A Novel Potent and Selective Histamine H Receptor Antagonist Enerisant: In Vitro Profiles, In Vivo Receptor Occupancy, and Wake-Promoting and Procognitive Effects in Rodents.

Histamine H receptor antagonists/inverse agonists are known to enhance the activity of histaminergic neurons in the brain, thereby promoting arousal and cognition. Here, we report the in vitro and in vivo pharmacological profiles for a newly synthesized histamine H receptor antagonist/inverse agonist: [1-(4-{3-[(2)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1-pyrazol-4-yl](morpholin-4-yl)methanone monohydrochloride (enerisant hydrochloride). In vitro assays showed that enerisant was a competitive antagonist/inverse agonist with a high affinity and selectivity for human and rat histamine H receptors.

[Construction of a Home-Visiting System as a Family Pharmacy].

"The Vision for Patient-centered Pharmacies," published by the Ministry of Health, Labour and Welfare(MHLW)in October 2015 specifies three functions of family pharmacies, including home medical care. In 1994, home-visits by pharmacists officially began; however, before then, we had already visited patients whose medications and life situations were of concern, at their homes. Based on that experience, as we were planning to undertake home-visits after their institutionalization, we conducted a study of a system that would promote home care using pharmacists handling various duties, including prescriptions and health consulting.

[Significance of Allowing Pharmacy Students to Attend Visits to Home Care Patients].

In 2006, with the admission of a new batch of students, pharmaceutical education became a 6-year course. This was a result of the urgent need to train a new generation of pharmacists to respond to increasingly advanced and intricate medical care as well as the specific need to coordinate with multiple occupational categories. Meanwhile, with Japan becoming an aged society, medical care has undergone functional differentiation, and home care is now being promoted.

[Empathy to be Shown by Pharmacists toward Home Patients - Initiatives Undertaken by Pharmacists to Promote the Proper Use of Pharmaceutical Products].

Separation of medical and dispensary services has taken root in Japan as a healthcare system;8 00 million prescriptions have been issued, and 70% of medical institutions now participate in this practice. Additionally, discussions are ongoing regarding patient-oriented family pharmacies from a"back-to-basics"perspective of the separation drug dispensing from medical practice. Through a series of such discussions, the Ministry of Health, Labour and Welfare published a paper entitled"Vision for Pharmacies Working for Patients"with a focus on 3 functions to be implemented by family pharmacists and pharmacies.

Stimulation of the metabotropic glutamate (mGlu) 2 receptor attenuates the MK-801-induced increase in the immobility time in the forced swimming test in rats.

Background: Negative symptoms of schizophrenia are poorly managed using the currently available antipsychotics. Previous studies indicate that agonists of the metabotropic glutamate (mGlu) 2/3 receptors may provide a novel approach for the treatment of schizophrenia. However, the effects of mGlu2/3 receptor agonists or mGlu2 receptor positive allosteric modulators have not yet been clearly elucidated in animal models of the negative symptoms of schizophrenia.

Efficacy of a glycine transporter 1 inhibitor TASP0315003 in animal models of cognitive dysfunction and negative symptoms of schizophrenia.

Rationale: Since the hypofunction of the N-methyl-D-aspartate (NMDA) receptor is known to be involved in the pathophysiology of schizophrenia, the enhancement of NMDA receptor function through glycine modulatory sites is expected to be a useful approach for the treatment of schizophrenia.

Objectives: We investigated the efficacy of a glycine transporter 1 (GlyT1) inhibitor that potentiates NMDA receptor function by increasing synaptic glycine levels in animal models for cognitive dysfunction and negative symptoms, both of which are poorly managed by current antipsychotics.

Results: A newly synthesized GlyT1 inhibitor, 3-chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidin-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide (TASP0315003) significantly improved cognitive deficit induced by MK-801 in the object recognition test in rats.

Antipsychotic profiles of TASP0443294, a novel and orally active positive allosteric modulator of metabotropic glutamate 2 receptor.

Glutamatergic dysfunction has been implicated in psychiatric disorders such as schizophrenia. The stimulation of metabotropic glutamate (mGlu) 2 receptor has been shown to be effective in a number of animal models of schizophrenia. In this study, we investigated the antipsychotic profiles of (2S)-5-methyl-2-{[4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]methyl}-2,3-dihydroimidazo[2,1-b][1,3]oxazole-6-carboxamide (TASP0443294), a newly synthesized positive allosteric modulator of the mGlu2 receptor.

