Nucleation and growth of orbital ordering.

The dynamics of the first-order phase transitions involving a large displacement of atoms, for example, a liquid-solid transition, is generally dominated by the nucleation of the ordered phase and the growth of the nuclei, where the interfacial energy between the two phases plays an important role. On the other hand, electronic phase transitions seldom exhibit such a nucleation-growth behavior, probably because two-phase coexistence is not dominated by only the interfacial energy in such phase transitions. In the present paper, we report that the dynamics of a phase transition associated with an ordering of d orbitals in a vanadate exhibits a clear nucleation-growth behavior and that the interfacial energy between the orbital-ordered and -disordered phases dominated by the orbital-spin coupling can be experimentally obtained.

Superconductivity at 38 K at an electrochemical interface between an ionic liquid and FeSe0.8Te0.2 on various substrates.

Superconducting FeSe0.8Te0.2 thin films on SrTiO3, LaAlO3 and CaF2 substrates were electrochemically etched in an ionic liquid, DEME-TFSI, electrolyte with a gate bias of 5 V. Superconductivity at 38 K was observed on all substrates after the etching of films with a thickness greater than 30 nm, despite the different Tc values of 8 K, 12 K and 19 K observed before etching on SrTiO3, LaAlO3 and CaF2 substrates, respectively. Tc returned to its original value with the removal of the gate bias. The observation of Tc enhancement for these thick films indicates that the Tc enhancement is unrelated to any interfacial effects between the film and the substrate. The sheet resistance and Hall coefficient of the surface conducting layer were estimated from the gate bias dependence of the transport properties. The sheet resistances of the surface conducting layers of the films on LaAlO3 and CaF2 showed identical temperature dependence, and the Hall coefficient was found to be almost independent of temperature and to take values of -0.05 to -0.2 m2/C, corresponding to 4-17 electrons per FeSe0.8Te0.2 unit cell area in two dimensions. These common transport properties on various substrates suggest that the superconductivity at 38 K appears in the surface conducting layer as a result of an electrochemical reaction between the surface of the FeSe0.8Te0.2 thin film and the ionic liquid electrolyte.

A Clinical Quantitative Evaluation of Hepatobiliary Transport of [11C]Dehydropravastatin in Humans Using Positron Emission Tomography.

Various positron emission tomography (PET) probes have been developed to assess in vivo activities in humans of drug transporters, which aid in the prediction of pharmacokinetic properties of drugs and the impact of drug-drug interactions. We developed a new PET probe, sodium (3R, 5R)-3, 5-dihydroxy-7-((1S, 2S, 6S, 8S)-6-hydroxy-2-methyl-8- ((1-[11C]-(E)-2-methyl-but-2-enoyl) oxy) -1, 2, 6, 7, 8, 8a-hexahydronaphthalen-1-yl) heptanoate ([11C]DPV), and demonstrated its usefulness for the quantitative investigation of Oatps (gene symbol SLCO) and Mrp2 (gene symbol ABCC2) in rats. To further analyze the species differences and verify the pharmacokinetic parameters in humans, serial PET scanning of the abdominal region with [11C]DPV was performed in six healthy volunteers with and without an OATP1Bs and MRP2 inhibitor, rifampicin (600 mg, oral), in a crossover fashion. After intravenous injection, [11C]DPV rapidly distributed to the liver and kidney followed by secretion into the bile and urine. Rifampicin significantly reduced the liver distribution of [11C]DPV 3-fold, resulting in a 7.5-fold reduced amount of excretion into the bile and the delayed elimination of [11C]DPV from the blood circulation. The hepatic uptake clearance (CLuptake, liver) and canalicular efflux clearance (CLint, bile) of [11C]DPV (544 ± 204 and 10.2 ± 3.5 µl/min per gram liver, respectively) in humans were lower than the previously reported corresponding parameters in rats (1800 and 298 µl/min per gram liver, respectively) (Shingaki et al., 2013). Furthermore, rifampicin treatment significantly reduced CLuptake, liver and CLint, bile by 58% and 44%, respectively. These results suggest that PET imaging with [11C]DPV is an effective tool for quantitatively characterizing the OATP1Bs and MRP2 functions in the human hepatobiliary transport system.

Cr3+/Er3+ co-doped LaAlO3 perovskite phosphor: a near-infrared persistent luminescence probe covering the first and third biological windows.

