The susceptibility to ouabain of the heart muscle of the house musk shrew (Suncus murinus), an insectivore, was investigated by means of in vitro experimentation, and compared with the rat, guinea pig, and rhesus monkey. Contraction of the electrically driven heart muscles of all species slowly increased following application of ouabain. The shrew was approximate 100-fold more sensitive than the rat and 10-fold less than the guinea pig and rhesus monkey. Only the rat heart preparation that was arrested by the highest concentration of ouabain could be restored by a few washings with medium. The pharmacological characteristics of the shrew differ from those of the rat and were comparatively similar to those of the guinea pig and rhesus monkey.

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The pharmacokinetics and pharmacodynamics of piretanide in rabbits were investigated. After intravenous administration, the plasma concentrations and the urinary excretion rates of piretanide, as well as the pharmacologic effects, were measured under two different hydrated conditions. In one experiment, the amount of the body fluid which was lost during diuresis was replaced by infusing Ringer's solution at exactly the same rate with the urine flow rate (treatment I). In another experiment, no compensatory infusion was made (treatment II). There was no appreciable difference between treatment I and II, as far as the plasma concentrations and urinary excretion rate were concerned. In spite of the similarities in the pharmacokinetic properties, the pharmacologic effects of piretanide were influenced considerably by the hydrated conditions of the body. The diuretic effect expressed as the excretion rate of the sum of urinary sodium and potassium was plotted against the corresponding urinary excretion rate of unchanged piretanide. The shape of the each graph showed a similar sigmoid like curve ; however, the curve in treatment I was significantly shifted to the right compared to that in treatment II. This fact indicated that the pharmacologic effect of piretanide seemed to be modified by the contents of water and electrolytes in the body. The plasma concentrations and urinary excretion of piretanide were reasonably described by a linear three compartment open model. Although the diuretic effect of piretanide was related to the hypothetical biophase compartment using the conventional Hill's equation, the difference of pharmacologic intensity between the treatments could not be explained. Then, we introduced a feedback mechanism representing the depletion of body fluid into the Hill's equation and applied this equation to the pharmacologic response of piretanide. The results indicated that the diuretic effects of piretanide in treatment II (in the progressive hydropenic state) as well as in treatment I (in the hydrated state) were well explained.

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In order to induce the primary antibody response to sheep erythrocytes in vitro in murine lymphocytes, the cells are usually cultured in RPMI-1640 medium containing 10% fetal calf serum (FCS). When FCS was replaced by calf serum (CS) or newborn bovine serum (NBS), the antibody response was poor compared with that obtained with FCS. However, a comparable response was induced when CS or NBS was added at 1% to the culture medium in combination with 500 μg/ml β-cyclodextrin (β-CD). In the presence of β-CD, the response was the highest when CS or NBS was added at 1%. An important observation was that all the lots of CS (5 lots) and NBS (2 lots) tested supported the response equally in the presence of β-CD. The anti-sheep erythrocytes response induced by 1% CS or NBS in the presence of β-CD was shown to be completely dependent on the added antigen, suggesting that β-CD is not a polyclonal activator. β-CD showed neither mitogenic nor cytotoxic effects on murine lymphocytes. These results in dicate that β-CD is a useful additive for inducing the primary antibody response in vitro in the culture medium containing CS or NBS which is usually less supportive but less expensive than FCS.

