SUN 1165 is a newly synthesized antiarrhythmic drug with class Ic properties in vitro.We assessed acute electrophysiologic and hemodynamic effects of SUN 1165 in 18 patientswith supraventricular tachycardia (SVT) [6 patients with AV nodal reentrant tachycardia (AVNRT), and 12 patients with AV reentrant tachycardia (AVRT)]. All patients werefree from organic heart disease. Electrophysiologic and hemodynamic studies were performedbefore and 60 min after a single oral administration of SUN 1165 (150 or 200 mg).SUN 1165 significantly shortened sinus cycle length, lengthened sinoatrial conductiontime (98±21 to 112±21 msec, P< 0.01), AH interval (83±11 to 100±15, P<0.01), HVinterval (42±8 to 63±17, P<0.001), and RV effective refractory period (220±28 to 231±27, P<0.05).Antdrograde conduction via accessory pathway (AP) was abolished in 6out of 7 patients. Retrograde conduction via AP and AV node were abolished in 9 out of12 and 2 out of 6 patients respectively. Induction of SVT was completely suppressed in9 out of 13 patients. By hemodynamic studies (10 patients), decrease of stroke volumeindex and increase of mean pulmonary arterial pressure were demonstrated. No adverseeffects were observed. In conclusion, oral SUN 1165 has potent electrophysiologic effectson impulse propagation through AV node and AP with mild negative inotropic action. Andthe suppression of SVT induction was mediated through predominant effect on retrogradeconduction.

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The efficacy and overall safety of levocarnitine chloride (LC-80) in treatment of patientswith ischemic heart disease (effort angina, effort and rest angina, and silent myocardialischemia), were investigated, using serial multistage treadmill exercise test, and were comparedwith that of dilazep hydrochloride used as the control treatment, by the method ofmulticenter double-blind, group comparison study. The results obtained were as follows.
1. The study comprised 166 patients, with 134 of them compared for efficacy, 166 for safety, and 112 for overall usefulness.
2. Global improvement: “better than ‘moderately improved’ ” was the finding in 45.6%of the levocarnitine chloride-treated group (LC group) and in 33.3% of the dilazephydrochloride-treated group (D group). There was no significant difference in globalimprovement between these two groups.
3. Overall safety: no problem was observed in 95.0% of the LC group, and 95.3% of the D group.No patient in the LC group had to discontinue the test, but two patients inthe D group did so.
4. Overall usefulness: “better than ‘useful’ ” was the finding in 43.7% of the LC group andin 31.0% of the D group.In the X² test, no significant difference in overall usefulnessbetween these two groups was observed, but in the U test, significant difference wasnoted.
5. Overall evaluation of the findings of exercise electrocardiogram: “better than ‘moderatelyimproved’” was the finding in 46.3% of the LC group, and in 30. 3% of the Dgroup.There was no significant difference in overall evaluation of the findings ofexercise electrocardiogram between these two groups.
6. The maximal exercise duration was prolonged in the LC group compared to pre-treatmentlevels, but in the D group such prolongation was not observed. However, therewas no significant difference in the maximal exercise duration between these two groups.
7. The time to onset of the 1mm ST segment depression was significantly prolonged inthe LC group after the treatment. This prolongation was not observed in the D group.However, there was no significant difference in the time to onset of the 1mm ST segmentdepression between these two groups.
8. The extent of ST depression after the treatment was significantly improved in the LCgroup, when compared at the same period of exercise, but there was no significantimprovement in the D group.There was no significant difference in the extent of STdepression after the treatment between these two groups.
9. Side effects: four patients (5.0%) complained of side effects in the LC group, and fivepatients (5.8%) complained in the D group.But no severe case was reported.
10. Abnormal laboratory findings: GOT and LDH levels increased in one case in the LCgroup ; on the other hand, CPK level increased in one case in the D group.Neitherwas clinically significant.
The results suggested that the treatment with levocarnitine chloride (LC-80), administeredat a level of 1, 800 mg/day (in 3 doses), improved significantly the exercise tolerancecapability in patients with ischemic heart disease (effort angina, effort and rest angina, andsilent myocardial ischemia), and is as useful as, or more useful than dilazep hydrochloride.We concluded that levocarnitine chloride is a clinically useful drug for the treatment ofischemic heart disease.