We have developed a novel persistent phosphor of LaAlO3 perovskite doped with Er3+, Cr3+, and Sm3+ (LAO:Er-Cr-Sm), which exhibits long persistent luminescence (PersL) at 1553 nm due to the Er3+:4I13/2→4I15/2 transition as well as at 734 nm due to the Cr3+:2E(2G) →4A2(4F) transition. The intense near-infrared (NIR) PersL bands from Cr3+ and Er3+ match well with the first (NIR-I, 650-950 nm) and third (NIR-III, 1500-1800 nm) biological windows as well as response curves of commercial Si and InGaAs detectors. The photon emission rates of Cr3+ (6.06 × 1016 cps sr-1 m-2) and Er3+ (3.69 × 1016 cps sr-1 m-2) at 60 min after ceasing ultraviolet (UV) illumination were comparable with that of the widely used ZnGa2O4:Cr3+ red persistent phosphor (5.41 × 1016 cps sr-1 m-2). Furthermore, we also show the first in vitro autofluorescence-free imaging through pork tissues by Si/InGaAs cameras monitoring Cr3+/Er3+ PersL, and demonstrate that the Er3+ emission can achieve higher spatial resolution than the Cr3+ emission due to the reduced light scattering at longer wavelengths. It is indicated that this material can act as a promising bio-probe for in vivo optical imaging, especially in the NIR-III biological window.

Exploration of Antiemetics for Osteoporosis Therapy-Induced Nausea and Vomiting Using PET Molecular Imaging Analysis to Gastrointestinal Pharmacokinetics.

PURPOSE: To select appropriate antiemetics relieving teriparatide-induced nausea and vomiting during osteoporosis treatment using PET molecular imaging and pharmacokinetic analysis. METHODS: Rats were pretreated with subcutaneous teriparatide, followed by oral administration of antiemetics with different pharmacological effects. The pharmacokinetics of antiemetics were assessed by oral administration of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) under free moving conditions in vivo. The effect of teriparatide on the permeability of Caco-2 cell membranes to [(18)F]FDG was assessed in vitro. The effects of antiemetics on teriparatide-induced suppression of gastrointestinal motility in vivo was assayed by positron emission tomography (PET) using orally administered [(18)F]FDG. RESULTS: Teriparatide delayed the time-radioactivity profile of [(18)F]FDG in blood and significantly reduced its absorption rate constant (k a ), determined from non-compartmental analysis, to 60% of control. In contrast, co-administration of granisetron or mosapride restored the time-radioactivity profile and k a of [(18)F]FDG to control levels. Teriparatide had no effect on Caco-2 membrane permeability to [(18)F]FDG. Pharmacokinetic PET imaging data analysis quantitatively showed the pharmacological effects of teriparatide-induced suppression of upper gastrointestinal motility and its restoration by granisetron and mosapride. CONCLUSIONS: Teriparatide-induced abdominal discomfort might be attributed to GI motility, and PET imaging analysis is a useful tool to for the selection of appropriate antiemetics.

Extension of recovery time from fatigue by repeated rest with short-term sleep during continuous fatigue load: Development of chronic fatigue model.

Homeostasis is known to be involved in maintaining the optimal internal environment, helping to achieve the best performance of biological functions. At the same time, a deviation from optimal conditions often attenuates the performance of biological functions, and such restricted performance could be considered as individual fatigue, including physical and mental fatigue. The present study seeks to develop an animal model of chronic or subacute fatigue in which the recovery time is extended through the gradual disruption of homeostasis. We show that repeated short-term rest periods with certain lengths of sleep during continuous fatigue loading extend recovery from spontaneous nighttime activity but not physical performance in comparison with a continuous fatigue-loading procedure. Furthermore, the immobility time in a forced swimming test was extended by repeated short-term rests. These results suggest that repeated short-term rest with certain lengths of sleep during continuous fatigue loading is able to extend the recovery from mental fatigue but not from physical fatigue and that this effect might occur via the disruption of a homeostatic mechanism that is involved in restoring the optimal internal environment.

Visualization of drug translocation in the nasal cavity and pharmacokinetic analysis on nasal drug absorption using positron emission tomography in the rat.

