithological part of the Institute where he had worked in his youth. Schiff classified the birds of South America and collaborated with Prince Charles Bonaparte, nephew of Napoleon I, who was a renowned authority in ornithology. In 1848, Schiff was swept by the liberal movement and joined the Baden army as a physician in a failed attempt to liberalize Germany. He was barely saved from execution and resumed his work at the Institute. The following years were very productive.

Haloperidol had the following actions in these volunteers: (i) it

Haloperidol had the following actions in these volunteers: (i) it increased neuronal activity in the caudate/putamen

(presumably a disinhibition); (ii) it increased neuronal activity in the thalamus (presumably associated with a diminished inhibitory reticulothalamic signal); (iii) it decreased anterior cingulate neuronal activity (presumably secondary to reduced activity in the thalamocortical excitatory afferent pathway); and (iv) it decreased middle frontal cortical activity (ie, Inhibitors,research,lifescience,medical the same explanation as for [iii]).22 The “explanations” (given in parentheses above) represent the interpretation we have made of the functional data to shed light on the question of the neural mechanism of antipsychotic drug action. Wc propose that the disinhibition that haloperidol (or any D2 dopamine receptor antagonist) produces in the caudate/putamen is transmitted through the basal Inhibitors,research,lifescience,medical ganglia and thalamus to ultimately inhibit key areas of the neocortex. These PET findings have been replicated in our laboratory using rCBF,23 and the data are entirely consistent. These results are consistent with many of the functional imaging results from other laboratories doing similar kinds of studies.24,25 Animals Experiments in our laboratory over the last few years have involved the administration

of traditional and new antipsychotic drugs to laboratory rats for subchronic time periods (6 months) for the purpose Inhibitors,research,lifescience,medical of examining critical neurotransmitter systems in the central nervous system (CNS)

regions (the basal ganglia-thalamocortical neural circuit) and their alteration with chronic drug treatment. We postulated that Inhibitors,research,lifescience,medical the neurochemical marker for D2 dopamine receptor blockade (D2 upregulation) and the “transmitted” signals through this system would both vary between the traditional and new drugs. We measured D2 dopamine receptor density in rat caudate, GABAa (GABA: gamma-aminobutyric acid) receptor density and Dj dopamine receptor density in rat substantia nigra, and GABAA Inhibitors,research,lifescience,medical receptor density and glutamic acid decarboxylase (GAD) mRNA expression in rat thalamus. With haloperidol, all these “markers” significantly changed in each region, implying a potent drug action in the caudate/putamen and a strong transmitted signal through next the rest of the basal ganglia to the thalamus and thereafter to the cortex.26 These data are direct evidence from the experimental animal of the idea of a transmitted antipsychotic action through the basal ganglia and the thalamus to the cortex. With the new antipsychotics, these neurochemical changes were milder and not as broad, but research always involved the basal ganglia and the thalamus. While the dopaminergic component of antipsy-chotic drug action is putativcly mediated through these defined neural circuits, other transmitter-specific components of drug action (eg, antiserotonergic or anti- adrenergic) are likely produced directly in the neocortex.

5 Apixaban Apixaban was studied in two atrial fibrillation trials

5 Apixaban Apixaban was studied in two atrial fibrillation trials: AVEROES

and ARISTOTLE, both at 5 mg twice daily and 2.5 mg twice daily for patients at high risk of bleeding. In AVEROES, apixaban proved to be superior to aspirin monotherapy in reducing stroke and systemic embolism (1.6% per year vs. 3.7% per year, P <0.001). Major bleeding was Inhibitors,research,lifescience,medical similar between the two groups (1.4% per year vs. 1.2% per year, respectively; P=0.57).6 In ARISTOTLE, apixaban was proven superior to warfarin for stroke and systemic embolism (1.27% per year vs. 1.6% per year, P=0.01). Significant reductions in major bleeding was also seen in apixaban patients (2.13% per year vs. 3.09% per year, P=0.047).7 The cardiorenal advisory committee for the

