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Biomedical subjects

N Yamamura

Publications and source records attributed to N Yamamura.

At least 19 recordsLinked to original sources
PubMed2006

Renal handling of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, in rabbits in comparison with meropenem.

The plasma half-life of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, is longer than that of meropenem in animals and humans. To address this issue, renal clearance studies were conducted in rabbits. A constant rate infusion of CS-023 and meropenem was conducted in male Japanese White rabbits. Concentrations in the plasma, urine and renal cortex were measured to evaluate renal clearance and renal tissue uptake. CS-023 showed a clearance ratio (renal clearance/glomerular filtration rate) of around 1, which was not affected by co-administration of probenecid or p-aminohippurate. On the other hand, meropenem exhibited a clearance ratio of around 3, which was significantly decreased to 1 by co-administration of probenecid. p-Aminohippurate, in contrast, had no effect. The renal cortex/plasma concentration ratio of CS-023 was around 0.6 with or without probenecid co-administration. This ratio of meropenem was around 3, which was decreased significantly by co-administration of probenecid to around 0.6. These data suggest that meropenem is secreted in the renal tubules via organic anion transporters, but CS-023 is not. The present findings in rabbits would indicate that a lack of renal tubular secretion of CS-023 is a reason for the long plasma half-life compared with meropenem.

Animals↗
PubMed2006

Asymmetric gene flow and constraints on adaptation caused by sex ratio distorters.

Asymmetric gene flow is generally believed to oppose natural selection and potentially impede adaptation. Whilst the cause of asymmetric gene flow has been seen largely in terms of variation in population density over space, asymmetric gene flow can also result from varying sex ratios across subpopulations with similar population sizes. We model the process of adaptation in a scenario in which two adjacent subpopulations have different sex ratios, associated with different levels of infection with maternally inherited endosymbionts that selectively kill male hosts. Two models are analyzed in detail. First, we consider one host locus with two alleles, each of which possesses a selective advantage in one of the subpopulations. We found that local adaptation can strongly be impeded in the subpopulation with the more female biased population sex ratio. Second, we analyze host alleles that provide resistance against the male-killing (MK) endosymbionts and show that asymmetric gene flow can prevent the spread of such alleles under certain conditions. These results might have important implications for the coevolution of MK bacteria and their hosts.

Acclimatization↗
PubMed2005

Population pharmacokinetics of epinastine, a histamine H1 receptor antagonist, in adults and children.

AIMS: Our objective was to develop a population pharmacokinetic (PPK) model for epinastine, a histamine H(1) receptor antagonist, in adults and children and to obtain pharmacokinetic information to support dosing recommendations in children. METHODS: A total of 1510 plasma samples were collected from 62 healthy adult volunteers and 62 paediatric atopic dermatitis patients. The data were analysed using the NONMEM program according to a two-compartment model with first-order absorption. In addition, the final PPK model was evaluated by means of bootstrapping resampling. RESULTS: The oral clearance (CL/F) was found to be associated with body weight, formulation and food status. The volume of distribution of the central compartment (V(1)/F) was related to body weight and food status. An absorption lag time was apparent in fed subjects. On the other hand, other covariates (formulation on V(1)/F, volume of distribution of the peripheral compartment (V(2)/F), first-order absorption rate constant (Ka) and absorption lag time (ALAG); food status on V(2)/F and Ka; body weight on V(2)/F) were not statistically significant. No effect of age on CL/F, V(1)/F or V(2)/F was found. The mean parameter estimates obtained with an additional 200 bootstrap replicates of data were within 90-117% of those obtained with the original data set. These results suggest that the pharmacokinetics of epinastine are similar in adults and in children, except for the effect of the difference of body weight. The result of the application of the PPK model to the clinical trial in paediatric patients, in which dosage was determined based on the body weight (from 14 kg to less than 24 kg; 10 mg dose, 24 kg or more; 20 mg dose), showed that the C(max) and AUC (25.6 +/- 6.9 ng ml(-1) and 246.8 +/- 68.2 ng h ml(-1)) were almost same levels with those of adults after administration of 20 mg (26.9 +/- 9.1 ng ml(-1) and 281.6 +/- 90.5 ng h ml(-1)). CONCLUSIONS: A PPK model for epinastine was established and further evaluation by bootstrapping indicated that this model is stable. The model shows that, if dosage is adjusted based on the body weight, the epinastine exposure in paediatric patients is similar to that in adults.

