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Biomedical subjects

T Iga

Publications and source records attributed to T Iga.

At least 73 records · Page 4Linked to original sources
PubMed1998

[The cause of polyurethane catheter cracking during constant infusion of etoposide (VP-16) injection].

We studied the cause of cracking of a clinically used polyurethane (PU) catheter during the constant infusion of etoposide (VP-16) injection (Lastet), administered without dilution to patients as a part of combination high-dose chemotherapy. After VP-16 injection was infused into the PU catheter at a constant infusion rate (30 ml/h) for 24 h, a decrease in the elasticity (36% of untreated) and on increase in the length of the catheter (3.7%) were observed. These changes were significantly higher than those treated with the control saline. The similar changes of the PU catheter were observed after treatment with a basal solution containing polyethylene glycol 400 (PEG 400), polysorbate 80 and ethanol, which is the vehicle of the VP-16 injection, and with ethanol alone. Moreover, obvious degeneration of the internal wall (occurrence of spots like melting) and cutting face (micro-cracking) of the catheter was observed with an electron microscope after treatment with the vehicle. On the other hand, the elasticity or extension of the PU catheter were not changed after treatment with saline or PEG 400. From these findings, it was suggested that the degeneration and subsequent cracking of the PU catheter during the infusion of VP-16 injection was caused by ethanol contained in its injection solution. No cracking or morphological changes of polyvinyl chloride (PVC) and silicone catheters were found after treatment with the vehicle solution. However, since it has been reported in previous reports that di(2-ethylhexyl)phthalate was leached from PVC bags, the high dose chemotherapy with the dilution-free VP-16 injection should be achieved safely and effectively using a silicon catheter, rather than the PU catheter.

Antineoplastic Agents, Phytogenic↗
PubMed1998

[Therapeutic effects of beclomethasone dipropionate enemas on colon damage of inflammatory bowel disease model rats].

The effects of beclomethasone dipropionate (BDP) enemas on ulcerative colitis were investigated by administrating BDP enemas to Fischer male rats with an inflammatory bowel disease induced by 2,4,6-trinitrobenzensulfonic acid (TNB). After administration of a TNB ethanol solution to rats, diarrhea and melena were found in all rats, and the wet tissue weights of the colons in the rats increased by erosion and thickness of epithelial mucous membranes with edema. BDP enemas were administered to the rats one time a day at a dose of 20 or 50 micrograms of BDP for 4 or 11 days from the day 3 after TNB treatment, respectively. After dosing of BDP, the rate of rats developing diarrhea and melena decreased more with time in comparison with that of BDP-free rats, and the symptoms of all rats developing the diseases were improved on the day 4 after administration of a dose of 50 micrograms of BDP. A dose dependent recovery in the wet tissue weights and scores of damages, and the myeloperoxidase (MPO) activity in the tissue were found at the early days (until the day 4). However, their measurements on the day 11 at each dose of BDP were not different from those of control rats significantly, as the damages in the colons of the control rats were recovered naturally with time. In conclusion, the clinical usefulness of BDP enemas was supported by elucidating the dose dependent effect of BDP at the early days in the model rats with an inflammatory bowel disease induced by TNB.

Animals↗
PubMed1998

Pharmacokinetic and pharmacodynamic study of a new nonsteroidal 5 alpha-reductase inhibitor, 4-[3-[3-[Bis(4-isobutylphenyl)methylamino]benzoyl]-1H-indol-1-yl]-butyr ic acid, in rats.

