Biomedical subjects

T Hatanaka

Publications and source records attributed to T Hatanaka.

At least 55 records · Page 3Linked to original sources

PubMed1999

A novel combretastatin A-4 derivative, AC-7700, shows marked antitumor activity against advanced solid tumors and orthotopically transplanted tumors.

AC-7700, a novel combretastatin A-4 derivative, suppresses the growth of solid tumors by inhibiting tumor perfusion. We evaluated the antitumor activity of AC-7700 on solid tumors in two experimental models, an advanced tumor model (murine colon 26 (c26) adenocarcinoma, colon 38 (c38) adenocarcinoma, MethA fibrosarcoma, Sarcoma 180 (S180), Lewis lung carcinoma (3LL), human LS180 adenocarcinoma) and an orthotopically transplanted tumor model (c26), compared with that of cisplatin (CDDP). The maximum tolerable dose (MTD) of CDDP suppressed early-stage c26 and c38 tumor growth when treatment was started after the tumor volume (TV) reached 0.2-0.5 cm3, but it showed reduced activity against the same tumors at an advanced growth stage when TV exceeded 2 cm3. At its MTD, AC-7700 was active against all tumors tested except 3LL in both early and advanced growth stages, reducing the tumor mass and having a curative effect in advanced c38 tumors. AC-7700 was also effective on orthotopically transplanted c26 tumors, showing a comparable activity to that on subcutaneous tumors. Unlike flavon acetic acid, which damages tumor vasculature by inducing endogenous tumor necrosis factor-alpha production, AC-7700 potently suppressed the growth of advanced c26 tumors in athymic as well as euthymic mice. These results suggest that AC-7700 is a novel antivascular agent that may have potent activity against advanced-stage cancer in the clinical setting.

Animals↗

PubMed1999

Influence of plasma dialysate from normal and renal dysfunction rats on the electroencephalogram and gamma-aminobutyric acid A receptor complex modulation of thiopental.

We have previously reported that brain sensitivity to thiopental with respect to electroencephalogram (EEG) is enhanced in uranyl acetate pretreated renal dysfunction rats. The results were attributed to pharmacodynamic factors. In this study, in vivo EEG and in vitro binding studies for gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex were performed to investigate the mechanism of the enhanced effect of thiopental. The receptor binding properties in the brain membrane from normal and renal dysfunction rats were examined using [3H]tertbutylbicycloorthobenzoate (TBOB), [3H]flunitrazepam and [3H]muscimol. The effect of plasma dialysate from normal (ND) and renal dysfunction rats (RDD) on the thiopental induced EEG and receptor binding were also examined to confirm the role of endogenous compounds. The intrinsic receptor binding characteristics of various sites and their allosteric interaction with thiopental was similar in membrane preparations from normal and renal dysfunction rats. However, RDD, when compared to ND, enhanced the EEG induced by thiopental. At the receptor level, RDD significantly enhanced the thiopental induced inhibition of TBOB. No difference was found between the influence of ND and RDD on the interaction between thiopental and flunitrazepam or muscimol binding. These results showed that the thiopental induced allosteric inhibition of TBOB binding was potentiated by some endogenous compounds in RDD and suggests that this action might be the mechanism, at least in part, for the increased sensitivity of thiopental in renal dysfunction rats.

Animals↗

PubMed1999

Simultaneous transport and metabolism of nicotinic acid derivatives in hairless mouse skin.

In vitro simultaneous transport and metabolism of three ester prodrugs of nicotinic acid (NA), methyl nicotinate (MN), ethyl nicotinate (EN) and butyl nicotinate (BN) were studied using excised skin from hairless mouse. Hydrolysis studies of these esters with and without skin homogenate were also done at 37 degrees C. Both the ester and NA were detected in all receiver solutions in permeation studies, and no chemical hydrolysis of the esters was found, indicating that the esters were hydrolyzed during the skin permeation process. The total (ester+NA) flux from a saturated solution of ester prodrugs was higher than that of NA and was highest for MN, followed by EN and BN, whereas the total permeability coefficient of ester prodrugs increased from MN to BN. A difference in the NA/total flux ratio was found among these prodrugs; thus, esterase activity was also dependent on the alkyl chain length of the esters. The total flux from each ester solution increased linearly with the donor concentration. NA flux from MN and EN solutions increased with an increase in the donor concentration and reached a plateau at the high concentration range, suggesting that metabolic saturation occurred. NA fluxes at the plateau were similar among ester prodrugs and corresponded to the Vmax estimated from the hydrolysis experiment. The order of donor concentration at which NA reached a plateau also corresponded to the order of Km. It was confirmed that a difference in alkyl chain length of the ester prodrugs affected not only permeability but also metabolism in the skin permeation process.

