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Clenbuterol is a long-acting β2-adrenoceptor agonist and bronchodilator that is used for the treatment of asthma, but the desired activities reside almost exclusively in the (-)-R-enantiomer. This study examined enantioselectivity in the disposition of clenbuterol following administration of clenbuterol racemate to rats. Concentrations of clenbuterol enantiomers in plasma, urine and bile were determined by LC-MS/MS assay with a Chirobiotic T column. This method was confirmed to show high sensitivity, specificity and precision, and clenbuterol enantiomers in 0.1 ml volumes of plasma were precisely quantified at concentrations as low as 0.25 ng/ml. The pharmacokinetic profiles of clenbuterol enantiomers following intravenous and intraduodenal administration of clenbuterol racemate (2 mg/kg) in rats were significantly different. The distribution volume of (-)-R-clenbuterol (9.17 l/kg) was significantly higher than that of (+)-S-clenbuterol (4.14 l/kg). The total body clearance of (-)-R-clenbuterol (13.5 ml/min/kg) was significantly higher than that of the (+)-S-enantiomer (11.5 ml/min/kg). An in situ absorption study in jejunal loops showed no difference in the residual amount between the (-)-R- and (+)-S-enantiomers. Urinary clearance was the same for the two enantiomers, but biliary excretion of (-)-R-clenbuterol was higher than that of the (+)-S-enantiomer. The fractions of free (non-protein-bound) (-)-R- and (+)-S-clenbuterol in rat plasma were 48.8% and 33.1%, respectively. These results indicated that there are differences in the distribution and excretion of the clenbuterol enantiomers, and these may be predominantly due to enantioselective protein binding.

Translational research is the development of new treatments for currently incurable illnesses, based on cutting edge findings in scientific research. The main purpose of translational research for cancer is the evaluation of safety and pharmacokinetics of current phase I trials. In order to conduct translational research and to maintain the highest medical ethics and scientific methods, Translational Research Coordinators (TRCs) at the Research Hospital of the Institute of Medical Science of the University of Tokyo objectively monitor intra-institutiona research from the third party perspective. The present paper describes: 1) the role of TRCs in translational research; 2) activities related to informed consent; and 3) aspects related to advanced ethical problems.TRCs comprise pharmacists, research nurses, certified clinical psychologists, registered dieticians, and medical technologists. TRCs monitor and oversee ethical and scientific compliance in their specialized field. Activities related to informed consent are as follows: 1) indicate inappropriate descriptions in informed consent documents, and propose alternative descriptions to physicians; 2) arrange schedules for the interview of informed consent; 3) provide physicians for exercises on the explanation of informed consent; 4) explain the content of protocols to participants before informed consent is obtained; 5) when informed consent is obtained, confirm and evaluate the adequacy of explanations given by physicians, and check the understanding and mental condition of participants.The role of TRCs is nearly established, however, such a careful monitoring system will be necessary in the future to achieve a higher level of medical ethics.

Bromocriptine is a selective agonist for dopamine D2-receptors and is used in the treatment of Parkinson's disease. In this study, we performed pharmacokinetic and pharmacodynamic (PK/PD) analyses of the antiparkinsonian effect of bromocriptine and evaluated drug-induced contralateral rotations in rats in which unilateral striatal lesions had been generated by microinjection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. The plasma concentration (Cp) and D2 receptor occupancy (Phi(D2)) were quantitated by HPLC and with an in vivo back-titration method using [(3)H]-raclopride, respectively. Bromocriptine induced contralateral rotations (E(rot)) in a dose-dependent manner following intraperitoneal administration in an animal model of Parkinson's disease. The Cp of bromocriptine peaked at 15-30 min after the administration and decreased time-dependently, whereas the Phi(D2) of bromocriptine increased gradually for 180 min after administration. The relationship between Cp and E(rot) exhibited an anticlockwise hysteresis, whereas the relationship between Phi(D2) and E(rot) showed a linear correlation. These results suggest that in vivo Phi(D2) is a good pharmacological indicator of the effect of a D2 agonist.

Disopyramide, a class la antiarrhythmic agent, has been reported to induce torsades de pointes (TdP) associated with excessive QT prolongation in electrocardiogram (ECG), especially when concomitantly administered with erythromycin, a macrolide antibiotic agent. In this study, we have evaluated the effects of erythromycin on action potential duration (APD) and potassium currents in rat ventricular myocytes in comparison with disopyramide. We have evaluated the relationship between in-vitro potassium current inhibition and in-vivo QT prolongation observed in a previous study. Action potentials and membrane potassium currents, including delayed rectifier current (IK) and transient outward current (Ito), were recorded using a whole-cell patch clamp method in enzymatically-dissociated ventricular cells. Erythromycin and disopyramide prolonged APD in a concentration-dependent manner. Disopyramide (10–100 μm) and erythromycin (100 μm) led to increases in the APD at 90% repolarization level. Disopyramide reduced IK (IC50 = 37.2 + 0.17 μm) and Ito (IC50 = 20.9 + 0.13 μm) while erythromycin reduced IK (IC50 = 60.1 + 0.29 μm) but not Ito. The observed prolongation of APD might be ascribed to the inhibition of potassium currents. Erythromycin produced the prolongation of APD and the inhibition of potassium currents with a lag time after addition of the drugs, which suggested that erythromycin might not reach potassium channels from outside the ventricular cells. The potency of disopyramide was almost equivalent under in-vitro and in-vivo conditions. However, potency of erythromycin in-vitro was far weaker than that in-vivo reported in a previous study, presumably due to a difference in the uptake of erythromycin into ventricular myocytes between in-vivo and in-vitro conditions. Therefore, when drug-induced risks of QT prolongation are to be evaluated, the difference of potencies between in-vitro and in-vivo should be taken into consideration.

