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Plastic crystals that show ferroelectricity are highly promising materials for a wide range of applications. Their inherent remarkable malleability and highly symmetric cubic structures in the plastic crystal phase ensure that their ferroelectricity and related properties are retained in their bulk polycrystals. To develop functional materials based on such plastic/ferroelectric crystals, methods to tune their properties for specific applications are required. Here, we report the preparation of solid solutions of plastic/ferroelectric ionic crystals by mixing crystals with a common anion but different cations, or crystals with a common cation but different anions, which allows a continuous modification of the Curie temperature of the ferroelectric system over a range of 100 K. This adjustment of the Curie temperature allows the flexible tuning of the pyroelectric properties of the solid solutions, including a significant enhancement of room-temperature performance. The solid solutions also exhibit morphotropic phase boundaries in the composition-temperature phase diagrams, which shows an abrupt change in crystal structures with a variation of composition. This study showcases a simple and versatile property-tuning method that can be expected to pave the way for major progress in the development of materials based on plastic/ferroelectric crystals, which will eventually advance to the stage of pursuing tailor-made functional materials with desired properties.
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A 76-year-old woman with a suspected double extrahepatic bile duct was referred to our hospital. MRCP revealed that the left hepatic and posterior ducts combined to form the ventral bile duct and that the anterior duct formed the dorsal bile duct. ERCP demonstrated that the ventral bile duct was linked with the Wirsung duct. Amylase levels in the bile were unusually high. Based on these findings, we diagnosed a double extrahepatic bile duct with pancreaticobiliary maljunction and choledocholithiasis. Duplicate bile duct resection and bile duct jejunal anastomosis were performed considering the risk of biliary cancer due to pancreaticobiliary maljunction. The resected bile duct epithelium demonstrated no atypia or hyperplastic changes.
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Ductos Biliares Extra-Hepáticos , Procedimentos Cirúrgicos do Sistema Biliar , Má Junção Pancreaticobiliar , Feminino , Humanos , Idoso , Má Junção Pancreaticobiliar/cirurgia , Ductos Biliares Extra-Hepáticos/diagnóstico por imagem , Ductos Biliares Extra-Hepáticos/cirurgia , Ductos Pancreáticos/diagnóstico por imagem , Ductos Pancreáticos/cirurgia , Ductos Biliares/diagnóstico por imagem , Ductos Biliares/cirurgia , BileRESUMO
This study aimed to develop and validate a simple scoring system to determine the high-risk group for pancreatic cancer (PC) in the asymptomatic general population. The scoring system was developed using data from PC cases and randomly selected non-PC cases undergoing annual medical checkups between 2008 and 2013. The performance of this score was validated for participants with medical checkups between 2014 and 2016. In the development set, 45 PC cases were diagnosed and 450 non-PC cases were identified. Multivariate analysis showed three changes in clinical data from 1 year before diagnosis as independent risk factors: ΔHbA1c ≥ 0.3%, ΔBMI ≤ -0.5, and ΔLDL ≤ -20 mg/dL. A simple scoring system, incorporating variables and abdominal ultrasound findings, was developed. In the validation set, 36 PC cases were diagnosed over a 3-year period from 32,877 participants. The AUROC curve of the scoring system was 0.925 (95%CI 0.877-0.973). The positive score of early-stage PC cases, including Stage 0 and I cases, was significantly higher than that of non-PC cases (80% vs. 6%, p = 0.001). The simple scoring system effectively narrows down high-risk PC cases in the general population and provides a reasonable approach for early detection of PC.
