Liver damage may cause abnormalities in the absorption, metabolism, and excretion of drugs, thus, it may influence the in vivo effectiveness of antibiotics and the incidence of their side effects. In this respect, a study on the tissue levels of antibiotics in liver damaged rats may be justified. Galactosamine (GalN), a-naphthylisothiocyanate (ANIT), and carbon tetrachloride (CCl₄)were administered to rats to obtain liver damage models, and the tissue levels of carbenicillin (CBPC), cefazolin (CEZ), and gentamicin (GM) in these animals were measured b y bioassay (Okubo's band culture method). The results obtained were as follows:
1) CBPC levels: These levels in the liver tissues damaged by GalN, ANIT, or acute CCl₄administration were found to be significantly lower than in the control livers. The blood levels, although higher in the ANIT group, were generally similar to those of the controls. In the kidneys, a slight accumulation of CBPC was found only in the rats damaged by chronic CCl₄administration.
2) CEZ levels: In all of the liver damaged group, the CEZ levels in the liver were significantly lower than in the controls. In the blood and kidneys, the liver damages had less influence on the CEZ levels than on the CBPC levels.
3) GM levels: In contrast to CBPC and CEZ, the accumulated GM in damaged livers of all kinds showed remarkably higher levels than in the controls. The levels in the blood were similar in all groups. Those in the spleen and kidneys were high only in the ANIT group.
4) In order to examine the relationship between the degrees of liver damage and t he changes in the antibiotic concentrations in the liver, rats were administered various dosages (1000, 400, 200mg/kg) of GalN, as its liver damaging activity is known to be dose dependent. Of the three antibiotics used (CBPC, CEZ, and GM), only GM showed levels in the liver corresponding to the degrees of liver damage detected by GOT, GPT, and ALP in the serum.
These findings suggest that liver damages may cause quite different changes in the dist ribution of antibiotics, especially changes in the liver according to the kind of antibiotic used: Contradiatory behavior may be seen even among antibiotics excreted mainly through the renal route. These facts should affect antibiotic chemotherapy in hepatic diseases with reference both to effectiveness and to side effects.

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In Part I of this study, the results obtained by bioassay (Okubo's band culture method)revealed that the carbenicillin (CBPC) and cefazolin (CEZ) levels were lower, while gentamicin (GM) levels were higher in experimentally damaged rat livers than in normal controls.
In this Part of the study, the accumulation and localization of these antibi otics in damaged livers were directly observed by the micro-autoradiographical method.
Mice, pretreated with a-naphthylisothiocyanate (ANIT) or carbon tetrachloride (CCl₄)received ¹⁴C-benzylpenicillin (¹⁴C-PCG),¹⁴C-CEZ, or ³H-GM intramusclarly. Micro-autoradiography (MAR) was carried out on the liver tissues removed from the mice 30∼60 min. (60120 min, for GM) after injection of the labeled antibiotics.
The results obtained were as follows:
1) ¹⁴C-PCG: In the CCl₄ damaged liver, the accumulation of grains produced by exposure to ¹⁴C-PCG was found to be delayed in the bile duct, but similar in the portal veins and in the hepatic cell regions in comparison with the controls. In the ANIT damaged liver, these grains were fewer in the bile ducts and hepatic cell regions, and more in the portal veins than in the normal liver.
2) ¹⁴C-CEZ: In the CCl₄ damaged liver, the grain accumulation was decreased in the bile ducts and in the hepatic cell regions, but increased in the portal veins. In the ANIT damaged liver every tissue site presented more grains in the experimentals than in the controls.
3) ³H-GM: In the CCl₄ damaged liver, abundant grains were found irregu larly accumulated in the hepatic cell regions around the central veins, where they never accumulate in a normal liver, and later on the grains were seen diffused throughout the whole of the fatty degenerated hepatic cell regions. Already during the early stage, more grains were also found in these bile ducts than in those of the normal Hiver. In the ANIT damaged liver, more grains were found in the Glisson's sheath regions, difusing into the hepatic cell regions, than in the control liver. Besides, it was note-worthy that the grains had accumulated in the spotty necrotic sites of the hepatic cell regions.
Although all three of the antibiotics examined are those which are overwhelmingly excreted through the kidneys without being metabolized in the body, the above mentioned data show that GM completely differs in its kinetics in the damaged liver from CEZ or PCG, as GM is the only one which accumulates there.
Although these findings require further study for interpretation in the clinical field, they may at least warn against the careless administration of aminoglicosides to liver damaged patients, even if not so imperatively as to patients with renal failure.