Adult↗
PubMed2002

Relation between ultrasonographic and histologic findings of tracheal invasion by differentiated thyroid cancer.

Between 1988 and 1999 a total of 24 patients with differentiated thyroid cancer invading the airway underwent various types of tracheal resection at the Osaka Police Hospital. Preoperative ultrasonographic (US) findings in these patients were compared with postoperative histologic results of the resected specimens to confirm the relation between the preoperative and postoperative diagnoses and to determine the indications for operative procedures. Preoperative US revealed cancer invasion to the adventitia in 2 cases, to the intercartilage space in 13, and to the tracheal mucosa in 9. Histologically, cancer invasion to the adventitia was confirmed in 4, to the intercartilage space in 10, and to the mucosa in 10. Among 13 cancer invasion instances to the intercartilage revealed by US, overdiagnosis occurred in 3 cases and underdiagnosis in 1. The actual overall diagnostic rate by US was 83.3%, which is a great improvement over other available methods. In conclusion, preoperative US findings of the trachea agreed with the histologic findings of the resected specimens, indicating US to be the first choice when making decisions about resecting the trachea and about the operative procedure.

Carcinoma, Papillary↗
PubMed2001

Cysteine conjugate of methazolamide is metabolized by beta-lyase.

Bovine kidney and liver homogenates degraded a cysteine conjugate of methazolamide, S-(5-acetylimino-4-methyl-Delta2-1,3,4-thiadiazolin-2-yl)cysteine. We isolated the degradation product following incubation with kidney homogenate by high-performance liquid chromatography on reversed-phase columns. The chemical structure was confirmed by proton and carbon-13 nuclear magnetic resonance spectroscopy (1H NMR and 13C NMR, respectively), and elemental analysis by high-resolution mass spectrometry to be N-(3-methyl-5-mercapto-Delta4-1,3,4-thiadiazol-2-yl)acetamide, a thiol compound. The reaction is thought to be catalyzed by a pyridoxal-dependent enzyme(s) as indicated by an inhibition study using aminooxyacetic acid. Possible involvement of the thiol compound in the development of an adverse effect is discussed.

Animals↗
PubMed2001

Expression of messenger RNA for gonadotropin receptor in the granulosa layer during the ovulatory cycle of hens.

The present experiments were conducted to evaluate the mRNA levels of luteinizing hormone receptor (LHR) and follicle-stimulating hormone receptor (FSHR) in granulosa layers during the ovulatory cycle of hens, in relation to the release of LH and steroid hormones. After the release of LH, progesterone (P4) and estradiol-17beta (E2), found 4-5 h before ovulation, LHR and FSHR mRNA levels were observed to decrease in the granulosa layers of the largest (F1) and second largest (F2) preovulatory follicles, with the greatest in the LHR mRNA level of F1. P4 concentrations in the granulosa layers of F1 and F2 increased 4-5 h before ovulation, with greater in F1 than in F2. F2 concentrations in the theca layers were greater in F2 than in F1 throughout the ovulatory cycle. Also, the injection of ovine LH caused decreases in the mRNA levels of LHR and FSHR in the granulosa layers. However, these decreases were abolished by the injection of aminoglutethimide, an inhibitor of steroid synthesis. These results suggest that in hen granulosa cells, the mRNA levels of not only LHR but also FSHR are down-regulated by LH and the down-regulation may be mediated steroid hormones.

Aminoglutethimide↗
PubMed2000

Profitability of prey determines the response of population abundances to enrichment.

