PubMed Health⌕ Search

Biomedical subjects

F Ichimura

Publications and source records attributed to F Ichimura.

At least 37 records · Page 2Linked to original sources
PubMed1995

Human MCAF gene transfer enhances the metastatic capacity of a mouse cachectic adenocarcinoma cell line in vivo.

PURPOSE: To evaluate the effect of monocyte chemotactic and activating factor (MCAF/MCP-1/JE) on tumor progression and metastasis. METHODS: Cachexia-inducing adenocarcinoma cells (cell line colon 26, clone 20) were transfected with either a control plasmid or MCAF expression vector. Spontaneous lung metastases were determined in mouse. RESULTS: The production of MCAF reached 0.4 ng/ml in vitro when transfectant cells were cultured at a cell density of 5 x 10(4) cells/ml for 3 days. Transfection of MCAF expression vector did not affect the growth rate in vitro. Also, after MCAF-transfection, the size of tumors after intra-footpad inoculation was similar to that of the parental cells. When the primary tumors were resected on the 10th day after inoculation, the incidence of spontaneous lung metastasis was less than 20% in both cells. The number of endothelial cells in the primary tumor rapidly increased from the 10th to the 14th day after inoculation, as revealed by immunohistochemical staining. In accordance with enhanced angiogenesis, the incidence rates of spontaneous metastasis increased when the primary tumors were resected on the 14th day after inoculation. Moreover, the spontaneous lung metastases were augmented in the animals injected with MCAF-transfectants compared to those injected with parental cells with a concomitant increase of angiogenesis. CONCLUSIONS: These results suggest that MCAF may augment the metastastic potential by modulating tumor associated angiogenesis.

Adenocarcinoma↗
PubMed1995

Systematic approach to a dosage regimen for phenytoin based on one-point, steady-state plasma concentration.

A systematic approach to individualizing the phenytoin (PHT) dose from a previous dose (D) and steady-state concentration (Css) pair was established by the combined use of two methods based on recently reported population pharmacokinetic parameters. This system applies the Michaelis-Menten equation to the initial data pair (D1-Css1) and solves for (a) maximum metabolic rate constant (Vmax) assuming the population mean for the Michaelis constant (Km) (method 1), and (b) Km assuming the population mean for Vmax (method 2). The derived estimates of Vmax and Km are then put through a series of filters, which results in the selection of method 1 and/or method 2 or allocation of a third category that needs further evaluation. A simulation study was performed to find a series of filters. The presented approach was applied retrospectively to the patients' data of 35 sets. Accurate predictions of the Css error within 5 micrograms/ml were obtained in 84% of the 25 cases, and in 30% of the 10 cases excluded. This systematic approach gives better prediction performance in mean error, mean absolute error, and root mean square error than a Bayesian feedback method.

Adult↗
PubMed1995

Quantitative relationship between structure and peritoneal membrane transport based on physiological pharmacokinetic concepts for acidic drugs.

To describe quantitatively the peritoneal transport of drugs, the kinetic model, which involves changes in the volume and osmolality of the dialysate as well as the diffusion and convection of drugs across the peritoneum, was applied. The apparent peritoneal permeability (Pd) of unbound drugs in rats and the partition coefficient (Papp) in an octanol:water system at pH 7.4 were estimated among acidic drugs. Using the values of unbound fraction (fS), the Pd values of the drugs were estimated from concentration-time profiles in serum and the peritoneal dialysate after intraperitoneal administration of drugs. The intrinsic membrane permeability (Pdm) was calculated based on a physiological pharmacokinetic model. The fS.Pdm values of thiopental and thiamylal (6.5 and 5.4 ml/min) were 2-3 times greater than the effective peritoneal blood flow, indicating that the peritoneal transport of the barbiturates with high lipophilicity was dominantly blood flow-limited. Evidence shows a high degree of correlation between log Pdm and log Papp. By considering the relationships, we estimated the Pdm of quinolonecarboxilic acids. The fS.Pdm values of quinolonecarboxilic acids were < 10% of the peritoneal effective blood flow rate, indicating that the peritoneal transport of quinolonecarboxilic acids was dominantly diffusion-limited because of low lipophilicity. In conclusion, there was a good correlation between log Pdm and log Papp. The prediction of Pdm can be useful to describe the peritoneal pharmacokinetics.