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Furosemide disposition in man was studied. Six male young healthy volunteers were given 20 mg furosemide by bolus intravenous injection and 10, 20, 30 and 40 mg furosemide (solution) orally. The serum drug concentration was determined by high performance liquid chromatography and the urinary excretion was determined spectrophotometrically after diazotization. The experimental data from serum and urine samples were simultaneously subjected to computer analysis. On the basis of the results, it was demonstrated that disposition of furosemide in man can be described by a two-compartment open model with the following average parameters : t_1/2α=0.237±0.069 h, t_1/2β=1.29±0.20 h and V_ss=8.46±2.17 l. After oral administration of furosemide solution, the drug was rapidly absorbed from the gastrointestinal tract with a first-order absorption rate constant k_a of 2.33±0.93 h^-1 but there was a lag time of about 6.45 min for drug resolution and entering the absorption site. The oral relative bioavailability was estimated as 83±14%, which was higher than reported values. The elimination of furosemide was very rapid and was mainly via the renal route. The systemic clearance (CL_s) and renal clearance (CL_r), following bolus intravenous dosing were 7.60±2.29 and 6.44±1.81 l/h, respectively. The oral route did not influence CL_s and CL_r on the whole, but the nonrenal clearance ratio (CR_nr) after oral dosing (15.7±4.8%) was significantly higher than that after intravenous administration (11.2±4.0%), which can be explained by a first-pass effect of the liver-portal system.

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Experiments concerning the diuretic effect and disposition of furosemide were performed in nine healthy male volunteers. During the test period, each of subject was given 50 ml of water every half an hour. Under this experimental condition, interesting phenomena, such as almost identical duration of diuretic effect independent of given dose and the socalled clockwise hysteresis of the concentration-effect curve were observed. These phenomena revealed that the body water regulation system had intervened in the pharmacodynamics of furosemide. Based on experimental results, a model and a new equation are presented, which describe the quantitative relationship of the drug disposition, the diuretic response and the body water regulatory function.

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To determine the plasma concentrations and to clarify pharmacokinetic behavior from a pharmaceutical application viewpoint, indomethacin (IND) and its calcium salt (IND-Ca) in the form of gel ointments were applied singly and repeatedly to rat abdominal skin under occlusions. In order to describe the plasma IND concentration profile during repeated percutaneous administration, a highly simple pharmacokinetic model including a first-order absorption process with a lag time was applied. IND and IND-Ca were readily absorbed with a short lag time from IND-Ca ointment (1% as IND, 0.14 g/cm², 3.0×1.2 cm area) containing Azone^[○!R]. Even when the applied dose of IND-Ca ointment was decreased to one-fourth (1.0×1.0 cm area), the plasma IND concentrations were maintained above the effective levels for 24h. The use of the pharmacokinetic model was justified by good agreement with observed data obtained after repeated percutaneous application of ointments. Thus, the plasma IND concentration-time courses during repeated percutaneous administration can be predicted by using the model.

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The effects of β- and γ-cyclodextrins (CyDs) on the pharmacokinetic behavior of prednisolone after intravenous or intramuscular administration in rabbits were investigated. The serum levels of prednisolone after intravenous administration were little affected by the two CyD complexes. This might have been due to the rapid dissociation of the complexes in the large volume of body fluid. On the other hand, the serum levels of prednisolone after intramuscular administration of the CyD complexes in the form of a suspension to rabbits were significantly higher than those of the drug alone. In addition, the mean residence times of both CyD complexes were shorter than that of prednisolone alone. In contrast, there was little or no difference in pharmacokinetic parameters after intramuscular administration of the drug in the form of a solution except for T_max between prednisolone and its CyD complexes. The enhanced rate of bioavailability of prednisolone after intramuscular administration in the form of a suspension may be due to the rapid dissolution of CyD complexes.

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The ultrastructural changes of single smooth muscle cells of guinea pig taenia coli during contraction evoked by Ca²⁺ (Ca) and carbachol (CCh) were investigated by transmission and scanning electron microscopy. Cells, prepared in the presence of a high concentration (140 mM) of KCl, without addition of Ca, exhibited smooth surfaced contour. The contraction of these cells were dose dependent upon Ca. With the increase in Ca concentration, the contraction was accompanied with formation of processes (0.15 μm thick and 1 μm long), membrane evaginations of various sizes and shapes and cores densely packed with filaments at the bottoms of all evaginations. Cells, prepared in the presence of 0.18 mM Ca and at a physiological concentration (2.7 mM) of KCl, had two populations : One had shallow invaginations of the cell membrane and the other had spinous processes. Cells of both types were responsive to CCh and the spinous processes disappeared during contraction but evagination did not appear. Differences in ultrastructural changes during contractions between single smooth muscle cells and intact tissues may be due to the fact that single cells are mechanically free from adjacent cells and connective tissues. It is also possible that membrane properties change during isolation, particularly when cells are isolated in Ca free medium.

