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T Iga

Publications and source records attributed to T Iga.

At least 109 records · Page 6Linked to original sources
PubMed1995

The relationship between pharmacokinetic behaviour of glycyrrhizin and hepatic function in patients with acute hepatitis and liver cirrhosis.

The pharmacokinetic behavior of glycyrrhizin in four patients with acute hepatitis (hepatitis group) and six patients with liver cirrhosis (cirrhosis group) receiving chronically an IV administration of a 120 mg dose once a day or once every other day of glycyrrhizin was investigated. The plasma concentration of glycyrrhizin declined monoexponentially in both groups. The elimination half-life (t1/2) for glycyrrhizin in the hepatitis and cirrhosis groups varied significantly in the range of 2.7-7.6 h and 6.2-40.1 h, and the total body clearance (CLtot) in the range of 2.8-23.2 mL h-1 kg-1 and 1.4-12.9 mL h-1 kg-1, respectively. The t1/2 for glycyrrhizin in the hepatitis and the cirrhosis groups was about twice and eight times that in normal subjects, respectively, as reported previously, and CLtot values were about 0.7 and 0.23 times that in normal subjects, respectively. There was significant correlation between the CLtot and hepatic function (aspartate aminotransferase and alanine aminotransferase in serum) in both patient groups. With improvement of the liver function, the CLtot for glycyrrhizin increased from 2.8 ml h-1 kg-1 to 11.4 mL h-1 kg-1, and the t1/2 shortened from 7.6 h to 3.4 h. These findings indicated that the variation of pharmacokinetic behaviour of glycyrrhizin in both groups was closely related to the extent of the liver function.

Adult↗
PubMed1995

Antibronchospasmic, tachycardiac, and hypokalaemic effects of L-isoproterenol in guinea-pigs.

The relationship between antibronchospasmic, tachycardiac, or hypokalaemic effects and plasma concentration of L-isoproterenol (ISP) hydrochloride was investigated in guinea-pigs in vivo. ISP was infused at the rate of 10, 30, 50, 100, and 300 ng kg-1 min-1. The antibronchospasmic effect was expressed as the attenuation of methacholine-induced bronchospasm. The EC50 values of ISP for antibronchospasmic and tachycardiac effects were 5.12 nM and 3.95 nM, respectively. Although they were comparable to the values reported in vitro (7.23-0.358 nM, 1.77 nM), the concentration response relationship of ISP for antibronchospasmic effect was quite steep with a slope factor of more than six. Moreover, a decrease in plasma potassium level was not clearly detected. The experimental procedure in our present study was useful for evaluating antibronchospasmic and tachycardiac effects of beta-agonists.

Adrenergic beta-Agonists↗
PubMed1995

Risk assessment of adverse pulmonary effects induced by adrenaline beta-receptor antagonists and rational drug dosage regimen based on receptor occupancy.

To clarify the beta-1 selectivity of beta-adrenergic receptor blocking agents (beta-blocking agents) after typical oral doses, the relationships between the effects on exercise heart rate or FEV1 and beta-1 or beta-2 receptor occupancies (phi 1, phi 2) of seven beta-blocking agents, acebutolol, atenolol, metoprolol, oxprenolol, timolol, propranolol, and pindolol were analyzed retrospectively. Nonlinear relationships between the pharmacologic effect and phi 1 and between the pulmonary adverse effect and phi 2 were obtained. Based on these findings, a new index of cardiovascular selectivity is proposed, given by the ratio of beta-1 receptor occupancy to beta-2 receptor occupancy (phi 1/phi 2). Using this new index, there was a little difference in beta-1 selectivity between acebutolol and pindolol (3.1:1.0), in contrast to a marked difference in beta-1 selectivity (320:1) as a conventional index between these two drugs. This finding indicates that even beta-1 selective drugs must be administered carefully to patients with pulmonary disease. Furthermore, the relationship between the pharmacologic or pulmonary effects and phi 1 or phi 2 has been analyzed quantitatively with a ternary complex model and used to develop rational dosage regimens for beta-1 selective beta-blocking agents, such as atenolol, to obtain the desired pharmacologic effects with minimum adverse pulmonary effects.

