Biomedical subjects

Hiroyuki Yasui

Publications and source records attributed to Hiroyuki Yasui.

31 records · Page 2Linked to original sources

PubMed2003

A recirculatory model with enterohepatic circulation by measuring portal and systemic blood concentration difference.

The present study describes a recirculatory model for the evaluation of pharmacokinetic characteristics of drugs possessing enterohepatic circulation (EHC). The advantage of the model is to separately define the extent and rate of absorption for the dosage and EHC after oral administration. Cephradine was used as a model drug and was intravenously or orally administered to rats. Portal and systemic bloods were simultaneously collected in order to estimate various local moments after defining the global moments obtained by non-compartment analysis. For the zero-order moments, bioavailability (BA), the hepatic recovery ratio (Fh), the sum of the local absorption ratio for the dosage and recirculatory local absorption ratio for EHC (F(a)po), and the recirculatory local absorption ratio for EHC (F(a)ehc) after oral administration were estimated to be 95.6, 77.9, 172, and 71.5%, respectively. These data indicate that a complete absorption and substantial EHC contribute high oral exposure of cephradine. For the first-order moments, the sum of the mean local absorption times for the dosage and EHC (t(a)po) and the mean transit time for a single pass of EHC (tc) were 2.50 and 0.117 hr, suggesting a rapid EHC of cephradine compared with the absorption from the dosage. With this model, the absorption rate-time profiles for the dosage and EHC were separately simulated by using a program of nonlinear least squares (MULTI) with fast inverse Laplace transform (FILT). The cumulative biliary excretion ratio (Fbile) calculated by the model was in good agreement with the experimental value obtained in the bile ductcannulated rats. These results suggest that the model proposed in this study would be useful for evaluating the extent and rate of ECH along with absorption from the dosage after oral administration of drugs.

Administration, Oral↗

PubMed2003

The therapeutic potential of insulin-mimetic vanadium complexes.

Throughout the world, the number of patients suffering from diabetes mellitus (DM) is increasing on a daily basis, probably due to change in lifestyle. DM is mainly classified as either insulin-dependent Type 1 or non-insulin-dependent Type 2, according to the definition of WHO. To treat DM, which has many severe complications, several types of insulin preparations and synthetic drugs for Type 1 and Type 2 DM, respectively, have been developed and are in clinical use. However, there are several problems concerning the insulin preparations and synthetic drugs, such as physical and mental pain due to daily insulin injections and defects involving side effects, respectively. Consequently, a new class of therapeutic agents is anticipated. For this purpose, vanadium-containing complexes are expected to treat or improve both types of DM by using unique characteristics of the transition metal. In this article, the current state of research on insulin-mimetic vanadium complexes are reviewed, with special focus on the paramagnetic vanadyl (+4 oxidation state of vanadium) complexes with different coordination modes. To analyse the blood glucose-lowering effects of the vanadyl complexes, new results on the organ distribution and pharmacokinetic analysis of the vanadyl state in the blood of rats are also described.

Animals↗

PubMed2002

Total synthesis of (+/-)-mycoepoxydiene, a novel fungal metabolite having an oxygen-bridged cyclooctadiene skeleton.

[reaction: see text] The first total synthesis of (+/-)-mycoepoxydiene has been accomplished. A ring-closing olefin metathesis (RCM) approach was employed for the construction of the oxygen-bridged eight-membered bicyclic skeleton. The RCM product was converted to the target natural product featuring the oxidative rearrangement of a furfuryl alcohol introduced as the side chain and the stereoselective 1,2-reduction of a delta-keto-beta,gamma-unsaturated alpha-lactol intermediate.

Bridged-Ring Compounds↗

PubMed2002

Structure-dependent metallokinetics of antidiabetic vanadyl-picolinate complexes in rats: studies on solution structure, insulinomimetic activity, and metallokinetics.

