p-Chlorophenoxy isobutyryl glycine amide (CGA) is a newly synthesized antilipidemic drug, which has been proved to lower serum concentrations of triglyceride and cholesterol in amimal experiments.
The pharmacokinetics of CGA have been studied in six healthy volunteers. Determination of the drug and its metabolites in the blood and urine was carried out using high pressure liquid chromatography and gas chromatography-mass spectrometry.
After oral ingestion of 500mg of CGA, CGA and its active metabolite p-chlorophenoxyisobutyric acid (CPIBA) were detected in blood samples.The peak concentration of CPIBA was observed after that of CGA.These results suggest that CGA is a so-called prodrug or latent form of CPIBA.A multiple dosing study (12-hour intervals for 3 days) reveals that ingestion of CGA at 1000 mg once daily might be sufficient to maintain steady-state plasma concentration of CPIBA.
p-Chloroisobutyryl grycine (CG) was identified as a main metabolite in urine from the mass spectrum.

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The pharmacokinetics of theophylline were studied in six premature infants (gestation: 31.7±3.1 weeks;birth-weight: 1062±304g).They received 5.5±0.4 mg/kg of aminophylline as a loading dose, and 1.5 mg/kg as a maintenance dose intravenously from average age of 6.1±3.3 days.Samples of blood were collected by heel-stick technique and plasma theophylline concentration was measured by high-performance liquid chromatography.
The plasma data were analyzed by a two-compartment open model. The apparent volume of distribution was 0.662±0.107 1/kg, which was slightly larger than those of children and adults. However, the volume of central compartment (0.509±0.084/1/kg) was approximately two times larger.Plasma half-life for the elimination phase was 33.9±16.5 hours and body clearance was 16.9±7.4ml/kg/hr. Theophylline elimination in premature infants was extremely slower than that in children and adults, and highly variant.
The results indicated that 6.6 mg/kg of aminophylline as a loading dose and 0.17 mg/kg/hr as a maintenance dose would generate a mean plasma concentration of 8μg/ml.Since theophylline elimination is highly variant and increases with maturation of infants, the dosage should be adjusted individually by monitoring the plasma theophylline concentration.

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In order to clarify the etiology of the sensation of heat caused by 1-hexylcarbamoyl-5-fluorouracil (HCFU), a new antitumor agent, the effects of HCFU and main metabolite, 1-ω-carboxypentylcarbamoyl-5-fluorouracil (CPEFU), on single neuron activity of the rat preoptic area (POA) were studied using multibarreled electrodes.
Of the 114 neurons tested, 52 were histologically localized in the POA and 62 in the other regions.Electrophoretic application of HCFU or CPEFU increased the discharge rate of POA warm sensitive neurons (which also increased in discharge rate with heat stimulation of the scrotum), and decreased the discharge rate of POA cold sensitive neurons (which also decreased with heat stimulation of the scrotum). However, both compounds non-specifically affected not only POA neurons but also neurons in other regions. In contrast to the effects of HCFU and CPEFU, electrophoretic application of sulpiride, a neuroleptic agent, inhibited spontaneous discharge of POA warm sensitive neurons and facilitated that of POA cold sensitive neurons.
Although iontophoretic application of noradrenaline (NA) inhibited spontaneous discharge of POA warm sensitive neurons and facilitated that of POA cold sensitive neurons, neither acetylcholine (ACh) nor serotonin (5-HT) had any obvious affect on either activity.
These findings suggest that the heat sensation induced by HCFU might be explained by its effect on the thermosensitive neurons in the POA and that this adverse effect might be relieved by treatment with sulpiride.