In the present study, we investigated the effect of inter-individual variation and dispensing experience as a factor of variation when mixing digoxin powders.Sixteen of the post-graduate trainees (non-experienced group) who entered the Department of Pharmacy, University of Tokyo Hospital in April 1996, and had no dispensing experience with powders, and six pharmacists (experienced group), who had individually amassed 3 to 5-years of dispensing experience, participated in our study.The mean CV values (n=3) of the digoxin contents in the experienced group were 2.7% on the first experiment, 2.7% on the second and 2.5% on the third. Eight of the non-experienced group members produced a CV of less than 6.08% in all experiments. However, the CV values generated by the other eight members of the non-experienced group exceeded the standards of good mixing, and in addition, wide variations were observed. The eight above described trainees had received 3 weeks of training, and, when the mixing experiments were performed again, the registered CV values were less than 6.08% in all experiments.These results showed that, even in the case of digoxin powders requiring a high degree of mixing, good mixing was obtained under our proposed mixing conditions in half of the trainees with no dispensing experience, and in addition, good mixing was generally obtained after all had received 3 weeks of training.

Clenbuterol is a long-acting β2-adrenoceptor agonist and bronchodilator that is used for the treatment of asthma, but the desired activities reside almost exclusively in the (-)-R-enantiomer. This study examined enantioselectivity in the disposition of clenbuterol following administration of clenbuterol racemate to rats. Concentrations of clenbuterol enantiomers in plasma, urine and bile were determined by LC-MS/MS assay with a Chirobiotic T column. This method was confirmed to show high sensitivity, specificity and precision, and clenbuterol enantiomers in 0.1 ml volumes of plasma were precisely quantified at concentrations as low as 0.25 ng/ml. The pharmacokinetic profiles of clenbuterol enantiomers following intravenous and intraduodenal administration of clenbuterol racemate (2 mg/kg) in rats were significantly different. The distribution volume of (-)-R-clenbuterol (9.17 l/kg) was significantly higher than that of (+)-S-clenbuterol (4.14 l/kg). The total body clearance of (-)-R-clenbuterol (13.5 ml/min/kg) was significantly higher than that of the (+)-S-enantiomer (11.5 ml/min/kg). An in situ absorption study in jejunal loops showed no difference in the residual amount between the (-)-R- and (+)-S-enantiomers. Urinary clearance was the same for the two enantiomers, but biliary excretion of (-)-R-clenbuterol was higher than that of the (+)-S-enantiomer. The fractions of free (non-protein-bound) (-)-R- and (+)-S-clenbuterol in rat plasma were 48.8% and 33.1%, respectively. These results indicated that there are differences in the distribution and excretion of the clenbuterol enantiomers, and these may be predominantly due to enantioselective protein binding.

In order to evaluate the arrhythmogenic potency of macrolide antibiotics in a quantitative manner, we analyzed the influence of clarithromycin (CAM), roxithromycin (RXM), and azithromycin (AZM) on Q-T intervals from pharmacokinetic and pharmacodynamic points of view and in comparison with the potency of erythromycin (EM) previously reported by us for rats. Male Sprague-Dawley rats were anesthetized, and CAM (6.6, 21.6, and 43.2 mg/kg of body weight/h), RXM (20 and 40 mg/kg/h), and AZM (40 and 100 mg/kg/h) were intravenously injected for 90 min to obtain the time courses of drug concentrations in plasma and the changes in the Q-T intervals during and after the drug injections. Distinct Q-T interval prolongation of up to 10 ms was observed with CAM at its clinical concentrations. RXM and AZM evoked Q-T interval prolongation at concentrations higher than their clinical ranges. The potencies for Q-T interval prolongation, assessed as the slope of the concentration-response relationship, were 6.09, 0.536, and 0.989 ms · ml/μg for CAM, RXM, and AZM, respectively. There was hysteresis between the change in the Q-T intervals and the time course of the plasma concentration of each drug. The rank order of clinical arrhythmogenicity was estimated to be EM > CAM > RXM > AZM, as assessed from the present results and our previous report for EM. In conclusion, RXM and AZM were estimated to be less potent at provoking arrhythmia than EM and CAM. These results should be useful for making a safer choice of an appropriate agent for patients with electrocardiographic risk factors.

In the initial phase of clinical studies, it was shown that E3040, a new type of anti-inflammatory drug, reduced plasma uric acid levels. The present study describes a comparison of the excretion of uric acid in the proximal tubules of the kidney after administration of E3040 and its conjugates, sulphate and glucuronide, with that of other general uricosuric agents in DBA/2N mice. The aim of this investigation was to elucidate the mechanism for the uricosuric action of E3040. It was found that E3040 increased the excretion rate of uric acid in a dose-dependent manner, and the excretion rates following 10 and 50 mg/kg doses were significantly greater than that of the control group. The paradoxical effect observed with probenecid was not seen in the E3040 dose-response curve for the uric acid excretion rate. Neither E3040-sulphate nor E3040-glucuronide increased the excretion rate of uric acid significantly, even at a high dose, such as 200 mg/kg. In the pyrazinoic acid suppression test, the uric acid excretion rate after concomitant administration of E3040 and pyrazinoic acid was significantly higher than that after administration of pyrazinoic acid alone, and the rate after concomitant administration was 30% of the level after administration of E3040 alone. The change in the excretion rate of uric acid after concomitant administration of E3040 and pyrazinoic acid was similar to that of AA193, a selective inhibitor of the presecretory reabsorption of uric acid. From these results, it appears that E3040 may exert its uricosuric action by reducing the presecretory reabsorption of uric acid rather than increasing its secretion.

Ebastine (EBS), a novel nonsedative antiallergic agent, is similar to terfenadine in its chemical structure. However, clinical arrhythmogenicity of EBS remains controversial. In this study, we evaluated the possible arrhythmogenic potency of EBS as assessed by QT prolongation from a pharmacokinetic-pharmacodynamic viewpoint in comparison with that of terfenadine. EBS was intravenously infused into anesthetized rats at a rate of 3.0 or 10 mg/kg/h for 60 min, and electrocardiographic effects were continuously monitored from lead II. The plasma concentrations of EBS and its major metabolite, carebastine, were also measured under the same conditions. When intravenously administered, EBS exhibited QT prolongation in an infusion rate-dependent manner, with a lag time. Pharmacokinetic-pharmacodynamic analysis of EBS based on the effect-compartment model revealed values of EC50, Emax and EC(10 ms), (where 10 ms of QT prolongation was evoked) of 0.73 microg/mL, 12.5 ms and 2.90 microg/mL, respectively. The EC(10 ms) value of EBS was five times higher than that of terfenadine reported previously (Ohtani et al., J. Pharm. Pharmacol., 49, 458-462 (1997)). In conclusion, EBS was suggested to be less arrhythmogenic than terfenadine.