We performed positron emission tomography (PET) using 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) to evaluate the pharmacokinetics of nasal drug absorption in the rat. The dosing solution of [(18)F]FDG was varied in volume (ranging from 5 to 25 µl) and viscosity (using 0% to 3% concentrations of hydroxypropylcellulose). We modeled the pharmacokinetic parameters regarding the nasal cavity and pharynx using mass balance equations, and evaluated the values that were obtained by fitting concentration-time profiles using WinNonlin® software. The regional nasal permeability was also estimated using the active surface area derived from the PET images. The translocation of [(18)F]FDG from the nasal cavity was visualized using PET. Analysis of the PET imaging data revealed that the pharmacokinetic parameters were independent of the dosing solution volume; however, the viscosity increased the absorption rate constant and decreased the mucociliary clearance rate constant. Nasal permeability was initially higher but subsequently decreased until the end of the study, indicating regional differences in permeability in the nasal cavity. We concluded that the visualization of drug translocation in the nasal cavity in the rat using PET enables quantitative analysis of nasal drug absorption, thereby facilitating the development of nasal formulations for human use.

Quantitative Evaluation of mMate1 Function Based on Minimally Invasive Measurement of Tissue Concentration Using PET with [(11)C]Metformin in Mouse.

PURPOSE: To evaluate the function of multidrug and toxin extrusion proteins (MATEs) using (11)C-labeled metformin ([(11)C]metformin) by positron emission tomography (PET). METHODS: PET was performed by intravenous bolus injection of [(11)C]metformin. Pyrimethamine at 0.5 and 5 mg/kg was intravenously administered to mice 30 min prior to the scan. Integration plot analysis was conducted for calculating liver (CLuptake,liver), kidney (CLuptake,kidney) tissue uptake, intrinsic biliary (CLint,bile) and urinary (CLint,urine) excretion clearances of [(11)C]metformin. RESULTS: Visualization by PET showed that pyrimethamine increased concentrations of [(11)C]metformin in the liver and kidneys, and decreased the concentrations in the urinary bladder without changing the blood profiles. Pyrimethamine had no effect on the CLuptake,liver and CLuptake,kidney, which were similar to the blood-flow rate. CLint,bile with regard to the liver concentration was unable to be determined, but administration of 0.5 and 5 mg/kg of pyrimethamine increased the liver-to-blood ratio to 1.6 and 2.3-fold, respectively, indicating that pyrimethamine inhibited the efflux of [(11)C]metformin from the liver. CLint,urine with regard to the corticomedullary region concentrations was decreased 37 and 68% of the control by administration of 0.5 and 5 mg/kg of pyrimethamine, respectively (P < 0.05). CONCLUSIONS: Tissue concentration based investigations using [(11)C]metformin by PET enables the functional analysis of MATEs in the liver and kidneys.

The synthesis and biodistribution of [(11)C]metformin as a PET probe to study hepatobiliary transport mediated by the multi-drug and toxin extrusion transporter 1 (MATE1) in vivo.

In order to develop a new positron emission tomography (PET) probe to study hepatobiliary transport mediated by the multi-drug and toxin extrusion transporter 1 (MATE1), (11)C-labelled metformin was synthesized and then evaluated as a PET probe. [(11)C]Metformin ([(11)C]4) was synthesized in three steps, from [(11)C]methyl iodide. Evaluation by small animal PET of [(11)C]4 showed that there was increased concentrations of [(11)C]4 in the livers of mice pre-treated with pyrimethamine, a potential inhibitor of MATEs, inhibiting the hepatobiliary excretion of metformin. Radiometabolite analysis showed that [(11)C]4 was not degraded in vivo during the PET scan. Biodistribution studies were undertaken and the organ distributions were extrapolated into a standard human model. In conclusion, [(11)C]4 may be useful as a PET probe to non-invasively study the in vivo function of hepatobiliary transport and drug-drug interactions, mediated by MATE1 in future clinical investigations.

Evaluation of Oatp and Mrp2 activities in hepatobiliary excretion using newly developed positron emission tomography tracer [11C]dehydropravastatin in rats.