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In order to clarify the mechanism of the pollakisuria caused in subjects by 1-hexylcarbamoyl-5-fluorouracil (HCFU), a new .antitumor agent, in a Phase 1 study, the effects of HCFU and its metabolites on a cat bladder movement were studied.
HCFU and 1-ω-carboxypropylcarbamoy1-5-fluorouracil (CPRFU), one of its main metabolites, slightly accelerated bladder movement whereas 1-ω-carboxypentylcarbamoyl-5-fluorouracil (CPEFU), another main metabolite of HCFU, caused marked acceleration. However the other metabolites, such as 5-fluorouracil (5-FU), α-fluoro-β-alanine and ε-aminocaproic acid, had no such effect. Furthermore CPEFU also accelerated rabbit and rat bladder movements.
These data suggested that the pollakisuria caused in subjects by HCFU might be the result of stimulation of the bladder by CPEFU.
The effect of CPEFU was inhibited by atropine and hexamethonium but not by diphenhydramine. CPEFU significantly potentiated the bladder contractions induced by stimulation of the central end of the pelvic nerve but not with a peripheral end. The acceleration of the bladder movement caused by CPEFU remained present in the intercollicular-prepontine decerebrate cat but disappeared in the spinal cat and postcollicular-midpontine decerebrate cat.
Anticholinergic drugs, chlorpromazine and sulpiride, inhibited not only the acceleration of cat bladder movement due to CPEFU but also the pollakisuria caused in subjects by HCFU.
These findings lead to the postulation that the pollakisuria caused by HCFU is due to stimulation by CPEFU of the micturition reflex center in the brain stem.

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In Part I, the criterion for the evaluation of chest X-ray films was provided, the correlation between various symptoms and X-ray film findings in bacterial pneumonia was investigated by factor analysis, and a tentative rating scale for overall assessment of chemotherapy was proposed.
The present report deals with data newly obtained in 91 cases together with the data of the 72 previous cases. Reproducibility between the results of factor analyses on the previous and the present data was examined and analysis was again carried out on the total data. Cluster analysis was then performed on the total data to observe agreement with the results of the factor analysis and to confirm the classification structure of various symptoms.
(1) Factor analysis of the initial severity of symptoms observed at the start of chemotherapy reveals the following classification structure, common to both the previous and the present data: group 1 (basic symptoms), including dyspnea, rales, cyanosis, cardiac failure and two items on the X-ray film (by each physician and by the central committee); group 2 (respiratory tract inflammation), including cough, character and volume of sputum ; and group 3 (systemic reaction), including fever, leucocytosis and chest pain. The fact that the erythrocyte sedimentation rate did not show a definite relation to the third group in the present study was the only point of disagreement with the previous results. The same classification as above was also derived from cluster analysis.
(2) According to the changes in symptoms during two weeks of chemotherapy, it was mentioned in Part I that the result of factor analysis was almost the same as that of the initial severity except for the fact that the changes in the X-ray films correlated to the changes in groups 1 and 3 simultaneously with the status of X-ray film findings in the classification structure being characterized as a problem for further investigation. In the present report, cluster analysis was performed together with factor analysis adding new data to those already obtained. The common findings from these results can be summarized as follows: group 1 concerning basic symptoms (same as in group 1 of (1) except for the X-ray film findings), group 2 concerning respiratory tract inflammation (same as in group 2 of (1)), group 3 (fever and leucocytosis) and group 4 (X-ray film findings and erythrocyte sedimentation rate). However, the changes in X-ray films also correlated with group 1 so the problem previously mentioned still remains.
(3) The change in each individual symptom was investigated during the twoweek period of chemotherapy. The “life table survival curve” method was applied in this investigation, except that “disappearance of symptom” was used in place of “death” in the life table . It was found that the symptoms which showed rapid disappearance and those which showed slow change became separated, corresponding to the characteristic classification into the above four groups: the symptoms in the first and the third groups showed the most rapid changes, followed in decreasing order by those in the second group and those in the fourth group.The, method, aggregating various symptoms in the above four groups, was applied to the analysis of a clinical trial to compare the effects of different antibiotics. It was illustrated that a fairly compact and reasonable summary could be given for the results of the trial since the method arranges various symptoms in a few characteristic groups and focuses on the alleviation of symptoms which is believed to be the final goal of chemotherapy.

