Objective: The ethical requirement of GCP (the Standard for Clinical Trial for Medicine) confronts physicians with the dilemma of obtaining informed consent prior to trials. The patient response when physicians requested patients to participate in a trial strictly in obedience to the GCP ethical guidelines was investigated in the present study.
Subjects: All patients admitted to the department of Hematology/Oncology of the Second Tokyo National Hospital, with hematologic disorders during the 5 month period of the present study.
Method: Patients were asked about their response toward a hypothetical trial of intra venous antibiotics that would be a double-blind, randomized trial using an active drug as control. To standardize the manner of informing the patient about the trial, a recorded explanation about the trial was given to the patient; the patient could then discuss withthe interviewer.
Results: Fifty-four (68%) of 79 patients interviewed agreed to participate in the trial, and 25 (32%) refused. The two major motivations to enter the trial were altruism and the patient-physician relationship, and the main reason not to enter was anxiety, especially about adverse drug reactions. Twelve patients (15%) stated they had an ill feeling about the randomization, and 17 (22%) stated the same about the double-blind procedure. People who were more willing to enter the trial, did not have a negative feeling towards a double-blind trial, were elderly, had stayed longer in the hospital, and had experienced parenteral antibiotic therapy.
Comments: This kind of study can investigate the influence of ethical requirements like GCP on clinical trials and can make physician more comfortable with GCP.

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A new patient-side immunoassay system, Biotrack Theophylline^®, was evaluated and compared with the widely-used monitoring analysis methods, enzyme-multiplied immunoassay (EMIT^®) and fluorescence polarization immunoassay (TDx^®). Blood samples were obtained from five healthy subjects who received oral multiple doses of aminophylline for three days. The theophylline concentrations obtained by Biotrack Theophylline correlated well with those by EMIT (r=0.974) and TDx (r=0.982), respectively. A good correlation was also observed between EMIT and TDx (r=0.986). The mean (±2standard deviation) discrepancy between two methods was as follows: EMIT-Biotrack: -0.23±14.93μmol/L, TDx-Biotrack: -4.83±11.96μmol/L, TDx-EMIT: -4.52±15.01μmol/L. These results indicate that Biotrack Theophylline is a reliable method for the therapeutic monitoring of theophylline by immediate determination of the drug concentration.

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In debilitated elderly patients in whom renal function must be evaluated to determine drug dosages for treatment, it is very difficult to obtain the complete 24-hour urine collections required to measure creatinine clearance (C_cr). Additionally, C_cr in these patients can not be predicted accurately based on their age, sex, actual body weight (BW) and the level of serum creatinine (S_cr). To evaluate C_cr without 24-hour urine collections, we attempted to develop the following formula to estimate C_cr based on sex, BW, S_cr, and the value of serum albumin (Alb).
C_cr (ml/min) = {4×Alb (g/dl) +5} ×BW (kg) /20×S_cr (mg/dl)
(for females, use 75% of BW)
This equation provided a good correlation coefficient between the measured and predicted C_cr (r=0.828), and a regression line which was not significantly different from the line of identity (y=0.889x+4.654). We suggest this formula using Alb as a new parameter could be clinically useful in predicting C_cr in the debilitated elderly.

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E6010 is a novel modified human tissue plasminogen activator, in which cysteine 84 inthe epidermal growth factor domain of human tissue-type plasminogen activator (t-PA) isreplaced by serine.
The safety, pharmacological activity and pharmacokinetics of E6010 were studied in 6healthy volunteers following a rapid infusion (3-min intravenous infusion) of a dose of 0. 25to 6. 0 mg. No drug related subjective symptoms or objective findings were observed . Noclinically significant change was found in clinical laboratory findings. There was a dosedependent decrease of plasminogen and α₂-PI. In the 6. 0 mg dose study, plasminogen andα₂-PI decreased maximally by 19% and 40% of the preinfusion value at 2 hours after thestart of infusion, respectively. The half-lives for α-and β-phases of plasma E6010 concentration measured by enzyme-linked immunosorbent assay (ELISA) were 22. 85-47. 06 min and7. 39-10. 29 hr, respectively. A one-compartment model was used for the analysis of the plasma E6010 concentration measured by the fibrin plate method since a β-phase for fibrin plate activity could not be defined due to insufficient analytical sensitivity of this assay . The half-lifeof plasma E6010 concentration measured by the fibrin plate method was 25 . 75-33. 12 min.
These results suggest that a rapid infusion of E6010 could be effective for clot lysis as E6010 has a long duration of fibrinolytic activity due to its longer half-life than other fibrinolytic agents.