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A phase I study of OPC-8212: 3, 4-dihydro-6- [4-(3, 4-dimethoxybenzoyl)-1-piperazinyl] -2 (1H)-quinolinone, a new oral inotropic agent, wascarried out in 6 healthy Japanese malevolunteers. A double-blind test was performed to evaluate the safety, the pharmacodynamics, and the hemodynamic action with oral administration of a placebo, 30 mg and 60 mg of OPC-8212. The tolerance and the pharmacokinetic profile were also studied by oral administrationof 480 mg of OPC-8212. No pronounced change was noted in vital signs (bloodpressure and pulse rate). Echocardiographic study showed a decrease of the left ventricularendo-systolic dimension without change of the left ventricular end diastolic dimensionand an increase of the left ventricular ejection fraction. Mechanocardiograms showed ashortening of the left ventricular ejection time. No abnormalities were found in therespiratory system, the digestive system, or the laboratory data. The maximum concentrationincreased nonlinearly, increasing with dosage, peak time (T_max) was about 4 to 8 hr.In conclusion, OPC-8212 has an inotropic action without chronotropic and arrhythmogenicaction, andhad no side effects in healthy volunteers.

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A multicenter double-blind controlled study was conducted in 146 patients with ventricularpremature contractions (VPC) to find an optimal dose regimen for SUN 1165 (N- [2, 6-dimethylphenyl] -8-pyrrolizidinylacetamide hydrochloride hemihydrate), a new antiarrhythmicagent.
Patients were administered any one of a daily oral dosage of 75 mg (low), 150 mg (intermediate), and 225 mg (high) of SUN 1165, divided into three doses a day for twoweeks after one to two weeks of control period.
Improvement of arrhythmia was assessed by the reduction in frequency and the gradeof premature contractions, and global improvement was assessed from the results of improvementof arrhythmia and subjective symptoms. In the improvement of arrhythmia aswell as global improvement, the high-and intermediate-dose groups showed significantlyhigher response rate than the low-dose group, whereas no significant difference was observedbetween the intermediate-and high-dose groups.
There were no significant differences in the overall safety rating among the three doselevels.Incidences of the cases in which some problems concerning safety were pointed outin the low-, intermediate-and high-dose groups, were 6%, 9%, and 15%, respectively andno serious case was observed.
The clinical usefulness of the drug was assessed, based on the results of global improvementand the overall safety. The drug was assessed to be useful or better in 30% of thepatients of the low-dose group, 61% of the intermediate-dose group, 74% of the highdosegroup.The high-and intermediate-dose groups showed significantly higher usefulnessrating than the low-dose group, but no significant difference was observed between thehigh-and intermediate-dose groups.
In conclusion, SUN 1165 was shown to be useful in the treatment of ventricular prematurecontractions, and an optimal dosage of 150mg/day was suggested.

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The pharmacokinetic disposition of Cepharanthin, a biscoclaurine alkaloid, was investigatedin healthy subjects following single oral doses of 10, 30, 60, and 120mg. For 30, 60, and 120mg, 5 subjects were studied for each dose ; for 10 mg, only 2 subjects were studied.Plasma and urine Cepharanthin levels were measured by the HPLC method and wereanalyzed by the one-compartment open model. Linear relationships were obtained betweenthe dose from 10 to 120mg of Cepharanthin and the C_max or the AUC. The T_max and thet_1/2 ranged from 1.1 to 2.5 hr and from 4.1 to 9.2 hr (t_1/2α: 3.3 ± 1.0 ; t_1/2β: 17.1 ± 4.1 hrin 120mg), respectively. The mean (±SE) of percent urinary excretion of unchanged drugwas 1.4 ± 0.3%. No side effect has been observed throughout the study period.