We developed a pravastatin derivative, sodium (3R,5R)-3,5-dihydroxy-7-((1S,2S,6S,8S)-6-hydroxy-2-methyl-8-((1-[(11)C]-(E)-2-methyl-but-2-enoyl)oxy)-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)heptanoate ([(11)C]DPV), as a positron emission tomography (PET) probe for noninvasive measurement of hepatobiliary transport, and conducted pharmacokinetic analysis in rats as a feasibility study for future clinical study. Transport activities of DPV in freshly isolated rat hepatocytes and rodent multidrug resistance-associated protein 2 (rMrp2; human, MRP2)-expressing membrane vesicles were similar to those of pravastatin. Rifampicin diminished the uptake of DPV and pravastatin by the hepatocytes, with similar inhibition potency. [(11)C]DPV underwent biotransformation to produce at least two metabolites in rat, but metabolism of [(11)C]DPV occurred negligibly in human hepatocytes during a 90-minute incubation. After intravenous injection, [(11)C]DPV was mainly distributed to the liver and kidneys, where the tissue uptake clearances (CLuptake,liver and CLuptake,kidney) were blood-flow-limited (73.6 ± 4.8 and 24.6 ± 0.6 ml/min per kilogram, respectively). Systemic elimination of [(11)C]DPV was delayed in rifampicin-treated rat and an Mrp2-deficient mutant rat, Eisai hyperbilirubinemic mutant rat (EHBR). Rifampicin treatment decreased both CLuptake,liver and CLuptake,kidney of [(11)C]DPV by 30% (P < 0.05), whereas these parameters were unchanged in EHBR. Meanwhile, the canalicular efflux clearance (CLint,bile) of [(11)C]DPV, which was 12.2 ± 1.5 ml/min per kilogram in the control rat, decreased by 60% and 89% in rifampicin-treated rat and EHBR (P < 0.05), respectively. These results indicate that [(11)C]DPV is taken up into the liver by organic anion-transporting polypeptides (rodent, Oatps; human, OATP) and excreted into bile by Mrp2 in rat, and that rifampicin may inhibit Mrp2 as well as Oatps, and consequently increase systemic exposure of [(11)C]DPV. PET using [(11)C]DPV is feasible for studies prior to the future clinical investigation of OATP and MRP2 functionality, especially for personalized medicine.

Dynamic analysis of fluid distribution in the gastrointestinal tract in rats: positron emission tomography imaging after oral administration of nonabsorbable marker, [(18)F]Deoxyfluoropoly(ethylene glycol).

To develop potent drugs for oral use, information on their pharmacokinetic (PK) properties after oral administration is of great importance. We have recently reported the utility of positron emission tomography (PET) for the analysis of gastrointestinal (GI) absorption of radiolabeled compounds. In this study, PET image analysis was performed in rats using a novel PET probe, [(18)F]deoxyfluoropoly(ethylene glycol)s, with an average molecular weight of 2 kDa ([(18)F]FPEG), as a nonabsorbable marker to elaborate the GI physiology in more detail, such as segmental transition of the administered water, and fluid volume and distribution in the intestine. After oral administration of [(18)F]FPEG solution to rats, a 90 min PET scan with continuous blood sampling was performed, and then the disposition of radioactivity in each part of GI tract was investigated. From blood PK analysis, it was confirmed that the bioavailability of [(18)F]FPEG was quite low in rats. PET image analysis showed that the radioactivity after oral administration of [(18)F]FPEG solution rapidly passed through the stomach, spread into the proximal small intestine, and then transited toward the distal region of the small intestine without decreasing the radioactivity during GI transition. Radiometabolite analysis revealed that the radioactivity in intestinal mucosal tissues, blood, and urine was mainly derived from unchanged [(18)F]FPEG. It was also found that the volume of interest (VOI) after oral administration of the radiotracer enables an understanding of the time-dependent manner of effective fluid volume changes in the stomach and the small intestine. In addition, the rate constant of the intestinal transition of radioactivity in each intestinal segment was calculated by kinetic model analysis, which revealed that PET analysis enables us to determine the GI transit from the same individuals and that it is applicable to determine site-specific intestinal absorption. In conclusion, we demonstrated the high potency of PET imaging technique to elucidate the distribution of orally administered solution in the GI tract in vivo.

Evaluation of breast cancer resistance protein function in hepatobiliary and renal excretion using PET with 11C-SC-62807.