Disopyramide (DP) is known to induce QT prolongation and Torsades de Pointes (TdP) when administered concomitantly with erythromycin (EM). To define and evaluate quantitatively the arrhythmogenic risk of the concomitant administration of DP and EM, we investigated the influence of EM on the pharmacokinetics and pharmacodynamics of DP in rats. The time profiles of change in QT interval and plasma concentration of each drug were evaluated during and after constant intravenous infusion of DP (6.0 or 15.0 mg/kg/h), EM (4.0 or 8.0 mg/kg/h), and coadministration of DP and EM (DP 6.0 mg/kg/h plus EM 4.0 mg/kg/h). Each agent induced QT prolongation at plasma concentrations within the therapeutic range in humans. DP-induced QT prolongation was proportional to its plasma concentration. In the case of EM, the Emax model with an "effect compartment" could explain the relationship between plasma EM concentrations and changes in QT interval. Although coadministration of EM with DP gave enhanced QT prolongation compared to dosing with DP alone, EM did not affect the pharmacokinetics of DP. In conclusion, it was shown that a pharmacodynamic interaction contributes to the electrocardiographic adverse reaction (i.e., QT prolongation) induced by coadministration of DP and EM in rats.

Effects of mouth wash (mouth rinsing and gargling) on the removal of drug residues in both mouth and pharynx after the use of pressurized aerosol metered-dose inhaler (MDI) were studied. The concentration of beclomethasone dipropionate (BM) in mouth wash after a splay of Becotide inhaler was measured by the method using HPLC. The total amount of the removed BM was measured by a sum of the concentrations of BM in 4 or 5 times of mouth washes in the following 4 kinds of methods. In method 1, mouth wash was done with 5 times of water change after a splay of MDI on wetted mouth. In method 2, mouth wash was done with 5 times of change water on dried mouth. In method 3, mouth wash was done with 4 times of change saliva on wetted mouth. In these methods, the actual inhalation of BM was not done. In method 4, mouth wash was done with 5 times of change water after a splay and a inhalation on wetted mouth. The mouth wash procedures removed totally 47.9%, 51.1%, 31.3%, and 33.3% of a splayed amount of BM in each method, respectively. It was required for the removal of 90% of the totally recovered BM to do one time of mouth wash in method 1, two times in method 2, three times in method 3, and two times in method 4, respectively. These data suggest that the mouth wash procedure is shown to have prophylactic benefit for candidiasis induced by steroid delivered by MDI.

Beta-adrenoceptor blocking agents (beta-blockers) have been widely used for the treatment of angina pectoris. The average/standard therapeutic doses vary widely among beta-blockers with the maximum of about a 120-fold difference. In order to clarify the mechanism of this difference, we analyzed retrospectively the pharmacological effects of beta-blockers in consideration of the beta 1-receptor binding affinity and the vasodilative activity on the basis of pharmacokinetics and the receptor occupancy theory. The analysis was performed on eight beta-blockers without a vasodilative effect and on four beta-blockers with a vasodilative effect. The beta 1-receptor occupancies at the steady-state condition after oral administration of standard doses were calculated by the use of the data on the concentration of unbound agents in plasma and on the dissociation constant of receptors. The estimated receptor occupancies were 87 +/- 6% or 88 +/- 10% for the beta-blockers with or without a vasodilative effect, respectively, and a significant difference was not observed between these groups. These results suggest that the beta 1-receptor occupancies may be a principal indicator for the therapeutic effects for angina pectoris regardless of their vasodilative effects.

The relationship between plasma concentration of ticlopidine and its inhibitory effect on platelet aggregation in human was analyzed using a pharmacokinetic/pharmacodynamic (PK/PD) model. The data of plasma concentration and inhibitory effect on platelet aggregation were taken from the literature. A two-compartment open model was fitted to plasma ticlopidine concentrations. Assuming that ticlopidine acts on platelet precursors in the bone marrow, the apparent reaction rate constant of ticlopidine and platelet precursors (K), apparent transformation rate constant of platelet precursors (kr) and apparent elimination rate constant of platelets (k e ) were estimated. The estimated values ± S.D. were 1.01 ± 1.08 ml μg −1 hr−1 for K, 0.265 ± 0.259 hr−1 for kr and 0.0747 ± 0.0112 hr −1 for k e . The antiaggregation effects of ticlopidine on platelets after administration of 100, 200, and 300 mg (bid for 8 days) were simulated using the PD parameters of K, kr, and ke. While the antiaggregation effect reached steady state within 3–4 days without dose dependency of the interval, the maximum effect increased with dose. Furthermore, changing the elimination rate constant of ticlopidine from the central compartment in the model significantly changed the duration of inhibitory effect of ticlopidine on platelet aggregation. Therefore, the reported long duration of antiplatelet effect after discontinuation of ticlopidine, which is believed to be irreversible binding to the platelet, might have been partially caused by the delayed plasma elimination after a long therapy of ticlopidine. On the other hand, the mean life-span of platelets in the blood estimated by 1/ke after administration of ticlopidine was 14 hr, far below the life-span of platelets in the blood. For a more detailed analysis of the antiplatelet effect of ticlopidine, the possible contribution of reversible binding of the drug to glycoprotein IIb/IIIa should be considered in future PK/PD models.

