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Biomedical subjects

R Nishigaki

Publications and source records attributed to R Nishigaki.

At least 19 recordsLinked to original sources
PubMed1990

Synergistic effect of ultrasound and hematoporphyrin on sarcoma 180.

The antitumor effects of combined use of ultrasound (US) and a photosensitizer, hematoporphyrin (Hp), were determined in mice bearing sarcoma 180. In order to find the optimum timing of the US irradiation after the administration of Hp, the Hp concentrations in the tumor and in the plasma were determined and were analyzed pharmacokinetically. Antitumor effects were evaluated by measuring the tumor size and the tumor weight. Hp alone showed no antitumor effect but US alone showed a slight antitumor effect. The combined treatment with US and Hp showed marked synergistic effects on sarcoma 180 (inhibition ratio was 74% of the control). From these results, the enhancement of antitumor effect is thought to be caused by the sensitization of tumor cells to US mediated by Hp.

Animals↗
PubMed1990

Mechanism of cell damage by ultrasound in combination with hematoporphyrin.

The mechanism of cell damage by ultrasound in combination with hematoporphyrin was studied. Mouse sarcoma 180 cell suspensions were exposed to ultrasound for up to 60 s in the presence and absence of hematoporphyrin, with and without active oxygen scavengers. The cell damage enhancement by hematoporphyrin was suppressed by adding histidine but not by mannitol. The enhancement was doubled in rate by substitution of deuterium oxide medium for normal water. Sonoluminescence was produced in a saline solution under similar acoustic conditions and observed to have spectral components that can excite hematoporphyrin molecules. These results suggest that cell damage enhancement is probably mediated via singlet oxygen generated by ultrasonically activated hematoporphyrin.

Animals↗
PubMed1989

[Increase in the generation of superoxide radicals and in the inhibitory effect on Yoshida sarcoma of anthracycline antitumor agents by ultrasound].

The antitumor effects of ultrasonic (US) irradiation in combination with the administration of an anthracycline drug, such as adriamycin and THP-adriamycin, were investigated from a viewpoint of the generation of superoxide radicals (SOR). In the in vitro experiments, the generation of SOR by US irradiation was measured by the amount of cytochrome c reduced. The addition of the drug stimulated the generation of SOR by US irradiation. In the in vivo experiments, Donryu rats inoculated subcutaneously by Yoshida sarcoma were treated with US irradiation in combination with the drug. During US irradiation, the temperature of the rat tissue irradiated was kept below 37 degrees C to avoid thermal effects. To know the optimum timing of US irradiation after the administration of the drug, the drug concentrations in the tumor and blood were determined and the time course of drug concentrations was analyzed pharmacokinetically. The effects of drugs and/or US irradiation showed antitumor activity judged by the growth of the tumor size or the survival time of rats. The combination treatments of US irradiation with the drug marked additional or synergistic effects on Yoshida sarcoma. Considering the relationship between the antitumor effect in vivo and the generation of SOR in vitro, the increase of anti-tumor effect of US irradiation by the anthracycline drug may be caused by the stimulation of the generation of SOR.

Animals↗
PubMed1989

Hematoporphyrin as a sensitizer of cell-damaging effect of ultrasound.

Mouse sarcoma 180 or rat ascites hepatoma (AH) 130 cells were exposed to ultrasound (US; 1.27, 2.21 and 3.18 W/cm2; 1.92 MHz) for up to 60 s in vitro in the presence or absence of hematoporphyrin (Hp; 10, 25 and 50 micrograms/ml). The cell-damaging effects of treatments were determined by means of the Trypan Blue dye exclusion test. Hp alone did not show any cell-damaging effect, whereas US alone damaged 30 and 50% of sarcoma and AH 130 cells, respectively, at the maximum intensity for 60 s. In the presence of 50 micrograms/ml Hp, US damaged 99 and 95% of the above tumor cells, respectively. These results show that Hp increased the sensitivity of tumor cells to US.

Animals↗
PubMed1989

Transport of salicylamide from intestinal lumen to serosal compartment.