Acids↗
PubMed1993

Pharmacokinetics of anticholinergic drugs and brain muscarinic receptor alterations in streptozotocin diabetic rats.

We studied the effects of experimental diabetes on the pharmacokinetics of biperiden (BP) and scopolamine (SP) and brain muscarinic receptor alterations in rats after the injection of streptozotocin (STZ) (60 mg kg-1 i.v.). The serum levels of BP and SP differed significantly between the rats 14 weeks after the STZ treatment and age-matched control rats. The values of total body clearance (CLtot) of BP and SP were significantly increased by STZ treatment. The values of volume of distribution (Vdss) of SP were slightly increased in the STZ-treated rats, although Vdss of BP was decreased. Because of the high lipophilicity of BP, Vdss of BP may be decreased due to the reduced fat tissue volume caused by STZ treatment. The density of the muscarinic receptors in whole brain was measured by a radioligand receptor binding assay using [3H]-quinuclidinyl-benzylate ([3H]-QNB). The density in the diabetic rats two weeks after the STZ treatment was significantly decreased compared to age-matched control rats. However in the diabetic rats 14 weeks after the STZ treatment, there was no difference in the density of muscarinic receptors. The IC50 of muscarinic antagonist for the binding of [3H]-QNB to the receptor did not change on STZ treatment. Modulation of the receptor following repeated anticholinergic drug exposure was studied. In control rats, the number of muscarinic receptors in the brain increased by 6.9% on chronic treatment with BP for two weeks. When diabetic rats were treated with BP and SP, the number of muscarinic receptors in the brain increased by 9.6% and 33.8%, respectively.

Animals↗
PubMed1993

Time course of dopamine-D2 and serotonin-5-HT2 receptor occupancy rates by haloperidol and clozapine in vivo.

In vivo occupancy of dopamine-D1, D2 and serotonin-5-HT2 receptors by haloperidol 10 mg/kg and clozapine 20 mg/kg were studied. Rats were injected intravenously with [3H]-YM-09151-2, [3H]-SCH23390, or [3H]-ketanserin 10 min after the administration of the tested drugs. Fifteen to 240 min after the ligand injection, the receptor occupancy rates of the drugs in the striatum and frontal cortex were calculated. Clozapine demonstrated the higher 5-HT2 and lower D2 occupancies in the respective regions. A dose-response analysis of D2 and 5-HT2 receptor occupancy by the drugs consolidated the higher 5-HT2 binding affinity of clozapine in comparison with haloperidol. The present methodology may serve as an accurate tool to evaluate the peculiarity of various antipsychotics.

Animals↗
PubMed1992

Brain regional pharmacokinetics of biperiden in rats.

The pharmacokinetic profiles of biperiden (BP) in blood and in specific brain regions were investigated in rats after acute i.v. administration. The regional brain-to-blood unbound concentration ratios (Kpf) were also determined after 16 h intravenous infusion of BP. The Kpf values ranged from 30 to 75 in the different brain regions and showed decreasing concentrations in the following order: pons + medulla oblongata, basal ganglia, amygdala, hypothalamus, thalamus, mesencephalon, bulbus olfactorius + septum, hippocampus, frontal cortex, occipital cortex, cerebellum. The relationship between BP and acetylcholine (ACh) concentrations in the brain regions was examined. ACh levels in the various brain regions ranged from 8 to 44 ng g-1 tissue. There was a significant correlation between the Kpf values of BP and the levels of ACh in the brain regions except for the pons + oblongata. BP concentrations in the brain regions after BP administration were predicted based on the physiological pharmacokinetics. There was reasonable agreement between the model predictions and the observed data.

Acetylcholine↗
PubMed1990

Relationships in the structure-tissue distribution of basic drugs in the rabbit.