Theoretical and empirical evidence in a one-predator two-prey system consistently indicates a regular trend that the less profitable (therefore, less vulnerable) prey increases in abundance with enrichment. The response in the abundance of the more profitable (more vulnerable) prey to enrichment has, however, remained unclear. Previous theoretical models have assumed the less profitable prey as inedible, though its actual profitability is unknown. Here, relaxing this assumption, we show that the response of the more profitable prey abundance to enrichment depends critically on the profitability of the less profitable prey. Specifically, the more profitable prey increases in abundance with enrichment if the profitability of the less profitable prey is lower than a critical value so that it cannot support the predator population by itself even at high densities (in this case, the prey is referred to as 'unpalatable') and decreases otherwise. This establishes a more general rule which unifies the previous works and resolves the indeterminacy on the response of the more profitable prey.

Animals↗
PubMed2000

Evolution of seed dormancy due to sib competition: effect of dispersal and inbreeding.

The effect of dispersal and inbreeding on the evolution of seed dormancy to avoid sib competition is theoretically investigated, using a model which assumes a plant population with patchy spatial structure in a constant environment. Applying the inclusive fitness method, the evolutionarily stable dormancy rates are analytically derived for three cases: (a) an asexual haploid population, (b) a diploid-hermaphrodite population in which the dormancy rate is controlled by seeds, and (c) a diploid-hermaphrodite population in which the dormancy rate is controlled by mother plants. The evolutionarily stable dormancy rates decrease in the order of case (c), case (a), and case (b). In all the cases, the evolutionarily stable dormancy rates increase with decreasing the dispersal rate. Although inbreeding generally increases the evolutionarily stable dormancy rates, inbreeding due to selfing reduces the rate exceptionally in case (c).

Biological Evolution↗
PubMed2000

In vitro metabolism of human and salmon calcitonins in rat liver and kidney evaluated by liquid chromatography-tandem mass spectrometry.

1. Using LC-MS and LC-MS/MS, an in vitro study was conducted on the metabolism of human calcitonin (hCT) and salmon calcitonin (sCT) in rat liver and kidney to determine the rates of metabolism and the positions of hydrolytic cleavage in both peptides. 2. In lysosomal fractions of rat liver and kidney, hCT was degraded 9-12 times faster than sCT. Many metabolites of hCT were produced in the lysosomal fractions, whereas the metabolites of sCT were scarcely found. 3. In the case of the cytosolic fractions, three positions of initial endoproteolytic cleavage were found in hCT, leading to the production of many peptide fragments via subsequent exoproteolytic metabolism. The initial cleavage position of sCT could not be identified precisely, but it was postulated that the rate-determining step in the metabolism of sCT is the endoproteolytic hydrolysis. 4. The studies using pure proteases and protease inhibitors indicated that the metabolism of calcitonins proceeds by initial endoproteolytic cleavage and subsequent exoproteolytic digestion, catalysed by an aspartate-protease in lysosomes and by a metalloprotease and cysteine-protease in combination in the cytosol. 5. The result suggested that the higher in vivo pharmacological activity of sCT compared with that of hCT may be due to a slower metabolism of the former.

Amino Acid Sequence↗
PubMed2000

A deterministic genetic model for sympatric speciation by sexual selection.

A deterministic haploid genetic model confirms and explores in more detail the results of our previous individual-based simulation model for sympatric speciation by sexual selection. With the deterministic model, we are able to elucidate parameter dependence by phase plane analysis. We clarify how and why sympatric speciation by sexual selection can happen in a number of ways: (1) Female preferences for or against particular types of males have different effects. Whereas the former affects how readily speciation is invoked, the latter changes the stability of speciation equilibrium. (2) When there is no cost on male ornamentations, speciation is triggered regardless of initial haplotype frequencies if sufficient female preference is provided. (3) There exists a threshold for female initial frequencies for speciation to be invoked, but male initial frequencies have little effect. (4) A small cost on female mate choice does not cancel speciation, but when large, it greatly reduces the possibility of speciation.