FDA is to meet during Inhibitors,research,lifescience,medical the summer of 2012 to make recommendations for apixaban’s application. Clinical Considerations in Drug Use Renal Function Careful attention to renal function is necessary when considering any of the three new agents. All require dose reductions for impaired renal function and avoidance in end-stage renal disease and dialysis patients, whereas no such restrictions apply to warfarin. The minimum renal function, Inhibitors,research,lifescience,medical Dapagliflozin measured by CrCl, at enrollment in RE-LY and ROCKET-AF was 30 mL/min. However, the approved dosing for dabigatran allows a reduced dose for CrCl as low as 15 mL/min despite not having clinical outcomes from a randomized controlled trial.1, 3, 4 The ARISTOTLE trial allowed a serum creatinine level up to 2.5 Inhibitors,research,lifescience,medical mg/dL or a CrCl >25 mL/min for inclusion into the trial and reduced the dose to 2.5 mg daily when two of following criteria were met: age ≥80 years, weight <60 kg, or serum creatinine ≥1.5 mg/dL.7 Drug Interactions Drug interactions have plagued the patient on warfarin Inhibitors,research,lifescience,medical therapy. Currently, all oral anticoagulants have drug interactions with commonly used medications for rhythm or rate control of atrial fibrillation, although dose reductions for most of these drug interactions are not recommended with the new agents. Dabigatran is metabolized by ester hydrolysis with minimal conjugation and bypasses the Cytochrome P-450 (CYP-450)

system. It does compete with P-glycoprotein pathways, and therefore a dose reduction is recommended for patients with a CrCl between 30–50 Terminal deoxynucleotidyl transferase mL/min who are also taking dronedarone.3 Rivaroxaban and apixaban both are metabolized through the CYP-450 system. Specifically, rivaroxaban is metabolized by CYP 3A4, 3A5, and 2J2, and apixaban is metabolized by 3A4 and 3A5.5, 8 Specific dosing recommendations concerning drug interactions is minimal, and the current recommendation is to avoid concomitant therapy with metabolic inhibitors when possible due to increased risk for bleeding.5 There are no practical/proven anticoagulation assays to help direct dosage adjustment for any of the newer anticoagulants to account for these interactions.

The majority of investigations of copy number variation to date h

The majority of investigations of copy number variation to date have been in www.selleckchem.com/products/wp1066.html neuropsychiatric disease and, happily, they have led immediately to real, replicable and very strong associations. A summary of CNVs recently strongly associated with neuropsychiatric disease is shown in Table I. These variants confer considerable risk, but they are not completely penetrant. Although the specific variants are very rare in the general Inhibitors,research,lifescience,medical population, they are occasionally seen in controls (Table I) , and where families have been examined, the variants

are often inherited from unaffected or only mildly affected parents.73-77 Additionally, as can be seen in Table I , many of the variants have been Inhibitors,research,lifescience,medical associated with more than one neuropsychiatric condition. This is consistent with the characteristics of neuropsychiatrically-associated rare

variants that were found before the GWAS era, such as DISC1 in schizophrenia, which associated with a range of phenotypes from psychiatrically normal to suicide, recurrent major depression, and schizophrenia.78 Inhibitors,research,lifescience,medical It seems that these variants, rather than predisposing to a specific neuropsychiatric condition, may strongly confer some sort of “neural vulnerability,” the ultimate manifestation of which depends on other interacting genetic and environmental factors. Because, to date, the only rare variants that we have been able to associate with neuropsychiatric illness are very large deletions Inhibitors,research,lifescience,medical and duplications, it is not clear whether this lack of specificity will be a general rule, or is somehow related to the size of the lesion. However, there is some evidence from the associations with common SNPs that this is a characteristic of the disease rather than the size of the associated variant.

For instance, bipolar-associated common variants in CACNA1 C may also confer risk of depression and schizophrenia.79 Table I Copy number variants (CNV) strongly associated with neuropsychiatric disorders.. Inhibitors,research,lifescience,medical Frequencies are given only when the CNV was found in a large case-control study design. *Controls may not have been carefully screened for neuropsychiatric illness. NR, not … The future for neuropsychiatric genetics There are two, not incompatible, possible directions for neuropsychiatric genetics research. One approach is Thalidomide to continue searching for common variants of small effect size using much larger cohorts in the tens or hundreds of thousands. This has been suggested as a future direction for schizophrenia genetics.80 Although this will require a considerable effort, there are already established worldwide collaborations for schizophrenia,68,80 so very large collections should be achievable in the relatively near future.