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OBJECTIVES: In patients with unresectable malignant hilar biliary obstruction (UMHBO), drainage of ≥ 50% liver volume correlates with better clinical outcomes. Accurately measuring the liver volume to be drained by biliary stents is required. We aimed to develop a novel method for calculating the drained liver volume (DLV) using a 3D volume analyzer (3D volumetry), and assess the usefulness for drainage in patients with UMHBO. METHODS: Three-dimensional volumetry comprises the following steps: (1) manual tracing of bile duct using 3D imaging system; (2) 3D reconstruction of bile duct and liver parenchyma; and (3) calculating DLV according to the 3D distribution of bile ducts. Using 3D volumetry, we reviewed data of patients who underwent biliary drainage for UMHBO, calculated the DLV, and determined the association between DLV and biliary drainage outcome. RESULTS: There were 104 eligible cases. The mean DLV was 708 ± 393 ml (53% ± 21%). and 65 patients (63%) underwent drainage of ≥50% liver volume. The clinical success rate was significantly higher in patients with DLV ≥ 50% than in patients with DLV < 50% (89% vs. 28%, P < 0.001). The median time to recurrence of biliary obstruction (TRBO) and survival time were significantly longer in patients with DLV ≥ 50% than in patients with DLV < 50% (TRBO, 292 vs. 119 days, P = 0.03; survival, 285 vs. 65days, P = 0.004, log-rank test, respectively). CONCLUSIONS: Three-dimensional volumetry, a novel method to calculate DLV accurately according to bile duct distribution was useful for drainage in UMHBO patients.
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Neoplasias dos Ductos Biliares , Colestase , Humanos , Neoplasias dos Ductos Biliares/complicações , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Neoplasias dos Ductos Biliares/patologia , Fígado/diagnóstico por imagem , Fígado/patologia , Colestase/diagnóstico por imagem , Colestase/etiologia , Colestase/cirurgia , Ductos Biliares/patologia , Stents , Drenagem/métodos , Resultado do TratamentoRESUMO
Biomimetic visual sensors utilizing bacteriorhodopsin (bR) were fabricated by using an inkjet method. The inkjet printer facilitated the jetting of the bR suspension, allowing for the deposition of bR films. The resulting inkjet-printed bR film exhibited time-differential photocurrent response characteristics similar to those of a dip-coated bR film. By adjusting the number of printed bR film layers, the intensity of the photocurrent could be easily controlled. Moreover, the inkjet printing technique enabled unconstrained patterning, facilitating the design of various visual information processing functions, such as visual filters. In this study, we successfully fabricated two visual filters, namely, a two-dimensional Difference of Gaussian (DOG) filter and a Gabor filter. The printed DOG filter demonstrated edge detection capabilities corresponding to contour recognition in visual receptive fields. On the other hand, the printed Gabor filter proved effective in detecting objects of specific sizes as well as their motion and orientation. The integration of bR and the inkjet method holds significant potential for the widespread implementation of highly functional biomaterial-based visual sensors. These sensors have the capability to provide real-time visual information while operating in an energy-efficient manner.
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In this paper, the structure and properties of transparent films composed of bisphenol-A polycarbonate (PC) and a commercially available copolyester, poly(1,4-cyclohexanedimethanol-co-2,2,4,4-tetramethyl-1,3-cyclobutanediol-co-terephthalate) (CPE), were studied. Both PC and CPE films are known to be transparent with good mechanical toughness. It was found that PC/CPE (50/50) showed miscibility in both the molten and solid states, indicating that there is a high possibility for the blend system to be miscible in the whole blend ratios. Because of the miscibility, the blend films showed no light scattering originating from phase separation. The mechanical properties of the films, such as Young's modulus, yield stress, and strain at break, were determined by the blend ratio, and the glass transition temperature increased with the PC content, which corresponded well with the values predicted by the Fox equation. These results demonstrate that the thermal and mechanical properties of the films can only be controlled by the blend ratio. Since these transparent films showed excellent mechanical toughness irrespective of the blend ratios, they can be employed in various applications.
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The diagnosis of autoimmune pancreatitis (AIP) and immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) may require a somewhat invasive pathological examination and steroid responsiveness. This retrospective study assessed the complemental diagnosis of AIP and IgG4-SC using submandibular gland (SG) ultrasonography (US) in 69 patients, including 54 patients with AIP, 2 patients with IgG4-SC, and 13 patients with both AIP and IgG4-SC. The data from the physical examination and US of SGs to diagnose AIP (n = 67) and IgG4-SC (n = 15) were analyzed. The steroid therapy efficacy in resolving hypoechoic lesions in SGs was evaluated in 36 cases. The presence of IgG4-related pancreaticobiliary disease with multiple hypoechoic lesions in SGs was reduced from 31 to 11 cases after steroid therapy, suggesting that multiple hypoechoic lesions in SGs are strongly associated with IgG4-positive cell infiltrations. Multiple hypoechoic lesions in SGs were observed in 53 cases, whereas submandibular swelling on palpation was observed in 21 cases of IgG4-related pancreaticobiliary diseases. A complemental diagnosis of IgG4-related pancreaticobiliary diseases without a histological diagnosis and steroid therapy was achieved in 57 and 68 cases without and with multiple hypoechoic lesions in SGs, respectively. In conclusion, multiple hypoechoic lesions in SGs are useful for the complemental diagnosis of IgG4-related pancreaticobiliary diseases.