Animals↗
PubMed2000

Panipenum, a carbapenem antibiotic, increases the level of hepatic UDP-glucuronic acid in rats.

To investigate the mechanism for the enhanced glucuronidation of valproic acid (VPA) by panipenem (PAPM), a carbapenem antibiotic, in rat liver, we carried out studies to investigate whether PAPM increases the activity of UDP-glucuronosyltransferase or the level of hepatic UDP-glucuronic acid (UDPGA) in rats. PAPM had no effect on the UDP-glucuronosyltransferase activity toward VPA both in vivo and in vitro. On the other hand, in vivo treatment with PAPM significantly increased the hepatic UDPGA level by about 1.7-fold (control: 434.5 +/- 65.5 nmol/g of liver; PAPM-treated: 755.2 +/- 92.3 nmol/g of liver). The in vitro formation of VPA glucuronide increased proportionally as a function of the UDPGA concentration up to 0.8 mM. Therefore, the increase in the level of hepatic UDPGA by PAPM is likely to be one of the causal factors for enhancing VPA glucuronidation in vivo.

Animals↗
PubMed1999

Sympatric speciation by sexual selection.

There is increasing evidence for the process of sympatric speciation, in which reproductive isolation of species occurs without physical isolation. Theoretical models have focused on disruptive natural selection as the crucial pressure for splitting a species. Here we report the theoretical finding that sympatric speciation may be caused by sexual selection even without disruptive natural selection. Specifically, we show that variation in a male secondary sexual character with two conspicuous extremes and the corresponding variance in female mating preference around no preference may jointly evolve into bimodal distributions with increasing modal divergence of the male and female traits, pulling a population apart into two prezygotically isolated populations. This mode of speciation, driven by two runaway processes in different directions, is promoted by an increase in the efficiency of females in discriminating among males or a decrease in the cost of male conspicuousness, indicating that sympatric speciation may occur more readily if barrier-free or predator-free conditions arise. Although even a slight cost of female preference would cancel the runaway process of sexual selection, it would not cancel the divergent runaway processes of sympatric speciation.

Animals↗
PubMed1999

Evolution of mutualistic symbiosis without vertical transmission.

Mutualistic symbioses are considered to evolve from parasitic relationships. Vertical transmission, defined as the direct transfer of infection from a parent organism to its progeny, has been suggested as a key factor causing reduction of symbiont virulence and evolution of mutualism. On the other hand, there are several mutualistic associations without vertical transmission, such as those between plants and mycorrhizal fungi, legumes and rhizobia, and some corals and dinoflagellates. It is expected that all mutualisms evolve perfect vertical transmission if the relationship is really mutualistic, because hosts may fail to acquire symbionts if they do not transmit the symbionts by vertical transmission. We have developed a mathematical model to clarify the conditions under which mutualistic symbiosis without vertical transmission should evolve. The evolution may occur when and only when (i) vertical transmission involves some costs in the host, (ii) the symbiont suffers direct negative effects if it exploits the host too intensively, (iii) the host establishes the ability to make use of waste products from the symbiont, and (iv) the mechanism of vertical transmission is controlled by the host. We also clarify the conditions under which mutualistic symbiosis with vertical transmission evolves.

Animals↗
PubMed1999

Pharmacokinetic analysis of 123I-labeled medium chain fatty acid as a radiopharmaceutical for hepatic function based on beta-oxidation.