The pharmacokinetic and pharmacodynamic behaviors of 4-[3-[3-[Bis(4-isobutylphenyl) methylamino] benzoyl]-1H-indol-1-yl]-butyric acid (FK143), a new nonsteroidal steroid 5 alpha-reductase inhibitor, in the ventral prostate were investigated after i.v. administration to rats. The relationship between blood concentrations at 24 hr and doses was linear in the range of 0.1 to 20 mg/kg. However, the levels of FK143 in the prostate were saturated over the dose of over 5 mg/kg. The dissociation constant (Kd) and maximum amount of binding substances (Bmax), calculated according to nonlinear kinetic analysis including a specific binding pool, was 0.0553 +/- 0.0117 microgram/ml (92 nM, estimated value +/- S.D.) and 0.908 +/- 0.092 microgram/g tissue, respectively. A combined pharmacokinetic/pharmacodynamic (PK/PD) model was constructed using change in dihydrotestosterone (DHT) levels in the prostate after i.v. administration of FK143 as an index for its pharmacological effect and blood concentration as an input function. The apparent reaction rate constant of drug and enzyme (K) was 39.7 +/- 25.1 g tissue/microgram/hr (estimated value +/- S.D.), the apparent turn-over rate constant of enzyme (k) was 0.140 +/- 0.107 hr-1, the elimination rate constant of DHT (kel, DHT) was 1.13 +/- 0.94 hr-1 and the fraction of FK143-insensitive DHT synthesis (F) was 0.461 +/- 0.037. The PK/PD analysis suggested that the duration of the effect of FK143 was related to its accumulation in the binding pool of the prostate. After i.v. administration of FK143 in the range of 0.1 to 20 mg/kg, the DHT levels in the prostate decreased to about 40% of control value, after which despite the rapid decline of blood FK143 concentration, slowly recovered according to the elimination rate of FK143 in the prostate. Moreover, the PK/PD profiles of FK143 after repeated i.v. administration were predictable by using the PK/PD parameters obtained after single administration of FK143.

5-alpha Reductase Inhibitors↗
PubMed1998

Quantitative prediction of the interaction of midazolam and histamine H2 receptor antagonists in rats.

To quantitatively evaluate drug-drug interactions involving metabolic processes in the liver, we attempted to predict the increasing ratio of the plasma concentration of midazolam (MDZ) in the presence of cimetidine (CIM) or nizatidine (NZD) in rats. Under steady-state conditions for the plasma concentration of CIM or NZD, MDZ was administered through the portal vein. The AUC of MDZ in the presence of CIM was 2.5-fold higher than that in the absence of CIM. There was no effect of NZD on the AUC of MDZ. The liver/plasma concentration ratios for CIM and NZD were 4.0 and 2.7, respectively. The estimated liver unbound concentration (CH,f)/plasma unbound concentration (Cp,f) ratios for CIM and NZD were 1.9 and 2.4, respectively, suggesting concentrative hepatic accumulation of both drugs. The oxidative metabolism of MDZ in rat liver microsomes was competitively inhibited by CIM or NZD, and the Ki values of CIM and NZD were 110 and 2600 microM, respectively. Based on these data obtained in vivo and in vitro, the increasing ratios for MDZ in the presence of CIM or NZD were predicted using the equations Rp = 1 + Cp,f/Ki and RH = 1 + CH,f/Ki. The observed increasing ratios in the presence of CIM were very close to RH, compared with Rp. However, Cp, f and CH,f were much less than Ki and there was no difference between Rp and RH in the presence of NZD. Consequently, Cp,f and CH, f were greater than or equal to Ki and Cp,f was not equal to CH,f, as in the presence of CIM, and it was indicated that CH,f was more suitable for quantitatively predicting the drug-drug interactions than was Cp,f.

Animals↗
PubMed1997

Determination of erythromycin concentrations in rat plasma and liver by high-performance liquid chromatography with amperometric detection.

A simple method for the quantitative determination of erythromycin (EM) concentrations in rat plasma and liver by high-performance liquid chromatography with amperometric detection was developed. EM was extracted from 200 microl of plasma or liver homogenate sample under sodium hydroxide alkaline conditions with tert.-butyl methyl ether. Oleandomycin was used as an internal standard. The recovery rate of EM was up to 100%. The detector cell potential for the oxidation of EM was +1100 mV. The calibration curves were linear over the concentration ranges 0.1-20.0 microg/ml for plasma and 0.5-100.0 microg/g for liver. The method was applied to the determination of the plasma and liver concentrations of EM in rats after intravenous administration (50 mg/kg dose). The method presented here has proved to be of great use for the investigation of the pharmacokinetic characteristics of EM in small animals such as rats.