Alkylation↗

PubMed1999

Influence of enzyme distribution and diffusion on permeation profile of prodrug through viable skin: theoretical aspects for several steady-state fluxes in two transport directions.

A physical modeling and theoretical simulation aspect for the simultaneous transport and metabolism of prodrug in viable skin were described to understand the influence of enzyme distribution and diffusion. The physical model was formulated assuming that the viable epidermis and dermis have distinct diffusional and metabolic characteristics and that the metabolic reaction in each layer follows a first-order kinetics. The differential equations were analytically solved, and the steady-state flux of prodrug into receiver and that of metabolite into receiver and donor and the total flux in forward (epidermis to dermis) and backward (dermis to epidermis) directions were derived. The flux of prodrug in the forward direction always equals that in the backward direction. The metabolite flux into receiver became transport direction-dependent when the diffusional characteristic of epidermis was different from that of dermis regardless of enzyme distribution. The metabolite flux into donor in the backward direction relative to that in the forward direction increased with increase of dermis/epidermis ratio of any parameters among metabolic rate constant, partition coefficient and diffusion coefficient of prodrug and metabolite. The difference of total flux between the 2 transport directions was caused by the difference in metabolic rate constant, partition coefficient and diffusion coefficient of prodrug between epidermis and dermis. The higher any parameters were for dermis, the higher was total flux in the backward direction.

Biological Transport↗

PubMed1999

Single dose pharmacokinetics and pharmacodynamics of oxazepam in normal and renal dysfunction rats.

The purpose of this work was to investigate the disposition characteristics and pharmacodynamics of a benzodiazepine, oxazepam, in renal dysfunction rats. For the in vivo experiment, normal and renal dysfunction rats were given 40 mg/kg of oxazepam as the bolus dose. A quantitative electroencephalographic (EEG) method was used as the surrogate measure of the pharmacological response. The oxazepam concentration in plasma and cerebrospinal fluid (CSF) was assayed by the HPLC method. The steady-state volume of distribution and clearance based on total and unbound plasma did not change in renal dysfunction rats. Amplitude changes in the EEG induced by oxazepam in normal and renal dysfunction rats were characterized by a log-concentration response model or sigmoidal Emax model. The pharmacodynamic parameters from these models were not altered in renal dysfunction. In in vitro binding studies for gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex, the oxazepam-induced effect was not potentiated by the plasma dialysate from renal dysfunction rats. Thus, it was suggested that the brain sensitivity to benzodiazepines was not altered in renal insufficiency.

Animals↗

PubMed1999

Synthesis and antitumor activities of amino acid prodrugs of amino-combretastatins.

The synthesis and antitumor activity of water-soluble amino acid prodrugs of amino-combretastatins were reported. Among the synthesized compounds, 7e (CS-39-L-Ser HCI, AC-7700) showed enhanced antitumor activity and decreased toxicity in a Colon 26 murine adenocarcinoma model. Compound 7e showed improved solubility and was easily formulated for in vivo administration. Compound 7e was cleaved to generate the parent compound, CS-39, in the whole blood of mice as well as man, possibly by the action of amino peptidase on the erythrocyte membrane.

Animals↗

PubMed1998

Novel B-ring modified combretastatin analogues: syntheses and antineoplastic activity.

A series of B-ring modified combretastatin analogues were synthesized and their inhibitory activity against microtubule assembly, cytotoxic activity against Colon 26 adenocarcinoma cancer cell line were evaluated. Among these, pyridone derivative (19) showed strong antimitotic activity and cytotoxicity, along with excellent water-solubility.

Antineoplastic Agents, Phytogenic↗

PubMed1998

Syntheses and antitumor activity of cis-restricted combretastatins: 5-membered heterocyclic analogues.