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Background: There is no robust evidence on the contribution of reduced hamstring flexibility to the development of low back pain (LBP) in cohort studies.Purpose: To investigate whether individuals with LBP have impaired hamstring flexibility and stiffness and what measures have been used to compare hamstring flexibility and stiffness between individuals with and without LBP.Methods: A systematic literature search was undertaken in PubMed, EMBASE, MEDLINE, CINAHL, SCOPUS, and Cochrane databases from inception to April 2018. The GRADE system was used to determine the quality of evidence for each measure evaluated in meta-analysis.Results: Respectively, seventeen and two studies having acceptable methodological quality were analyzed with regard to hamstring flexibility and stiffness. Four measures were identified for hamstring flexibility and five for stiffness. Meta-analyses were undertaken in straight leg raising (SLR), sit and reach and knee extension in 90° hip flexion for hamstring flexibility and for hamstring stiffness measures of stiffness at 50° SLR and gradient of stiffness from 20° to 50° SLR (Me-grad). Significantly reduced hamstring flexibility or increased stiffness (P < .05) was detected in SLR, 90/90 knee extension and Me-grad. However, the validity of measures for hamstring flexibility was problematic and GRADE scores for all measures in the meta-analyses were very low.Conclusion: There have been four measures for hamstring flexibility and five for stiffness to evaluate individuals with and without LBP. It was impossible to conclude whether individuals with LBP have impaired hamstring flexibility and stiffness due to very low quality of evidence for meta-analyses.
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Músculos Isquiossurais/fisiopatologia , Dor Lombar/fisiopatologia , Amplitude de Movimento Articular/fisiologia , HumanosRESUMO
Some heterojunction interfaces formed with molecular solids show metal-like transport behavior. In order to clarify the requirement, interfaces are fabricated by lamination of single-crystal electron-accepting 2,5-difluoro-7,7,8,8-tetracyanoquinodimethane (F2TCNQ) and electron-donating molecules with a wide range of ionization potentials. Carrier injection between the acceptor and donor crystals leads to highly conducting interfaces, some of which exhibited band-like charge transport behaviors. Combinations with weak donors also resulted in interfaces with band-like transport properties. Accordingly, band-like conduction was achieved for interfaces where the donor and acceptor crystals do not have well-matched band energies. The results indicate that the wide range of candidates have great potential for modification of the electronic structure of organic crystals. The present method is expected to enable control of the electronic properties of the interface.
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Brown adipose tissue (BAT) is a central organ that acts to increase energy expenditure; its regulatory factors could be clinically useful in the treatment of obesity. Tetrahydrobiopterin (BH4) is an essential cofactor of tyrosine hydroxylase and nitric oxide synthase (NOS). Although BH4 regulates the known regulatory factors of BAT, such as noradrenaline (NA) and NO, participation of BH4 in BAT function remains unclear. In the present study, we investigate the role of BH4 in the regulation of BAT. Hph-1 mice, a mouse model of BH4 deficiency, exhibit obesity, adiposity, glucose intolerance, insulin resistance, and impaired BAT function. Impaired BAT function was ameliorated together with systemic metabolic disturbances by BAT transplantation from BH4-sufficient mice (control mice) into BH4-deficient mice, strongly suggesting that BH4-induced BAT has a critical role in the regulation of systemic energy metabolism. Both NA derived from the sympathetic nerve and NO derived from endothelial NOS in the blood vessels participate in the regulation of BH4. In addition, a direct effect of BH4 in the stimulation of brown adipocytes via NO is implicated. Taken together, BH4 activates BAT and regulates systemic energy metabolism; this suggests an approach for metabolic disorders, such as obesity and diabetes.
