The hypotensive efficacy of (S)-1-[6-amino-2 [ [hydroxy (4-phenylbutyl) phosphinyl] oxy]-1-oxohexyl]-L-proline (SQ 29 852), a phosphorus-containing novel angiotensin converting enzyme inhibitor (ACEI) was examined in conscious two-kidney, one-clip Goldblatt hypertensive dogs. The acute hypotensive effect of SQ 29 852 was compared with that of captopril or enalapril at 3 mg/kg, p.o., for each, and the potencies were ranked as follows, enalapril > SQ 29 852 > captopril. On the other hand, the hypotension caused by repetitive dosing with SQ 29 852 (3 mg/kg, p.o./d for 7 d followed by another 7-d treatment with 10 mg/kg, p.o./d) was somewhat more marked than that by enalapril at the same dosage. Blood urea nitrogen (BUN) increased in all the animals given enalapril, while that in all of the SQ 29 852-treated animals did not increase. These results indicate that SQ 29 852 is a potent, and long-lasting ACEI with a possible low incidence of side effects.

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Activation of the alternative (APC) and classical (CPC) pathways of complement by fungal (1→3)-β-D-glucans having different degrees of branching (DB) and different conformations were examined by using human serum and plasma. The glucans used in this study were curdlan (no branch ; 0/1), grifolan (one branch in every third main chain unit ; 1/3), schizophyllan (1/3), SSG (1/2), and OL-2 (2/3). Triple or single helix conformer of these glucans were prepared by heating at 150°C or dissolution in sodium hydroxide. Activation of APC by these glucans were dependent on incubation time, concentration, molecular weight, and DB. Interestingly, the triple helix conformer of all glucans tested activated APC stronger than a single helix one. The activity of branched glucans in plasma was weaker than those in serum. On the other hand, in the case of CPC, a single helix conformer activated CPC stronger than a triple helix one, and the activity was dependent on DB. Activation of CPC by a single helix conformer was thought to be dependent on the binding of β-glucan to immunoglobulin in serum, because the complex was clearly detected by gel permeation chromatography only in the case of single helix one. From these results, it appears that the different conformers were recognized by the host complement systems in different ways. (1→3)-β-D-Glucan is one of the major constituents of fungal cell wall and is thought to be clearly recognized by the host immune systems. Conformation of these glucans in the cell wall was not determined in detail, but it is likely that both of the conformers are present in appropriate proportions in the cell wall. Considering these facts, recognition of glucans, dependent on the conformation, by both APC and CPC would be critically important in the host defense mechanisms.

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Seven hours after suicidal ingestion of about 21 g of boric acid, a 26-year-old female admitted to our hospital in a state of slightly impaired consciousness, with frequent vomiting, shivering, fever and skin flush. Immediately, gastric lavage, followed by administration of activated charcoal and laxative (MgSO₄), was performed. In order to ensure her urination, fluid infusion therapy was conducted with the aid of diuretics (furosemide). Since the serum concentrations of boric acid was very high, hemodialysis was carried out twice during the first 39 h. She responded well to the above mentioned treatment and was discharged 12 d post-admission without any sequelae. The concentrations of boric acid in serum and urine were measured in appropriate intervals with our modified Miyamoto's method, and the pharmacokinetics of boric acid were analyzed. The concentration of boric acid in serum and urine at the beginning of treatment was 465 μg/ml and 3.40 mg/ml, respectively. The half-life of boric acid in serum was 13.46 h, whereas it was shortened to 3.76 h during hemodialysis. The total body clearance was 0.99 l/h, while it increased to 3.53 l/h by hemodialysis. The additional removal of boric acid by hemodialysis was estimated to be about 5 g. It was concluded that the hemodialysis was very useful in the treatment of boric acid poisoning, because it accelerated the elimination of boric acid about four times faster than with conventional treatment.

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The distribution of metoprolol tartrate (MPL) into the brain and cerebrospinal fluid (CSF) from plasma was determined at 2 different steady-state plasma concentrations (2 and 20 nmol/ml) and following intravenous bolus administration (100 nmol/kg) in rats. Under steady-state condition, no difference in the brain and CSF distributions of MPL was observed between 2 different plasma MPL concentrations, and the value of brain-or CSF-to-plasma partition coefficients were 5.7 and 1.5, respectively. Following intravenous administration, MPL distributed into CSF very rapidly and its initial uptake phase was not detected. On the other hand, MPL distribution into the brain was relatively slow with the uptake phase. Thus, the brain uptake of MPL from the plasma was pharmacokinetically analyzed using a modified 2-compartment model and deconvolution method, whereas the CSF distribution of MPL was not adequate for kinetic analysis because of the lack of uptake phase. The analysis of brain uptake of MPL by both compartment model and deconvolution gave the same results and the calculated brain K_p value of MPL was almost comparable with thet of observed K_p value under steady-state plasma concentration. The distribution of MPL into CSF was considered mainly depending on the pH difference between the plasma and CSF, and the mutual transfer of MPL between CSF and the brain tissue was considered to be negligible from an in vitro study.