A series of cis-restricted combretastatin analogues with 5-membered heterocycles were synthesized and their inhibitory activity against microtubule assembly and cytotoxic activity against the colon 26 adenocarcinoma cancer cell line were evaluated. Some of the heterocyclic analogues showed potent antitubulin activity and cytotoxicity. Compounds 16 and 35 showed marked tumor growth suppression in the colon 26 murine tumor model.

Animals↗

PubMed1998

Novel combretastatin analogues effective against murine solid tumors: design and structure-activity relationships.

A series of combretastatin A-4 (CA-4) analogues were synthesized, and their cytotoxic effects against murine Colon 26 adenocarcinoma and inhibitory activity on tubulin polymerization were evaluated. Since CA-4 has limited aqueous solubility, the target compounds were designed to improve solubility by introduction of a nitrogen-containing group. Among the compounds synthesized, those with an amino moiety in place of the phenolic OH of CA-4 showed potent antitubulin activity and cytotoxicity against murine Colon 26 adenocarcinoma in vitro. Some of the compounds which were potent in vitro were evaluated in the murine tumor model Colon 26 in vivo. Among these, 13bHCl, 21aHCl, and 21bHCl showed significant antitumor activity in the animal model, while CA-4 was ineffective. 13bHCl and 21aHCl were further evaluated in two murine tumor models (Colon 38 and 3LL) and human xenografts HCT-15. These compounds showed potent antitumor activity comparable or superior to that of CDDP. The structure-activity relationships of this series of compounds are also discussed.

Acrylonitrile↗

PubMed1998

Pharmacokinetic and pharmacodynamic evaluation for tissue-selective inhibition of cholesterol synthesis by pravastatin.

The tissue-selective inhibition of cholesterol synthesis by pravastatin was evaluated pharmacokinetically and pharmacodynamically. Plasma, tissue, urine, and bile concentrations were measured after i.v. bolus injection of pravastatin to rats at various doses. The total body clearance and steady state volume of distribution decreased with increasing dose. A saturable biliary excretion was also observed. The time course of plasma and liver concentrations was described by a three-compartment model, consisting of a central compartment, a deep compartment with an nonsaturable uptake process, and a shallow compartment with saturable uptake and nonsaturable elimination processes. It suggests that a mechanism for the decrease in the total body clearance and distribution volume might be explained by a saturation of pravastatin uptake into the liver. Plasma concentration data after oral administration was also fitted to the same model by connecting an absorption compartment to the shallow compartment. The inhibitory activity of pravastatin against cholesterol synthesis in liver could be related to the concentration in the shallow compartment via a sigmoidal Emax model and the obtained pharmacodynamic parameters were comparable to those in vitro. Results suggest that the carrier-mediated hepatic uptake of pravastatin is actually responsible for the hepatoselective inhibition of cholesterol synthesis under physiological conditions.

Administration, Oral↗

PubMed1998

Pharmacokinetic and pharmacodynamic consequences of thiopental in renal dysfunction rats: evaluation with electroencephalography.

The purpose of this work was to investigate the disposition characteristics and pharmacodynamics of a barbiturate, thiopental, in renal dysfunction rats. Normal and renal dysfunction rats were infused with 40 and 20 mg/kg of thiopental, respectively. The quantitative electroencephalographic (EEG) method was used as the surrogate measure of pharmacological response. Signals from two electrodes fitted on the skull of rats were continuously measured, recorded and subjected to off-line analysis. Total amplitude (0.5-29.9Hz) from aperiodic analysis was taken as the EEG parameter. Thiopental concentration in plasma and cerebrospinal fluid (CSF) was assayed by an HPLC method. Steady-state volume of distribution was increased in renal dysfunction rats due to decreased plasma protein binding, while no change in clearance or volume of distribution based on the plasma unbound concentration was observed. Amplitude changes induced by thiopental in both normal and renal dysfunction rats were characterized by the sigmoidal Emax model. The unbound plasma concentration at half maximal effect was lowered by 30% in renal dysfunction rats as compared to the normal rats. In addition to considerable alteration in the pharmacokinetics of thiopental, it was also evident that renal impairment is associated with an increase in apparent pharmacological sensitivity, which is related to affinity.

Analysis of Variance↗

PubMed1996

The possible risk of lower-limb sclerotherapy causing an extended hypercoagulable state.