This study was aimed to clarify the fate of the perfused drug and the characteristics of the serosal compartment. A portion of rat small intestine immersed in a solution regarded as the serosal compartment was perfused in situ and the permeability of drugs into the mesenteric venous blood and into the serosal solution were determined. The cumulative amounts of salicylamide (SAM) transported to the mesenteric venous blood and the serosal compartment were 19.7 and 45.8% of amount disappeared from the intestinal lumen, respectively and those of benzoic acid (BA) were 47.4 and 12.7%, respectively. The permeability of SAM into the serosal compartment was 2.8 times of that into the mesenteric venous blood, while the permeability of BA into the serosal compartment was only one fourth of that into the mesenteric venous blood.

Animals↗
PubMed1989

Effects of cimetidine on quinidine distribution and tissue pH in rats.

To elucidate the mechanism(s) of the decrease of the volume of distribution at steady state (Vdss) and the tissue-to-plasma concentration ratio (Kp) of quinidine after cimetidine treatment, the following were studied; (1) the effect of cimetidine on the tissue binding of quinidine in vitro, (2) the non-linear tissue distribution of quinidine and (3) the effect of cimetidine on tissue pH. The in vitro binding of quinidine to rat tissue homogenates was not affected by cimetidine treatment. The tissue distribution of quinidine in rats was linear from 1 to 5 micrograms/ml of plasma concentration except for lung. The plasma disappearance of 5,5-dimethyl-2,4-oxazolidinedione (DMO) after a 200 mg/kg intravenous injection was fitted to a two compartment open model. In the cimetidine-treated rats (50 mg/kg), the pharmacokinetic parameters of DMO, such as the plasma total body clearance (Cltot), Vdss and the rate constant at the terminal phase (beta) increased to 230, 110 and 210% of those of the non-treated rats, respectively. The intracellular pH calculated by Kp of DMO increased significantly in liver, spleen, intestine, brain, muscle and skin. This suggests that cimetidine decreased the tissue-to-plasma pH partition coefficient (q) of unbound quinidine in several tissues. The decreases of Vdss and Kp of quinidine by cimetidine was attributed to the decrease of q resulting from the increase of tissue pH.

Acid-Base Equilibrium↗
PubMed1989

Intestinal absorption kinetics using a laminar flow model.

The drug concentration profile at non-steady state in the intestine was simulated using a laminar flow model. The transport equation with cylindrical coordinates was solved by a finite difference method to stimulate the concentration profile in the tube and the exit cup-mixing concentration. A drug with a various wall permeability coefficient (Pw = zero or 10(-5) to 10(-3) cm/s) and diffusion constant (D = 10(-6) to 10(-4) cm2/s) was assumed to be introduced into the tube in a pulse form. The spatial intervals of the grid and the time step were varied to yield the optimum condition for calculation. The concentration profile in the tube as the time elapsing and the exit cup-mixing concentration versus time profile were shown graphically. Pw and D influenced the concentration profiles. This suggests the possibility of the estimation of Pw and D by determining the exit cup-mixing concentration after a pulse input to a perfused intestine under a laminar flow condition.

Intestinal Absorption↗
PubMed1989

The inhibitory effects of cimetidine on elimination and distribution of propranolol in rats.

We studied the effects of cimetidine on the pharmacokinetics, blood and tissue distribution and plasma protein binding of propranolol in rats. The plasma disappearance of propranolol after a 10 mg/kg intravenous injection and oral administration were fitted to a two compartment open model. In the cimetidine treated rats, the area under concentration curve after an intravenous injection (AUCiv) was increased by 64% and the plasma total body clearance (Cltot) and the rate constant at the terminal phase (beta) were decreased by 38% and 33% of those of the non-treated rats, respectively. The area under the concentration curve after oral administration (AUCpo) was increased by 62% and the plasma oral clearance (Clpo) was decreased by 39% by cimetidine treatment, whereas the bioavailability (F) was not changed. The hepatic blood flow rate (Qh) and the product of the plasma unbound fraction and the hepatic intrinsic clearance (fp x Clint,h) calculated from Cltot and Clpo were decreased by 30% and 39%, respectively. The blood-to-plasma concentration ratio (Rb) and the tissue-to-plasma concentration ratio (Kp) of propranolol were not affected by cimetidine treatment, while the binding constant (Kb) in plasma was decreased by 45%. The plasma unbound fractions (fp) of propranolol were increased by 25-70% in the in vivo plasma concentration range (0.1-1.0 microgram/ml) resulting in the decrease of tissue-to-plasma unbound concentration ratio (Kp,u) in lung, heart, spleen, brain and muscle. Cimetidine was shown to have the inhibitory effects on elimination and distribution of propranolol in rats.