Unfortunately we have a very poor

Unfortunately we have a very poor understanding of the retention of the effects of physical activity. Third,

we have a very poor understanding of the types of exercises that might be most useful to promote a healthier brain. It is conceivable that competitive sports like tennis offer additional benefits beyond noncompetitive sports because of their dependence on physical coordination, cognitive effort, and social interaction. In sum, although we have a solid understanding of the potential for physical activity to enhance cognitive and brain health in late life there remain many Tyrphostin AG-1478 in vivo unanswered questions for future research to pursue. Inhibitors,research,lifescience,medical Acknowledgments KIE was supported by the University of Pittsburgh Alzheimer’s Disease Research Center (P50 AG005133) and a research

grant from the National Inhibitors,research,lifescience,medical Institutes of Health (R01 DK095172). AGG was supported by National Institutes of Health grants R01 MH084921 and ACISR P30 MH090333. MAB was supported by the National Institutes of Health’s University of Pittsburgh Alzheimer’s Disease Research Center (P50 AG005133), ACISR P30 MH090333 and R01 MH080240.
Development of traditional pharmacological treatments for major depression has been based on the monoamine hypothesis of depression, inferring a depletion in the levels of serotonin, norepinephrine, and dopamine in the central nervous system as the underlying Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical pathophysiology of depression This hypothesis is supported by the mechanism of action of antidepressants, although the mechanism of action is not precisely understood and only about 50% of patients respond to antidepressants with this action.1 Thus, new types of antidepressants (eg, κ-receptor antagonists, melatonin receptor agonists, cytokines) Inhibitors,research,lifescience,medical are the subject of active research.1 The antidepressant effect of neuromodulation approaches (eg, vagus nerve stimulation therapy, deep brain

stimulation) have also challenged the monoamine hypothesis and favored the network hypothesis of depression. This Cell Metabolism hypothesis assumes that dysfunctions of large neuronal networks in the brain can be normalized through a modulation of one node of the respective network. In this article, we will rely on another explanatory approach to depression, namely on the neurogenesis hypothesis of depression.2 This hypothesis posits that changes in the rate of neurogenesis are the underlying mechanism in the pathology and treatment of major depression.3 We then discuss in what way depression according to the neurogenesis hypothesis can be used as model disease for cerebral aging, and possible implications for new treatment methods. Current knowledge on neurobiological effects of depression In current concepts, depression is seen as a chronic disease with recurrent episodes in the majority of cases.

1985) Most cases of ICH involve brain regions commonly affected

1985). Most cases of ICH involve brain regions commonly affected in hypertensive ICH (Ho et al. 2009). Histopathological evidence support that repeated amphetamine abuse can result in blood vessel injury, leading to vessel wall necrosis, microinfarcts in small vessels, and atherosclerosis (McGee et al. 2004; Ho et al. 2009). Amphetamine-related SAHs mostly frequently Inhibitors,research,lifescience,medical report underlying aneurysms (Ho et al. 2009; Kaku and Lowenstein 1990). Ecstasy Ecstasy is a nonspecific name for a variety of

“designer drugs” used mainly by young adults. They are derivatives of amphetamine. The majority of Ecstasy in use is 3,4-methylenedioxymeth-amphetamine, or MDMA, N-ethyl-3,4-methylenedioxyamphetamine or MDEA (sometimes called “Eve”), or 3.4-methylenedioxyamphetamine (MDA). Recent epidemiological Inhibitors,research,lifescience,medical data indicate that Ecstasy use is increasing among college students (Strote et al. 2002). Pathophysiology Though Ecstasy is derivative of amphetamine, the drug more closely resembles the hallucinogen mescaline, rendering it to be a blend of hallucinogenic and catecholaminergic effects. Ecstasy increases the release of, and inhibits Inhibitors,research,lifescience,medical the reuptake of, serotonin

and norephinephrine, with lesser effects on dopamine. The toxicity, time course, and intensity of reaction can differ significantly between preparations. The drug is usually ingested in pill form, metabolized by the liver, and generally achieves peak concentration in the blood approximately two hours after ingestion. Ecstasy and CHIR-258 in vitro stroke There are no epidemiological studies specifically studying the incidence

