The characteristics of exsorption and/or excretion of furosemide into the small intestinal lumen in rats with acute renal failure (ARF rat) were investigated by an in situ single-pass perfusion technique. The amount of furosemide, which was exsorbed into the intestinal lumen after an intravenous administration of the drug to rats was only very slight. The exsorption rate of the drug was significantly increased in ARF rats as compared with normal rats. The average amount of the drug exsorbed into the perfusate in normal rats was 0.83% of dose, whereas that in ARF rats was 1.83% of dose. The amounts of furosemide excreted into the bile in normal rats and ARF rats were 1.53% and 2.64%, respectively. The increased exsorption of furosemide in ARF rats appeared to be due primarily to the decreased binding of the drug to the serum protein, because only the unbound drug permeates through the intestinal membrane into the gastrointestinal (g.i.) tract, and, to some extent, to the increased nonrenal excretion caused by poor renal excretion. Oral activated charcoal had little effect on the serum furosemide levels after intravenous administration of the drug at a dose of 10 mg/kg in ARF rats. The lack of effect of activated charcoal on the elimination of the drug may be due to the small amount of the drug excreted into the g.i. tract.

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Interaction of tobramycin (TOB) with latamoxef (LMOX) was studied in vitro. Solutions containing TOB alone, LMOX alone or both of these compounds in varying molar ratios (TOB : LMOX=1 : 1, 1 : 2, 1 : 4 and 2 : 1) were incubated at 37°C for 0.5, 1, 3 and 5 h after adjusting to pH 7.4. Aliquots sampled at a suitable time were subjected to paper electrophoresis (PE) and thin layer chromatography (TLC). In PE, the spots of TOB and LMOX were observed as single spots on the cathode and anode sides, respectively. Howerver, the spot associated with TOB overlapped with that associated with LMOX on the cathode side when aliquots of the solution containing both TOB and LMOX were analyzed. It seemed that the degree of overlapping became stronger with an increase in incubation time, and there were no spots corresponding to TOB alone in the mixture of TOB-LMOX (1 : 4). TLC analysis showed that the spot of LMOX radiated fluorescence with Rf value 0.38. On the other hand, in the mixtures, there was a difinite decrease in fluoresence of LMOX at the position of Rf value 0.38, compared with that of LMOX alone. Furthermore, the spot associated with LMOX, which overlapped with that associated with TOB, also appeared at the origin on the TLC plate. The ultraviolet spectrum of the mixture of TOB-LMOX (1 : 2) showed a decrease in the intensity of absorption of LMOX at 268 nm. These interactions between TOB and LMOX were also observed in rat serum and its filtrate in vitro. In addition, we used infrared (IR) spectrophotometry to obtain some information on the manner of the interaction of TOB with LMOX. The IR spectrum of the reactive product of TOB with LMOX indicated disappearance of the β-lactam (1750 cm^-1) ring of LMOX. These results indicate that TOB chemically reacts with LMOX in vitro.

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The effects of chlorpromazine (4 mg/kg i.v.) on the disposition and duration of loss of the righting reflex (LRR, sleeping time) produced by intravenous pentobarbital (5 to 50 mg/kg) were studied in rats. The plasma concentration time profile following i.v. administration of pentobarbital alone was reasonably well described by a three compartment open model with Michaelis-Menten type elimination kinetics. The brain to plasma concentration ratio of pentobarbital was 1.5 and was almost constant during the experiment. Coadministration of chlorpromazine significantly reduced the systemic clearance of pentobarbital. Since pentobarbital is eliminated from the body mainly by hepatic metabolism, reduction of systemic clearance reflects the reduction of hepatic metabolism of pentobarbital. The hepatic intrinsic clearance of pentobarbital was decreased from 0.438 to 0.331 l/h by chlorpromazine coadministration. Hepatic blood flow was also decreased significantly, whereas the plasma protein binding and the distribution to the red blood cell were not appreciably altered. The profile of duration of LRR versus the logarithm of the dose of pentobarbital was linear over a 20 to 70 mg/kg dose range irrespective of chlorpromazine coadministration. The awakening plasma and brain concentrations of pentobarbital without chlorpromazine were estimated as 12.4 μg/ml and 17.8 μg/g, respectively. The sleeping time versus the logarithm of pentobarbital dose under chlorpromazine coadministration was shifted to the left and the slope of the linear portion was also decreased. There was no single value of awakening plasma or brain concentration. Plasma concentration at the end of the action decreased with decreasing dose. These facts indicated that the sensitivity of the central nervous system to pentobarbital might be increased by chlorpromazine. In conclusion, chlorpromazine inhibited the hepatic metabolism of pentobarbital, resulting in significant increases in plasma and brain concentrations. However, this pharmacokinetic change could not fully explain the pharmacodynamic alternation.