Administration, Oral↗
PubMed1988

Effects of cimetidine on lidocaine distribution in rats.

The effects of cimetidine on the disappearance from plasma, plasma protein binding, tissue distribution, tissue binding in vitro and uptake by erythrocytes of lidocaine were studied in rats. The plasma disappearance of lidocaine after a 10 mg/kg bolus injection was analyzed by a two-compartment open model. In the cimetidine-treated rats (50 mg/kg bolus injection, the plasma total body clearance (Cltot), the volume of distribution at the steady state (Vdss) and the elimination rate constant of the central compartment (kel) of lidocaine decreased by 27, 28 and 32% of those of the non-treated rats, respectively. The plasma concentration of lidocaine at the steady state, after a loading dose (7.62 mg/kg body weight) followed by an infusion (0.16 mg/min/kg), increased from 1.62 to 2.69 micrograms/ml after cimetidine treatment. The tissue-to-plasma concentration ratio (Kp) in spleen, stomach and skin decreased to 64, 62 and 62% of the values of the non-treated rats. In addition, the blood-to-plasma concentration ratio (Rb) decreased by 26% in cimetidine-treated rats. In vitro tissue-to-plasma concentration ratios (Kp, vitro) of lidocaine in spleen, stomach and skin homogenate were decreased to 58, 45 and 68% by cimetidine treatment. In these tissues, the percentage decreases of Kp, vitro agreed with those of Kp determined in vivo. The decrease of Kp by cimetidine treatment may be due to the inhibition of tissue binding of lidocaine. The uptake of lidocaine by erythrocytes was decreased by cimetidine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effects of cimetidine on quinidine distribution in rats.

The effects of cimetidine on the time course of plasma concentration, plasma protein binding and tissue distribution of quinidine were studied in rats. The plasma disappearance of quinidine after a 25 mg/kg intravenous injection was fitted to a two compartment open model. In the cimetidine-treated rats (50 mg/kg), the pharmacokinetic parameters of quinidine, such as the plasma total body clearance (Cltot), the volume of distribution at steady state (Vdss) and the elimination rate constant of the central compartment (kel) decreased to 62, 60 and 73%, respectively of those of the non-treated rats. The plasma concentration of quinidine at steady state, after an intravenous injection (20 mg/kg body weight) followed by a constant rate infusion (0.2 mg/min/kg), increased from 3.02 to 5.11 micrograms/ml after cimetidine treatment. The tissue-to-plasma concentration ratio (Kp) of heart, brain and muscle, determined in homogenates at steady state, decreased after cimetidine treatment. The effect of cimetidine lasted several hours after a cimetidine bolus intravenous injection. These decreases of Kp could satisfy quantitatively the decrease of Vdss. It may be concluded that the decrease of Vdss was due to the inhibition of tissue distribution (binding and/or partition to tissue components) of quinidine by cimetidine treatment.

Animals↗
PubMed1985

The mechanism of intestinal transport of sulfamethoxazole and the effect of chlorpromazine in rat everted intestine.