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Tetrahydrobiopterin (BH4) is a common coenzyme of phenylalanine-, tyrosine-, and tryptophan hydroxylases, alkylglycerol monooxygenase, and NO synthases (NOS). Synthetic BH4 is used medicinally for BH4-responsive phenylketonuria and inherited BH4 deficiency. BH4 supplementation has also drawn attention as a therapy for various NOS-related cardio-vascular diseases, but its use has met with limited success in decreasing BH2, the oxidized form of BH4. An increase in the BH2/BH4 ratio leads to NOS dysfunction. Previous studies revealed that BH4 supplementation caused a rapid urinary loss of BH4 accompanied by an increase in the blood BH2/BH4 ratio and an involvement of probenecid-sensitive but unknown transporters was strongly suggested in these processes. Here we show that OAT1 and OAT3 enabled cells to take up BP (BH4 and/or BH2) in a probenecid-sensitive manner using rat kidney slices and transporter-expressing cell systems, LLC-PK1 cells and Xenopus oocytes. Both OAT1 and OAT3 preferred BH2 and sepiapterin as their substrate roughly 5- to 10-fold more than BH4. Administration of probenecid acutely reduced the urinary exclusion of endogenous BP accompanied by a rise in blood BP in vivo. These results indicated that OAT1 and OAT3 played crucial roles: (1) in determining baseline levels of blood BP by excluding endogenous BP through the urine, (2) in the rapid distribution to organs of exogenous BH4 and the exclusion to urine of a BH4 excess, particularly when BH4 was administered, and (3) in scavenging blood BH2 by cellular uptake as the gateway to the salvage pathway of BH4, which reduces BH2 back to BH4.
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Biopterinas/análogos & derivados , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Animais , Transporte Biológico Ativo/efeitos dos fármacos , Transporte Biológico Ativo/fisiologia , Biopterinas/genética , Biopterinas/metabolismo , Linhagem Celular , Oócitos , Proteína 1 Transportadora de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Probenecid/farmacologia , Ratos , Ratos Sprague-Dawley , XenopusRESUMO
An axially ligated Co(tmp) (tmp = 5,10,15,20-tetramethylporphyrinato) anion, [CoIII(tmp)(CN)2]-, has been prepared and subjected to electrochemical oxidation to obtain the open shell tmp π-ligand. With acetone as the solvent, solvent-free neutral radical crystals of CoIII(tmp)(CN)2 are obtained, whereas solvent-inclusive crystals of CoIII(tmp)(CN)2·2CH3CN are obtained with CH3CN as the solvent. In both crystals, the open shell tmp ring deforms into a ruffled form, which makes the π-π interactions in the crystal weak. Thus, the electrical conductivity is low, and the crystals behave as semiconductors with a room temperature resistivity of 106 Ω cm and an activation energy of about 0.3 eV. When the solvent is acetone, non-oxidized crystals of the CN-bridged polymer {[CoIII(tmp)(CN)](acetone)}n are obtained as a byproduct. The closed shell tmp ring deforms into a ruffled form, and there π-π interactions in the crystal are negligible. The room temperature resistivity is rather high at about 108 Ω cm.
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This study examined isometric strength (maximal voluntary contraction [MVC]) and endurance of cervical flexor and extensor muscles in healthy individuals at the craniocervical (CC) and cervicothoracic (CT) axes. MVC and endurance measures (time to task failure in seconds [s]) at 50% MVC were recorded in 4 directions (CC flexion, CC extension, CT flexion, and CT extension) in 20 males and 20 females, and 6 strength and endurance ratios were calculated. The findings showed that the cervical extensor muscles are not only much stronger than the flexors (1.3-2 times greater MVC), but also have greater capacity for endurance (2-2.4 times greater). While males produced significantly greater MVC recordings than females (P < .003), strength ratios (P > .06) and endurance measures (P > .11) were similar. Endurance ratios were also similar except the CT extension to CC flexion ratio, which was significantly larger in females compared with males (P = .03). These findings demonstrate that substantial but normal variation exists in strength and endurance parameters between cervical flexor and extensor muscles. This is informative to clinicians when evaluating the performance of these neck muscles or when deciding on exercise parameters (eg, load, duration) when training their performance.