Animals↗
PubMed1997

Prediction of the therapeutic dose for benzodiazepine anxiolytics based on receptor occupancy theory.

Many benzodiazepines (BZPs) are now used as anxiolytics with nearly 200-fold variety of therapeutic doses. The variation of the doses of BZPs is due to differences both in their pharmacokinetics and in their receptor binding characteristics. The purpose of this study is to clarify the mechanism of the differences in therapeutic dose by retrospective analyses and to develop a system for the quantitative estimation of optimal doses of BZPs. The values of receptor dissociation constant (Kd), which indicates the binding affinity of each BZP at the receptor site, were obtained from a number of works based on in vitro binding experiments. The plasma unbound concentrations of the BZPs and their active metabolites were calculated using the reported values of their total plasma concentrations after average oral doses of the BZPs and the values of their plasma unbound fractions, which were also taken from the literature. There were log-linear relationships between the Kd values of BZPs and their average therapeutic doses or maximum plasma concentrations, but the correlation coefficients were relatively small (r < 0.77). In contrast, a good log-linearity (r = 0.96) was observed in the correlation between their Kd values and the effective plasma unbound concentrations considering the active metabolites. This finding indicates that the receptor occupancy after administration of therapeutic dose of BZPs is consistent (52.3 +/- 3.2%) among the BZPs. In this study, we also develop a possible system for estimating the appropriate doses of BZPs based on receptor occupancy theory.

Administration, Oral↗
PubMed1997

The pharmacokinetics of glycyrrhizin and its restorative effect on hepatic function in patients with chronic hepatitis and in chronically carbon-tetrachloride-intoxicated rats.

The relationships between the pharmacokinetic behaviour of glycyrrhizin and its restorative effect for hepatic function were investigated in patients with chronic hepatitis and in rats chronically treated with carbon tetrachloride (CCl4-treated rats). In patients, the restorative effects in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were 62.2 +/- 7.4 and 64.4 +/- 7.5%, respectively, after daily 80 mg intravenous (i.v.) doses of glycyrrhizin for 2 weeks, and 63.1 +/- 19.1 and 68.7 +/- 15.2% after 120 mg doses. The present work suggests that the threshold plasma glycyrrhizin concentration for sufficient effect is near 5 micrograms mL-1. In rats, the total body clearance (Cltot) for glycrrhizin in the CCl4-treated rats after i.v. administration of glycyrrhizin (5 mg kg-1 dose) was three-tenths of that of the control, and the t1/2 for glycyrrhizin was 3.4-fold longer than that of the control. A good correlation was observed between Cltot and AST (r = -0.838) or ALT (r = -0.873) activity in both rats. When glycyrrhizin was administered intraperitoneally (i.p.) three times a week for 2 weeks, both the AST and ALT activities in the CCl4-treated rats showed a greater improvement than for a 10 mg kg-1 dose. Furthermore, the finding on the threshold plasma concentration in patients as above was also supported from the results of the experiments in rats.

Alanine Transaminase↗
PubMed1997

Inhibitory effect of new quinolones on GABA(A) receptor-mediated response and its potentiation with felbinac in Xenopus oocytes injected with mouse-brain mRNA: correlation with convulsive potency in vivo.