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The pharmacokinetics of disopyramide and its effects on the electrocardiogram were studied in five healthy male volunteers after intravenous (50 mg) and oral (200 mg) administration.
The apparent half-times of the distribution phase and elimination phase after intravenous administration were 3.78 min and 4.75 hr, respectively. The apparent volume of distribution for the central compartment was 11.95 liters with an eli-mination rate of 0.575 hr^-1. These pharmacokinetic parameters in intravenous administration were compatible with previous reports which had been obtained using a pharmacokinetic model with a 2-compartmental system, but they were far from the results previously obtained using a single-compartmental system.
The peak-time and peak-concentration after oral administration were 2.67 hr and 1.11% dose/liter, respectively, with the bioavailability calculated at 0.67. These values also agreed with previous reports of the pharmacokinetics of diso-pyramide (free base). These results showed that the pharmacokinetics of diso-pyramide in Japanese subjects was not different from that previously reported with subjects in other countries.
In these administrations no significant change was observed in the heart rate, the P-R interval, the duration of QRS complex, and the Q-T corrected interval of electrocardiogram. However, a small but significant change in the shape of the T-wave developed in right precordial leads in all series during the phase of high drug concentration in plasma.

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The hemodynamic effects on both pulmonary and systemic circulation of 10 mg/kg intravenously injected dibutyryl cyclic AMP (db-cAMP), a cyclic AMP derivative, were studied using Swan-Ganz catheterization and hemodilution methods with the following results:
1. Cardiac output increased about 40% maximally due to increased stroke volume and heart rate. Enhanced stroke volume played a more important role in cardiac output increase than did the heart rate.
2. Peripheral resistance was lowered, as evidenced by the increased cardiac output and decreased arterial pressure.
3. Pulmonary vascular resistance was also seen to be lowered slightly, from the relatively constant pulmonary arterial pressure and increased cardiac output.
4. The effects noted attained their peak values at 10 to 20 minutes after injection, continued for about 20 minutes, and returned gradually to the control values in 90 minutes.
From these results, db-cAMP at 10 mg/kg was found to have little adverse effect on pulmonary circulation. Therefore the usefulness of this drug as a ther-apeutic agent in the treatment of shock characterized by low cardiac output along with increased peripheral resistance may be presumed, provided that it be administered with great care for low circulating volume.

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The effects of dibutyryl cyclic AMP (db-cAMP) on cardiovascular hemodyna-mics and changes in blood sugar and serum insulin levels were evaluated in GOF-anesthetized man. Observations were made on 15 patients of both sexes and ranging in age from 24 to 63 yrs who were to undergo surgery. Sixty minutes before induction, each patient was given a moderate dose of atropine as preme-dications. Stroke volume and cardiac output were measured by a Minnesota impedance cardiograph, arterial blood pressure was measured by auscultation, total peripheral resistance was calculated from the mean arterial pressure and cardiac output, the heart rate was obtained from an ECG monitor, blood sugar and serum insulin levels were determined from venous blood, and the insulin-glucose ratio was calculated from the insulin and blood sugar levels. Twenty minutes after GOF anesthesia, 5mg/kg of db-cAMP were injected and its effects were studied for 30 minutes prior to surgery with the following results:
1) Db-cAMP increased the heart rate slightly and lowered systolic and diastolic pressure while increasing pulse pressure slightly.
2) Both the stroke volume and cardiac output increased after db-cAMP injec-tion.
3) Total peripheral resistance decreased remarkably after db-cAMP injection.
4) Blood sugar and serum insulin levels both increased remarkably, with a slight increase in the insulin-glucose ratio after db-cAMP administration.