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To characterize passive cutaneous anaphylaxis (PCA) in the mouse ear, reactions caused by non-heated and heated antiserum were compared to those caused by monoclonal immunoglobulin E antibody (mc-IgE) and monoclonal immunoglobulin G₁ antibody (mc-IgG₁). Heat treatment at 56°C did not alter the activity of antiserum or mc-IgG₁ to elicit the 1.5-h PCA. The 1.5-h PCA mediated by mc-IgE and 48-h PCA's mediated by both antiserum and mc-IgE were abrogated almost completely by heating at 56°C for 2 h. The 48-h PCA was not elicited by mc-IgG₁. The sensitized state persisted at least for 7 d when mice were sensitized with non-heated antiserum or mc-IgE. In contrast, the sensitized state disappeared rapidly in cases of heated antiserum and mc-IgG₁. In 48-h PCA's mediated by antiserum and mc-IgE, extravasated dye in the ear was detected 5 min after challenge and the reaction was terminated in 15 min. In contrast, in the 1.5-h PCA mediated by heated antiserum, the accumulation of dye in the ear was delayed slightly when compared to the 48-h PCA. In mc-IgG₁-mediated 1.5-h PCA, the delay was significant. Both 1.5-h PCA's mediated by heated antiserum and mc-IgG₁, and the 48-h PCA's mediated by antiserum and mc-IgE were not observed in WBB6 F₁-W/W^v mice, which lack mast cells. All these PCA's were inhibited equally by tranilast, an inhibitor of mediator release from mast cells. The 1.5-h PCA was abrogated completely when heated antiserum was absorbed with a rabbit anti-mouse IgG₁ serum coupled-Sepharose 4B. On the other hand, the 48-h PCA was abrogated completely by absorption of the antiserum with goat anti-mouse IgE serum coupled-Sepharose 4B. These results indicated that the 48-h PCA in mice sensitized with antiserum is mediated by IgE antibody. In the 1.5-h PCA in mice sensitized with heated antiserum, it is considered that IgG₁ antibody plays a major role to elicite PCA. However, it is also considered that the reaction is modified by other serum components.

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The efficacy of a liposome preparation on ocular steroid availability was investigated by both tracer studies and investigation of in vivo steroid uptake by the cornea. Dexamethasone and its ester derivatives were used as model drugs and aqueous suspensions of each served as control preparations. The liposome preparation containing dexamethasone valerate provided the highest ocular drug levels among the examined preparations. In the case of dexamethasone or dexamethasone palmitate, the liposomal form provided a lower drug level in comparison with the suspension. High esterase activity for dexamethasone valerate was observed in the corneal homogenate supernatant, and most of the steroid taken up after instillation of dexamethasone valerate was metabolized to free alcohol. The corneal dexamethasone level was almost proportional to the concentration of free dexamethasone valerate in the liposome preparation. Only the addition of stearylamine (SA) to the liposomal membrane had an added extra effect on the corneal absorption of dexamethasone valerate.

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The effect of chlorpromazine on the duration of loss of righting reflex (LRR, sleeping time) of pentobarbital and vice versa in a various dosage ranges were studied in rats. The logarithm of the dose versus sleeping time profile of pentobarbital was shifted to the left and the slope of the profile was decreased as the dose of chlorpromazine was increased. The logarithm of chlorpromazine dose versus duration of LRR during pentobarbital coadministration also showed a distinct dose-dependent profile. However, chlorpromazine itself showed ambiguous duration of LRR because the terminal point of the pharmacologic effect, i.e., the recovery of the righting reflex (RRR, the awakening time), was often difficult to determine clearly. The isobolographic method was introduced to describe the drug interaction of pentobarbital and chlorpromazine quantitatively. Assuming that the sites of action of chlorpromazine and pentobarbital were in the brain, the brain concentrations of pentobarbital at RRR were plotted against the brain concentration of chlorpromazine at RRR. The plots showed a hyperbola-like curve, indicating that there was a supra-additive interaction. In order to clarify the relationship between brain concentrations of the two drugs at RRR, a theoretical consideration was made under the following assumptions : (1) chlorpromazine and pentobarbital have a common central depressant effect, (2) the concentration-effect relationship is described by Hill's equation and (3) the mode of interaction of these drugs is simple additive. The results indicated that the isobolographic plot of pentobarbital and chlorpromazine was reasonably described by the theory and that chlorpromazine enhanced the effect of pentobarbital at least in an additive manner.

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The blood concentrations of salicyluric acid and salicylic acid following intracecal and rectal administration of salicyluric acid were determined in rabbits. Immediate and very extensive salicylic acid formation in the cecum was found following intracecal administration. After rectal administration, a small amount of salicyluric acid was absorbed in intact form. The rest was rapidly hydrolyzed to salicylic acid, which was subsequently absorbed. The blood concentration of salicylic acid was maintained at 1.3-1.8 μg/ml from 2 to 12 h. Three doses of salicyluric acid were administered rectally. The peak level of salicyluric acid increased with dose. However, salicylic acid concentration in the blood following administration of salicyluric acid at 10.0 mg/kg (salicylic acid equivalent) was not double that observed following administration of salicyluric acid at 5.0 mg/kg (salicylic acid equivalent). It appears that a larger amount of salicyluric acid in the rectal lumen may have saturated the glycine deconjugation system.

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The inhibitory effect of polygalactosamine (PF102), which was isolated from Paecilomyces sp. I-1 strain, on a syngeneic murine solid tumor and its antitumor mechanism were studied. After an intraveneous injection of PF102, 1 μg/kg, an increase in cell mediated and humoral immunities in mice was observed and the growth inhibition of MM46 solid tumor in vivo was also evident. Macrophages induced by PF102 into the peritoneal cavity inhibited deoxyribonucleic acid synthesis of target cells. Moreover, PF102 caused a significant increase in the incorporation of ³H-thymidine into the thymic cells and the culture supernatant of T lymphocytes, stimulated with PF102, exhibited a marked activation of the cytostatic effect of the peritoneal macrophages. Furthermore, this culture supernatant fluid was found to contain interferon (IFN). Therefore, the antitumor activity of PF102 might be due in part to the activation of the macrophage lineage cells by macrophage activating factor and/or IFN produced from T lymphocytes stimulated by PF102.

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