PubMed Health⌕ Search

Biomedical subjects

N Watari

Publications and source records attributed to N Watari.

At least 19 recordsLinked to original sources
PubMed1990

Long-term survival of grafted cells, dopamine synthesis/release, synaptic connections, and functional recovery after transplantation of fetal nigral cells in rats with unilateral 6-OHDA lesions in the nigrostriatal dopamine pathway.

In animal models of hemi-Parkinson's disease, survival of grafted nigral cells, their synaptic connections, dopamine (DA) synthesis/release, and recovery from motor disturbances were investigated, and these were compared among 3 groups of animals raised for 3 months, 1 year and 2 years after the transplantation. Fetal nigral DAergic cell suspensions were transplanted in the ipsilateral caudate nucleus of rats with unilateral 6-OHDA lesions in the nigrostriatal DA pathway. Motor disturbances, assessed by methamphetamine-induced rotation, recovered partly in the 2nd week, significantly in the 4th week after the grafting, and remained stable thereafter. Many tyrosine hydroxylase (TH)-positive cells were detected along the grafting tracks. The number of TH-positive cells was similar in the 3 groups of animals. These TH-positive cells made synaptic connections in the host caudate. By in vivo microdialysis measurement, extracellular DA, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) around the grafted sites recovered to 30-100% of those of controls. No significant differences were observed in the concentration of DA, DOPAC and HVA among 3 groups of animals. They also responded to methamphetamine loading though the magnitudes were smaller. Using a TH cDNA probe, TH-positive cells were found to express TH mRNA in in situ hybridization-autoradiographic analysis. Data indicate that grafted fetal DAergic cells survive, synthesize and release DA, make synaptic connections in the host brain and ameliorate motor disturbances for over 2 years. There were no differences in these parameters among the 3 groups of animals, and no untoward side effects were observed even at 2 years after the grafting. Thus it was confirmed that the grafting of neuronal cells into the brain is a promising approach to restore disturbed function.

Animals↗
PubMed1989

Determination of mean input time, mean residence time, and steady-state volume of distribution with multiple drug inputs.

A general treatment for determination of mean residence time (MRT) and steady-state volume of distribution (Vss) after multiple drug inputs via any mode of administration is presented. For multiple inputs, either simultaneous or consecutive, the mean input time (MIT) can be readily calculated using the general equations presented here. Sample calculations for MIT, MRT, and Vss following different combinations of multiple drug inputs are presented. Errors inherent in noncompartmental area determinations are discussed.

Models, Biological↗
PubMed1989

Comparison of disposition parameters of quinidine and quinine in the rat.

The difference in disposition of quinidine (Qd) and its diastereomer quinine (Qn) after intravenous administration was examined in rats at doses ranging from 5 to 20 mg/kg. Dose-dependent kinetics in total clearance and in distribution volume of tissue based on a two-compartment model was observed for Qd; there was no evidence of nonlinearity for Qn. However, there was no significant difference between Qd and Qn for blood clearance at doses of 5 and 10 mg/kg, at which the blood clearances were almost equal to hepatic blood flow for both Qd and Qn since the excretion of Qd and Qn into the urine and bile was minimal. This indicates the elimination of these diastereomers to be non-restrictive in the liver. A concentration dependence in unbound volume of tissue distribution and in plasma protein binding was observed for Qd; there was no concentration dependence for Qn. Although affinity of the drug for components on or within the blood cells was not concentration-dependent for either Qd or Qn, a significantly higher binding capacity for Qn than for Qd was observed attributable to blood cell binding. Based on these results, it is suggested that a larger number of binding sites exist for Qn than for Qd in the body. However, the dissociation binding constant for Qd is much lower than for Qn, resulting in a higher binding of Qd and Qn at low concentrations, with a reversal at high concentrations.

Animals↗
PubMed1989

Acetylcholine-induced activation of the eccrine sweat glands in a case of hypohidrotic congenital ectodermal dysplasia.

In a male patient suffering from congenital ectodermal dysplasia with sweating only on the plantar and palmar surface, we found that the anhidrotic eccrine sweat glands became able to produce sweat after repeated local application of acetylcholine. We ultrastructurally examined the sweat glands in skin biopsies before and after acetylcholine treatment. The secretory portion of the sweat glands of the right plantar region was characterized by well-developed basal infoldings and intercellular interdigitations, and also by dilated intercellular spaces and canaliculi. In the flexor region of the right brachium (anhidrotic area), the secretory portion showed hypoplastic features, especially denoted by the presence of few locally distributed basal infoldings and intercellular canaliculi. The secretory cells seemed to be hypofunctional with the nuclei containing much heterochromatin. After treatment, in the flexor region of the left brachium and the right infraclavicular region, where sweating was induced, the secretory portion appeared to be considerably activated, though hypoplastic structures were unchanged: the secretory cell nuclei contained dispersed chromatin, the Golgi apparatus in the dark cells was well developed, and both in the clear cells and the myoepithelial cells micropinocytotic vesicle-like structures increased in number. In ductular cells, mitochondria also increased in number.