Beta-oxidation is the most important pathway to provide energy for the liver. Our recent findings indicated that radiolabeled medium chain fatty acid analogs could be used as radiopharmaceuticals in the liver, allowing us to monitor alterations in energy metabolism on the cellular level. In the present study, pharmacokinetical analysis of a radioiodinated medium chain fatty acid analog, 6-[123I]iodophenylenanthic acid ([123I]IPEA), was carried out in normal and hepatitis model rats to investigate the index for the measurement of beta-oxidation activity in hepatocytes. The rate constant for metabolism of [123I]IPEA in the liver showed a strong correlation with the ATP level, which was determined as an indicator of beta-oxidation activity in hepatocytes. The radioactivity profile in the liver after [123I]IPEA administration provided important information regarding hepatic viability, and the metabolic rate constant of [123I]IPEA calculated by a pharmacokinetic method was a useful criterion for hepatic diagnosis based on hepatic cellular energy metabolism.

Animals↗
PubMed1999

Evaluation of radioiodinated medium chain fatty acids as new diagnostic agents for the determination of hepatic viability.

Radiopharmaceuticals which reflect beta-oxidation in hepatocytes will provide useful information on the prognosis after surgery or on the efficacy of treatment, since beta-oxidation is the main pathway responsible for adenosine triphosphate in hepatocytes. We have previously developed [1-11C]octanoate as a diagnostic agent for determination of hepatic viability by means of positron emission tomography (PET). The goal of the present study was to develop a new radiopharmaceutical for single-photon emission tomography (SPET), which has the advantage of being more widely used than PET. To this end, two radioiodinated omega-(4-iodophenyl)-medium chain fatty acids, p-iodophenylvaleric acid (IPVA) and p-iodophenylenanthic acid (IPEA), were synthesized and evaluated as radiopharmaceuticals for determination of hepatic viability. Metabolite analyses in vitro and in vivo and a biodistribution study in normal mice indicated that both compounds were taken up by the liver actively and metabolized by beta-oxidation. However, these studies also indicated that IPEA is more suitable as an imaging agent than IPVA. Based on these results, SPET imaging studies were performed in normal and hepatitis model rats using [123I]IPEA. The time-activity curves of the liver showed two-phase clearance of radioactivity in both normal and hepatitis model rats, but the clearance was delayed depending on the severity of hepatitis. Furthermore, the clearance rate of the first phase was correlated with the ATP level in hepatocytes, which was used as an index of the energy production capacity of hepatocytes. In conclusion, IPEA was metabolized predominantly by beta-oxidation, and the clearance of IPEA from the liver was closely associated with the ATP concentration in the liver. Thus, [123I]IPEA is a potentially useful new radiopharmaceutical for diagnosis of hepatic viability based on energy metabolism.

Animals↗
PubMed1999

Panipenem, a carbapenem antibiotic, enhances the glucuronidation of intravenously administered valproic acid in rats.

Previously, a significant decrease in the trough plasma-concentration of valproic acid (VPA) owing to the concomitant administration of panipenem (PAPM)/betamipron, a carbapenem antibiotic, in epileptic patients was reported. To determine the site and mechanism of the drug interaction between VPA and PAPM, we performed in vivo and in vitro experiments using rats. A 30 mg/kg bolus dose of VPA was given i.v. to normal Sprague-Dawley rats, nephrectomized rats, and hepatectomized rats, with and without prior treatment of PAPM. PAPM treatment resulted in a significant reduction of biological half-life and a significant increase of total body clearance in normal rats. The effects of PAPM on the disposition kinetics of VPA were also observed in nephrectomized rats, whereas hepatectomy abolished the interaction completely. Thus, the site of interaction was identified as the liver. At steady state, PAPM treatment significantly increased total body clearance, the biliary excretion rate of VPA glucuronide, and the apparent metabolic clearance of VPA by glucuronidation, but did not affect the biliary excretion clearance of VPA glucuronide. Initial uptake velocity of VPA into rat hepatocytes proportionally increased as a function of VPA concentration added and was not affected by PAPM. The plasma-unbound fraction of VPA in vitro was not altered by PAPM. These data demonstrate that PAPM does not affect the uptake of VPA into the liver, the plasma-unbound fraction, and the excretion process of VPA glucuronide. Consequently, PAPM appears to enhance the rate of metabolism of VPA to VPA glucuronide in the liver.

Animals↗