Sarpogrelate hydrochloride is an antiplatelet drug, and expected to be useful in the treatment of chronic arterial occlusive diseases. Sarpogrelate and its active metabolite (M-1) are potent inhibitors of human platelet aggregation, and selectively inhibit 5-HT2-serotonergic receptors on human platelets. However, the plasma concentrations of these inhibitors do not correlate to the inhibitory effect on platelet aggregation after administration. Sarpogrelate disappears from the plasma more rapidly in comparison to the duration of its pharmacological effect, and the plasma concentration of M-1 is very low (< 1/10 of sarpogrelate). In this paper, we describe a pharmacokinetic-pharmacodynamic model for ascertaining the antiplatelet effects of sarpogrelate and M-1, by considering both the competitive reversible inhibition and the association/dissociation process of these drugs at the 5-HT2 receptors on platelets (Most data used for analysis were obtained from the literatures, except for the serum protein binding rate of M-1). The developed model was well fitted to the actual data, and suggested that M-1 was more effective for the inhibition of platelet aggregation than sarpogrelate. On the basis of these findings, a new method was developed for predicting inhibitory effects on platelet aggregation after oral administration of sarpogrelate hydrochloride. This method is useful for planning a rational dosage regimen of sarpogrelate hydrochloride and predicting the duration of antiplatelet activity after the discontinuance of the drug.

The pharmacist should provide the patient with suflcient information, including any expected adverse effects, to ensure that the patient can safely and appropriately use medication. However, informing patients of possible adverse effects might also induce the patients not to take the medication. Therefore, in an attempt to facilitate the counseling about adverse reactions of the dispensed medicine, the effect of illustrating adverse reactions on the rational use of the medication was studied. A total of 125 types of drugs prescribed for 107 out-patients with rheumatoid arthritis (RA) were classified into two groups. One was a group in which consultation by the pharmacist is extremely important for (64%), and the other is the one in which such consultation is only moderately required (36%). The former group has potentially severe adverse reactions, frequent mild adverse reactions, or the ability to change the color of urine, stool, or tears. The illustration cards were developed and provided for 30 out-patients with RA. These patients were also counseled by the pharmacist about the adverse reactions listed in the card. This information trial was found to help relieve the anxiety in 57% of the patients, and to help patients understand adverse reactions in 77%. From these.results, in order to improve the clinical effectiveness and avoid the adverse effects of the medication, it is thus important to develop proper drug information cards which provide patients with correct knowledge on the adverse reactions for the patients.

An enema containing beclomethasone dipropionate (BDP), with a strong anti-inflammatory action and few systemic side effects, was prepared and a pharmaceutical study of this enema was performed regarding its clinical application for the treatment of ulcerative colitis patients.The enemas were prepared by adding BDP ethanol to an aqueous solution consisting of 1% methylcellose, and this was divided into 50 ml (containing 1 mg of BDP) doses in plastic syringes. The pH, osmolarity and specific gravity of these enemas were approximately 5, 100 mOsm/kg·H20 and 1.0, respectively. The mean residual concentration of BDP in these enemas (n=6), preserved in dark under refrigeration at 4°C, declined to 93.4% after one week and 85.6% after four weeks, when compared, to the concentration determined immediately after preparation. Although the residual concentration of BDP enemas, preserved in light at 40°C, declined to 93.9% after one week and remained almost constant thereafter, the crystallization of BDP was observed the first day after preparation. Furthermore, the stability of BDP in the enemas was reduced by adjusting the pH of the enemas to 3 and 7, but it was improved by adding methyl p-hydroxybenzoate to these solutions.These BDP enemas were administered to three patients with ulcerative colitis. An improvement was seen in all three subjects regarding both the clinical symptoms and blood data (values related to inflammatory: white blood cells and C-reactive protein). In addition, the disappearance of side effects was also confirmed after administration of BDP enemas to two of the subjects who had developed such side effects as moon face and edema with prednisolone enemas.Based on these results, BDP enemas were thus suggested to be effective for of ulcerative colitis.

A new computerized information system for therapeutic drug monitoring (TDM), which is intended to be linked to the other hospital information systems such as the prescription entry system or accounting system, was developed. This newly developed system provides an on-line real-time transmission of the data regarding order reception and the results of an assay to the host computer, and also adds up the number of assays and the medical charge for TDM on the request. The terminal emulation of this medical information system is also available in order to refer any essential information for dosage consultation, such as the diagnostic disease names and clinical laboratory data. Since February 1996, this newly developed system has been used and has allowed as to improve the checking and chargeability of TDM by up to more than 90% for outpatients, while additional charges are still frequently over looked because of a lack of the essential information. The complete fulfillment of the essential information for TDM using the TDM-order-entry system and its link with the medical information system and accounting system is thus called for in the future.

Cilostazol is an antithrombotic drug expected to be useful in the treatment of chronic arterial occlusive diseases. Cilostazol is a potent inhibitor of human platelet aggregation and selectively inhibits human platelet cyclic adenosine monophosphate phosphodiesterase type III. In this paper, we describe a pharmacokinetic-pharmacodynamic model for ascertaining the antiplatelet effect of cilostazol considering the reversible inhibition of phosphodiesterase in the platelet. All data used for analysis were obtained from the literature. The estimation of average inhibition of phosphodiesterase was 59.7% following an oral administration with usual dose. A significant linear relationship between the calculated inhibitory effects on phosphodiesterase and on collagen-induced platelet aggregation was obtained (p< 0.05). Based on this finding, a new method was developed. for predicting inhibitory effects on the collagen-induced platelet aggregation following oral administration of cilostazol. This method is useful for planning a rational dosage regimen of cilostazol and for predicting the duration of antiplatelet activity after discontinuance of the drug.

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.

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.