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Hemodynamic studies (using radiocardiography) were performed before and 9 weeks after oral administration of prazosin (av. 8.0mg/day), and 5 weeks afterthat of ecarazine (av. 115 mg/day), metoprolol (av. 195mg/day) or pindolol (av. 27mg/day) in 61 outpatients with essential hypertension (av. 46.2 yrs., WHO I-II). Metoprolol reduced mean arterial pressure (MAP) from 132± 5mmHg to 115±4 mmHg (P< 0.01). The cardiac index (CI) fell from 4.10±0.24 1/min/m² to 3.30±0.221/min/m² (P<0.01) without any change in the total peripheral resistanceindex (TPRI). Pindolol reduced MAP from 130±3 mmHg to 116±2 mmHg (P <0.01).TPRI fell from 2, 781±136 dyne·sec·cm^-5·m² to 2, 442±156 dyne·sec·cm^-5·m², although the decrease was not significant. However, there was a significant correlation between the changes in TPRI and MAP in the pindolol-treated group (n=23, r=0.716, P<0.005). Both prazosin and ecarazine reduced MAP (prazosin, from 128 ± 3mmHg to 116±3mmHg, P<0.025; ecarazine, from 130±3mmHg to117±4 mmHg, P<0.005). Both of these vasodilators induced a small and insignifi-cant decrease in TPRI (prazosin, from 3, 062±231 dyne·sec·cm^-5·m² to 2, 837±287dyne·sec·cm^-5·m²; ecarazine, from 2, 655±175 dyne·sec·cm^-5·m²) without any change in CI.
The addition of prazosin or ecarazine to the pretreated group with metoprolol tended to lead to a further decrease in MAP and a reduction in TPRI (from av. 3, 315dyne·sec·cm^-5·m² to av. 2, 743 dyne·sec·cm^-5·m², not significant) with aslight increase in CI. These changes were similar to those observed with the use of prazosin or ecarazine alone. In contrast, the addition of metoprolol to the vasodi-lator therapy induced a decrease in CI, although statistically insignificant. After pretreatment with pindolol, the addition of prazosin or ecarazine induced a re-duction in MAP and a further decrease in TPRI without a concomitant increase in CI. When pindolol was given to patients pretreated with ecarazine, MAP and TPRI tended to decrease further, but not significantly.
Increased peripheral resistance has been considered the hemodynamic hallmark in most cases of essential hypertension, and the antihypertensive action of some beta-adrenergic blockers may be attributed mainly to a decrease in vascular re-sistance as observed in the pindolol therapy in this study. This study revealed that the beta-adrenergic blockers induced less reduction in TPRI in the non-responders than in the responders. These results suggest that vasodilators such as prazosin and ecarazine may induce a further reduction in TPRI in the beta-blocker-treated patients, and so the vasodilators may be useful as adjuncts to beta-blockade in the treatment of essential hypertension.

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We have reported that the concomitant administration of urokinase (UK) and dextran sulphate (DS) has induced higher fibrinolytic activity than that expected from the simple addition of UK alone or DS alone. For clarifying the mechanism of the accelerated (or sustained) fibrinolytic activity induced by concomitant administration of UK and DS, a large amount (3g) of DS alone was administered to the three healthy adults, and the change of the fibrinolytic activity was then estimated using fibrin plates and the content of the various factors of coagulation, fibrinolysis and kinin system in the blood were estimated by the method of single radial immunodiffusion. After DS administration, three volunteers did not have any side effects and plasmin activity in the blood increased two folds before DS administration.
Furthermore, % reduction of fibrinogen content in plasma after DS administration was 19.9, that of α₂-macroglobulin content was 10, that of α₁-antitrypsin content was 10, that of C₁'-inactivator content was 7.4, that of prothrombin content was 7.2, that of antithrombin III content was 5.6 and that of plasminogen content was 2.0.
On the other hand, the fibrinolytic activity in the euglobulin fraction increased markedly after DS administration, the fibrinolytic activity curvemoved upwords and counter-clockwise.
Based on the above-mentioned results, it was appeared that the acceleration of the fibrinolytic activity after the concomitant administration of UK and DS was due to decreasing the inhibitory activity of inhibitors after DS administraion alone.