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Continuous intraperitoneal infusion of a macrophage colony-stimulating factor (M-CSF or CSF-1) for 6 d resulted in a 2.3-fold increase in the frequency of progenitor cells (CFUc) of macrophages in femoral marrow in C3H/HeN mice but there was no significant increase in the number of blood leukocytes in these animals. Infusion of bacterial lipopolysaccharide (LPS) also increased femoral macrophage CFUc frequency to the same extent as the above. Furthermore, the effect of the M-CSF preparation was much less pronounced in LPS-resistant C3H/HeJ mice than in LPS-sensitive C3H/HeN mice. The results show that the effect of M-CSF on bone marrow CFUc is marginal, even when it is administered in large amounts in the animals.

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The inhibitory mechanism of β-lactam antibiotics on rat platelet activation was studied using carbenicillin (CBPC) as a representative of the antibiotics. CBPC suppressed all thrombin-induced cellular responses, including shape change, secretion and aggregation ; however, it only suppressed aggregation of adenosine diphosphate (ADP)-induced responses. This suggested that ADP-binding to its own receptor was not affected by CBPC while thrombin-binding was inhibited. Inhibition of thrombin binding was confirmed using [¹²⁵I] thrombin. In the case of ADP-stimulated platelets, fibrinogen-binding, which has an essential role for ADP-induced primary aggregation, was significantly suppressed by CBPC. Increase in a net negative charge of the membrane surface was observed after treatment of platelets with antibiotics and a good correlation was obtained between suppression of the platelet responses and increase in net negative charge of the antibiotics. These findings strongly suggest that the inhibition of ligand binding to their own receptors was due to the increase in the negative charge of the platelet membrane, which was probably caused by the antibiotic bound to the platelet membrane.

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A jaundiced rat strain was derived from a cross between Gunn and Wistar-Imamichi rats, and inbreeding was continued by forced heterozygosis with jaundice locus. These Gunn rats have black pigment on heads and a black stripe on their backs similar to Long-Evans rats. Wistar rats with low activity in androsterone (AD) glucuronidation were selected and inbred (LA Wistar rats). The levels of hepatic uridine diphosphate-glucuronosyltransferase (GT) and sulfotransferase (ST) activities as well as cytochrome P-450 contents were compared in these mutant strains. Gunn rats were devoid of bilirubin (BL) GT activity but had high AD GT activity. LA Wistar rats had very low AD GT activity but showed high BL GT activity. Native and Triton X-100-stimulated GT activities toward 2-aminophenol and 4-nitrophenol (NP) were much lower in Gunn rats than in LA Wistar rats. When N-nitrosodiethylamine was added to the incubation media, these GT activities were stimulated equally to high levels in both mutants. N-Nitrodiethylamine provided a similar stimulatory effect on NP GT activity. There were no significant differences in ST activities toward cortisol, AD and NP and cytochrome P-450 contents in the two mutant strains. These results indicate that Gunn and LA Wistar rats have a different deficiency in GT isoenzymes.

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An interaction of Ca entry blockers, D600 and diltiazem, with histamine receptors was tested in rabbit aorta and basilar artery. D600 caused a parallel rightward shift of the concentration response curve for histamine. The slope values from Schild plot analysis in aorta were not different from unity. Dibenamine pretreatment caused reduction of maximum response to histamine in aorta. Such reduction was diminished markedly by the presence of D600 or chlorpheniramine in aorta but not in basilar artery. However, diltiazem did not influence the concentration response curve for histamine. These findings suggest that pharmacological property of histamine receptors in rabbit aorta is distinct from that in basilar artery. Furthermore diltiazem seems not to interact with histamine receptors in both vascular tissues.

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