The Enantioselective Synthesis of Eburnamonine, Eucophylline, and 16'-epi-Leucophyllidine.

A synthetic approach to the heterodimeric bisindole alkaloid leucophyllidine is disclosed herein. An enantioenriched lactam building block, synthesized through palladium-catalyzed asymmetric allylic alkylation, served as the precursor to both hemispheres. The eburnamonine-derived fragment was synthesized through a Bischler-Napieralski/hydrogenation approach, while the eucophylline-derived fragment was synthesized by Friedländer quinoline synthesis and two sequential C-H functionalization steps.

Design and synthesis of novel δ opioid receptor agonists with an azatricyclodecane skeleton for improving blood-brain barrier penetration.

We designed and synthesized novel δ opioid receptor (DOR) agonists 3a-i with an azatricyclodecane skeleton, which was a novel structural class of DOR agonists. Among them, 3b exhibited high values of binding affinity and potent agonistic activity for the DOR that were approximately equivalent to those of 2 which bore an oxazatricyclodecane skeleton. In vitro assays using the blood-brain barrier (BBB) permeability test kit supported the idea that 3b achieved an excellent BBB permeability by converting an oxygen atom of 2 to a carbon atom (methylene group) in the core skeleton.

Novel delta opioid receptor agonists with oxazatricyclodecane structure showing potent agonistic activities.

We recently reported oxazatricyclodecane derivatives 1 as δ opioid receptor (DOR) agonists having a novel chemotype, but their DOR agonistic activities were relatively low. Based on the working hypothesis that the dioxamethylene moiety in 1 may be an accessory site and that it may interfere with the sufficient conformational change of the receptor required for exerting the full agonistic responses, we designed and synthesized new oxazatricyclodecane derivatives 2-4 lacking the dioxamethylene moiety. As we expected, the designed compounds 2-4 showed pronouncedly improved agonistic activities for the DOR.

Human nitrilase-like protein does not catalyze the hydrolysis of vildagliptin.

Nitrilase, which is found in plants and many types of bacteria, is known as the enzyme that catalyzes hydrolysis of a wide variety of nitrile compounds. While human nitrilase-like protein (NIT), which is a member of the nitrilase superfamily, has two distinct isozymes, NIT1 and NIT2, their function has not been well understood. In this study, we investigated whether human NIT1 and NIT2 are involved in the hydrolysis of drugs using vildagliptin as a substrate.

Novel delta opioid receptor agonists with oxazatricyclodecane structure.

We synthesized compounds 4a,c-f,h,i containing the oxazatricyclodecane structure from a novel rearrangement reaction product 2a. All the prepared compounds 4a,c-f,h,i exhibited full agonistic activities for the δ opioid receptor (DOR). Among them, the N-methyl derivative 4c was highly selective, and the most effective DOR agonist in functional assays.

Prognostic value of pretreatment 18F-FDG PET/CT parameters including visual evaluation in patients with head and neck squamous cell carcinoma.

Objective: The purpose of this study was to determine whether pretreatment quantitative and visual parameters seen on PET/CT using (18)F-FDG add prognostic information for clinical staging in patients with head and neck cancer.

Materials And Methods: We enrolled 108 patients with histologically proven oral, oropharyngeal, hypopharyngeal, and laryngeal squamous cell carcinomas who underwent FDG PET/CT before treatment and, later, definitive therapy in our study. PET/CT parameters-maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and uptake pattern (sphere-shaped or ring-shaped)-were recorded.

A multicenter brain perfusion SPECT study evaluating idiopathic normal-pressure hydrocephalus on neurological improvement.

Purpose: This study was designed to investigate the specific cerebral blood flow (CBF) pattern in patients with idiopathic normal-pressure hydrocephalus (iNPH) and a predictive value for shunt responsiveness in a multicenter study (Study of Idiopathic Normal-Pressure Hydrocephalus on Neurological Improvement: SINPHONI).

Methods: Eighty-four iNPH patients underwent shunt operations using MRI selection criteria from the SINPHONI and were subjected to CBF single photon emission computed tomography (SPECT). The perfusion patterns on SPECT were classified: anterior-dominant CBF reduction type (A type), posterior-dominant CBF reduction type (P type), and mixed or diffuse CBF reduction type (M type).