Adrenergic beta-Antagonists↗
PubMed1995

Prediction of sleep disorders induced by beta-adrenergic receptor blocking agents based on receptor occupancy.

beta-adrenergic receptor blocking agents (beta-blocking agents) have been widely used clinically for the treatment of various cardiovascular conditions. However, beta-blocking agents are liable to cause sleep disturbance, such as vivid dreams, nightmares, increased waking, and insomnia. The mechanisms of the sleep disorders are not known, but several may conceivably be responsible for these CNS-related side effects. In the present study, we hypothesized that the sleep disorders are induced by the blockade of central or peripheral beta 2 receptors and/or central serotonin (5-HT) receptors. To verify the hypothesis, we retrospectively analyzed the relationships between the extent of the sleep disorders and the beta 1, beta 2, or 5-HT receptor occupancies for four beta-blocking agents (atenolol, metoprolol, pindolol, and propranolol). No significant correlations were observed among pharmacokinetic/physicochemical parameters (therapeutic dose, plasma concentration, plasma unbound concentration, cerebrospinal fluid concentration, and lipid solubility) and pharmacodynamic parameters (the scores of the sleep disorders such as the number of dreams). Furthermore, no significant relationship (correlation coefficient: r < 0.3) was observed between beta 1 receptor occupancies of the drugs and the number of dreams. On the other hand, good relationships (r > 0.95) were observed between central and peripheral beta 2 or central 5-HT receptor occupancies and the number of dreams. These findings suggest that beta 2 and/or 5-HT receptor occupancy is superior to beta 1 receptor occupancy as an index for the sleep disorders.

Adrenergic beta-Antagonists↗
PubMed1995

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

PURPOSE: We investigated the effect of acute renal failure on the neurotoxicity of cimetidine in rats. METHODS: Experimental acute renal failure was produced by bilateral ureteral ligation. Cimetidine was intravenously infused to ureter ligated (UL) and control rats, and cimetidine concentration in plasma, brain and cerebrospinal fluid (CSF) were compared. RESULTS: The cimetidine concentration in plasma was rapidly increased in UL rats as compared to control rats. The cimetidine concentration in CSF at the onset of convulsion did not depend on the infusion rate, suggesting that cimetidine in CSF equilibrates rapidly with the site of action for clonic convulsion. The cimetidine concentration in CSF of UL rats at the onset of clonic convulsion was lower than those of control rats. CONCLUSIONS: Increased sensitivity to the drug on the central nervous system may contribute to increased toxicity of cimetidine with renal failure.

Acute Kidney Injury↗
PubMed1995

Toxicodynamic analysis of inflammatory reactions by an angiotensin converting enzyme inhibitor (lisinopril) in guinea-pig skin.

There have been reports of rash and angioedema in the treatment of hypertension with angiotensin converting enzyme (ACE) inhibitors. To evaluate the inflammatory reaction, we continuously infused lisinopril for three days into the peritoneal cavity of ovalbumin-sensitized guinea-pigs and tested intradermal inflammation with ovalbumin. Inflammatory responses were measured in two perpendicular directions serially, and the areas of rash were used as an index of inflammatory reaction induced by lisinopril. Inflammatory responses were dose-dependently enhanced by treatment with lisinopril. Plasma concentration of lisinopril required to produce 50% of the maximum potentiation of the inflammatory reaction in guinea-pig skin was 40 times plasma unbound concentration after the clinical treatment of lisinopril in patients.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Comparative pharmacokinetics of four cholinesterase inhibitors in rats.