The risk of thrombosis after lower-extremity sclerotherapy is still an unresolved issue. This study was conducted to investigate the influence of sclerotherapy on coagulation and fibrinolysis by examining 20 patients who underwent surgical procedures, 10 of whom were treated by surgery alone (control group), while the other 10 were given sclerotherapy using 1% hydroxypolyaetoxydodecan as polidocanol (sclerotherapy group). Sex, age, and severity of disease was comparable between the two groups. No significant difference was found in the transient elevation of acute phase proteins, C-reactive protein (CRP), or fibrinogen. Thrombin antithrombin III complex (TAT), a marker of coagulation, transiently increased following treatment. In the control group, TAT peaked 3 days after treatment, whereas in the sclerotherapy group the elevation was prolonged, peaking 7 days after treatment. Elevation of the markers of fibrinolysis, plasmin plasmin inhibitor complex (PIC) and fibrin degradation products (FDP), was slower than that of TAT, peaking 7 days after treatment in both groups, the plasma PIC being significantly enhanced 7 days after treatment in the sclerotherapy group. A significant decrease in the platelet count was observed 3 days after treatment in the sclerotherapy group. These results suggest that sclerotherapy may enhance coagulation or fibrinolysis after surgical procedures.

Adult↗

PubMed1996

Analysis of simultaneous transport and metabolism of ethyl nicotinate in hairless rat skin.

PURPOSE: Simultaneous skin transport and metabolism of ethyl nicotinate (EN), a model drug, were measured and theoretically analyzed. METHODS: Several permeation studies of EN or its metabolite nicotinic acid (NA) were done on full-thickness skin or stripped skin with and without an esterase inhibitor. Permeation parameters such as partition coefficient of EN from the donor solution to the stratum corneum and diffusion coefficients of EN and NA in the stratum corneum and the viable epidermis and dermis were determined by these studies. Enzymatic parameters (Michaelis constant Km and maximum metabolism rate Vmax) were obtained from the production rate of NA from different concentrations of EN in the skin homogenate. Obtained permeation data were then analyzed by numerical method based on differential equations showing Fick's second law of diffusion in the stratum corneum and the law with Michaelis-Menten metabolism in the viable epidermis and dermis. RESULTS: Fairly good steady-state fluxes of EN and NA through the skin were obtained after a short lag time for all the concentrations of EN applied. These steady-state fluxes were not proportional to the initial donor concentration of EN: EN and NA curves were concave and convex, respectively, which suggests that metabolic saturation from EN to NA takes place in the viable skin at higher EN application. The steady-state fluxes of EN and NA calculated by the differential equations with resulting permeation and enzymatic parameters were very close to the obtained data. CONCLUSIONS: The present method is a useful tool to analyze simultaneous transport and metabolism of many drugs and prodrugs, especially those showing Michaelis-Menten type-metabolic saturation in skin.

Animals↗

PubMed1996

Kinetics of swelling of compressed cellulose matrices: a mathematical model.

PURPOSE: A model for swelling time course of compressed cellulose matrix is presented. METHODS: The model incorporates the two most important features: water penetration by diffusion and volume change due to swelling. Approximations of the model for small t values and for large t values are also derived, which are utilized in a handy routine for estimation of swelling parameters. RESULTS: The observed time courses of thickness change with compressed matrices of methyl cellulose and hydroxypropyl cellulose agree well with the calculated values of the proposed model. CONCLUSIONS: The proposed model is compatible with the observed swelling kinetics.

Cellulose↗

PubMed1996

Influence of pH on skin permeation of amino acids.

Skin permeation of amino acids through excised rat skin was measured at various pH values. The permeabilities varied with the donor pH and amino acid, indicating that each ionic species of amino acid may have a different permeability. The permeability coefficient of each ion was estimated from the permeability-pH profiles using the dissociation constants. The estimated values for mono-cation and uncharged zwitterion were not dependent on the lipophilicity but on the size of the amino acid, suggesting a porous mechanism of transport. The permeability coefficient was highest for di-cation, followed by mono-cation, positively charged, uncharged and negatively charged zwitterions. The electrical potential difference across the skin was too small to affect the permeation of ions. The permselective property of skin thus seems to be determined by the difference of diffusivity in aqueous pores of skin due to the hydration of ions and other factors.