Convulsions induced by the interaction of new quinolone antimicrobial agents (NQs) and nonsteroidal anti-inflammatory drugs (NSAIDs) were previously reported, and blockade of GABA(A) receptor by NQs and its potentiation with NSAIDs were considered as one of its possible mechanisms. However, useful methodology for prediction of convulsive potencies of NQs with or without NSAIDs in vivo based on in vitro screening was not established. Therefore, we applied the Xenopus oocytes translation system of exogenous messenger RNA (mRNA) to examine the mechanism of convulsion induced by interaction of NQs and NSAIDs, and the relationship between convulsive potencies in vivo and inhibitory effect on GABA-induced current response in vitro was investigated. This system also has alternative possibility for the in vivo toxicological studies sacrificing innumerous animals. Glutamic acid, kainic acid, quisqualic acid, NMDA, and serotonin-induced currents were not modified by ENX of NQs and/or FLB of NSAIDs, while glycine- and ACh-induced currents were slightly inhibited. GABA (10 microM)-induced current was inhibited by norfloxacin (NFLX), ciprofloxacin, ENX, and ofloxacin (OFLX) with IC50 of 17, 33, 58, and 280 microM, respectively. IC50 of NQs decreased to 1/3 (OFLX)-1/165 (NFLX) in the presence of 10 microM FLB, while FLB did not modulate the GABA response in the absence of NQs. CSF concentration of ENX at the time of convulsion in clinical situation approximated the IC50 of ENX for the GABA response. The increase of incidence for NQs-induced convulsion by concomitant NSAIDs in vivo could also be explained by the potentiation of inhibitory effects of NQs with FLB in the normal range of CSF concentration of these drugs. We also examined convulsive potency (threshold dose for convulsion) in CNS by intracerebral infusion of NQs to mice with or without FLB pretreatment, and significant correlations between the convulsive potencies and IC50 of NQs for the GABA response were observed. These findings suggested that the blockade of GABA-ersic neurotransmission in CNS is a dominant mechanism of convulsion induced by NQs and that the convulsant-adverse reaction of NQs in vivo may be predicted from the inhibitory effect on the GABA(A) receptor in vitro using the Xenopus oocytes translation system of exogenous mRNA.

Animals↗
PubMed1997

Pharmacodynamic modeling for change of locomotor activity by methylphenidate in rats.

PURPOSE: The locomotive activity changes after intravenous (i.v.) administration of methylphenidate (MPD) in rats were pharmacodynamically analyzed. METHODS: MPD concentration in plasma, MPD concentration and dopamine (DA) level in striatal dialysate collected by microdialysis method, and the locomotor activity after i.v. administration of MPD (2, 5 and 10 mg/kg doses) were used for the analysis. RESULTS: The transport of MPD from plasma to the interstitial fluid in the brain could be expressed by the linear two-compartment model. The clockwise hysteresis between the MPD concentration and the DA level in the dialysate could be explained by the pharmacodynamic model considering Michaelis-Menten type reuptake process of the extracellular DA into the terminal of the dopaminergic nerve and its competitive inhibition by the extracellular MPD. The inhibition constant (Ki) of MPD for DA reuptake was estimated to be 41.3 +/- 73.8 nM (mean +/- SE), which was closely consistent with the in vitro value after correction with dialysis recovery. The relationship between DA level in dialysate and locomotor activity was expressed by the Emax model considering two contrary effects, hyperkinesia and stereotypy. The bi-phasic locomotor activity-time profiles after high dose of MPD could be represented by this model. CONCLUSIONS: The developed model made it possible to explain the tolerance in DA increase and the complicated locomotive change induced by MPD, and may by useful for other DA reuptake inhibitors, such as amphetamine and methamphetamine.

Animals↗
PubMed1997

Pharmacokinetic analysis of benzodiazepine receptor binding of [123I]iomazenil in human brain.

PURPOSE: The purpose of this study is to evaluate the central benzodiazepine (BZP) receptor binding of iomazenil (IMZ) by pharmacokinetic analysis and to establish a methodology for the diagnosis of CNS disorders with abnormalities in BZP receptor binding. METHODS: BZP receptor binding of IMZ was analyzed kinetically using plasma concentration-time profiles and dynamic single photon emission computed tomography (SPECT) data obtained after the intravenous administration of IMZ to patients with neuropsychiatric disease. The analysis was based on a 3-compartmental model including the processes of both blood-brain barrier (BBB) transport and BZP receptor binding. RESULTS: Hydrolized metabolite of IMZ was detected in plasma, indicating the need for separation by HPLC. The BBB influx clearance and the receptor binding potential of IMZ in the medial temporal region was reduced in the epileptic patient. CONCLUSIONS: Our findings suggest the possibility of detecting the epileptic focus by using our method.