The insulinomimetic effect of vanadium is the most remarkable and important among its several biological actions. Vanadyl ion (+4 oxidation state of vanadium) and its complexes have been found to normalize the blood glucose levels of both type 1 and 2 diabetic animals. We have developed insulinomimetic vanadyl complexes having different coordination modes, emphasizing the possible usefulness of vanadyl-picolinate [VO(pa)(2)] and its related complexes with the VO(N(2)O(2)) coordination mode. In order to apply these complexes clinically in the future, the relationship between the chemical structure, insulinomimetic action, organ distribution of vanadium, and blood disposition of vanadyl species must be closely investigated. In the present investigation, we studied the blood disposition of the vanadyl-picolinate complexes in healthy rats, and tried to understand comprehensively the relationship between the structures, insulinomimetic activity, and metallokinetic parameters of the complexes, which had been recently prepared and specifically synthesized for the present study, by using an in vivo blood circulation monitoring -- electron spin resonance (BCM-ESR) method for analyzing ESR signals due to paramagnetic metal ions and complexes in the blood in real time. Metallokinetic parameters were estimated based on the blood clearance curves in terms of a two-compartment pharmacokinetic model, and vanadyl species were indicated to be distributed in peripheral tissues and gradually eliminated from the circulating blood, depending on their chemical structures. Vanadyl concentrations in the blood of rats given bis(5-iodopicolinato)oxovanadium(IV) [VO(5ipa)(2)] and bis(3-methylpicolinato)oxovanadium(IV) [VO(3mpa)(2)] with electron-withdrawing and donating groups, respectively, remained significantly higher and longer, due to their slower clearance rates from the blood, than in rats given other complexes, suggesting that the high exposure and long residence of vanadyl species bring about the high normoglyceric effect in diabetic animals. We then examined the relationship between insulinomimetic activity and metallokinetic parameters in the family of VO(pa)(2) for further development of insulinomimetic vanadyl complexes. IC(50), the 50% inhibitory concentration of the complexes on the free fatty acid release from isolated rat adipocytes treated with epinephrine, was found to be sufficiently correlated with metallokinetic parameters such as area under the concentration curve, mean residence time, total clearance, and distribution volume at steady-state. Furthermore, the in vivo antidiabetic activity of the complexes was enhanced with increasing exposure and residence of vanadyl species in the blood of animals. On the basis of these results, we concluded that in vitro insulinomimetic activity, metallokinetic character, and in vivo antidiabetic action of vanadyl-picolinate complexes are closely related to their chemical structures.

Adipocytes↗

PubMed2002

Topological stability and self-association of a completely hydrophobic model transmembrane helix in lipid bilayers.

Investigation of interactions between hydrophobic model peptides and lipid bilayers is perhaps the only way to elucidate the principles of the folding and stability of membrane proteins (White, S. H., and Wimley, W. C. (1998) Biochim. Biophys. Acta 1367, 339-352). We designed the completely hydrophobic "inert" peptide modeling a transmembrane (TM) helix without any of the specific side-chain interactions expected, X-(LALAAAA)(3)-NH(2) [X = Ac (I), 7-nitro-2-1,3-benzoxadiazol-4-yl (II), or 5(6)-carboxytetramethylrhodamine (III)]. Fourier transform infrared-polarized attenuated total reflection measurements revealed that I as well as II assume a TM helix in hydrated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayers. Dithionite quenching experiments detected no topological change (flip-flop) in the helix II for at least 24 h. Thus, the TM helix itself is a highly stable structure, even in the absence of flanking hydrophilic or aromatic amino acids which are suggested to play important roles in stable TM positioning. Helix self-association in lipid bilayers was detected by fluorescence resonance energy transfer between II and III. The peptide was in a monomer-antiparallel dimer equilibrium with an association free energy of approximately -13 kJ/mol. Electron spin resonance spectra of 1-palmitoyl-2-stearoyl-(14-doxyl)-sn-glycero-3-phosphocholine demonstrated the presence of a motionally restricted component at lower temperatures.

Lipid Bilayers↗

PubMed2002

A recirculatory model for local absorption and disposition of ciprofloxacin by measuring portal and systemic blood concentration difference.

A recirculatory model for the portal-systemic blood concentration difference (P-S difference) was developed to separately evaluate the rate and extent of absorption from the gastrointestinal tract into the portal system and disposition of a drug in the body. To apply this model to pharmacokinetic analysis, ciprofloxacin was selected as a model drug possessing a moderate intestinal absorption, and renal and hepatic elimination. The portal and systemic blood samples were simultaneously taken from rats at appropriate time points after intravenous and oral administration of ciprofloxacin at a dose of 5 mg/kg. After intravenous administration, little or no difference in the concentrations between the portal and systemic blood was observed, whereas after oral administration the concentrations of ciprofloxacin in the portal blood were consistently higher than those in the systemic blood over the time studied. This difference observed after oral administration is attributed to the absorption of ciprofloxacin from the gastrointestinal tract into the portal system. On the basis of the moment analysis deduced from the recirculatory model, the portal blood flow rate (Q(p)), the local absorption ratio from the gastrointestinal tract into the portal system (F(a)), the hepatic recovery ratio (F(h)), and bioavailability (BA) were then estimated. The obtained Q(p) of 2.81 L/h/kg, F(a) of 32.6, F(h) of 68.1, and BA of 22.2% were found to be in good agreement with the reported values. Furthermore, the mean local absorption time from the gastrointestinal tract into the portal system (t(a)) calculated by a nonlinear least-squares program [MULTI (FILT)] was almost identical with that by the global moments. These results suggest that the model proposed in this study would be useful for evaluating both in vivo absorption and disposition of drugs.