UNLABELLED: A quantitative PET imaging method was used to assess the in vivo kinetics of hepatobiliary and renal excretion of the breast cancer resistance protein (Bcrp) substrate (11)C-SC-62807 in mice. METHODS: Serial abdominal PET scans were collected in wild-type and Bcrp knockout (Bcrp(-/-)) mice after intravenous injection of (11)C-SC-62807. Venous blood samples and PET images were obtained at frequent intervals up to 30 min after radiotracer administration. Dynamic PET data were analyzed to determine the canalicular and brush-border efflux clearances in the liver and kidney (CL(int,bile,liver) and CL(int,urine,kidney), respectively). RESULTS: SC-62807 is an in vitro substrate of mouse Bcrp and human BCRP. Radioactivity associated with (11)C-SC-62807 was predominantly found in the blood, liver, bile, and urine 30 min after administration. Both biliary and urinary excretion of radioactivity was markedly lower in Bcrp(-/-) mice than in wild-type mice, suggesting greater systemic exposure in Bcrp(-/-) mice. Both the CL(int,bile,liver) and the CL(int,urine,kidney) were significantly lower in Bcrp(-/-) mice (74% ± 10% and 99% ± 1% lower than controls, respectively). We also found that (11)C-SC-62807 is a substrate of the organic anion-transporting polypeptides OATP1B1 and OATP1B3 in vitro. CONCLUSION: The present study demonstrated that Bcrp plays a significant role in the efflux of (11)C-SC-62807 in mouse liver and kidney. We also demonstrated the feasibility of PET using (11)C-SC-62807 to study the activity of BCRP in humans.

Dynamic analysis of GI absorption and hepatic distribution processes of telmisartan in rats using positron emission tomography.

PURPOSE: To dynamically analyze the processes of oral absorption and hepatobiliary distribution of telmisartan using positron emission tomography (PET). METHODS: (11)C-labeled telmisartan ([(11)C]TEL) was orally administered to rats with or without non-radiolabeled telmisartan (0.5, and 10 mg/kg). PET scanning of abdominal region and whole body was performed under conscious condition. In situ intestinal closed loop study in rats and in vitro permeation study in MDR1-MDCK II cell monolayers were also conducted. RESULTS: After oral administration of [(11)C]TEL, systemic bioavailability and hepatic distribution of radioactivity increased non-linearly with dose. In the intestinal lumen, both telmisartan and its glucuronide were detected and the ratio of telmisartan decreased dramatically at high dose of telmisartan. In situ closed loop study showed most of telmisartan-glucuronide detected in the intestinal lumen was derived from the bile excretion. In addition, in vitro permeation study revealed that telmisartan is a substrate of P-glycoprotein. CONCLUSION: PET imaging analysis successfully demonstrated the processes of intestinal absorption and hepatic distribution of telmisartan. PET study combined with appropriate in situ and in vitro experiments is highly expected to be a potent tool for better understanding of GI absorption and subsequent tissue distribution of various drugs and drug candidates.

Synthesis of [¹¹C]uric acid, using [¹¹C]phosgene, as a possible biomarker in PET imaging for diagnosis of gout.

The synthesis and in vivo evaluation of (11)C -labeled uric acid ([(11)C]1), a potential imaging agent for the diagnosis of urate-related life-style diseases, was performed using positron emission tomography (PET) image analysis. First, the synthesis of [(11)C]1 was achieved by reacting 5,6-diaminouracil (2) with (11)C-labeled phosgene ([(11)C]COCl(2)). The radiochemical yield of [(11)C]1 was 37±7% (decay-corrected based on [(11)C]COCl(2)) with specific radioactivities of 96-152GBq/µmol at the end of synthesis (n=6). The average time of radiosynthesis from the end of bombardment, including formulation, was about 30min with >98% radiochemical purity. Second, the synthetic approach to [(11)C]1 was optimized using 5,6-diaminouracil sulfate (3) with [(11)C]COCl(2) in the presence of 1,8-bis(dimethylamino)naphthalene. [(11)C]1 was synthesized in 36±6% radiochemical yield, 89-142GBq/µmol of specific radioactivities, and 98% radiochemical purity by this method (n=5). This allowed the synthesis of [(11)C]1 to be carried out repeatedly and the radiochemical yield, specific radioactivities, average time of synthesis, and radiochemical purity of [(11)C]1 were similar to those obtained using 2. PET studies in rats showed large differences in the accumulation of radioligand in the limbs under normal and hyperuricemic conditions. Thus, an efficient and convenient automated synthesis of [(11)C]1 has been developed, and preliminary PET evaluation of [(11)C]1 confirmed the increased accumulation of radioactivity in the limbs of a rat model of hyperuricemia.