Clinical value of FDG-PET for preoperative evaluation of endometrial cancer.

Objective: Whole body positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) has been widely used in various malignancies, but the clinical value of FDG-PET for endometrial cancer has not been fully investigated. The purpose of this study was to evaluate the usefulness of FDG-PET for preoperative evaluation of endometrial cancer.

Methods: Forty female patients suspected of having endometrial cancer were included in this study.

Multicenter evaluation of a standardized protocol for rest and acetazolamide cerebral blood flow assessment using a quantitative SPECT reconstruction program and split-dose 123I-iodoamphetamine.

Unlabelled: SPECT can provide valuable diagnostic and treatment response information in large-scale multicenter clinical trials. However, SPECT has been limited in providing consistent quantitative functional parametric values across the centers, largely because of a lack of standardized procedures to correct for attenuation and scatter. Recently, a novel software package has been developed to reconstruct quantitative SPECT images and assess cerebral blood flow (CBF) at rest and after acetazolamide challenge from a single SPECT session.

Quantitative mapping of basal and vasareactive cerebral blood flow using split-dose 123I-iodoamphetamine and single photon emission computed tomography.

A new method has been developed for diffusible tracers, to quantify CBF at rest and after pharmacological stress from a single session of dynamic scans with dual bolus administration of a radiotracer. The calculation process consisted of three steps, including the procedures of incorporating background radioactivity contaminated from the previous scan. Feasibility of this approach was tested on clinical SPECT studies on 16 subjects.

Renal circulatory effects of acetazolamide in patients with essential hypertension.

Background: Reports indicate that acetazolamide (ACZ) induces the vasodilation of all vessels in animal models, as well as in small and medium kidney vessels in animal models. However, the effect of ACZ on the renal circulation of patients with essential hypertension remains unknown. In this study we examined the effects of a carbonic anhydrase inhibitor, acetazolamide (ACZ), on the renal circulation of patients with essential hypertension.

[Acute brain infarction clearly demonstrated by using the three-dimensional stereotactic surface projections (3D-SSP) of 99mTc-HMPAO SPECT].

We report a 66-year-old ambidextrous man who suddenly developed aphasia seven days after coronary artery bypass grafting surgery. CT scan performed 30 minutes after onset failed to depict acute ischemic lesion. MR imaging could not be performed because of intrathoracic wires.

Circulating CD34-positive cells provide an index of cerebrovascular function.

Background: Increasing evidence points to a role for circulating endothelial progenitor cells, including populations of CD34- and CD133-positive cells present in peripheral blood, in maintenance of the vasculature and neovascularization. Immature populations, including CD34-positive cells, have been shown to contribute to vascular homeostasis, not only as a pool of endothelial progenitor cells but also as a source of growth/angiogenesis factors at ischemic loci. We hypothesized that diminished numbers of circulating immature cells might impair such physiological and reparative processes, potentially contributing to cerebrovascular dysfunction.

Gated myocardial SPECT to predict response to beta-blocker therapy in patients with idiopathic dilated cardiomyopathy.

Unlabelled: Because of the difficulty of predicting the response of patients with idiopathic dilated cardiomyopathy (IDC) to beta-blocker therapy, this study was performed to evaluate whether gated myocardial SPECT (gated SPECT) could be useful for predicting that response.

Methods: We performed gated SPECT with (99m)Tc-sestamibi on 38 patients with IDC before treatment with a beta-blocker and standard medication. Perfusion abnormalities, left ventricular (LV) function, and spheric distortion were assessed by a quantitative software program.

Database of normal human cerebral blood flow, cerebral blood volume, cerebral oxygen extraction fraction and cerebral metabolic rate of oxygen measured by positron emission tomography with 15O-labelled carbon dioxide or water, carbon monoxide and oxygen: a multicentre study in Japan.

Measurement of cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO(2)) by positron emission tomography (PET) with oxygen-15 labelled carbon dioxide (C(15)O(2)) or (15)O-labelled water (H(2)(15)O), (15)O-labelled carbon monoxide (C(15)O) and (15)O-labelled oxygen ((15)O(2)) is useful for diagnosis and treatment planning in cases of cerebrovascular disease. The measured values theoretically depend on various factors, which may differ between PET centres. This study explored the applicability of a database of (15)O-PET by examining between-centre and within-centre variation in values.