Pharmacokinetics of a very short-acting, a short-acting and two long-acting cholinesterase (ChE) inhibitors, edrophonium, neostigmine, pyridostigmine and ambenonium, respectively, were compared to elucidate the major determinant of their pharmacokinetics. No dose-dependency in pharmacokinetic behavior was observed within the range of 2-10 mumol/kg for edrophonium, 0.5-2 mumol/kg for pyridostigmine, 0.1-0.5 mumol/kg for neostigmine and 0.3-3 mumol/kg for ambenonium, respectively. Neostigmine has the shortest elimination half-life, and edrophonium, pyridostigmine and ambenonium follow in that. Four ChE inhibitors have similar Vdss values within the range of 0.3-0.7 l/kg, which is similar to the muscle/plasma concentration ratio of these drugs. The liver or kidney to plasma concentration ratio of all ChE inhibitors at 20min after i.v. administration ranged from 5 to 15. Small distribution volumes estimated from the plasma concentration profiles may reflect the distribution to muscle and to the extracellular space of other organs/tissues, while the rapid disappearance of ChE inhibitors from plasma may reflect the concentrative uptake to the liver and kidney.

Ambenonium Chloride↗
PubMed1995

Administration-route dependency of absorption of glycyrrhizin in rats: intraperitoneal administration dramatically enhanced bioavailability.

The pharmacokinetic behavior of glycyrrhizin after intravenous (i.v.), oral and intraperitoneal (i.p.) administration was compared in rats. The elimination half-life, total body clearance and volume of distribution at steady-state of glycyrrhizin were not significantly different among doses (2, 10 and 50 mg/kg i.v.). Glycyrrhizin was only detected in the plasma (maximum level: 1.3 micrograms/ml) after oral administration of 50 mg/kg. From comparison of the area under the plasma concentration-time curves after i.v. and oral administration of 50 mg/kg, the bioavailability of glycyrrhizin was estimated to be approximately 1%. Glycyrrhizin was stable for at least 3 h in gastric juice. The plasma concentration of glycyrrhizin after oral administration to neomycin-treated rats was not significantly different from that after administration to untreated rats. Furthermore, in in situ absorption study the cumulative ratio of glycyrrhizin in the mesenteric venous plasma after injection was only 1-2% of the dose. From these results, it appeared that the extremely low bioavailability by the oral route may be due to poor absorption of glycyrrhizin from the intestinal tract. On the other hand, the plasma concentration of glycyrrhizin rapidly increased after i.p. administration of doses of 2, 10 and 50 mg/kg, and reached a maximum level (4.7, 33.0 and 238.9 micrograms/ml, respectively) within 30 min. The bioavailability (65-90%) of glycyrrhizin after i.p. administration was enhanced dramatically. The i.p. route of administration may thus improve the bioavailability of glycyrrhizin.

Animals↗
PubMed1995

The relationship between the pharmacological effect of amitriptyline based on an improved forced-swimming test and plasma concentration in rats.

The relationship between the plasma concentration of amitriptyline (AMI) and its pharmacological effect was investigated in rats. The plasma concentration of AMI was maintained constantly from 5 h to 7 d after intraperitoneal infusion by the implantation of an osmotic minipump with an adjusted release rate of 20 mg/kg/d of AMI. Neither the plasma or brain concentrations of AMI in a 24-h infusion group were significantly different as compared with those in the 7-d group. The pharmacological effect of AMI was measured by our improved forced-swimming test. When AMI (dose of 20 and 50 mg/kg/d) was infused, the pharmacological effect in both infusion groups of rats was increased significantly at each dose in comparison to that of the control rats (p < 0.05). With 10 mg/kg/d infusion, the effect in the 7-d group increased significantly as compared with that of the control (p < 0.05), although the effect in the 24-h group did not change. The effect was increased in both groups with an increase of dose. When the effect was plotted to the area under the plasma concentration-time curve (AUC), the effect approached a limiting value (12 micrograms/ml.h). Therefore, it was suggested that 12 micrograms.ml/h as the AUC for AMI was enough to obtain a maximum AMI pharmacological effect in rats. From these results, we concluded that the AUC for AMI may be a useful index to evaluate its pharmacological effect, rather than the plasma concentration.

Amitriptyline↗
PubMed1995

Toxicodynamic analysis of cough and inflammatory reactions by angiotensin-converting enzyme inhibitors in guinea pig.