Effects of a glycine transporter-1 inhibitor and D-serine on MK-801-induced immobility in the forced swimming test in rats.

Glutamatergic dysfunction, particularly the hypofunction of N-methyl-D-aspartate (NMDA) receptors, is involved in the pathophysiology of schizophrenia. The positive modulation of the glycine site on the NMDA receptor has been proposed as a novel therapeutic approach for schizophrenia. However, its efficacy against negative symptoms, which are poorly managed by current medications, has not been fully addressed.

Neurophysiologic and antipsychotic profiles of TASP0433864, a novel positive allosteric modulator of metabotropic glutamate 2 receptor.

Excess glutamatergic neurotransmission has been implicated in the pathophysiology of schizophrenia, and the activation of metabotropic glutamate 2 (mGlu2) receptor may exert antipsychotic effects by normalizing glutamate transmission. In the present study, we investigated the neurophysiologic and antipsychotic profiles of TASP0433864 [(2S)-2-[(4-tert-butylphenoxy)methyl]-5-methyl-2,3-dihydroimidazo[2,1-b][1,3]oxazole-6-carboxamide], a newly synthesized positive allosteric modulator (PAM) of mGlu2 receptor. TASP0433864 exhibited PAM activity at human and rat mGlu2 receptors with EC50 values of 199 and 206 nM, respectively, without exerting agonist activity at rat mGlu2 receptor.

Involvement of glutamatergic and GABAergic transmission in MK-801-increased gamma band oscillation power in rat cortical electroencephalograms.

Hypofunction of the N-methyl-D-aspartic acid receptor (NMDAr) has been considered to play a crucial role in the pathophysiology of schizophrenia. In rodent electroencephalogram (EEG) studies, non-competitive NMDAr antagonists have been reported to produce aberrant basal gamma band oscillation (GBO), as observed in schizophrenia. Aberrations in GBO power have attracted attention as a translational biomarker for the development of novel antipsychotic drugs.

Differential effects of NMDA receptor antagonists at lower and higher doses on basal gamma band oscillation power in rat cortical electroencephalograms.

Schizophrenic patients have been shown to exhibit abnormal cortical gamma band oscillation (GBO), which is thought to be related to the symptoms of schizophrenia, including cognitive impairment. Recently, non-competitive NMDA receptor (NMDAr) antagonists such as MK-801 and ketamine have been reported to increase the basal GBO power in rat cortical electroencephalograms. However, the mechanisms underlying the increase in basal GBO power induced by non-competitive NMDAr antagonists remain unclear.

Stimulation of postsynapse adrenergic α2A receptor improves attention/cognition performance in an animal model of attention deficit hyperactivity disorder.

A 5-trial inhibitory avoidance test using spontaneously hypertensive rat (SHR) pups has been used as an animal model of attention deficit hyperactivity disorder (ADHD). However, the roles of noradrenergic systems, which are involved in the pathophysiology of ADHD, have not been investigated in this model. In the present study, the effects of adrenergic α2 receptor stimulation, which has been an effective treatment for ADHD, on attention/cognition performance were investigated in this model.

Metabotropic glutamate receptors regulate cortical gamma hyperactivities elicited by ketamine in rats.

Abnormalities in electroencephalogram gamma oscillations have been implicated in schizophrenic symptoms. N-methyl-d-aspartate (NMDA) receptor antagonists produce behavioral abnormalities that are similar to the symptoms of schizophrenia, including social and cognitive impairment, and also increase the power of spontaneous gamma oscillations in the frontal cortex in rodents. Both mGlu2/3 receptor agonists and mGlu1 receptor antagonists reportedly improve behavioral abnormalities elicited by NMDA receptor antagonists in rodents.

Stimulation of metabotropic glutamate (mGlu) 2 receptor and blockade of mGlu1 receptor improve social memory impairment elicited by MK-801 in rats.

Glutamatergic dysfunction has been implicated in psychiatric disorders such as schizophrenia. Both the stimulation of the metabotropic glutamate (mGlu) 2/3 receptor and the blockade of the mGlu1 receptor have been shown to be effective in a number of animal models of schizophrenia. However, the efficacy for social cognition, which is poorly managed by current medication, has not been fully addressed.

AMPA receptor mediates mGlu 2/3 receptor antagonist-induced dopamine release in the rat nucleus accumbens shell.