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In the present study, bactericidal activity in the blood, an important factor in the host defence mechanism against infection, was estimated in cases of diabetes mellitus, blood disorders, cancers, and liver cirrhosis. This activity was also measured in rabbits treated with immunosuppressants, i.e. βmethasone (βM) (2mg/kg/day × 5, i.m. ) and cyclophospham ide (CPM) (50mg/ kg/day × 5, i.m. ).
The results obtained were as follows:
1) In diabetes mellitus, the bacter icidal activity in the whole blood was found to be depressed in 42.8% of the cases, while that in the sera was similar to that in the controls.
2) In aplastic anemia and leukemia, the activity in the whole blood was depress ed in 30%of the patients, while that in their sera was similar to that in the controls.
3) In cancers,36% of the patients showed enhanced bactericidal activity in the blood, while in hepatoma, this activity was depressed.
4) In liver cirrhosis, the pati ents presented remarkable findings: 1) the bactericidal activity of both their whole blood and their sera was significantly depressed; 2) the phagocytic and bactericidal activities of the neutrophils depressed in the patients' sera would recover when replaced by normal sera; and 3) the NBT reduction and βgalactosidase activities of the neutrophils were similar both in the liver cirrhotic patients and in normal individuals, while the muramidase activity was slightly decreased and the complement activity was markedly depressed in these patients. Thus, the low bactericidal activity in the liver cirrhotic patients seems to be attributable to a depletion of the opsonizing activity for the phagocytosis of bacteria, which is exerted by antibody plus complement and not to the neutrophilic function itself
5) CPM administration to rabbits resulted in depressed bactericidal activity in the whole blood, although the monocytic activity was elevated during the neutropenic phase induced by CPM,
6) βM administration caused neutrophilic leukocytosis, while the bactericidal activity of each neutrophilic cell was depressed.
These findings may con tribute to the analysis of host defence-systems and also to the prevention of opportunistic infections.

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The behavior of leukemic sera as to MLC reaction and phytohemagglutinine (PHA) induced lymphocyte transformation was studied with the purpose of examining immunosuppressive factors in the sera. The results obtained were as follows:
Out of the 74 sera from 36 patients with var ious types of leukemia tested,18 showed inhibitory effect (at on Inhibitory Ratio greater than 75 %) against MLC, and 34 against PHA lymphocyte transformation. Such inhibitory activities were marked in sera from patients experiencing AML and CML blastic crisies.
As to MLC, the inhibitory effects were scarcely found in the sera before treatment, but, after intensive chemotherapy, the reaction was often remarkably suppressed, which seemed indicative of poor response to chemotherapy and poor prognosis. On the other hand, as to PHA lymphocyte transformation, the reaction was remarkably suppressed by the sera before treatment, but the inhibitory effect was mitigated in concomitance with the numerical decrease in leukemic blast cells brought on by intensive chemotherapy, and also in complete remission. In relapse, the inhibitory effect was again intensified, i.e the inhibitory effects of the sera against PHA lymphocyte transformation well correlated with the clinical state of the disease.
Further studies were made on these suppressive factors in the sera: Both the factor suppressing MLC and that suppressing PHA lymphocyte transformation were not dialysable, and remained stable for lyophilization. Fractionation of normal and leukemic sera was carried out using DEAE-Sephadex ion exchange column chromatography: The ellution patterns of the normal and leukemic sera were quite similar, but the inhibitory activities of leukemic sera against both MLC and PHA lymphocyte transformation were always found in Fraction 1.
These results fairly indicate the presence of suppr essive factors in leukemic sera, and the examination of these suppressive factors should be of great significance in the clinical evaluation of the immunocompetence of leukemia patients.