Acetylcholine↗
PubMed1989

Ultrastructural studies on a cadmium-storing cell in rat pancreatic tissues following cadmium chloride administration.

A new type of cell was found in the pancreatic connective tissues of rats following cadmium chloride administration. The cells contained several lipid droplets that were strongly electron-dense after the treatment with oxine, which made cadmium-oxine deposits. This suggested that the lipid droplets stored cadmium or related substances. These cells were named "cadmium-storing cells." Cadmium-storing cells are subdivided into two cell types according to their origins, "fibroblast type" and "pericyte type." The structure and function of the cadmium-storing cell were described and discussed.

Animals↗
PubMed1988

Simultaneous determination of nitroglycerin and its dinitrate metabolites by capillary gas chromatography with electron-capture detection.

A sensitive gas chromatographic-electron-capture detection method for the simultaneous determination of the antianginal drug nitroglycerin (GTN) and its dinitrate metabolites (1,2-GDN and 1,3-GDN) was developed. Human plasma samples (1 ml) spiked with 2,6-dinitrotoluene as the internal standard were extracted once with 10 ml of a methylene chloride-pentane mixture (3:7, v/v). Using this solvent system, less contaminants are extracted into the organic phase from plasma, resulting in cleaner chromatograms and prolonged column life. A break point was observed on the standard curves of GTN and GDNs. The two linear regions for the detectable concentrations of GTN are 0.025-0.3 and 0.3-3 ng/ml and for 1,2-GDN and 1,3-GDN they are 0.1-1 and 1-10 ng/ml. The limits of detection by this method for GTN, 1,2-GDN and 1,3-GDN in plasma are 0.025, 0.1 and 0.1 ng/ml, respectively.

Animals↗
PubMed1988

Prediction of hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit based on quantitative structure-pharmacokinetic relationships.

Based on the concept of physiological pharmacokinetics, the hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit was predicted based on the relationships between principle kinetic parameters and lipophilicity (chloroform-water partition coefficient). Good log-log linear relationships between kinetic parameters and lipophilicity were obtained for the seven barbiturates examined. The values of correlation coefficient were improved slightly by using the corrected values for partition coefficients of nonionic molecules in the cases of principle parameters such as drug-protein and drug-blood cell affinity, intrinsic hepatic clearance, and unbound volume of distribution. There was also a good linear relationship between absorption rate constant (mean absorption time) and lipophilicity. The mean hepatic transit time was negligible for the most lipophilic drug (hexobarbital) examined; this suggests that the mean absorption time for these barbiturates does reflect the absorption process. The available fraction in relation to hepatic first-pass metabolism was well predicted from the lipophilicity by both well-stirred and parallel-tube models, and the difference in the values predicted by both models was minimal. There were good relationships between predicted and observed values for plasma levels after intravenous and oral administration, except for two (cyclobarbital and phenobarbital) of the seven drugs used. The great difference between predicted and observed values for these two drugs was considered due to substituent effects in liver metabolism.

Administration, Oral↗
PubMed1987

Pharmacokinetic study of carbamazepine and its epoxide metabolite in humans.

A major metabolite of carbamazepine (CBZ), CBZ-10, 11-epoxide (EPO), has been reported to possess anticonvulsant properties. Therefore, the present study was undertaken in order to develop a pharmacokinetic model to predict the behavior of EPO in the body after administration of CBZ. The serum concentration-time curves after oral administration of solution of CBZ (200 mg) or EPO (150 mg) in six healthy subjects showed the characteristic "nose", suggesting that disposition of CBZ or EPO could be described by the two-compartment model. The kinetic parameters of disposition for CBZ and EPO were calculated by the method of Wagner, assuming the absolute bioavailabilities of CBZ and EPO to be 1.0 and 0.81, respectively. Total body clearance and elimination rate constant of EPO were very much larger than those of the parent drug but there was no statistically significant difference in the distribution volume between CBZ and EPO. The formation rate of EPO was calculated by a deconvolution method, and obeyed Michaelis-Menten kinetics. Based on these findings, a pharmacokinetic model of the fate of CBZ and EPO in humans was developed and the time courses of CBZ and EPO in serum after oral administration of three tablet preparations and a solution containing 200 mg of CBZ were simultaneously fitted to this model by solving the differential equations by the Runge-Kutta-Gill method. There was good agreement between calculated and observed serum values, suggesting that the present model is appropriate to describe the formation and disposition of EPO from CBZ. The formation rate constant of EPO (Vmax/Km/V1) was approximately one-fifteenth of the elimination rate constant of EPO. This suggested a flip-flop model in which the formation of EPO was rate-limiting in humans. The observation that the serum concentrations of EPO after administration of CBZ were one-tenth to one-twentieth of those of the parent drug was well explained by the flip-flop kinetics of EPO, together with the large differences in total body clearance and elimination rate constant between CBZ and EPO.

Adult↗
PubMed1986

Study of the absorption site of cimetidine.