Blood-Brain Barrier↗
PubMed1997

A comparative pharmacokinetic-pharmacodynamic study of the electrocardiographic effects of epinastine and terfenadine in rats.

The effects of epinastine hydrochloride and terfenadine on electrocardiographic (ECG) parameters in rats were investigated from a pharmacokinetic and pharmacodynamic perspective. Epinastine hydrochloride (1 or 3 mg kg-1 h-1) or terfenadine (5, 10 or 15 mg kg-1 h-1) was intravenously infused into rats anaesthetized with urethane and alpha-chloralose. The changes in the QT interval derived from limb lead II and the chest lead, heart rate and PR interval were analysed. The time-course of the plasma drug-concentration of each drug was also investigated. Terfenadine prolonged the QT interval in an infusion-rate-dependent manner, its EC50 value was 792-1039 ng mL-1. An obvious QT prolongation was, moreover, observed even at a plasma terfenadine concentration of 100-200 ng mL-1, which is clinically quite high, but might be achieved under a definite condition such as a restrained terfenadine metabolism. Terfenadine also induced PR prolongation and bradycardia in an infusion-rate dependent manner. Epinastine slightly increased the heart rate, but did not affect any of the other ECG parameters even at a plasma concentration of 400 ng mL-1, which is more than 10 times the maximum concentration attained after an ordinary dosage regimen in man. We conclude that epinastine might have an advantage over terfenadine in avoiding adverse electrocardiographic reactions.

Animals↗
PubMed1997

Neurotoxic study of H2 antagonists using Xenopus oocytes injected with mouse-brain mRNA.

To clarify the dominant mechanism for the convulsant activity of H2 antagonists, the effects of an H2 antagonist, cimetidine, on membrane currents induced by various agonists were investigated. In Xenopus oocytes injected with mouse-brain mRNA, acetylcholine (ACh), serotonin (5-HT), gamma-aminobutyric acid (GABA), glycine (Gly), glutamic acid (Glu), kainic acid (KA), quisqualic acid (QA) and N-methyl-D-aspartic acid (NMDA)-induced current responses were recorded under a voltage-clamp condition. Cimetidine inhibited GABA-induced currents in a concentration-dependent manner; however, the current responses induced by the other agonists were not modified. The IC50 of various H2 antagonists, famotidine, nizatidine, cimetidine and ranitidine, for GABA (10 microM)-induced current response were 66, 260, 450 and 980 microM, respectively. However, these values of cimetidine and ranitidine were 40-400 times higher than the reported brain and cerebrospinal fluid (CSF) concentration of H2 antagonists at the occurrence of a clonic convulsion in vivo. In conclusion, we observed an inhibitory effect of H2 antagonists on the GABA response; however, this inhibition of GABA-mediated neurotransmission may not be the dominant mechanism for H2 antagonist-induced clonic convulsion in vivo.

Animals↗
PubMed1997

Pharmacokinetic/pharmacodynamic analysis of neutrophil proliferation induced by recombinant granulocyte colony-stimulating factor (rhG-CSF): comparison between intravenous and subcutaneous administration.

Pharmacological effect after intravenous (i.v.) or subcutaneous (s.c.) administration of human recombinant granulocyte colony stimulating factor (rhG-CSF) was evaluated by using a physiologically based pharmacokinetic/pharmacodynamic model. The increase of neutrophil counts in blood after s.c. administration of rhG-CSF (0.5-1.0 microgram/kg) was larger than that after i.v. administration of the same dose, while area under the curves of plasma concentration of rhG-CSF after s.c. administration was smaller than that after i.v. administration (Azuma et al., J. Clin. Therap. Med., 5, 1579-1603, 1989). Based on the pharmacokinetic/pharmacodynamic model considering metabolic turnover of neutrophil in vivo, time course of absolute neutrophil counts in blood after either type of rhG-CSF administration to normal healthy volunteers was analyzed. The nonlinear relationship between the concentration of rhG-CSF and in vitro activity for proliferation of neutrophil could be explained by the drug-receptor-effector ternary complex model. These in vivo and in vitro models made it possible to understand the above-mentioned discrepancy of pharmacokinetic/pharmacodynamic behavior between i.v. and s.c. administration of rhG-CSF. Simulation of the neutrophil count-time profiles after repeated i.v. and s.c. dosing of rhG-CSF according to these models showed good agreement with the observed data. In order to obtain the rational dosage regimen of rhG-CSF from pharmacological and economical points of view, a slow constant infusion method may be more useful than rapid infusion.