of Ecstasy-related strokes. There are a small number of case studies of both ischemic and hemorrhagic strokes occurring within hours of ingestion of Ecstasy Inhibitors,research,lifescience,medical (Hughes et Inhibitors,research,lifescience,medical al. 1993; Harries and De Silva 1992; Gledhill et al. 1993; Manchanda and Connolly 1993; Hanyu et al. 1995; Kalant 2001; Auer et al. 2002). Mechanisms of stroke The vascular distribution of AISs related to Ecstasy use is variable. The possible etiologies of MDMA-induced stroke are similar to those of cocaine- and amphetamine-related strokes. Cardiac arrhythmias, have been implicated in Ecstasy-related cardiac death, and are potential causes of Ecstasy-related stroke via cardioembolism (Hughes et al. 1993). Cardiomyopathy has also been described in Ecstasy users and is associated with congestive heart failure, arrhythmia, Sitaxentan and stroke. After exposure to Ecstasy, vasospasm and necrosis have been observed in the vasculature of the globus pallidus and occipital cortex, making damage from AIS most likely in these areas (Reneman et al. 2000; Rojas et al. 2005; Hagan and Burney 2007). Damage to the vessel walls over time from chronic vasospasm and necrosis may also lead to both thrombosis and aneurysmal dilatation of cerebral vessels. This can then lead to AIS, ICH, or SAH (Kalant 2001; Auer et al. 2002).

Interestingly, one of the documents (e g EAPC II) supports a mor

Interestingly, one of the documents (e.g. EAPC II) supports a more nuanced participation of the patient in the decision-making process, thus referring to a specific time in the disease progression, when it is right to honour the patient’s refusal of treatment that prolong selleck kinase inhibitor suffering without any gain for the patient’s condition. F – Quality of life A considerable number of documents consider quality of life as the main goal of care at the end of life. This goal is so important that is licit to forgo any other result, including prolonging life or keeping the patient alive. Most of these documents Inhibitors,research,lifescience,medical assume

that quality of life is a relevant parameter of an effective palliative care. In particular, three of the documents maintain that quality of life should be defined by each patient (i.e. CANADA CHPCA II) and by his/her family (i.e. Inhibitors,research,lifescience,medical CANADA CHPCA I, AUSTRALIA CARNA). Only one document (i.e. WHO I) acknowledges the need of instruments to measure the quality of remaining life, and provides a list of items that should be evaluated in order to establish it. All the other documents do not

provide a description of how to assess the quality of life of patients facing impending death. Some documents (i.e. WHO I, WHO V, CANADA CHPCA I, UK NCPC) explicitly refer to the quality of life of family members taking care of patients who suffer Inhibitors,research,lifescience,medical a life-threatening illness. One of the documents details specific therapies that might improve the patient’s quality of life (i.e. USA AAP). G – Dignity A few documents Inhibitors,research,lifescience,medical refer to the issue of dignity, although the meaning of this term is altogether nuanced and variable. Some documents (i.e. ICN, CANADA CHPCA I, USA ANA) refer to a “dignified death”, while others allude to a general “sense of dignity” (i.e. CANADA CHPCA II) or to the possibility of

maintaining “dignity and independence” (i.e. USA AGS) as something that should be guaranteed to dying patients. One of the documents affirms that the caring staff should approach death in a way that it “dignifies life” (i.e. UK SC). In general, a specific definition of the term “dignity” Inhibitors,research,lifescience,medical is lacking. Discussion Analysis of the documents shows that all the dimensions of end-of-life care found in the literature and included in the framework (see Table ​Table1:1: Thematic grid) are echoed in the statements of the most representative organizations committed to the definition of policies and guidelines for palliative and end-of-life care. It is worth noting Thiamine-diphosphate kinase that all the national organizations found according to our research strategy belong to English speaking countries. This might be due to the fact that it was in these countries that the palliative care movement first developed and flourished in the 60s and 70s. In general, the “sub-areas” of symptom control (i.e. A1, A2 and A3) as well as those referring to relational and social issues (i.e. B1, B2, B3 and B4) are more widely covered by the documents than the “sub-areas” related to “preparation” (i.e.

38-40 Thus, mental disorders do not preclude epilepsy surgery Ne

38-40 Thus, mental disorders do not preclude epilepsy surgery. Nevertheless, their appropriate assessment by a psychiatrist with specific expertise in epilepsy might help to anticipate acute anxiety, delusions, or aggressive behavior during long-term EEG monitoring (in particular following a cluster of seizures favored by the tapering of AEDs during invasive EEG monitoring), and in the immediate postoperative period (in particular following right temporal lobectomy).41 In addition, such assessment

allows better evaluation of the patient’s understanding of, and expectations from, the presurgical workup, and whether these are in line with the reality. Interictal Inhibitors,research,lifescience,medical EEGs often demonstrate epileptiform discharges in patients with drug-resistant epilepsy, providing important hints regarding the lateralization and localization of the EZ. However, these abnormalities might be falsely localizing in a minority of cases. In TLE’, the presence of unilateral anterior