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No standard form of protocol for assessment criteria in the chemotherapy of infections has been well established in the field of surgery. This report describes an attempt to establish a good protocol for clinical assessment ofchemotherapeutic agents in postoperative infections based on a comparative clinical study of cefotiam and cefazolin.
In order to secure reasonably homogeneous subgroups of subjects who would vary with respect to the symptoms and signs as well as the required duration of chemotherapy, the following categorical criteria for patient selection and stratifi-cation were provided: those with postoperative superficial purulent infections (stratum A); and those with postoperative localized peritonitis and/or dead space infections (stratum B), excluding those connected with an opened lumen of diges-tive tract. The duration of chemotherapy was determined to be 7 days for stratum A and 14 days for stratum B. As targets of observation, 8 items for stratum A and 11 for stratum B were selected among the symptoms and signs considered to be observable with high incidence in the patients of each respective stratum. The surgeons in charge were responsible for observing each patient by using these items throughout the trial and for judging the general outcome of the treatment.
The data obtained from 89 stratum A patients and 79 stratum B patients Were subjected to the statistical analyses. Tentative criteria for grouping the observation items were established from the results of principal component analysis and cluster analysis, after which regression analysis was carried out on the data of these groupings and the overall impressions of the surgeons. Changes in suppurative discharge, local signs, fever, WBC, and abdominal signs (stratum B only) were found to correlate with the overall impressions. From these facts tentative criteria for overall assessment of the chemotherapy were adopted.
When the patients who showed marked discrepancies between their surgeons' judgements and the results based on the criteria were examined, some minor cor-rections were found to be called for with regard to the criteria for patient selection, stratification and overall assessment.
Changes in clinical isolate (s) from the inflammatory focus highly correlated with the alterations in discharge. This fact indicates that bacteriological examination of clinical isolates is also indispensable in the clinical evaluation of chemotherapeutic agents in postoperative surgical infections.

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The phase 1 study of bucumolol, a new β-blocking agent was carried out to examine its pharmacological actions and safety in normal volunteer subjects. A single dose of 10 mg was orally administered as a suitable dose on the basis of the experimental results obstained in animals, and compared with 20 mg propranolol in the double blind manner.
The heart rate significantly decreased both at rest and during exercise on the use of each drug by almost equal extent. However, blood pressure lowering action was scarecely observed by bucumolol. The PEP and PEP/LVET in systolic time intervals were prolonged following administration of bucumolol in the supine position, indicating the presence of negative inotropic effect.
The administration was continued for 2 weeks, but no significant changes were noted in the subjective symptoms, hematological data and cardiothoracic ratio in chest X-ray films. From these results, it was confirmed that bucumolol of 10 mg has an effect to decrease heart rate and exerts a negative inotropic action without untoward actions.

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In order to find out an appropriate therapeutic dose of bucumolol, a newly developped β-blocker, the effects of 30mg/day and 60mg/day of the drug on angina pectoris and arrhythmias were studied by means of double blind group comparison method.
Of 66 patients with angina, general improvement rating was better in 28cases of 30mg/day group than in 38cases of 60mg/day group (P=0.085), while no signifi-cant difference in usefulness was observed between two groups.The rates of decrease of the anginal attacks and nitroglycerin consumption were higher in the former group (P=0.053 and P=0.024).
Of 46 patients with premature beats, general improvement rating and usefulness were significantly better in 24 cases of 30 mg/day group (P=0.025 and P=0.027), but no significant difference was seen in the rate of decrease of premature beats between two groups.
The incidence of side effects was 18 among 132 cases (13.6%).
These data indicate that 30 mg/day of bucumolol is recommended for the treatment of angina and arrhythmias.

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