We studied the effect of advising outpatients on the rational use of ophthalmic solutions and compliance by a questionnaire (n=158), in order to establish the optimal consultation method. A total of 41.8% of the patients answered the questionnaire. In compairing the actual use of ophthalmic solutions before and after consultation, the rates of rational use increased for all items except for “applications per day”, which decreased slightly from 93.4% before the consultation to 90.2% after that. In particular, “eyelid closure” and “nasolacrimal occlusion” after instillation, and “the 5 min interval of instillation in the case of plural medication”, considerably increased from 34.8% before the consultation to 60.6% after that, from 9.5% to 50.8% and from 45.9% to 73.8%, respectively. The compliance remarkably improved in glaucoma patients after consultation regarding “the 5min interval of instillation” .Based on these results, our consultation method for the rational use on ophthalmic solutions was thus evaluated. However, since some patients who still did not appreciate the need for the rational use of such medication still presented, further improvements in the consultation method requires for the rational use.

We conducted a survey to evaluate a system adopted by the Pharmacy Department of Tokyo University Hospital to address the problem of drug compliance under this system, patients are provided with a “Drug History Handbook”, or drug notebook. This survey attempted to determine the extent to which a “Drug History Handbook” helped patients understand the drug they were taking, and the extent to which it was utilized during visits to other institutions. Based on the results of the survey, we evaluated the efficacy of “Drug History Handbook” as a means to enable patients themselves to perform comprehensive drug information management.Out of 288 patients responding to the survey, 149 (52%) had a “Drug History Handbook” 149 out of 286 respondents or 40% had been diagnosed at other institutions. The respondents who said they had shown their “Drug History Handbook” to pharmacists or physicians at other pharmacies, hospitals, or medical institutions were numbered 71 out of 149 (48%), including duplicate responses.At community pharmacies conducted at the same time, responses were obtained from 48 pharmacies. Of the 48 responding pharmacies, 21 (44%) said that patients had presented either “Drug History Handbook” or “prescription cards” .From these results, it is clear that the patients thus realized the importance of keeping a complete record of the drugs they had taken, and that presenting information about drug history can be a very valuable aid in both prescribing and preparing appropriate medications.From thus survey, it was found that the use of a “Drug History Handbook” can help prevent the dispersal of information about purchase of over the counter drugs as well as prescription drugs. As a means of patient education, it can also be extremely effective for avoiding the duplicated administration of medications and drug-drug interactions.

The pyrogenic activity of 10% inulin injections prepared at a hospital pharmacy was measured using the Pyrogen test in Japanese Pharmacopeia (JP), while the endotoxin concentration in the injections was determined by the, Limulus test, which were JP Endotoxin test and a turbidmetric kinetic assay. After the intravenous administration of 30 ml of inulin injections to a rabbit, the rectal temperature rose to 1.5° compared with that before administration. As a result, the endotoxin was found in all lots of the inulin injections tested, and their values were markedly beyond the limit of Water For Injections prescribed in JP (0.25 EU/ml). In addition, the endotoxin content varied between the various lots of inulin powder, and also between the manufacturers. The endotoxin in inulin injection was removed (less than the quantitative limit of 0.031 EU/ml) by adding activated carbon black to the injection or the filtration using a Posidyne® Nylon 66 filter. No pyrogenic activity was observed in the inulin injections after the removal of endotoxin.Based on these results, the adverse effects induced by inulin injections may thus be caused by endotoxin derived from inulin. This method using either adsorption or filtration is thus considered to be useful for the removal of endotoxin when preparing inulin injections.

Although the efficacy and safety of ophthalmic solutions are known to be related to their use, so far little has been published on the patients use of ophthalmic solutions. In an attempt to facilitate the counseling for the patients prescribed with ophthalmic solutions, a fact-finding study on the rational use of ophthalmic solutions was carried out on ophthalmic outpatients from February 1994 to May 1994. Questionnaires were made a consisting of 22 items concerning the rational use of ophthalmic solutions, including the number of instilled drops per eye for each treatment, the treatment after the instillation of drops, the administration order for ophthalmic solutions, the administration intervals of other ophthalmic solutions, and adverse reactions. Completed questionnaires were collected from 287 patients. The mean age of these patients was 54.4 years and their mean period for eye disease was 5 years. The ophthalmic solutions exhibiting such systemic actions as ophthalmic ±-lockers were used in 53% of the patients. The inappropriate use of ophthalmic solutions was reported in 47% of the patients regarding the number of instilled drops, in 48% regarding the treatment after the instillation of drops, in 65% related to the administration order of the ophthalmic solutions, and in 78% related to the administration intervals of the other ophthalmic solutions. The directions for the use of ophthalmic solutions were under stood by the physicians and pharmacists in 45% of the patients regarding the number of instilled drops, in 35% regarding the administration order of the ophthalmic solutions, in 64% regarding the administration intervals of the other ophthalmic solutions. Three percent of the patients experienced systemic adverse reactions after the administration of ophthalmic solutions.Based on these results, in order to improve the clinical effectiveness and avoid any systemic adverse effects of ophthalmic solutions based on unsuitable use, it is thus important to provide the proper drug information and to educate patients on the correct administration techniques of ophthalmic solution.

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.

The rational use of medications has been a serious social problem since the Sorivudine accident occurred. One of the reasons why the use of medications is not always correct is that the presentation of medical information is sometimes insufficient.We performed another questionnaire survey mainly for outpatients at other hospitals to obtain the status of drug consultation. According to the survey at other hospitals (80 hospitals surveyed, 59 responded, rate of retrieval 73%), drug consultation to outpatients is done at 29/59 (49%) hospitals, and thus only half of all hospitals provide drug consultation to inpatients.We performed a questionnaire survey for outpatients at the University of Tokyo Hospital to find out the type of information and communication method requested by patients. In the study at the University of Tokyo Hospital, the patients wanted information regarding drug effects, adverse reactions, and directions for use. Furthermore, an explanation with pictures or samples of the tablets was also desired.These studies suggested that it is necessary to illustrate serious drug adverse reactions and interactions with pictures or samples using lay terms, and in addition, such consultations should be individualized for each patient.

Purpose. The locomotive activity changes after intravenous (i.v.) administration of methylphenidate (MPD) in rats were pharmacodynamically analyzed.