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Músculos do Dorso/fisiologia , Contração Muscular/fisiologia , Força Muscular/fisiologia , Músculos do Pescoço/fisiologia , Resistência Física/fisiologia , Adulto , Vértebras Cervicais/fisiologia , Feminino , Humanos , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Vértebras Torácicas/fisiologiaRESUMO
Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase (NOS) and aromatic amino acid hydroxylases. BH4 and 7,8-dihydrobiopterin (BH2) are metabolically interchangeable at the expense of NADPH. Exogenously administered BH4 can be metabolized by the body, similar to vitamins. At present, synthetic BH4 is used as an orphan drug for patients with inherited diseases requiring BH4 supplementation. BH4 supplementation has also drawn attention as a means of treating certain cardiovascular symptoms, however, its application in human patients remains limited. Here, we tracked biopterin (BP) distribution in blood, bile, urine, liver, kidney and brain after BH4 administration (5 mg/kg rat, i.v.) with or without prior treatment with probenecid, a potent inhibitor of uptake transporters particularly including organic anion transporter families such as OTA1 and OAT3. The rapid excretion of BP in urine was driven by elevated blood concentrations and its elimination reached about 90% within 120 min. In the very early period, BP was taken up by the liver and kidney and gradually released back to the blood. BH4 administration caused a considerable decrease in the BH4% in blood BP as an inevitable compensatory process. Probenecid treatment slowed down the decrease in blood BP and simultaneously inhibited its initial rapid excretion in the kidney. At the same time, the BH4% was further lowered, suggesting that the probenecid-sensitive BP uptake played a crucial role in BH2 scavenging in vivo. This suggested that the overproduced BH2 was taken up by organs by means of the probenecid-sensitive process, and was then scavenged by counter-conversion to BH4 via the BH4 salvage pathway. Taken together, BH4 administration was effective at raising BP levels in organs over the course of hours but with extremely low efficiency. Since a high BH2 relative to BH4 causes NOS dysfunction, the lowering of the BH4% must be avoided in practice, otherwise the desired effect of the supplementation in ameliorating NOS dysfunction would be spoiled.
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Biopterinas/análogos & derivados , Biopterinas/análise , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Probenecid/farmacologia , Animais , Bile/química , Bile/efeitos dos fármacos , Bile/metabolismo , Biopterinas/sangue , Biopterinas/química , Biopterinas/metabolismo , Biopterinas/farmacologia , Biopterinas/urina , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ciclosporina/farmacologia , Eritrócitos/química , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Feminino , Rim/química , Rim/metabolismo , Fígado/química , Fígado/metabolismo , Masculino , Óxido Nítrico Sintase/metabolismo , RatosRESUMO
Ferroelectrics are used in a wide range of applications, including memory elements, capacitors and sensors. Recently, molecular ferroelectric crystals have attracted interest as viable alternatives to conventional ceramic ferroelectrics because of their solution processability and lack of toxicity. Here we show that a class of molecular compounds-known as plastic crystals-can exhibit ferroelectricity if the constituents are judiciously chosen from polar ionic molecules. The intrinsic features of plastic crystals, for example, the rotational motion of molecules and phase transitions with lattice-symmetry changes, provide the crystals with unique ferroelectric properties relative to those of conventional molecular crystals. This allows a flexible alteration of the polarization axis direction in a grown crystal by applying an electric field. Owing to the tunable nature of the crystal orientation, together with mechanical deformability, this type of molecular crystal represents an attractive functional material that could find use in a diverse range of applications.
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The n-type organic field-effect transistors are fabricated with using four kinds of charge transfer (CT) complexes with PXX (peri-xanthenoxanthene) as a donor component. The CT complexes with four kinds of acceptors form mixed-stack type one-dimentional columns with different PXX-acceptor overlaps. Comparison of the field-effect properties reveals the correlation between the device performance and intermolecular interaction in the semiconducting CT complexes.