The relationship between the tissue-to-plasma partition coefficients (Kp) and drug lipophilicity was investigated using highly lipophilic drugs with apparent partition coefficients of 150 or above in an octanol-water system at pH 7.4. Ten clinically popular basic drugs with different dissociation coefficients (pKa) and lipophilicity were used. The Kp values were determined in nondisposing organs after the i.v. administration of individual drugs in rabbits. The free fraction in plasma and the blood-to-plasma concentration ratio were determined in vitro. Then the tissue-to-plasma ratios of nonionized and unbound drug concentrations (Kpfu) were calculated from Kpf (ratio of unbound drug). The true octanol-water partition coefficient of the nonionized drugs (P) was used to analyze the Kpf and Kpfu. In all tissues, log Kpfu was more highly correlated with log P than log Kpf.

Animals↗
PubMed1989

Prediction of the distribution volumes of cefazolin and tobramycin in obese children based on physiological pharmacokinetic concepts.

So as to estimate the appropriate dose of antibacterial drugs in obese children, prediction of the volume of distribution in these children was attempted based on physiological pharmacokinetic concepts which had been constructed from results in normal-weight children. Serum concentration-time data after intravenous drip infusions of tobramycin and cefazolin were analyzed using noncompartmental analysis of obese children in whom the degree of obesity ranged from 30 to 80%. Volume of distribution at steady state (Vss) per total body weight of tobramycin was significantly less than that for normal-weight children (P less than 0.05), whereas the value of cefazolin was almost equal to that for normal-weight children. The equation to express the difference of Vss between cefazolin and tobramycin obtained in normal-weight children failed in obese children, suggesting that there is a large decrease in the extracellular space in obese children exceeding the interindividual variations in normal-weight children. The Vss value (liter) for tobramycin was predicted by using the equation 0.261 . (ideal body weight (kg) + 0.4 . [total body weight (kg) - ideal body weight (kg)]). The Vss value of cefazolin was predicted to be 0.3 . (predicted Vss of tobramycin) + 0.052 . total body weight (kg). A good correlation between the predicted and the observed Vss values was obtained.

Blood Proteins↗
PubMed1988

Kinetics of peritoneal drug transport in rats: an application of the pore theory of transcapillary exchange.

In order to quantitatively describe the peritoneal transport of drugs, this paper proposes a kinetic model that is based on the hydrodynamic pore theory of transcapillary exchange, and incorporates an explicit description of volume and osmolality changes in the dialysate. Sulfisoxazole (SIX) and benzoic acid (BA) were used as model compounds. Following intraperitoneal administration of dialysate in rats, the osmolality, volume, and drug concentration in the dialysate were measured with respect to time. The obtained data were analyzed to give hydrodynamic parameters for solvent and a solute (including drug) by a computer-aided curve-fitting procedure according to the differential equations derived from the model. The present method, requiring no approximation of the changes in dialysate volume, made it possible to predict the concentration profiles of BA under different initial conditions of dialysate (i.e., different osmolality and volume). Solvent drag effect contributed little to the peritoneal transport of SIX and slightly to that of BA. It was also found that the peritoneal transport of BA is blood-flow limited while that of SIX is diffusion limited.

Animals↗
PubMed1988

Peritoneal transport of beta-lactam antibiotics: effects of plasma protein binding and the interspecies relationship.

In order to examine quantitatively the effect of plasma protein binding on the peritoneal transport of beta-lactam antibiotics, we employed a kinetic model based on the pore theory of transcapillary exchange. This model incorporates the changes in the volume, osmolality, and antibiotic concentration in the dialysate, so that the apparent capillary membrane permeability (Pd) and the reflection coefficient (sigma d) of an antibiotic could be assessed. Six cephalosporins (cefatrizine, cefazolin, cefpiramide, ceftazidime, ceftriaxone, cephaloridine) were used as model compounds. While the unbound fractions of these antibiotics ranged widely from 0.08 to 0.57, including linear and nonlinear protein binding, the concentration-time profiles in plasma and the peritoneal dialysate after intravenous administration in rats could be interpreted well by our model, assuming that only the unbound antibiotic is available for the peritoneal transport. The estimated Pd values were almost the same among the drugs examined. Moreover, the Pd values of cefazolin in mice, rats, and rabbits exhibited a 0.83-power dependency on the animal body weight, indicating that Pd is significantly related to the peritoneal surface area. On the other hand, the sigma d values of cefazolin were found to be almost the same among the animal species examined. Finally, the concentration-time profile of cefazolin in the dialysate after intravenous administration in a patient with end-stage renal failure was successfully predicted using the Pd value extrapolated from those of the experimental animals.