Six kinds of well-prescribed admixtures of commercially available ointments and/or creams were selected from the prescribed sheets in our hospital. The skin permeability of corticosteroid from these admixtures was investigated by in vitro experiments using hairless mice skin. The permeability of corticosteroid through skin after adaptation of corticosteroid creams (Lidomex®) alone was approximately 9-fold larger as compared with that of the ointments only.The pemeability of conicosteroid in the admixture of Nedsona Universal®cream or Lidomex®ointment and urea ointments respectively was 3-and 5-fold larger than that from the cream and ointments alone. However, urea ointments did not influence the permeability of the drug in Lidomex®creams.This suggested that the w/o-type urea ointments more greatly enhanced the permeability of corticosteroid as compared with the o/w type urea ointments. The extent of the stability of the emulsion after mixing was related to the permeability. These results suggest that admixing ointments and/or creams should be carried done among bases having similar physicochemical characteristics.

Peripheral neuropathy is a common side effect of the chemotherapeutic agent oxaliplatin (Oxp), and is associated with hypersensitivity to cold sensation in the acute stage. Recently, gosha-jinki-gan (GJG), a Japanese herbal medicine, was reported to improve Oxp-induced cold hypersensitivity. However, the mechanism for this effect was not elucidated. We hypothesized that the effect of GJG on Oxp-induced cold hypersensitivity may be associated with the expression of the transient receptor potential melastatin 8 (TRPM8) and transient receptor potential ankyrin 1 (TRPA1) channels, which are cold-gated ion channels. To assess this hypothesis, we examined alteration of the withdrawal response to cold stimulation following coadministration of GJG and Oxp in rats, and the relationship between this altered withdrawal response and the expression of TRPM8 and TRPA1 mRNA in the dorsal root ganglia (DRG). Assessment of cold hypersensitivity was performed at 4 and 10°C using a cold plate. Compared with Oxp administration alone, coadministration of GJG (oral dose: 1 g/kg/day for 12 days) and Oxp (intraperitoneal dose: 4 mg/kg twice a week) significantly reduced the withdrawal response to cold stimulation. On the 12th day of drug administration, the L4-L6 DRG were removed and the expression of TRPM8 and TRPA1 mRNA was determined using RT-PCR. The expression of TRPM8 and TRPA1 in the DRG of rats that were coadministered GJG and Oxp decreased significantly compared with that in the rats administered Oxp alone. These results suggest that coadministration of GJG may improve Oxp-induced cold hypersensitivity by suppressing the overexpression of TRPM8 and TRPA1 mRNA.

A high-performance liquid chromatographic (HPLC) method for the quantitative determination of epinastine, a non-sedating histamine H1 receptor antagonist, in rat plasma, was developed. A 100-microliters volume of plasma sample was spiked with a solution of internal standard (diphenidol) and extracted with dichloromethane under alkaline conditions. The extract was applied onto the HPLC system and detected by ultraviolet absorption at a wavelength of 220 nm. The linearity of the calibration curve was preserved over the concentration range of 20-1000 ng/ml. Both intra-assay variation and relative error were less than 5% for the plasma containing 50 ng/ml or 1000 ng/ml of epinastine hydrochloride. The analytical method presented here should be useful for the investigation of the pharmacokinetic properties of epinastine, which is of clinical significance.

We studied retrospectively the relationship between the clinical effect of development of side effects and blood cyclosporin (CyA) concentration in patients with psoriasis, based on the blood concentration monitoring data of CyA and the clinical chart. Sixty-five percent of 50 patients received CyA within the range of 3-5 mg/kg/day dose. Although the blood concentration rose as the dose increased, intra-individual variation of the blood concentration of CyA was extremely large. The blood CyA concentration in the patients evaluated as “fully effective” was within the range of 34-297 ng/ml, and that as “insufficiently effective” was 51-375 ng/ml. Based on the evaluation of the individual patients (n=9), the clinical effects were related to the blood CyA concentration in half of the patients. Hypertension (23%) as the side effect appeared with the highest frequency, followed by the reduction of renal function (12%).We found that hypertension developed frequently more over 100 ng/ml and renal function was reduced a more over 180 ng/ml.In conclusion, It was shown that the blood CyA concentration should be monitored individually, since the optimum concentration for onset of effect was largely different among patients. Furthermore, it was demonstrated that we could advise doctors to ensurer the proper therapy through the blood CyA concentration monitoring in an attempt to avoid the onset of hypertension and renal failure which was dependent on the increasing blood CyA concentration.

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 (p0.05). With 10 mg/kg/d infusion, the effect in the 7-d group increased significantly as compared with that of the control (p0.05), 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.

The relationships between plasma or brain concentrations and analgesic effects of both buprenorphine (BN) and its metabolite, norbuprenorphine (NBN), were investigated in rats. Maximal analgesic effects were obtained at 10 and 30 min after iv administration of BN (8 μg/kg) and NBN (100 μg/kg) administration. No correlation was observed between analgesic effect and the early plasma BN or NBN concentrations. However, a good correlation was found between the estimated specific binding concentration of BN in the brain and the analgesic effects. Further, it was suggested that the intrinsic analgesic activity of NBNwas one-fourth that of BN. We concluded that the remarkabley weak analgesic effect of NBN after iv administration may be due not only to the low permeability of NBN into the brain but also to its small intrinsic analgesic effect.Further, the toxicodynamics of BN and NBN on respiratory depression was studied. Although the respiratory rate after iv bolus administration of BN did not change within the range of 1-3 mg/kg dose, that after administration of NBN was decreased dose-dependently. The action of respiratory depression of NBN was approximately 10 times more potents than that of the parent drug. The respiratory rate was not influenced after directly injection of NBN into 3 different brain regions. The respiratory depression induced by NBN was rapidly reduced after supplement of naloxon and β-FNA. These results suggest that the respiratory depression by NBN may be mediated by opioid μ-receptors in the peripheral tissue, probably in the lung, rather than in the brain.

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.