The role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor activation in the regulation of dopamine release by the metabotropic glutamate (mGlu) 2/3 receptors in the nucleus accumbens (NAc) shell was investigated using an in vivo microdialysis evaluation. The local application of 10 microM of LY341495, an mGlu 2/3 receptor antagonist, significantly increased extracellular dopamine levels in the NAc shell in freely moving rats. Pretreatment with an AMPA receptor antagonist, NBQX (0.

Inhibitory effect of selective serotonin reuptake inhibitors on the vesicular monoamine transporter 2.

The neuronal vesicular monoamine transporter (VMAT2) is the target molecule of action of some psychostimulants, such as methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). The present study examined the effect of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), on VMAT2 activity by measuring adenosine triphosphate-dependent [(3)H]dopamine uptake into synaptic vesicles prepared from rat striatum. SSRIs, fluoxetine, paroxetine, and fluvoxamine, inhibited vesicular [(3)H]dopamine uptake in vitro.

[The role of pharmacists involved in drug therapy for home-care patients with the end-stage cancer].

Recently, a medical care function has become differentiated from medical system's perspectives, and accordingly the number of home-care patients has been increasing. Pharmacists working at drug stores not only prescribe drugs for home-care patients but also visit them at home to help them learn how to properly take their medications and to have correct dosages. To do this, drug store pharmacists have begun sharing information on their patients through care conferences attended with doctors at clinics and nurses at visiting nursing stations.

D-Serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats.

Compounds enhancing N-methyl-d-aspartate (NMDA) glutamate receptor function have been reported to improve cognitive deficits. Since cognitive deficits are considered to be the core symptom of schizophrenia, enhancing NMDA receptor function represents a promising approach to treating schizophrenia. In the present study, we investigated whether d-serine or a glycine transporter inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS), both of which enhance NMDA receptor function, could improve MK-801-induced cognitive deficits in rats, and compared their effects with those of the atypical antipsychotic clozapine and of the typical antipsychotic haloperidol.

[From hospital to home care].

When a patient was transferred from hospital to home care, various types of information about the patient are needed. To supply drugs to a home care patient, the pharmacy is required to supply not only prescription information about the medication while the patient was in the hospital, but also the information about a course of treatment, previous medical history, and the family situation with the patient. An acceptance of a home care patient involves a request to the pharmacy immediately prior to the patient being discharged, so that the pharmacy has the ability to deal with the patient.

Long-term outcome after STA-MCA anastomosis for moyamoya disease.

A long-term assessment was performed to determine the posttreatment clinical course of 113 patients with moyamoya disease. All patients sustained cerebral ischemic attacks and underwent superficial temporal artery-middle cerebral artery anastomosis with or without temporal muscle grafting. The follow-up duration was 3 to 24 years (mean 14.

A metabotropic glutamate 2/3 receptor antagonist, MGS0039, increases extracellular dopamine levels in the nucleus accumbens shell.

(1R,2R,3R,5R,6R)-2-Amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039), a potent and selective metabotropic glutamate 2/3 (mGlu 2/3) receptor antagonist, exhibits antidepressant-like activities in some animal models.

AMPA receptor stimulation mediates the antidepressant-like effect of a group II metabotropic glutamate receptor antagonist.

(1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039), a selective group II metabotropic glutamate receptor (mGluR) antagonist, exhibits antidepressant-like activities in rodent models.

Neuropharmacological profiles of antagonists of group II metabotropic glutamate receptors.

Glutamatergic abnormalities play roles in several psychiatric disorders. Glutamate acts at two classes of receptors, ionotropic and metabotropic glutamate receptors (mGluR), the latter is classified into three group, based on receptor homology and signaling mechanisms. Among them, recent pharmacological and histochemical studies suggest that the group II mGluR (mGluR2 and mGluR3) plays crucial roles in the control of emotional states.

Evaluation of cardiac sympathetic nerve function by myocardial 123I-metaiodobenzylguanidine scintigraphy before and after endoscopic sympathectomy.

Object: The purpose of this study was to analyze the change in cardiac sympathetic function by performing a 123I-metaiodobenzylguanidine (MIBG) imaging study after endoscopic upper thoracic sympathectomy (EUTS) in patients with palmar hyperhidrosis before and after surgery.

Methods: Between February 1999 and February 2002, 135 patients underwent bilateral EUTS to treat palmar hyperhidrosis. Between September 2001 and February 2002, 12 of these consecutively enrolled patients were also included in a 123I-MIBG imaging study.