The involvement of organic anion transporting polypeptide in the hepatic uptake of telmisartan in rats: PET studies with [¹¹C]telmisartan.

Telmisartan, a selective angiotensin II receptor antagonist, is primarily excreted via hepatobiliary transport. The predominant contribution of organic anion transporting polypeptide (OATP) 1B3 in its hepatic uptake of telmisartan has been demonstrated by in vitro transport studies. In the present study, a quantitative positron emission tomography (PET) methodology was developed for in vivo kinetic assessment of hepatobiliary transport of telmisartan. Serial abdominal PET scans were performed in rats following intravenous administration of [(11)C]telmisartan as a radiotracer. PET scans revealed that [(11)C]telmisartan was localized primarily in the liver and some of the radioactivity moved to the intestine, which corresponds to biliary excretion. Radiometabolite analysis by radiometric HPLC showed that [(11)C]telmisartan was converted to its acylglucuronide, which was mainly detected in bile, but little in plasma and liver. Integration plot analysis revealed that [(11)C]telmisartan was taken up into the liver as rapidly as the hepatic blood flow rate, and the radiometabolite was subsequently excreted into the bile. When rifampicin, a typical Oatp inhibitor, was coadministered with [(11)C]telmisartan in rats, hepatic uptake clearance of [(11)C]telmisartan was significantly decreased, whereas biliary efflux clearance was not changed. Coinjection with unlabeled telmisartan (4 and 10 mg/kg) also decreased hepatic uptake clearance of [(11)C]telmisartan. On the other hand, PET imaging analysis revealed a significant increase of biliary efflux when telmisartan dose was increased to more than 4 mg/kg. These results suggested that the hepatic uptake of [(11)C]telmisartan mainly consists of a saturable process mediated by Oatps in rats, according to noninvasive real-time measurement of tissue radioactivity with the use of PET. The present study with rats is expected to provide the feasibility of PET imaging study to quantitatively estimate OATP1B3 function in humans.

Efficient sequential synthesis of PET Probes of the COX-2 inhibitor [11C]celecoxib and its major metabolite [11C]SC-62807 and in vivo PET evaluation.

Synthesis of [(11)C]celecoxib, a selective COX-2 inhibitor, and [(11)C]SC-62807, a major metabolite of celecoxib, were achieved and the potential of these PET probes for assessing the function of drug transporter in biliary excretion was evaluated. The synthesis of [(11)C]celecoxib was achieved in one-pot by reacting [(11)C]methyl iodide with an excess of the corresponding pinacol borate precursor using Pd(2)(dba)(3), P(o-tolyl)(3), and K(2)CO(3) (1:4:9) in DMF. The radiochemical yield of [(11)C]celecoxib was 63±23% (decay-corrected, based on [(11)C]CH(3)I) (n=7) with a specific radioactivity of 83±23GBq/µmol (n=7). The average time of synthesis from end of bombardment including formulation was 30min with >99% radiochemical purity. [(11)C]SC-62807 was synthesized from [(11)C]celecoxib by further rapid oxidation in the presence of excess KMnO(4) with microwave irradiation. The radiochemical yield of [(11)C]SC-62807 was 55±9% (n=3) (decay-corrected, based on [(11)C]celecoxib) with a specific radioactivity of 39±4GBq/µmol (n=3). The average time of synthesis from [(11)C]celecoxib including formulation was 20min and the radiochemical purity was >99%. PET studies in rats and the metabolite analyzes of [(11)C]celecoxib and [(11)C]SC-62807 showed largely different excretion processes, and consequently, [(11)C]SC-62807 was rapidly excreted via hepatobiliary excretion without further metabolism. [(11)C]SC-62807 was shown to have a high potential as a PET probe for evaluating drug transporter function in biliary excretion.

Use of [18F]FDOPA-PET for in vivo evaluation of dopaminergic dysfunction in unilaterally 6-OHDA-lesioned rats.