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α₁, α₂-and β-Adrenoceptor densities and catecholamine responsiveness in established hepatoma cells, rat ascites hepatoma AH13, AH66, AH66F, AH109A, AH130 and AH7974 cells and human hepatocellular carcinoma HLF and HepG2 cells, were compared with those in normal rat hepatocytes and Chang liver cells. α₁-Adrenoceptor densities measured by [³H] prazosin bindings were not detected in all hepatoma cell lines. α₂-Adrenoceptor densities measured by [³H] clonidine bindings were also barely detected in hepatoma cell lines except for AH130 cells and HepG2 cells. Regarding β-adrenoceptor, AH109A, AH130 and AH7974 cells had much more [¹²⁵I] iodocyanopindolol binding sites than normal rat hepatocytes, although we could not detect the binding in HepG2 cells. Adenylate cyclase of normal rat hepatocyte and Chang liver cells were stimulated by β₂-adrenergic agonist salbutamol, while the cyclase in hepatoma cells had no β₂-adrenergic response but a β₁-type response. These findings indicate that the characteristics of adrenergic response in hepatoma cell lines is very different from that in normal hepatocytes, suggesting a participation in the hepatocarcinogenesis and/or the autonomous proliferation of hepatoma cells.

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Hepatic microsomal oxidation of 11-hydroxy-Δ⁸-tetrahydrocannabinol (11-OH-Δ⁸-THC) to 11-oxo-Δ⁸-THC was investigated. Hepatic microsomes from mice, rats, guinea pigs and rabbits catalyzed the oxidation of 11-OH-Δ⁸-THC to 11-oxo-Δ⁸-THC together with the formation of dihydroxy-Δ⁸-THCs oxidized at the 7-position or at the pentyl side chain of 11-OH-Δ⁸-THC. 11-Oxo-Δ⁸-THC formed under oxygen-18 gas was analyzed by gas chromatography-mass spectrometry (GC-MS) indicating that molecular oxygen was not significantly incorporated into the aldehyde formed. 11-Oxo-Δ⁸-THC formed from 11-¹⁸OH-Δ⁸-THC (¹⁸O/¹⁶O=0.81-1.05) was also found to lose oxygen-13 from the molecule. These results suggest that 11-oxo-Δ⁸-THC is hydrated in the incubation mixture and the aldehyde oxygen is exchangeable with the oxygen atom of water. When 11-oxo-Δ⁸-THC was incubated with hepatic microsomes and phosphate buffer containing H₂¹⁸O (44 atom%), GC-MS analysis indicated the incorporation of oxygen-18 into the aldehyde recovered from the incubation mixture. The results suggest that the hepatic microsomes may facilitate the hydration of 11-oxo-Δ⁸-THC and exchange an oxygen atom of the aldehyde group with that of water in the incubation mixture.

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Staphylococcus aureus 8325 (pEP2104), a transductant derived from S. aureus PM2104 isolated clinically in Hungary (L. Janosi, and E. Ban, Acta Microbiol. Acad. Sci. Hung., 29 : 187-200, 1982), exhibited an inducible resistance to the 14-membered macrolides [erythromycin (EM) and oleandomycin (OL)] and streptogramin B (MKM-B) antibiotics, but not to the 16-membered macrolides and lincosamides. This resistance was referred to as PMS-resistance phenotype (L. Janosi, Y. Nakajima, and H. Hashimoto, Microbiol. Immunol., 34 : 723-735, 1990). In addition to EM, OL, and MKM-B, however, the strain was recently and first observed to have inducible resistance to mycinamicin, a 16-membered ring macrolide. Thereby, we propose that the reference stated just above as PMS-resistance has to be extended to such 16-membered macrolides as mycinamicin. An optimum concentration of erythromycin or oleandomycin for induction of PMS-resistance was 1.35 μg/ml in the strain 8325 (pEP2104). The concentration was about 30 times as great as that (0.05 μg/ml) required for induction of well-known co-resistance to macrolide-lincosamide-streptogramin B antibiotics in S. aureus ISP447.

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