Inhibitors,research,lifescience,medical temporal spikes is a strong predictor of postoperative seizure Inhibitors,research,lifescience,medical freedom, whereas the lack of epileptiform discharge and bilateral abnormalities are associated with poorer prognosis.24 Nevertheless, bitemporal spikes, either synchronous or independent from each other, do not preclude successful temporal surgery, provided that they predominate on the side to be resected.42 Similarly, multifocal and generalized epileptiform discharges are compatible with successful surgery in children presenting with an epileptogenic unilateral brain lesion,17 as well as in patients with tuberous sclerosis.43 Specific EEG patterns, characterized by well localized repetitive fast Inhibitors,research,lifescience,medical spikes associated with

short burst of low-voltage, high-frequency oscillations might help to suspect an underlying MRIoccult focal cortical dysplasia.44 An optimal high-resolution MRI is of paramount importance to detect a structural abnormality most likely responsible for the seizure disorder. Inhibitors,research,lifescience,medical It is clear that the EZ might often extend outside the MRI-detected borders of such abnormality, and that epilepsy surgery can be successfully performed in patients with a normal MRI.45-47 However, in the great majority of patients who have been operated on, MRI discloses an epileptogenic brain lesion that represents the core of the presurgical and surgical strategy. 17-DMAG (Alvespimycin) HCl Indeed, other investigations will primarily assess the relationship between seizures and the MRI lesion, the amount of abnormal brain tissue and surrounding cortex included in the EZ, and the possibility of surgically removing part or all of the lesion and associated epileptogenic cortex. This framework is similarly applied to Adriamycin mw hippocampal sclerosis, malformation of cortical development, scars of various origins, and any space-occupying lesion. The quality of the MRI investigation has a major impact on its sensitivity.

PD symptoms reportedly occur in over 50% of all

PD symptoms reportedly occur in over 50% of all elderly patients receiving these agents and the cumulative annual incidence of TD in middle-aged and elderly patients is over 25%.56 The likelihood of reversing this potentially debilitating condition diminishes with age. Other adverse effects of these agents that are often intolerable in the older population include orthostatic hypotension and anticholinergic effects. Orthostasis is estimated

to occur in 5% to 30% of geriatric patients and is a major contributing factor to the occurrence of falls.57 The Inhibitors,research,lifescience,medical elderly are also more prone to the consequences of falls, such as bone fractures, injuries, and dependency. Low-potency antipsychotics and clozapine are more likely to cause significant drops in orthostatic blood pressure. Anticholinergic effects in the elderly may cause side effects, such as constipation, dry mouth, urinary retention, and cognitive impairment. The elderly are especially sensitive to these effects and the Inhibitors,research,lifescience,medical use of laxatives or stool softeners is already

particularly high in nursing homes. Cognitive impairments may lead to decreased independence, and a more rapid NSC683864 decline in cognitive functioning may occur in the elderly treated with antipsychotics than in the younger adult population. Clozapine has been used successfully in the elderly Inhibitors,research,lifescience,medical population at lower doses than adult patients. Mean dosages range from 50 to 300 mg/day with a much slower rate of titration. Inhibitors,research,lifescience,medical This may be a good choice for treating psychotic elderly patients with preexisting

PD, because of its lower affinity for D2 receptors in the striatum. Clinically, however, it is a poorly tolerated antipsychotic in geriatric patients and should Inhibitors,research,lifescience,medical be used with caution. The risk for agranulocytosis appears to be about 4% in the elderly population with older women being at highest risk.58 The risk for seizure activity is increased in the elderly59 and sedation is one of the major reasons for discontinuation.60 Clozapine therapy should be initiated at 12.5 to 25 mg/day given in two divided doses, titrating by increments of 12.5 Annual Review of Physiology mg over 5 to 7 days. Controlled studies examining the efficacy of clozapine in the elderly specifically for patients with schizophrenia are rare. Howanitz and colleagues61 studied clozapine (maximum 300 mg/day) compared with chlorpromazine (maximum 600 mg/day) in a 12-week, double-blind fashion in patients with chronic schizophrenia. Patients on clozapine tended to do better than the chlorpromazine group, although this did not reach significance, probably due to the sample size.62 Tachycardia and weight gain were problematic for clozapine-treated patients, while those treated with chlorpromazine were highly sedated. Clozapine should be used as a last resort in geriatric patients with schizophrenia and at least one trial of an SGA should be made first.