The mechanism of the intestinal transport of sulfonamides and the effect of chlorpromazine (CPZ) on it were studied using rat everted intestine in vitro. Sulfamethoxazole (SMZ) was accumulated in the serosal solution in the everted sac obeying the pH partition theory, while sulfisoxazole (SIX) was not accumulated despite the presence of the pH difference between the serosal and mucosal solutions. The reason was suggested that the microclimate pH on the mucosal surface of the intestine so decreased the amount of the unionized molecules of SIX that the transport rate of SIX was decreased to show no accumulation in the serosal solution within the sampling period. CPZ as well as metabolic inhibitors blocked the SMZ accumulation by inhibiting the growth of the pH difference. This effect was caused by the inhibition of the serosal alkalinization.

Animals↗
PubMed1985

Intestinal absorption of salicylamide and effect of atropine on it.

The effect of atropine (ATR), a parasynpatholytic agent, on the intestinal absorption of salicylamide (SAM) was studied using the absorption kinetic model proposed by Winne et al. The disappearance of SAM from perfusate and the appearance in intestinal blood were determined using perfused intestinal loop of the rat in vivo. The results showed that the absorption of SAM was simulated by the four compartment model consisting of luminal, interstitial, blood and serosal compartments. The model was assumed to have three rate determining factors, namely mucosal membrane permeability, clearance by blood flow and serosal membrane permeability. ATR decreased the absorption of SAM by decreasing the clearance factor relating to intestinal blood flow and increased the fraction of the transported amount of SAM from interstitial space to serosal compartment.

Animals↗
PubMed1985

Kinetics of bactericidal activity of aminoglycosides during dynamic dilution.

The time courses for viable microorganism count after addition of aminoglycosides were investigated in exponentially decreasing concentrations in in vitro using a continuous flow culture system. When aminoglycosides were added to the incubation medium containing Escherichia coli, the growth rate began to decrease after a lag phase and recovered gradually after the concentration fell below its effective level. To simulate this time course, the following equation including the retardation function was proposed; (Formula: see text) where N is the number of viables, ko is the generation rate constant, kd is the dilution rate constant, Pc is the bactericidal coefficient per unit concentration characteristic to the individual antibiotic, kr is the reciprocal of the retardation time and Co is the initial concentration of the antibiotic. Pc and kr were calculated using the nonlinear least square method and the calculated time course agreed with the observed experimental data indicating the appropriateness of this equation. Pc has a negative relationship to the minimum inhibitory concentration for six aminoglycosides studied, kanamycin, amikacin, kanamycin B, tobramycin, dibekacin and habekacin. The values of kr ranged between 3.12 X 10(-2) to 6.40 X 10(-2) min-1 and are thought to correlate with the mechanism of antibiotic actions.

Aminoglycosides↗
PubMed1985

Effects of diethyldithiocarbamate, a metabolite of disulfiram, on the pharmacokinetics of alcohol and acetaldehyde in the rat.

The effects of diethyldithiocarbamate (DDC), a metabolite of disulfiram which is known as Antabuse, on the blood concentrations of alcohol and acetaldehyde were determined simultaneously by head space gas chromatography in rats. After an intravenous injection of alcohol, the blood concentration of acetaldehyde was much lower than that of the alcohol. A pharmacokinetic model featuring the liver compartment for acetaldehyde was used to estimate pharmacokinetic parameters on the assumption that the distribution volumes of the central compartments were same for alcohol and acetaldehyde, and that the elimination rate of acetaldehyde from liver was large enough to isolate the liver compartment from the central compartment. The results showed that the clearance of alcohol was 0.0226 l/min/kg and the elimination rate constant of acetaldehyde from the liver compartment was very large and 35 min-1. The administration of DDC decreased the above significantly to 0.0132 l/min/kg and 20 min-1, respectively. After intravenous infusion of acetaldehyde, the time course of the blood concentration of acetaldehyde was analyzed by the one compartment model. The estimated elimination rate constants from blood and the distribution volume were in good agreement with those calculated from alcohol injection, indicating the appropriateness of the method used in this study. DDC had no effect on the elimination of infused acetaldehyde from blood indicating that the elimination may be due to the loss from lungs into breath, from skin surfaces and/or from the kidney but not by metabolism in the liver.

Acetaldehyde↗