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Trifluoromethylphenyl-substituted phthalimide derivatives favorably form triboluminescence (TL) active noncentrosymmetric crystals. Oligothienyl-, oligophenyl-, and naphthyl-substituted phthalimide derivatives were successfully developed as a series of metal free TL compounds. X-ray crystal structure analyses of bithienyl and naphthyl derivatives revealed noncentrosymmetric layer structures in the same direction. Introduction of suitable electron rich π-units such as thienyl groups enhances their photoluminescence and TL characteristics, and the colors can be also controlled in the visible region. A rigid naphthyl-substituted imide derivative exhibits extremely high TL performance.
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A novel method for the fabrication of a charge-transfer complex crystal was developed. Photoirradiation of a solution of TPP[Co(tbp)(CN)(2)] and TPP[Co(Pc)(CN)(2)] (tbp=tetrabenzoporphyrin, Pc=phthalocyanine, TPP=tetraphenylphosphonium) gave a molecular conducting crystal of a charge-transfer complex TPP[Co(tbp)(CN)(2)](2), which was produced by the process in which the photoexcited electron in tbp was transferred from the LUMO of tbp to that of Pc.
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Endothelial nitric oxide synthase (eNOS) dysfunction induces insulin resistance and glucose intolerance. Tetrahydrobiopterin (BH4) is an essential cofactor of eNOS that regulates eNOS activity. In the diabetic state, BH4 is oxidized to 7,8-dihydrobiopterin, which leads to eNOS dysfunction owing to eNOS uncoupling. The current study investigates the effects of BH4 on glucose metabolism and insulin sensitivity in diabetic mice. Single administration of BH4 lowered fasting blood glucose levels in wild-type mice with streptozotocin (STZ)-induced diabetes and alleviated eNOS dysfunction by increasing eNOS dimerization in the liver of these mice. Liver has a critical role in glucose-lowering effects of BH4 through suppression of hepatic gluconeogenesis. BH4 activated AMP kinase (AMPK), and the suppressing effect of BH4 on gluconeogenesis was AMPK-dependent. In addition, the glucose-lowering effect and activation of AMPK by BH4 did not appear in mice with STZ-induced diabetes lacking eNOS. Consecutive administration of BH4 in ob/ob mice ameliorated glucose intolerance and insulin resistance. Taken together, BH4 suppresses hepatic gluconeogenesis in an eNOS-dependent manner, and BH4 has a glucose-lowering effect as well as an insulin-sensitizing effect in diabetic mice. BH4 has potential in the treatment of type 2 diabetes.
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Biopterinas/análogos & derivados , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/enzimologia , Hipoglicemiantes/uso terapêutico , Fígado/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Biopterinas/uso terapêutico , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Gluconeogênese/efeitos dos fármacos , Gluconeogênese/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Immunoblotting , Imuno-Histoquímica , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo III/genética , RNA Interferente Pequeno , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Tetrahydrobiopterin (BH(4)) is an essential cofactor of aromatic amino acid hydroxylases and NO synthase. Supplementation of BH(4) potentially targets cardiovascular dysfunction as well as inherited BH(4) deficiencies and BH(4)-responsive phenylketonuria. However, the high cost/effect ratio of the recommended daily dose of BH(4) supplementation acts against further popularization of this therapy. The aim of this study was to attenuate urinary excretion with the intention of improving efficacy of BH(4) supplementation. The rapid excretion of BH(4) in the urine was confirmed to be the major route of supplemented BH(4) loss. In addition to glomerular filtration into the urine, a dominant rapid exclusion by renal secretion was observed in rats (T((1/2))=16 min) when the plasma BH(4) was higher than about 1 nmol/mL (more than 10 times higher than normal), due to BH(4) supplementation. The rapidity of the process was slowed by prior administration of cyclosporin A, a representative anti-excretory drug, and the excretion decelerated to a moderate rate (T((1/2))=53 min). By the combined administration of BH(4) plus cyclosporin A, the blood BH(4) levels were dramatically elevated. It was hypothesized that the drug interfered with kidney excretion of BH(4) rather than by attenuating organ tissue distribution by inhibiting biopterin uptake from the plasma. Consistent with this hypothesis, biopterin levels after BH(4) administration were elevated in major organs in the presence of anti-excretory drugs without notable change in their BH(4) fraction which was consistently 95% or higher regardless of combined administration with the drugs. Targeting these putative transporters would be a promising approach for improving the efficiency of BH(4) supplementation therapy.