Administration, Cutaneous↗
PubMed1997

Effect of acute renal failure on neurotoxicity of enoxacin in rats.

We investigated the effect of acute renal failure on the neurotoxicity of enoxacin (ENX) in rats. Experimental acute renal failure was produced by bilateral ureteral ligation. ENX was intravenously infused to ureter ligated (UL) and control rats, and its concentration in plasma, brain and cerebrospinal fluid (CSF) was compared. Plasma concentration of ENX increased rapidly in UL rats as compared with control rats. Brain/plasma concentration ratio (Kp)-time profile of ENX was similar in UL and control rats. Brain concentration of ENX at the occurrence of convulsion did not depend on the infusion rate, suggesting that in the brain tissue it equilibrates rapidly with the site of action for clonic convulsion. Brain concentration of ENX in UL rats at the occurrence of clonic convulsion was lower than that in control rats. A similar tendency was also observed with CSF concentration. In conclusion, the potentiation of neurotoxicity of ENX with acute renal failure may be caused by not only decreased capability for renal elimination of ENX but also increased sensitivity to convulsant activity of ENX in the central nervous system.

Acute Kidney Injury↗
PubMed1997

Effect of acute renal failure on the distribution of iomeprol, a nonionic contrast agent, to cerebrospinal fluid in rats.

The effect of acute renal failure on the pharmacokinetics concerning the cerebrospinal fluid (CSF) distribution of iomeprol, a nonionic contrast agent, was studied. The concentrations of iomeprol in the plasma and CSF were measured after intravenous (i.v.) administration at the dose of 50 or 500 mg/kg body weight. The time courses of plasma and CSF concentration were linear within the dose studied. Influx and efflux clearances estimated by simultaneous fitting were 4.6 x 10(-5) ml/min and 8.8 x 10(-4) ml/min, respectively, which suggested that the distribution of iomeprol to CSF low and linear. The distribution volume at steady state was 300-500 ml/kg, suggesting that iomeprol was readily distributed to the extracellular space but hardly distributed to the intercellular space. Total body clearance (9-13 ml/min/kg) indicated that iomeprol was mainly excreted by glomerular filtration. In the rat with acute renal failure induced by ligating the binary ureters, the concentration of iomeprol in CSF after i.v. administration of 500 mg/kg dose was much higher than that in the intact rat according to the delay of elimination from plasma (CLtot = 0.07 ml/min/kg). However, the time course of iomeprol concentration in CSF was predictable using the values of the influx clearance to CSF and the efflux clearance from CSF determined by intact rats. In conclusion, renal failure is one risk factor for central nervous system toxicity because of decreased total body clearance, while acute renal failure may not affect the transport of iomeprol to CSF.

Acute Kidney Injury↗
PubMed1997

[Quantitative evaluation of pharmacological effects and adverse effects based on receptor occupancy theory].

For the quantitative assessment of therapeutic/pharmacologic effects and adverse/toxic effects of drugs which interact with several specific receptors, we developed an integrated pharmacokinetic analysis system by considering a receptor occupancy theory and a ternary complex model. The developed system has made it possible to predict the optimal dosage for the investigation of drugs using pre-clinical and clinical data (phase I study) under development, and to assess quantitatively the intensity of adverse/toxic effects of drugs which are not observed in the stage of clinical study. As for commercially available drugs, the developed system may be useful for planning the rational drug dosage regimen to obtain desired therapeutic effects with minimum adverse/toxic effects. Our new methodology for the rational dosage regimen of a new drug will be established based on the results of this study.

Animals↗