Animals↗

PubMed2002

Local pharmacokinetic analysis of a stable spin probe in mice by in vivo L-band ESR with surface-coil-type resonators.

In vivo ESR spectroscopy using a low frequency microwave of approximately 1 GHz has been developed to measure non-invasive ESR spectra in animals given paramagnetic compounds, in which a loop-gap-type resonator was used and ESR spectra were measured at the animal's head or abdomen. Therefore, the concentrations of paramagnetic species in both the blood and organs were compositely contributed to the spectra. When we understand the kinetics of paramagnetic species in detail, it is essentially important to know how these kinetics are expressed in each organ. For this purpose, a surface-coil-type resonator, which enabled local ESR measurement in specific organs, has been developed. By using this method, we studied the real-time pharmacokinetics of spin clearance curves detected in the organs of mice given 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (4-hydroxy-TEMPO) intravenously (i.v.), by monitoring the inferior vena cava, liver and kidney. Quantified dearance curves in the organs were analyzed on the basis of a two-compartment model, and pharmacokinetic parameters were estimated based on the curve-fitting. The obtained pharmacokinetic parameters were found to depend on the measurement site, and the distribution and elimination processes of the spin probe were successfully separated between the blood and organs of mice.

Animals↗

PubMed2002

Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice.

Nitric oxide (NO) derived from endothelial NO synthase (eNOS) is regarded as a protective factor against atherosclerosis. Therefore, augmentation of eNOS expression or NO production by pharmacological intervention is postulated to inhibit atherosclerosis. We crossed eNOS-overexpressing (eNOS-Tg) mice with atherogenic apoE-deficient (apoE-KO) mice to determine whether eNOS overexpression in the endothelium could inhibit the development of atherosclerosis. After 8 weeks on a high-cholesterol diet, the atherosclerotic lesion areas in the aortic sinus were unexpectedly increased by more than twofold in apoE-KO/eNOS-Tg mice compared with apoE-KO mice. Also, aortic tree lesion areas were approximately 50% larger in apoE-KO/eNOS-Tg mice after 12 weeks on a high-cholesterol diet. Expression of eNOS and NO production in aortas from apoE-KO/eNOS-Tg mice were significantly higher than those in apoE-KO mice. However, eNOS dysfunction, demonstrated by lower NO production relative to eNOS expression and enhanced superoxide production in the endothelium, was observed in apoE-KO/eNOS-Tg mice. Supplementation with tetrahydrobiopterin, an NOS cofactor, reduced the atherosclerotic lesion size in apoE-KO/eNOS-Tg mice to the level comparable to apoE-KO mice, possibly through the improvement of eNOS dysfunction. These data demonstrate that chronic overexpression of eNOS does not inhibit, but accelerates, atherosclerosis under hypercholesterolemia and that eNOS dysfunction appears to play important roles in the progression of atherosclerosis in apoE-KO/eNOS-Tg mice.

Animals↗

PubMed2002

Enteric-coating capsulation of insulinomimetic vanadyl sulfate enhances bioavailability of vanadyl species in rats.

In recent years, there have been improvements in the treatment of type 2 diabetes by oral administration of vanadyl sulfate (VOSO4, VS). The maintenance of vanadyl levels in the blood of subjects with type 2 diabetes was found to be important for the insulinomimetic activity of VS. However, owing to low bioavailability of VS and the development of mild gastrointestinal symptoms and side-effects in some subjects, it is necessary to design more effective and safer dosages of VS. After discovering that VS is absorbed more thoroughly at the ileum than at other gastrointestinal sites, we investigated the absorption processes following oral administration of VS by preparing enteric-coated capsules (ECC). Although Cmax values were unchanged by the dosage forms, Tmax and MRT values associated with the enteric-coating capsulation were prolonged when compared with those observed with use of gelatin capsules (GC). An important finding was that the bioavailability of VS from ECC (9.8%) was almost double that of VS from either GC (4.0%) or the solution (4.8%). Administration of VS-containing ECC to diabetic patients is proposed to improve vanadyl absorption over that achieved by the administration of either GC or the solution.

Administration, Oral↗

PubMed2002

Direct reaction between shikonin and thiols induces apoptosis in HL60 cells.