The optimal absorption site of cimetidine was assessed in rats. The ileac pH value (measured by a pH meter with a micro pH combination electrode) was slightly higher than that in other intestinal sites, and the absorption rate constant (ka) following the administration of cimetidine into the ligated ileac loop was larger than that in the ligated duodenal and jejunal loops. It is suggested that the ileum is the optimal absorption site of cimetidine. On administration of cimetidine into the ligated and unligated intestines, the ka values of either the duodenum or the ileum were found to be almost the same between the ligated and unligated cases. However, the ka value of the jejunum in the unligated case was slightly larger than that in the ligated case. Thus, it is suggested that cimetidine is completely absorbed in the duodenum and ileum during its passage through these intestinal sites, but at the jejunum an unabsorbed fraction of cimetidine passes to the ileum, where it is absorbed completely. Based on these results, a pharmacokinetic model for the absorption of cimetidine following oral administration was designed, in which gastric, duodenal, jejunal, and ileac compartments were included separately but enterohepatic circulation was not included, because the biliary excretion of cimetidine following intravenous and oral administrations were generally lower than 2% of the dose. The value of k41 was ca. 4 times larger than that of k45, and the value of k45 could be approximated to zero in the model.

Animals↗
PubMed1985

Dose- and time-dependent kinetics of the renal excretion of nitrofurantoin in the rabbit.

A pharmacokinetic study on the renal excretion of nitrofurantoin was carried out in rabbits at doses ranging from 0.5 to 15 mg/kg. With increasing dose, nonlinear kinetics were observed in the tubular secretion, which appeared to show dose and time dependence. The disposition of nitrofurantoin after intravenous injection is well described by a one-compartment model with simultaneous first-order nonrenal elimination and renal elimination, which consists of glomerular filtration, active tubular secretion conforming to the Michaelis-Menten equation, and reabsorption clearance by nonionic diffusion. Plasma and urinary excretion data after intravenous injection of nitrofurantoin were fitted to this model. When the Michaelis constant was loosely restricted at a constant value, the maximum velocity decreased with increasing dose of nitrofurantoin. However, the Michaelis constant apparently increased with increasing dose when the maximum velocity was loosely restricted at a constant value. Although the results of this fitting suggested that the former case may occur in the active tubular secretory system, the latter case could not be completely eliminated because of limited data. The implications of these results are discussed on the basis of the available published data.

Absorption↗
PubMed1985

Enhancement of RNA synthesis in chick liver by food intake: possible role of high mobility group nonhistone proteins.

RNA synthesis in the nuclei of liver from newly hatched (4-d-old) chicks is enhanced by intake of food. The enhanced synthesis was ascribed not to an increase in the activity of solubilized DNA-dependent RNA polymerase but to an increase in the initiation of RNA synthesis. Enhanced RNA synthesis in fed chicks was accompanied by greater susceptibility of nuclei to digestion by micrococcal nuclease. Salt extraction abolished the difference in nuclease sensitivity between the fed and fasted groups. Reconstitution with either 0.35 M NaCl extracts or high mobility group (HMG) nonhistone proteins restored digestion susceptibility, but changing the source of extracted proteins did not equalize the extent of digestion in nuclei from livers of fed and fasted chicks. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of HMG proteins revealed the presence of HMGs 1 and 2 as well as a 38,000-dalton protein. The nuclear HMG protein content in fed chicks was greater than that of fasted chicks (121 +/- 17 micrograms/mg DNA vs. 31 +/- 12 micrograms/mg DNA). The electron microscopic examination of hepatocyte nuclei revealed the enlargment of nucleoli and scarcity of aggregated heterochromatin structures in the fed chicks as compared with the fasted chicks. These morphological features are compatible with the high transcriptional activity in liver of fed chicks.

Animals↗
PubMed1984

Prediction of blood levels following oral administration of weakly acidic drug particles such as sulfa drugs in rabbits from the in vitro dissolution behavior.

Prediction of blood levels following oral administration of weakly acidic drug particles such as sulfa drugs from data obtained in in vitro dissolution tests of drug suspensions was studied in the rabbit. The relationship between in vivo and in vitro dissolution rates or between absorption rate and in vitro dissolution rate was investigated. The drug absorption from aqueous solution was suggested to be rate-limited by the gastric emptying rate because the initial absorption rate constant in a biexponential time course of aqueous solution for the amount unabsorbed vs. time plot was almost the same among 9 of the 10 drugs tested, except for sulfacetamide. This indicated that when the in vivo dissolution rate constant is much slower than the initial absorption rate constant of aqueous solution, the time course of blood levels for the solid drug will deviate from that of aqueous solution. Based on the consideration, the critical in vitro dissolution rate constant corresponding to the initial absorption rate constants of aqueous solution was calculated by means of statistical analysis using the relationship between in vivo and in vitro parameters. The validity of this prediction was examined using four high-solubility drugs, and it was found that the prediction could be done whether the in vitro dissolution medium was distilled water or 0.1 N HCl solution. Although in the present study, the experiment was done using an aqueous suspension form in the rabbit, the applicability of this prediction method to other dosage forms and to the case of humans is discussed.

Absorption↗