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The pharmacokinetic disposition of Cepharanthin, a biscoclaurine alkaloid, was investigated in healthy subjects following single intravenous doses of 25, 50, and 100mg and during and after the 7 days repeated doses of 100mg per day . Each dose was studied in 5 subjects. Plasma and urine Cepharanthin levels were measured by the HPLC method and were analyzed by the one-compartment open model. Linear relationships were obtained between the dose of 3 doses of Cepharanthin and the Cmax or the AUC . The t1/2 ranged from 31.8 to 36.9 hr. The steady state levels were obtained for 5 to 6 repeated doses of 100 mg/day approximately and following the 7 repeated doses the mean (±SE) of t1/2 was 62.0±2.8hr. Using our previous study results of oral dosing, we obtained 0.06 to 0.09 of the absolute bioavailability of Cepharanthin. Total recovery amount of unchanged drug was 9. 6% of administered dose. Throughout the studies we did not observed any adverse effects. These results suggested that Cepharanthin could be extensively metabolized in liver and largely uptaken to the tissue, binding strongly.

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The pharmacokinetics of a tape formulation of isosorbide dinitrate (ISDN) was investigated in aorto-coronary bypass (A-Cbypass) surgical patients. Transdermal sustained-release dosage forms of ISDN (Frandol Tape^®) were applied to 6 patients (ages42 to 68 yr) with angina pectoris, prior to A-C bypass surgery. The plasma ISDN concentrations and urinary volume of these patients were evaluated before, during, and after cardiac operation.
The mean plasma ISDN concentrations fell from6.5ng/ml at the start of the extracorporeal circulation (ECC) to4.7ng/ml and 4.1ng/ml after 15 and 60min of ECC, respectively. Two hr after the end of ECC, however, the mean plasma concentrations of ISDN had risen to 6.8ng/ml. The forecast of plasma ISDN concentrations after 2 and 6hr were estimated from the end of ECC by using the population pharmacokinetic analysis.
The calculated concentrations of ISDN were successfully fitted to the observed plasrna data. The mean rate of urine flow showed significant correlation with percentage change in plasma ISDN concentration (P<0.05).
From these results, it is concluded that application of ISDN tape before A-Cbypass operation may be useful for drug treatment.

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A retrospective bibliographical review was carried out to evaluate objectively the antipepticulcer activity of various agents in experimental animal models. In the present study, we selected benexate, cetraxate, clebopride, plaunotol, sofalcone, teprenone, and troxipide, which have been approved in Japan from 1979 to 1988, as enhancers of mucosal defense.Relationship between ulcer inhibition rate (UIR) and pharmacological effective oral dosewas examined in rats, as regards eight experimental peptic ulcer models. Most of theagents inhibited stress-, indomethacin-, and acetic acid-induced ulcer. It was found thatthe dose exhibiting the, pharmacological effect was remarkably different .among agents ineach model or among models in each agent. Therefore, the dose for UIR 50%, UIR_50% (or UIR_30% in acetic acid ulcer), which was calculated by the least-squares linear regressionanalysis of UIR versus logarithm of dose, was used as an index for the evaluation of eachinhibitory activity against ulceration. It was found that cetraxate was relatively. effectivein ethanol ulcer, plaunotol in stress and aspirin ulcer, and teprenone in indomethacin andethanol ulcer. Clebopride and plaunotol showed smaller UIR_50% againststress ulcer, andteprenone and troxipide showed smaller UIR_50% against indomethacin ulcer. Smaller UIR50% for ethanol ulcer was found with sofalcone and teprenone, and smaller .UIR_30%for acetic acid ulcer was found with sofalcone. It is suggested that UIR_50% (or UIR_30%) may be a useful index for evaluating the preclinical anti-ulcer property and its rank orderamong various agents even in the absence of well-designed comparative studies.