Shikonin (beta-alkannin), a naphthoquinone compound, was found to induce apoptotic features such as chromatin condensation, DNA fragmentation, and activation of caspase 3 in HL60 cells. The mechanism was examined in terms of oxidative stress in the cells. Exposure of the cells to shikonin greatly reduced the total thiols, protein thiols, and glutathione levels, however, lipid peroxide levels were enhanced. The depletion of thiol levels in the cells was thus thought to induce lipid peroxidation and DNA fragmentation. An electron spin resonance study revealed that shikonin reacts directly with glutathione and other oxidative stress-relevant compounds in the lysate of HL60 cells. Pretreatment of such cells with N-acetylcysteine before shikonin treatment completely inhibited the DNA fragmentation. From these results, it was proposed that the chemical reaction between shikonin and cellular thiols such as glutathione and protein thiols induces apoptosis in HL60 cells.

Acetylcysteine↗

PubMed2002

Metallokinetic study of zinc in the blood of normal rats given insulinomimetic zinc(II) complexes and improvement of diabetes mellitus in type 2 diabetic GK rats by their oral administration.

In order to understand the insulinomimetic activity of zinc(II) complexes, we studied the metallokinetic features of zinc in the blood of normal rats given the zinc complexes, bis(maltolato)zinc(II) (Zn(mal)(2)) and bis(6-methylpicolinato)zinc(II) (Zn(6mpa)(2)) by comparing each of them with an ionic form of zinc chloride (ZnCl(2)). The bioavailability of the zinc(II) complexes following oral administration was enhanced to 1.4-1.5-fold that of ZnCl(2) with respect to zinc level. Based on the results of a metallokinetic analysis and administration method in normal rats, we examined the antidiabetic ability of the zinc(II) complexes in GK rats, a model animal of type 2 diabetes mellitus. High blood glucose levels of GK rats were normalized following intraperitoneal injections and oral administration of the zinc(II) complexes, in which the Zn(6mpa)(2) complex was found to be more effective than Zn(mal)(2). The present results are noteworthy, not only due to their potential relevance for clinical application, but also for the development of new zinc(II) complexes.

Journal Article↗

PubMed2002

Evidence for singlet oxygen involvement in rat and human cytochrome P450-dependent substrate oxidations.

Recently, we proposed that singlet oxygen ((1)O(2)) plays an essential role in microsomal cytochrome P450 (P450)-dependent p-hydroxylation of aniline and O-deethylation of 7-ethoxycoumarin. We then examined whether the role of (1)O(2) is general in the P450-dependent substrate oxidations. In the present study, we examined omega- and (omega-1)-hydroxylations of lauric acid, O-demethylation of p-nitroanisole, and N-demethylation of aminopyrine in rat liver microsomes. The addition of beta-carotene and NaN(3) significantly suppressed these reactions in a concentration-dependent manner, and (1)O(2) during the reactions was detected by ESR spin-trapping using 2,2,6,6-tetramethyl-4-piperidone (TMPD) as a (1)O(2)-spin trapping reagent, where the addition of (1)O(2) quenchers, SKF-525A as a P450 inhibitor, or p-nitroanisole decreased ESR signal intensities due to TMPD-(1)O(2) adduct. Next, we examined the effect of (1)O(2) quenchers on P450-dependent reactions in the human liver microsomes, and (1)O(2) was also indicated to be an active species in substrate hydroxylations and dealkylations such as nifedipine oxidation by CYP3A4. On the basis of the results, we concluded that (1)O(2) is an essentially important active oxygen species in both rat and human P450-dependent substrate oxidations.

Journal Article↗

PubMedDate not supplied

Suppressive effect of caffeic acid and its derivatives on the generation of UVA-induced reactive oxygen species in the skin of hairless mice and pharmacokinetic analysis on organ distribution of caffeic acid in ddY mice.

Caffeic acid (CA) and its analogues such as rosmarinic acid are well known as antioxidative agents. Exposure to UVA is known to generate reactive oxygen species (ROS) such as singlet oxygen (1O2) and superoxide anion radical (*O2-) in the skin of animals, which in turn induces skin photodamage and photoaging. Because CA and its analogues quench 1O2, these compounds were topically applied to the abdominal skin of live hairless mice and were found to suppress ROS generation upon UVA exposure. Furthermore, the generation of UVA-induced ROS was also suppressed in the skin of mice that were orally given CA. In order to understand the mechanism by which CA blocks ROS production in UVA-exposed skin, the pharmacokinetics of CA upon oral administration to mice was followed and CA was found to efficiently distribute in the skin. These results suggest that skin damage by UVA-induced ROS generation is reduced by oral supplementation of CA, which has a scavenging and quenching activity against ROS.

Animals↗