Angiotensin-converting enzyme (ACE) inhibitors are one of the first drugs of choice for the treatment of hypertension. However, there have been many reports of persistent chronic dry cough and inflammatory skin reactions (rash and/or angioedema, etc.) induced by ACE inhibitors. In this study, in order to evaluate the cough and inflammatory reaction, we measured the number of citric acid-induced coughs and the intradermal inflammation with ovalbumin in guinea pigs consecutively treated with ACE inhibitors (lisinopril, enalaprilat and imidapril) for 3 days. The number of citric acid-induced coughs and the inflammatory responses were significantly enhanced by treatment with lisinopril and enalaprilat, whereas imidapril produced no change in either response. These results correspond to the frequency of adverse effects in clinical practice, which suggests that imidapril has the least ability to induce the inflammatory skin response and cough. Furthermore, the enhancement produced by the ACE inhibitors in the number of coughs and the inflammatory responses were significantly reduced by pretreatment with indomethacin (prostaglandin synthesis inhibitor). This finding suggests that PGs at least participate in the mechanism for ACE inhibitor-induced cough and inflammatory skin response.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Comparative pharmacokinetic/pharmacodynamic study of proton pump inhibitors, omeprazole and lansoprazole in rats.

The relationship between plasma concentrations and inhibitory effects on gastric acid secretion by omeprazole (OPZ) and lansoprazole (LPZ), which are used as antiulcer drugs in the clinical stage, was analyzed using the pharmacokinetic/pharmacodynamic (PK/PD) model in rats. After intravenous administration of OPZ and LPZ (1 mg/kg), OPZ was eliminated 1-exponentially and LPZ was eliminated 2-exponentially from plasma. Elimination was rapid with total body clearance of 57.6 ml/min/kg for OPZ and 58.6 ml/min/kg for LPZ. The volumes of distribution at steady-state were 0.66 liter/kg for OPZ and 1.04 liter/kg for LPZ, and the plasma unbound fractions were 0.105 and 0.069. The dose at which 50% of the maximum effect is elicited for the suppression of gastric acid secretion stimulated by histamine was 0.28 +/- 0.13 mg/kg (estimated value +/- SD) for OPZ and 0.18 +/- 0.03 mg/kg for LPZ. Second-order rate constants for association of OPZ or LPZ and H+,K+-ATPase based on a PK/PD model were 72.5 +/- 30.0 (estimated value +/- SD) and 124 +/- 58 ml/micrograms/hr respectively. Apparent turnover rate of H+,K+-ATPase was 8.8 hr as half-life, assuming the same value for both drugs. We concluded that pharmacokinetic elimination patterns of OPZ and LPZ were different, whereas the pharmacodynamic characteristics of both drugs are nearly the same in rats.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1995

Comparative analysis of buprenorphine- and norbuprenorphine-induced analgesic effects based on pharmacokinetic-pharmacodynamic modeling.

The relationships between plasma or brain concentrations and analgesic effects of both buprenorphine (BN) and an active metabolite, norbuprenorphine (NBN), were investigated in rats. Maximal analgesic effects measured by a tail flick test were obtained at 10 and 30 min after intravenous (i.v.) administration of BN (8 micrograms/kg dose) and NBN (100 micrograms/kg dose), respectively. No correlation was observed between analgesic effect and the early plasma BN or NBN concentrations. However, at latency times, the concentration of BN in the plasma, cerebellum and the rest of the brain (including the brainstem, midbrain and cerebrum) was related in a counterclockwise hysteresis fashion to analgesia. There was no relationship between the estimated specific binding concentration of BN in the brain and the analgesic effects. After i.v. administration of BN or NBN, the analgesic effect of NBN was approximately one-fiftieth that of BN. The n-octanol/water partition coefficient of NBN was one-tenth that of BN. Further, the results of intraventricular administration of each drug suggested that the intrinsic analgesic activity of NBN was one-fourth that of BN. From these findings, we conclude that the remarkably weak pharmacological effect of NBN after i.v. administration may be due not only to the low permeability of NBN into the brain but also to its small intrinsic pharmacological effect.