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MS Cohtin (MS-C) is a controlled-release tablet of morphine sulfate developed by Muhdipharma AG, Switzerland, for the purpose of maintaining the blood concentration of morphine in an effective analgesic range by administration every 12 hr.
In this study, the pharmacokihetics of morphine (M), and its metabolites, morphine-6-glucuronide (M-6-G) and morphine-3-glucuronide (M-3-G), were investigated in patients with cancer pain at steady state following oral administration of MS-C.
MS-C was administered every 12 hr, with the dose being adjusted so as to control each patient's pain.
In the patients administered MS-C at doses of 20, 30, or 40 mg every 12 hr, the plasma concentrations of M, M-6-G, and M-3-G showed broad hill-like patterns over a period of 12 hr with the peaks occurring at 4 hr. The plasma cohcentrations were found to be almost proportional to the doses.
C_max and AUC values of M, M-6-G, and M-3-G were also almost proportional to the doses, and t_1/2 (k_ab), t_1/2 (k_el), τ, and T_max values were comparable between the doses.
Total urihary recovery rates from 24-hr urine and the recovery rates for M, M-6-G, and M-3-G were comparable between the doses.
These results indicate that there is no significant change in the pharmacokinetics following MS-C administration at various doses in cancer patients.

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Effects of pre-operative administration of ranitidine on pH and volume of gastric juicewere evaluated in 54 children (mean age: 5.4±1.0 yr) who underwent elective surgeryunder general anesthesia. Simultaneously, bromazepam suppository was evaluated as a premedicationagent for pediatric patients. Patients were randomly divided into four groups, and premedication agents were given 2 hr prior to induction of anesthesia. Patients ingroup A received diazepam syrup (0.5 mg/kg P. o.) ahd those in group B received bromazepamsuppository (3 mg). Patients in groups C and D received ranitidine (1 mg or2 mg/kg i. m.) together with bromazepam suppository (3 mg). Following induction ofanesthesia, a gastric tube (10 Fr. or 12 Fr.) was passed and stomach contents were collectedand analyzed for volume and pH, which was repeated every hr until the end ofthe operation. The gastric pH at the induction of anesthesia was observed to be 2.5 orless in 70% of the patients of groups A and B, 13% of group C, and O% of group D.The volume of gastric contents was less than 0.4 ml/kg in 87% of ranitidine-treatedpatiehts (groups C and D), in 29% of group A, ahd in 60% of group B. It was thenconcluded that pre-operative administration of ranitidine caused a significant reduction ofboth acidity and volume of gastric contents, which will contribute to preventing or reducingaspiration pneumonitis during general anesthesia. Plasma ranitidine concentrationsmeasured by high-performance liquid chromatography revealed 228±32 ng/ml in group Cand 487±59 ng/ml in group D at the induction.of anesthesia. Sedation at the inductionof anesthesia was evaluated utilizing our original pediatric premedication score, whichconsists of 3 check points: quietness (very good, 3 ; good, 2 ; fair, 1 ; bad, 0); crying (no, 2 ; a little, 1 ; yes, 0); and i. v. root (under local anesthesia, 1 ; following induction ofanesthesia, 0). The averaged scores were 4.5±0.4 in group A, 4.2±1.9 in group B, 4.1±0.6 in group C, and 4.8±0.5 in group D, respectively. There was no significantdifference in the score in 4 groups. A plasma bromazepam level was 414±49 ng/ml at theinduction of anesthesia. Our results showed that bromazepam suppository is as effectiveas diazepam syrup for premedication in children.

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At any stage from the drug research and development phase to the post-marketing clinical use of drugs, using epidemiologic methods would be useful. The authors evaluated and elaborated the concept of pharmacoepidemiology. For this purpose, the epidemiologic research methods, both observational and interventional, were examined for application to pharmaceuticals.
Providing a framework for epidemiologic research on pharmaceuticals, we proposed a new scheme of a “pharmacoepidemiologic decision-making process.” It revealed that three kinds of decision-making are important in the process: the decision-making at the research and development level; the decision-making at the population level; and the decision-making at the individual level.
Two examples relating to the pharmacological research and development process were illustrated: population pharmacokinetics and post-marketing studies. The authors showed the function and effectiveness of the concept of the pharmacoepidemiologic decision-making process in the examples, and discussed the relationship between the individual and the population in pharmacoepidemiology.

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