We tried to improve buprenorphine (BN) sublingual tablets (previous tablets) prepared previously [Yakuzaigaku, 46: 134-139 (1986)] by focusing on shortening the disintegration time because the disintegration of these tablets sublingually in man is quite long (7-9 minutes). Five different tablets (100mg) containing 100μg of BN were prepared, and the qualitative characteristics, pharmacokinetic behavior and clinical effect of BN were compared with the previous tablets. In the quality tests, one of the new tablets comprising 78.1 mg of 0.128% BN powder, 19.9 mg of lactose, 1 mg of magnesium stearate and 1 mg of powdered acacia per tablet was superior to the other products in terms of both disintegration and dissolution. The mean sublingual disintegration times fos the placebo of the new tablet in five healthy volunteers and five patients were 3.0 and 3.6 minutes, respectively, values which were significantly shorter than those (7.5 and 6.5 minutes) for the previous tablet. The plasma concentration of BN or analgesic effect arising after sublingual administratation of the new tablet in one healthy volunteer and two patients were closely comparable with those following sublingual administration of the previous tablet. The new tablet is biologically and pharmacologically equivalent to the previous one and is superior to the previous tablet in terms of disintegration characteristics.

To investigate the stereoselective distribution of methylphenidate (MPD) enantiomers in rats, the concentrations of each enantiomer were determined in plasma and brain regions (cerebellum, striatum, basal forebrain, brain stem, and cortex) after iv administration of racemic MPD and its individual enantiomers. The concentrations of MPD enantiomers in each brain region reached pseudo-steady state within 10 min after iv administration of racemic MPD (2 mg/kg dose). The influx clearances for MPD calculated from K Papp values in each brain region were not significantly different between MPD enantiomers and between the five brain regions. The mean K Papp values for (+ )-MPD in the striatum at 120 and 240 min after administration of racemic MPD were 10.1 and 10.5, respectively, and these values at each time were significantly larger than the K Papp values (7.5 and 7.0, respectively) for the (–)-isomer (P < 0.01). The K Papp value for (+ )-MPD in the striatum decreased by coadministration of mazindol as an inhibition of both dopamine and norepinephrine reuptake, but it was not changed by desipramine as a norepinephrine reuptake inhibitor. These results suggest that ( + )-MPD was bound specifically to the dopamine reuptake site in the striatum.

In order to classify opioid agonists and antagonists based on the receptor occupancy in the brain, the information on the therapeutic plasma concentration of these drugs and the binding affinity to μ opioid receptor was collected. The analysis was performed on eight opioid agonists (morphine, sufentanil, fentanyl, methadone, pethidine, levorphanol, buprenorphine and pentazocine) and two antagonists (naltrexon and naloxon) obtained data on the plasma concentration after therapeutic dosing, the plasma unbound fraction and dissociation constant (Kd) of the brain receptor binding. The mean plasma concentration and unbound plasma concentration varied 4000 and 10000 fold among the opioid agonists, respectively. Moreover, no difference in the plasma concentration or unbound plasma concentration was observed between the agonists and antagonists. On the other hand, the binding occupancy of the agonists to receptor (ranged 1.4-25.0%) calculated using the value of Kd with addition of sodium ions and therapeutic concentration of unbound drug was substantially smaller than that of the agonists (57.1-96.0%), although no difference in the binding occupancy calculated using the Kd without addition of sodium ions was observed between the agonists (ranged 1.8-89.0%) and antagonists (57.1-96.0%). From these results, the receptor occupancy of opioid calculated using the value of Kd with addition of sodium ions may be more useful index for the classification of opioid agonists and antagonists.

In an attempt to construct the rational use of suppositories, we developed an experimental method for the discharge of suppositories from rabbit rectum, and investigated the change of the pharmacokinetic behavior of the drug subsequent to discharge. Acetaminophen (ACA) was chosen as the model drug. The plasma concentration of ACA reached the maximum (Cmax: 25 μg/ml) at 17 minutes after rectal administration of one commercially available suppository containing 100mg of ACA. When the suppository was discharged from the rectum at 1 and 3 minutes after insertion using the pre-inserted device, the Cmax decreased markedly (4.5 and 11 μg/ml, respectively). However, the plasma concentration of ACA still increased even after discharge at 1 or 3 minutes after insertion, with their times required to reach the peak concentration being 7 and 9 minutes, respectively.Developed for the pharmacokinetic analysis of the plasma concentration after the discharge of suppository from the rectum was a pharmacokinetic model involving the assumption that only the undissolved portion (solid) of the suppository was discharged from the rectum and the dissolved portion (solution) remained. Consequently, the observed plasma concentrations well coincided with the predicted values.In conclusion, the experimental method employing the device for the artificial discharge of the suppository from the rectum should be a useful model for depicting suppository discharge from the rectum. Accordingly, the drug remaining in the rectum (dissolved portion) following the discharge of suppositories from the rectum should be considered.

We investigated the use of multiple antipsychotics and the manifestation of side effects in outpatients with schizophrenia and compared the results of patients who received 1 antipsychotic (monotherapy) with those of patients who received more than 1 antipsychotic (multidrug therapy). To achieve this, we visited 8 community life-support centers and conducted a face-to-face questionnaire survey with 47 outpatients. Sixteen (34%) of these patients had received monotherapy and 31 (66%), multidrug therapy. Complaints involving the central nervous system, anticholinergic symptoms, metabolic symptoms (weight gain, increase in blood glucose, etc.), and extrapyramidal symptoms were seen across the patients. The average incidence of side effects was 2.2 per person in the monotherapy group and 4.8 in the multidrug-therapy group. The number of nonantipsychotic drugs used concomitantly in the monotherapy group was also smaller than that used in the multidrug-therapy group (2.3 and 5.0 per person, respectively). Further, we analyzed the 47 patients as described above; 20 patients received typical antipsychotics (TA group), 10 patients received atypical antipsychotics (AA group), and 17 patients received both typical and atypical antipsychotics (MIX group). The average incidence of side effects in the TA, AA, and MIX groups was 2.8, 3.2, and 5.5 per person, respectively, and the number of nonantipsychotic drugs used concomitantly was 2.2, 3.2, and 6.1, respectively. On the basis of our results, it can be suggested that monotherapy with an atypical antipsychotic can reduce both the number of nonantipsychotic drugs used concomitantly and the average incidence of side effects.