Analgesia↗
PubMed1995

[Digitoxin].

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Cardiotonic Agents↗
PubMed1995

[Digoxin].

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Adult↗
PubMed1994

The effect of food on the interaction of ofloxacin with sucralfate in healthy volunteers.

We have studied the effect of food on the interaction of ofloxacin with sucralfate. Six healthy men took a single oral dose of ofloxacin (200 mg) on 4 occasions: alone after overnight fasting or after breakfast (non-fasting), and with sucralfate fasting or non-fasting. There were no significant differences in the plasma concentration-time profiles of ofloxacin after ofloxacin alone between fasting and non-fasting conditions. On the other hand, the peak plasma concentration and AUC of ofloxacin after co-administration with sucralfate while fasting fell by 70 and 61% compared with ofloxacin alone; the changes non-fasting were 39 and 31% respectively. The interaction of ofloxacin with sucralfate was markedly reduced by food, but still could not be disregarded.

Adult↗
PubMed1994

Prediction of brain delivery of ofloxacin, a new quinolone, in the human from animal data.

We attempted to predict the delivery of ofloxacin (OFLX), a new quinolone antibacterial agent (NQ), into cerebrospinal fluid (CSF) in the human based on the physiological properties and pharmacokinetic parameters of NQs in various animals. Physiological properties for evaluation of drug delivery into CSF such as volume and the bulk flow rate of CSF and weight of choroid plexus, were compared among the rat, rabbit, cat, dog, and human. Statistically significant correlations with power values of 0.82-0.89 in the linear regression were observed on log-log plots between brain weight and those properties of each species. Delivery of OFLX into CSF from blood was analyzed by "diffusion and flow model" with unidirectional efflux process from CSF to blood. The blood-CSF diffusion clearance and the efflux clearance of OFLX in the human were extrapolated from animal data based on the allometric correlations between brain weight and these parameters in the rat, rabbit, and dog. The apparent volume of distribution and the total body clearance of NQs in the human could also be predicted from animal data based on the classical Adolph-Dedrick approach. To simulate the CSF concentration-time profile of OFLX in the human by using these predicted parameters, it was necessary to consider both the lumbar CSF compartment and the ventricular CSF compartment. Both plasma and CSF concentration-time profiles of OFLX predicted from only animal experimental data were in good agreement with those observed clinically.

Animals↗
PubMed1994

Effect of perfusate pH on the influx of 5-5'-dimethyl-oxazolidine-2,4-dione and dissociation of epidermal growth factor from the cell-surface receptor: the existence of the proton diffusion barrier in the Disse space.

The influx clearance (PSinf.MID) of the weak acid 5,5'-dimethyl-oxazolidine-2,4-dione (DMO) was determined by the multiple indicator dilution method with the isolated perfused rat liver under various perfusate pH conditions, ranging from 6.4 to 7.6. Although the pH partition theory predicted an increase in influx clearance of ten times in proportion to the change in the unionized fraction of DMO, there was no measurable change in this value. The effect of medium pH on the steady-state cell/medium concentration ratio (C/M) ratio of DMO was also investigated using isolated hepatocytes. The C/M ratio increased while medium pH decreased, but this change was less marked than predicted by the pH partition theory. Finally the pH dependency of the dissociation rate constant (koff) of epidermal growth factor from its receptor was also investigated using both isolated rat hepatocytes and the perfused rat liver. When the extracellular pH was changed from 6.4 to 5.6, the koff value of isolated hepatocytes increased 44 times, while that of the perfused rat liver increased only 9 times. Therefore, the effect of changing the extracellular pH on pH-dependent dissociation of epidermal growth factor from its cell-surface receptor was less in the perfused liver than in isolated hepatocytes. These findings, in addition to the well-known existence of the Na(+)-H+ exchanger on the sinusoidal membrane and the possible existence of the unstirred water layer in the Disse space, seem to suggest the existence of the proton diffusion barrier in the rat liver, which remains stronger in the perfused liver than in isolated hepatocytes.

Animals↗