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For the quantitave evaluation of transient myocardial ischemia, serial 201-Tl myocardial scintigrams were performed at rest and under stress testing at intervals of one week in ischemic heart disease. Eight normal adults and forty-two patients with ischemic heart disease were studied by stress testing. The stress testing was multistage exercise by sitting bicycle ergometer to submaximal level. And 201-Tlwas injected 3 mCi intravenously one minute before the end of the test. In this study GCA-401 (Toshiba) as gammacamera, GAMMA 11 PDP 11/34 (DEC)as minicomputor and SIEMENS ELEMA 380B (Siemens) as bicycle ergometer were used. Myocardial scintigrams in three views (anterior, left anterior oblique and left lateral projectons)were obtained at ten minutes, one and two hours (phase 0,1 and 2) after the 201-Tl bolus injection.
The author showed that the washout rate was correlated with the peak double product (mmHg beats/min, × 10²). Based on the conception of 201-T1 redistribution report ed by Gewirtz et al., removing the influence of stress level using the correction of the washout rate the quantitative method was designed.
The myocardial wall was g eometrically divided into five segments each view. One segment was situated at apical region. The remained two segmeuts were placed at septal region and other two segments at postero-lateral region using the ROI of 7 × 7 matrix by manual. The washout rate from phase i to j (WRij) was defined as WRij= (maxCtsi-maxCtsj) /maxCtsi where maxCtsi denoted maximal Cts at phase i in the relevant view. The washout rate 02 (WR02)showed the decreasing rate of the net rate of 201-Tl for two hours after the injection.
The redistribution index (cRdsij) in each segment was defined as cRdsij= [Ctsi × WRij + (Ctsj-Ctsi) ]/maxCtsi, where Ctsi denoted mean Cts at phase i in the segment. cRds02 showed the redistributed counts which were estimated by adding WR02 for two hours.
The infarcted segment was identified by the findings of ECG and VC G. In remained segments, the ischemic segment was identified as 70% or less of maxCts 0 in phase 0 scintigram, while normal segment as 80% or more. The segments from 70% to 80% of maxCts 0 were removed from this study. ΣcRdsij denoted the sum of 15 cRdsij. MaxcRdsij indicated as the maximum of 15 cRdsij. Mean values (±SD) of cRds02 in the normal, ischemic and infarcted segments were -6.3 ±5.4, 9.9 ±6.9 and 3.4 ± 7.4%, respectively, and the differences were statistically significant each other (p<0.001). Mean values (± ±SD) of ΣcRds02 in normal, angina pectoris and MI groups were -48.3 ±46.8, 95.0 ±67.8 and 62.9 ± 35.8 resqectively. Between normal and angina pectoris group, and between normal and MI group, the differences were statistically significant respectively (p<0.001, q<0.01). When the peak double product attained at the test was 200 or more, it was significantly correlated with WR02 (r=0.81, p<0.01). All the thirty-two patients with angina except two showed that WR12 was greater than WR01, but eight normal cases showed that WRO1 was greater than WR12.
RI angiography was performed in the twenty-eight cases who had myocardial scintigram under stress testing in order to evaluate LV function using ejection fraction (EF), mean ejection rate (mER) and maximal ejection rate (maxER). The equilibrilium method at LAO 45°projection was used after 99m-Tc HSA 15 mCi intravenously at supine position. The indices were calculated from LV volume curve after the addition of six hundred cardiac cycle. The differences between MI with angina and MI without angina were significant statistically using maxcRds02, mER and EF (p<0.05, p<0.05 and p<0.01), though not significaut using maxER. As maxER decreased 4.00 or less, maxcRds02 increased. It was useful that twentyeight cases conld be classified to four groups (normal, angina pectoris.

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Digoxin is known to have a low margin of safety. Measuring the steady state level of digoxin in serum by radioimmunoassay technique has increased the safety of digoxin therapy, but the current clinical data concerning serum digoxin concentration is still insufficient for utilizing serum digoxin concentration as a reasonable guide for the proper digitalization. This study was aimed to evaluate the digoxin therapy in terms of serum digoxin concentration and to elucidate the pharmacokinetics of digoxin. Results obtained were as follows.
(1) After the oral administration of 0.5mg digoxin in tablet form to normal subjects, the peak serum levels were reached in 45 to 60 minutes and within five hours a relative ly stable plateau was attained.
(2) In 122 patients on chronic digoxin therapy, serum digoxin concentration was 1.17 ± 0.56(S. D. ) ng/ml, ranging from 0.22 to 2.8 ng/ml and daily maintenance dose was 0.25 ± 0.11mg, ranging from 0.125 to 0.5mg. Serum digoxin concentration correlated to maintenanc e dose per day and per kilogram (r= 0.49 and r=0.64, respectively).
(3) “Digoxin Index”, expressed as serum digoxin concentration (ng/ml) divided by daily maintenance dose (mg/kg), was proposed as one of the useful guides for the therapy and the value of 400 or more was considered as being suggestive of potential candidate for intoxication. This index was theoretically related to bioavailability, absorption, volume of distribution and biological half-life of digoxin.
(4) Hemodialysis in patients with chronic renal failure did not significantly influence the serum digoxin level.
(5) The mean digoxin concentration for 8 toxic patients was 3.14 ± 1.41 ng/ml, while the mean level of 122 nontoxic patients was 1.17 ± 0.56 ng/ml (p<0.001). All of the to x ic patients had levels above 2.0ng/ml. Above 2.0ng/ml of serum digoxin concentration and 400 or more of digoxin index carry a high probability of digitalis intoxication.

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In an attempt to clarify the mechanism of neuroleptanalgesia in the central nervous system, the following series of experiments were performed using droperidol and fentanyl citrate. The subjects for the experiments were rabbits.
1) Nine components (PPR₁, PPR₂, PPR₃, PPR₄, PPR₅, PPR₆, PPR₇, PPR₈ and PPR₉ )in PPR were observed in response to the photic stimulation through monopolar lead.
2) It was found that the PPR components were inhibited by the administratio n of droperidol or fentanyl citrate. But when droperidol and fentanyl citrate were simultaneously administered in the ratio of 50: 1, only PPR₆ was found to increase.
3) It was found that the components of PPR except PPR₆ were less inhibited following destruction of the VA and the CM when droperidol and fentanyl citrate were administered simultaneously. The PPR₆, however, was found also inhibited.
4) The results of the above mentioned series of e xperiments may lead us to the conclusion that the inhibitory effect becomes stronger for the components of PPR when droperidol and fentanyl citrate are administered simultaneously, and that this inhibitory effect is related to the VA or the CM, the thalamic nuclei which belong to the diffuse thalamocortical projection system.

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