Amino Acids↗

PubMed1996

Effect of arterial compliance on carotid sinus baroreceptor reflex control of the circulation.

Capacitive properties of the arterial and venous segments of the peripheral circulation are important in the regulation of cardiac output and arterial blood pressure. We examined whether an acute increase in arterial compliance C(a) would alter carotid sinus baroreflex control of the circulation. Eight mongrel dogs were anesthetized with pentobarbital sodium, and the carotid sinus regions were isolated and perfused with nonpulsatile pressures. Open-loop baroreflex response curves for systemic arterial pressure (SAP), heart rate (HR), aortic blood flow (ABF), peripheral vascular resistance (PVR), and left ventricular (LV) contractility were obtained when carotid sinus pressure (CSP) was changed in 25-mmHg steps between 50 and 200 mmHg under a control condition and when C(a) was increased by including two hydraulic compliant chambers to the arterial circulation (CS 1.72 ml/mmHg and CL 5.05 ml/mmHg). The compliant chambers significantly increased C(a) and altered the ratio of arterial to venous compliance C(a)/Cv). Changes in C(a)/Cv significantly decreased the maximal open-loop baroreflex gain (Gmax) for SAP (-2.3 +/- 0.5, -1.6 +/- 0.3, and -1.1 +/- 0.2 mmHg/mmHg, control vs. CS vs. CL, P < 0.05). Gmax for ABF was decreased by CS (-0.9 +/- 0.2 vs. -0.3 +/- 0.1 ml.kg-1.min-1, control vs. CS, P < 0.05), and CL reversed the reflex changes in ABF (Gmax: +0.6 +/- 0.3 ml.kg-1.min-1). Gmax for HR, PVR, and LV contractility was not altered when C(a) was increased (P > 0.05). These findings indicate that an increase in C(a) changes C(a)/Cv and alters carotid baroreflex control of SAP by modifying the ABF response. We conclude that a change in C(a)/Cv affects the reflex control of the circulation by altering the distribution of blood volume between the arterial and venous circulations.

Animals↗

PubMed1996

Invariance of the resistance to venous return to carotid sinus baroreflex control.

Despite the well-established fact that the carotid sinus baroreflex system has profound control over the physical properties of the systemic circulation, the resistance to venous return (RVR) seems to be invariant of such control. We hypothesized that this apparent paradox may be explained from the baroreflex changes in systemic arterial compliance. In 12 pentobarbital-anesthetized mongrel dogs, RVR was measured at controlled carotid sinus pressures (CSP) of 50 and 200 mmHg with normal and artificially increased arterial compliance. Arterial compliance was determined from the arterial pressure decay when systemic blood flow was stopped with total vena caval occlusion. Changing CSP between 50 and 200 mmHg changed RVR significantly only under the condition of artificially increased arterial compliance. A four-parameter lumped model of the systemic circulation revealed that the baroreflex changes in arterial compliance and arterial resistance, which occurred in opposite directions, prevented a change in RVR when CSP was changed. The data also suggested that approximately 75% of RVR was attributed to large and conduit veins, the resistances along which were insensitive to baroreflex control. We concluded that the invariance of RVR results from a combination of 1) baroreflex change in the arterial compliance, 2) baroreflex insensitivity of the resistance along large and conduit veins, and 3) spatially distinct location between the major site of reflex change in capacitance and the major site of compliance.

Animals↗

PubMed1996

Biodegradability of oxidized poly(vinyl alcohol).

Poly(vinyl alcohol) dehydrogenase (PVADH) purified from Pseudomonas sp. 113P3 catalyzed an oxidation of poly(vinyl alcohol) (PVA) in the presence of pyrroloquinoline quinone (PQQ) to give a beta-diketone structure on PVA. Although PVADH oxidized not only enzymatically oxidized PVA but also chemically oxidized PVA, PVA-degrading microorganisms, Pseudomonas sp. 113P3 and Arthrobacter tumescens sp. 52-1 grew on the enzymatically oxidized PVA, but not on the chemically oxidized PVA. This suggests that the growth of PVA-degrading microorganisms is affected by the structure of oxidized PVA.

Alcohol Oxidoreductases↗