BACKGROUND: We evaluated the utility of L-3,4-dihydroxy-6-[18F]fluoro-phenylalanine ([18F]FDOPA) positron emission tomography (PET) as a method for assessing the severity of dopaminergic dysfunction in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats by comparing it with quantitative biochemical, immunohistochemical, and behavioral measurements. METHODS: Different doses of 6-OHDA (0, 7, 14, and 28 µg) were unilaterally injected into the right striatum of male Sprague-Dawley rats. Dopaminergic functional activity in the striatum was assessed by [18F]FDOPA-PET, measurement of striatal dopamine (DA) and DA metabolite levels, tyrosine hydroxylase (TH) immunostaining, and methamphetamine-induced rotational testing. RESULTS: Accumulation of [18F]FDOPA in the bilateral striatum was observed in rats pretreated with both aromatic L-amino acid decarboxylase and catechol-O-methyltransferase (COMT) inhibitors. Unilateral intrastriatal injection of 6-OHDA produced a significant site-specific reduction in [18F]FDOPA accumulation. The topological distribution pattern of [18F]FDOPA accumulation in the ipsilateral striatum agreed well with the pattern in TH-stained corresponding sections. A significant positive relationship was found between Patlak plot Ki values and striatal levels of DA and its metabolites (r = 0.958). A significant negative correlation was found between both Ki values (r = -0.639) and levels of DA and its metabolites (r = -0.719) and the number of methamphetamine-induced rotations. CONCLUSIONS: Ki values determined using [18F]FDOPA-PET correlated significantly with the severity of dopaminergic dysfunction. [18F]FDOPA-PET makes it possible to perform longitudinal evaluation of dopaminergic function in 6-OHDA-lesioned rats, which is useful in the development of new drugs and therapies for Parkinson's disease (PD).

Evaluation of bispectral index (BIS) as an indicator of central nervous system depression in horses anesthetized with propofol.

The bispectral index (BIS) was evaluated as an indicator of central nervous system (CNS) depression in horses anesthetized with propofol. Five non-premedicated horses were anesthetized with 7 mg/kg, IV propofol and the minimum infusion rate (MIR) of propofol required to maintain anesthesia was determined during intermittent positive pressure ventilation in each horse. The BIS was determined 20 min later and after stabilization at 2.0 MIR, 1.5 MIR, and 1.0 MIR. The BIS was also recorded after the cessation of propofol infusion when the horses regained spontaneous breathing and swallowing reflex. The MIR and plasma concentration (Cp) of propofol were 0.20 +/- 0.03 mg/kg/min and 17.5 +/- 4.0 microg/ml, respectively. The BIS value and Cp were 59 +/- 13 and 26.7 +/- 8.6 microg/ml at 2.0 MIR, 63 +/- 9 and 22.9 +/- 9.7 microg/ml at 1.5 MIR, 64 +/- 13 and 20.1 +/- 5.9 microg/ml at 1.0 MIR, 64 +/- 24 and 13.0 +/- 2.8 microg/ml at return of spontaneous breathing, and 91 +/- 4 and 11.0 +/- 3.4 microg/ml when the swallowing reflex returned, respectively. The BIS value was significantly less in anesthetized horses compared to horses once swallowing returned (p=0.025). The BIS value was significantly correlated with the propofol Cp (r=-0.625, p=0.001). There was not a significant difference in the BIS values during the MIR multiples of propofol. The BIS was a useful indicator of awakening but did not indicate the degree of CNS depression during propofol-anesthesia in horses.

Ethyl alpha-D-glucoside increases urine volume and causes renal morphologic changes in rats.

Ethyl alpha-D-glucoside (alpha-EG) is a peculiar component in sake, a traditional Japanese alcoholic beverage. In this study, morphological changes in kidney and effects on urine excretion by alpha-EG ingestion were investigated. After the rats were fed with pellet diets containing 100% or 20% alpha-EG dietary level, alpha-EG was detected in urine and urine volume showed significant increase (p<0.05). Kidney weights were increased (p<0.05) and renal tubules were dilated in the rats by alpha-EG ingestion, whereas there was no detectable histopathological damage to renal cells. Plasma uric acid and urea levels were not affected. In conclusion, ingested alpha-EG was excreted in urine, increasing urine volume. Increase in kidney weight related to renal tubule dilation was observed with alpha-EG ingestion without deteriorate changes in the renal cells or functions.