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The pharmacokinetics of famotidine were studied in 7 elderly patients with normal renalfunction, 5 elderly patients with moderate renal insufficiency, 8 anuric elderly patients, and6 healthy young volunteers after intravenous administration of a 10 mg dose .
Although the elimination half-life was not significantly different among the elderly patients with moderate renal insufficiency, the elderly patients with normal renal function, andthe young healthy volunteers, it was considerably prolonged in the anuric elderly patients .There was a good correlation between creatinine clearance estimated by their serum creatinine concentration and the elimination rate constant of famotidine (r=0.754).

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The pharmacokinetic interactions of diltiazem and the antiarrhythmic drugs aprindineand mexiletine were studied in beagle dogs and in patients with arrhythmia.
In the animal experiments at 2 hours after diltiazem administration, the plasma concentration of aprindine was significantly higher than in dogs without diltiazem administration (p <0.05); the mean AUC for aprindine with diltiazem was approximately twice that foraprindine alone (p > 0.05). Moreover, the peak plasma concentration of diltiazem at 2 hoursafter oral administration was approximately twice as high with the combination of aprindineand diltiazem compared to diltiazem alone (p <0.05). In the clinical studies, diltiazeminduced a significant increase in the mean plasma concentration of aprindine, and a significant increase in the mean plasma concentration of diltiazem was observed in these trials (p <0. 05). Therefore, our findings indicate that diltiazem and aprindine have an effect oneach other's plasma concentration. It may be that the same isoenzyme, perhaps cytochrome P450-IID6, is involved in the metabolism of both diltiazem and aprindine.
On the other hand, the differences in the plasma concentration of mexiletine betweentrials with and without diltiazem were not significant, and neither time course changes indiltiazem concentration nor the AUC between trials with and without mexiletine were significant in beagle dogs or in patients with arrhythmia.
To our knowledge, drug interaction between aprindine and diltiazem has not yet beenreported. The present findings, however, clearly demonstrate the existence of such an interaction. Since many patients with ventricular arrhythmias have ischemic heart disease orhypertension, it seems feasible that these patients be treated concomitantly with aprindineand diltiazem. Aprindine displays dose-dependent non-linear kinetics. Moreover, the therapeutic range of aprindine is very narrow, and thus enhancing interactions between aprindineand diitiazem may be of clinical significance.

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The pharmacokinetics of roxatidine wes studied in 4 anuric patients with and without hemodialysis and in 10 healthy volunteers after oral administration of a 75mg dose of roxatidine acetate hydrochloride.
The elimination half-life was considerably prolonged in the anuric patients with and without hemodialysis. Serum concentrations of roxatidine during dialysis were somewhat lower than those without dialysis. Rebound increases in roxatidine concentrations were observed after dialysis was over.
These results indicate that a reduction in the roxatidine dose is necessary to avoid increase in the roxatidine concentration in anuric patients. A supplemental dose, however, is not necessary on the day of hemodialysis.

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Between September and November 1993, 15 people died due to the interaction between sorivudine (anti-virus drug: commercial name is Usevir) and fluorouracil analogs (anti-tumor drug). Questionnaires were completed by the physicians who had opportunities of prescribing fluorouracil analogs as part of post-marketing randomized clinical trials at that time. Two types of questionnaires were designed. One questionnaire was regarding the doctor's general recognition of interactions among drugs. The other questionnaire asked doctors about their specific action concerning individual patients. Questionnaires were collected from 270 doctors covering about 610 patients; 87.8% of the doctors had already been informed of the interaction between sorivudine and fluorouracil analogs. Newspapers (48.5%) were the largest source of information. Only 2.5% of the doctors acquired their information from the package insert with the drugs. Of the doctors questioned, 51.2% had the possibility to administrate the drug even though “combination should be avoided” was printed on the drug package insert. The 2nd questionnaire about the actions of the doctors showed that in 44.8% cases doctors checked whether sorivudine was used in any way and in 47.7% of cases doctors did not check at all.
There are several points regarding the tragedy of sorivudine. The factors related to this tragedy include the system to check the interaction between drugs, telling patients the truth about cancer, and patient consultation regarding medication. These problems originate from the Japanese system of tansmission of drug information. The results of the present survey indicate that it is very difficult to detect drug interaction, to transmit this information to doctors and to inform patients in today's Japanese system. The possibility of a second sorivudine tragedy cannot be denied.

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