Extracorporeal double filtration plasmapheresis in acute atherothrombotic brain infarction caused by major artery occlusive lesion.

Extracorporeal double filtration plasmapheresis (EDFP) can quickly lower plasma viscosity and fibrinogen concentration. EDFP has the potential to improve cerebral microcirculation in acute ischemic stroke and ultimately to salvage penumbral tissue. However, no evidence is available to show that EDFP can increase cerebra blood flow (CBF).

A theoretical model of oxygen delivery and metabolism for physiologic interpretation of quantitative cerebral blood flow and metabolic rate of oxygen.

The coupling of cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2) during physiologic and pathophysiologic conditions remains the subject of debate. In the present study, we have developed a theoretical model for oxygen delivery and metabolism, which describes the diffusion of oxygen at the capillary-tissue interface and the nonlinear nature of hemoglobin (Hb) affinity to oxygen, allowing a variation in simple-capillary oxygen diffusibility, termed "effective oxygen diffusibility (EOD)." The model was used to simulate the relationship between CBF and CMRO2, as well as oxygen extraction fraction (OEF), when various pathophysiologic conditions were assumed involving functional activation, ischemia, hypoxia, anemia, or hypo- and hyper-capnic CBF variations.

Visualization of interscapular brown adipose tissue using (99m)Tc-tetrofosmin in pediatric patients.

Unlabelled: Brown adipose tissue (BAT) is a site of nonshivering thermogenesis in mammals. The mitochondria of BAT operate in an uncoupled mode and increase fatty acid oxidation to produce heat at birth. Thus, the BAT of human infants and children contains more active mitochondria than that of adults.

Cerebral hemodynamic evaluation using perfusion-weighted magnetic resonance imaging: comparison with positron emission tomography values in chronic occlusive carotid disease.

Background And Purpose: Perfusion-weighted magnetic resonance imaging (PWI) is a reliable and semiquantitative method for estimating cerebral hemodynamics. We sought to evaluate the potential of PWI for assessing cerebral blood flow (CBF) and metabolism compared with positron emission tomography (PET) in patients with chronic occlusive carotid disease.

Methods: In 24 patients with chronic unilateral occlusive carotid disease, time-to-peak (TTP) delay (TTP-D) measured by PWI was compared with CBF, cerebral blood volume (CBV), and oxygen extraction fraction (OEF) obtained by PET.

Acetazolamide assisted Tc-99m MAG3 renography to assess renal blood flow reserve.

Objective: The present study examines whether or not baseline and acetazolamide (ACZ) Tc-99m MAG3 renography can assess renal blood flow reserve.

Methods: Renography proceeded for 50 min after sequential injections of 370 MBq Tc-99m MAG3 for baseline renography and 10 min after a 1,000 mg injection of ACZ for ACZ renography. Effective renal plasma flow of renal cortex (cERPF) in each kidney and the percentage change in cERPF of those parameters (deltaERPF) were obtained before and after the administration of ACZ in 10 subjects without hypertension or diabetes (normal group), in 10 with essential hypertension (hypertensive group) and in 10 who had Type 2 diabetes with hypertension (diabetic group).

Topographic distribution of misery perfusion in relation to internal and superficial borderzones.

Background And Purpose: Whether misery perfusion (MP) commonly accompanies brain borderzones (BZs) in patients with major cerebral artery occlusion remains unclear. We elucidated topographic patterns of chronic hemodynamic failure in such patients.

Methods: Twenty-four patients with unilateral occlusion or severe stenosis (>75% in diameter) of the internal carotid artery (ICA) or middle cerebral arterial (MCA) trunk with minimal or no infarct underwent PET with (15)O-labeled gas inhalation.

Cerebral hemodynamics and metabolism in patients with cerebral arteriovenous malformations: an evaluation using positron emission tomography scanning.

Object: The purpose of this study was to evaluate cerebral hemodynamic and metabolic features in patients with arteriovenous malformations (AVMs) by using positron emission tomography (PET) scanning.

Methods: Twenty-four patients with supratentorial cerebral AVMs participated in PET studies in which 15O inhalation steady-state methods were used. The authors recorded the values of regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), the regional oxygen extraction fraction (rOEF), and the regional cerebral metabolic rate of O2 (rCMRO2) at three designated regions of interest (ROIs) in each patient.