The pharmacokinetics of glycyrrhizin (G) in eight patients with chronic hepatitis receiving chronically i.v. administration of 120 mg dose of G was investigated. The plasma concentration of G in the patients after dosing declined in a monophasic manner. However, the pharmacokinetic profiles varied among patients. The mean elimination half-life (t1/2) and the total body clearance (CLtot) were 6.0 h (range 4.3-10.7 h) and 7.9 ml h-1 kg-1 (4.5-12.7 ml h-1 kg-1), respectively. The variation of the CLtot for G was closely related to that of aspartate aminotransferase (r = -0.739, p < 0.05) and alanine aminotransferase (r = -0.783, p < 0.05) activities in the plasma.

The role of enterohepatic circulation of glycyrrhetic acid (GA) in rats was determined by kinetic analysis of GA. The concentrations of GA in the plasma of the control rat (without bile duct cannulation) during the first 5 h after intravenous (iv) administration of GA (2, 5, 10, and 20 mg/kg) were similar to those in the bile duct-cannulated rat at each dose. No significant difference was observed in the values of the terminal half-life, the total body clearance, the distribution volume at steady state, the area under the curve of concentration in plasma versus time, and the mean residence time in each dose between both groups. When GA (2, 5, 10, and 20 mg/kg) was administered i.v. to the bile duct-cannulated rat, excretion of unchanged GA in bile was < 1% of each dose, that of the acid-hydrolyzed products was 14-16%, and that of GA-3-O-glucuronide was only 1-2%. In the control rat, a secondary peak of GA concentration was observed 12 h after i.v. administration of GA (20 mg/kg). The enterohepatic circulation of GA was confirmed by the linked-rat method in which bile of the donor rat after i.v. administration of GA (20 mg/kg) was allowed to flow directly into the duodenum of the recipient rat. GA was found in the plasma of the recipient rat after 6 h, and its concentration reached the maximum (approximately 0.5 microgram/mL) 8-12 h after dosing the donor rat.(ABSTRACT TRUNCATED AT 250 WORDS)

We surveyed sheets prescribed by dermatologists in our hospital during a 6-month period to investigate the stability of the admixture of commercially available ointments and/or creams. The total prescribed sheets numbered 21, 626, with 690 admixtures being found in 676 sheets. Seventy-two percent of these admixtures were combined corticosteroid preparations with white petrolatum or urea creams. Seven kinds of well-prescribed admixtures were presumed to develop some combinational problems. These admixtures were then prepared in our department, and the rate of air inclusion into the admixtures by mixing process was measured. The quantities of the water phase separated by centrifugation employed as an indice of the destruction of emulsion after mixing were measured, with a high value being obtained with the combination of corticosteroid ointments and o/w-type urea creams (ranging 10-30%). From the visual change noted by a naked eye supplemented with microscopic examinations, the emulsion in these admixtures was found to have already been destroyed after mixing. In contrast, the admixtures utilizing corticosteroid ointments and w/o-type urea creams were physically stable for a month. We also discussed on prescriptions made by many physicians. Consequently, it is strongly hoped that the information described in the package inserts and the naming of the products will be improved in relative to their physico-chemical properties.

Drug informations on a suitable insertion duration of suppositories and on a deal with the problem of the loss from rectal are essential for the proper therapy of patients. In the present study, we collected the data on drug disposition after administration of commercially available suppositories which had systemic pharmacological effects, and then analized pharmacokinetically on the problems of the insertion duration of them and the loss from rectal. The rectal absorption rate and the cumulative absorption ratio of drugs from commercially available suppositories were estimated by the deconvolution analysis. The plasma concentration data after rectal and intravenous administration were obtained in nine kinds of drugs, which were ampicilline, ketoprophene, indomethacine, acetoaminophene, phenobarbital, donperidone, bromazepam, buprenorphine and morphine. It was shown that the completion time of the absorption of drug from the suppositories varied largely from 50 min for ampicilline to 8 hours for donperidone. Comparing the time periods required to reach to 50% in the cumulative absorption ratio in those drugs, the fastest time was found in ampicilline (15 min), and the slowest was in aminophylline (90 min). These findings make it possible to the persue counseling for the patients on the proper insertion duration of each suppositories. The simulation of the time course of blood drug concentration after the loss of suppositories from rectal and the supplement of them was successfully performed, suggesting that the optimal drug concentration could be controled by the rational supplemental dose. In conclusion, the drug information based on the deconvolution analysis can be useful to instruct a rational use of suppositories to the pharmacist and/ or the patients.

Background Concern over the potential cardiotoxicity of anti-malarial drugs inducing a prolonged electrocardiographic QT interval has resulted in the almost complete withdrawal from the market of one anti-malarial drug - halofantrine. The effects on the QT interval of four anti-malarial drugs were examined, using the guinea pig heart. Methods The guinea pig heart was isolated, mounted on a Langendorff apparatus, and was then perfused with pyruvate-added Klebs-Henseleit solutions containing graded concentrations of the four agents such as quinidine (0.15 - 1.2 μM), quinine (0.3 - 2.4 μM), halofantrine (0.1 - 2.0 μM) and mefloquine (0.1 - 2.0 μM). The heart rate-corrected QaTc intervals were measured to evaluate drug-induced QT prolongation effects. Results Quinidine, quinine, and halofantrine prolonged the QaTc interval in a dose-dependent manner, whereas no such effect was found with mefloquine. The EC50 values for the QaTc prolongation effects, the concentration that gives a half-maximum effect, were quinidine < quinine ≈ halofantrine. Conclusions In this study, an isolated, perfused guinea pig heart system was constructed to assess the cardiotoxic potential of anti-malarial drugs. This isolated perfused guinea pig heart system could be used to test newly developed anti-malarial drugs for their inherent QT lengthening potential. More information is required on the potential variation in unbound drug concentrations in humans, and their role in cardiotoxicity.