Aged↗
PubMed1988

Interindividual changes in volume of distribution of cefazolin in newborn infants and its prediction based on physiological pharmacokinetic concepts.

The purpose of this study was to investigate factors affecting the volume of distribution of cefazolin (a beta-lactam antibiotic) in newborn infants with bacterial infections, and to propose a method for predicting the volume of distribution at steady state per body weight (Vdss/BW). Cefazolin and tobramycin (an aminoglycoside) were simultaneously given to newborn infants (aged 2 to 28 d), and plasma concentration-time data were analyzed on the basis of model-independent moment analysis. The Vdss/BW values ranged from 0.212 to 0.373 L/kg for cefazolin and from 0.384 to 0.541 L/kg for tobramycin. The unbound fraction of cefazolin in plasma (fp) fluctuated widely, from 0.22 to 0.83, among patients. The Vdss/BW value for cefazolin was characterized by both large extracellular water volume and a remarkable change in fp, and could be predicted as a function of fp using physiological pharmacokinetic concepts. Moreover, interindividual changes in the unconjugated bilirubin:albumin molar ratio were predominantly responsible for the individual variation in the fp values of cefazolin in newborn infants.

Blood Proteins↗
PubMed1987

Effects of fasting on biperiden pharmacokinetics in the rat.

The effects of fasting on the pharmacokinetics of biperiden in rats were examined. Total clearance of biperiden was greater than 90% ascribable to hepatic clearance and was essentially blood-flow dependent. The number of compartments in the preferred pharmacokinetic model of biperiden changed from three (for normal rats) to two (for fasted rats). The smaller mean residence time (MRT) values found for fasted rats were attributable to decreases in distribution volume. Biperiden showed much higher lipophilicity than haloperidol, thiopental, and hexobarbital, and its tissue-to-plasma partition coefficient in adipose tissue was 20-fold higher than that in muscle. The influence of changes in volumes of adipose tissue and muscle on distribution volume (Vdss/BW) was evaluated from tissue-to-plasma partition coefficients. The value of Vdss/BW was predicted to decrease with decrease of adipose tissue, and to increase with decrease of muscle tissue. These results suggest that the observed decrease of Vdss/BW in fasted rats reflects reduced capacity to trap biperiden in the body, especially in adipose tissue. Possible clinical implications of these results are discussed.

Adipose Tissue↗
PubMed1987

Comparative distribution kinetics of cefazolin and tobramycin in children.

The time courses of drug concentration in serum after i.v. drip infusion of 2 mg/kg of tobramycin and 25 mg/kg of cefazolin in children were analyzed by model-independent moment analysis. The volume of distribution at the steady state per body weight (Vdss/BW) of tobramycin was in the range of 212 to 335 ml/kg and that of cefazolin was 119 to 156 ml/kg. A plot of the differences of Vdss/BW obtained in the same child for tobramycin and cefazolin against the value of Vdss/BW of tobramycin gave a linear regression line (r = 0.971). The magnitude of Vdss (1) of tobramycin could be well interpreted as corresponding to the extracellular water volume. In the case of cefazolin, the extracellular water space accounts for about 60% of the total distribution volume. The remaining 40% of the total Vdss of cefazolin was considered to be accounted for by the disposing organs.

Blood Proteins↗
PubMed1986

Fundamental pharmacokinetic properties of biperiden: tissue distribution and elimination in rabbits.

The pharmacokinetics of biperiden in rabbits were examined at three doses (0.2, 0.8, and 3.2 mg/kg i.v.). The data were interpreted in terms of a three-compartment open model with a linear excretion rate. The serum unbound fraction and the blood-to-plasma concentration ratio were determined as 0.39 and 1.2, respectively, over a wide concentration range (25-10000 ng/ml). Rapid and complete absorption from the injection site in muscle to the systemic circulation was observed. The bioavailability of muscular injection was unity. The hepatic extraction ratio was 0.94, and the high plasma clearance could be explained in terms of hepatic blood flow rate-limited elimination. The major tissues in which biperiden was distributed were fat and muscle. The highest tissue-to-plasma partition coefficient in the steady-state was obtained for the lung. These three tissues comprised 56% of the total distribution volume.

Animals↗