For the risk assessment of human exposure to volatile halogenated hydrocarbons, a dynamic purge trap/on-column cryofocusing method using capillary gas chromatograph-$^{63}Ni$ electron capture detector and thermal desorption unit was applied to analyze the free forms, metabolites of 1, 1, 2-trichloroethylene and 1, 1, 2, 2-tetrachloroethylene. The urine sample was diluted with distilled water, hydrolyzed and sealed. Then the inert gas was infused to purge out free 1, 1, 2-trichloroethylene, free 1, 1, 2, 2-tetrachloroethylene and urichloroethanol. These compounds were trapped to $Tenax^R$ / GC-gas trap device throughout clean up tube. Being undertectable to gas chromatograph directly, trichloroacetic acid was methyl esterificated and trapped in the manner above mentioned. The optimal incubation time to get best recovery of methyl ester was 4 hours at $60^circ$C. The concentrations of free volatile halogenated hydrocarbons and their metabolites in urine were obtained of free volatile halogenated hydrocarbons and their metabolites in urine were obtained from 5 healthy volunteers. This analytical method is expected to make the biological monitoring more precise and convenient.

An attempt was made to investigate the effect of TMB-8[3, 4, 5-trimethoxybenzoate-8 (N, N-diethylamino) octyl ester], which is known to be an inhibitor of intracellular $Ca^{2+}$ release, on catecholamines (CA) secretion evoked by Ach, excess $K^+$, DMPP, McN-A-343 and caffeine from the isolated perfused rat adrenal glands and to cleaify its mechanism of action. The pretreatment with a low dose of TMB-8 $(10 \mu{M)}$ for 20 min led to marked inhibition in CA secretion evoked by Ach (5.32 mM), excess K^+$ (56 mM), DMPP $(100\;\mu{M)}$, McN-A-343 $(100 \mu{M)}$ and BAY-K 8644 $(10^{-5}M)$. Caffeine-induced CA secretion was simimlar to that of control only during the first periods (0-3 min) but thereafter maked inhibition in CA secretion evoked by caffeine was observed during the rest periods up to 30 min. The increased moderate concentration of TMB-8 $(30 \;\mu{M)}$ caused the result similar to that of $10 \;\mu{M}$ TMB-8. However, in adrenal glands preloaded with a high dose of TMB-8 $(100\;\mu{M)}$, CA releases evoked by Ach, excess $K^+$, DMPP, McN-A-343 and caffeine were almost completely blocked by the drug. These experimental data demonstrate that TMB-8 may inhibit cholinergic receptor-mediated and also depolarization-dependent Ca secretion, suggenesting that these TMB-8 effects seem to be mediated through inhibiting influx of extracellular calcium into the rat adrenal medullary chromaffin cells as well as reducing the release of calcium from intracellular sources.

The critical micelle concentrations (CMCs) of aqueous solutions of a nonionic surfactant, polyoxyl 23 lauryl ether in the presence of various concentration of urea and its derivatives were measured. The CMC of the surfactant increase in proportion to the concentration of the additives, and the CMC-raising activities increased with more and longer alkyl grups substituted in urea. The CMC shift values were successfully correlated with the cloud point shift values and the protein-denaturing activities of the additives, respectively. These results suggest that the micelle formation, clouding of the surfactant and the protein denaturation are a closely related phenomenon, and a common mechanism is operating which might be the hydrophobic interaction.

A series of copper complexes of some amino acid derivatives of 6-methoxy 3-methyl-coumarilic acid were prepared. The infrared, visible spectra and magnetic susceptibility of these compounds were reported. All copper complexes were foundt to have antimicrobial activity against gram-positive bacteria only.

The effect of papaverine on the contractions induced by adrenergic neurotransmission in the isolated mouse vas deferens was investigated. Papaverine, $10^{-7}-10^{-5}$M, showed a dose-dependent and reversible inhibition on the induced contractions. When the frequency of stimulation was varied (2.5-20.0 Hz), the inhibitory effect tended to be marked at the lower frequencies.

The new N-aryl-benz[f]-indole-4, 9-dione derivatives were synthesized via in tramolecular cyclization when triethylamine was employed as a base for the reaction of 2-chloro-3-$(\alpha$-cyano-$\alpha$-ethoxycarbonyl-methyl)-1, 4-naphthoquinone and arylamines.

A novel preparative method for hexaprofen, which is a potent antiinflammatory agent, is described. Friedel-Crafts reaction of cyclohexylbenzene with ethyl $\alpha$-chloro-$\alpha$-(methylthio) acetate 1 and $\alpha$-chloro-$\alpha$-(methylthio) acetonitrile 2 afforded ethyl 2-(methylthio)-2-(4-cyclohexylphenyl) acetate 7 and 2-methylthio-2-(4-cyclohexylphenyl) acetonitrile 8, respectively. Compounds 7 and 8 were converted into the corresponding ethyl 2-methylthio-2-(4-cyclohexylphenyl) propionate 9 and 2-methylthio-2-(4-cyclohexylphenyl) propionitrile 10 by methylation with sodium hydride and methyl iodide. Hexaprofen 13 was prepard by hydrolysis of ethyl 2-(4-cyclohexylphenyl) propionate 11 and of 2-(4-cyclohexylphenyl) propionitrile 12 followed by desulfurization of compounds 9 and 10.

The aim of this study was to evaluate capability of pertussis toxin (PT) to active mouse macrophages. The investigations were undertaken to determine whether the role played by this toxin required the A-protomer of the toxin to ADP-ribosylate a guanine nucleotide binding protein (a class I activity) or was dependent on the binding of B-oligomer of the toxin to the surface of target cells (a Class II activity). The results of these experiments have established that the mechanism of macrophage activation with PT seems to be dependent upon a Class II activity of the toxin.

Selective quenching of 1, 6-diphenyl-1, 3, 5-hexatriene (DPH) by trinitrophenyl groups was utilized to examine the transbilayer fluidity asymmetry of model membranes of phospholipids (SPMVPL) extracted from synaptosomal plasma membrane vesicles (SPMV). The polarization (P), anisotropy (r), limiting anisotropy $(r_\infty$), and order parameter (S) of DPH in the inner monolayer were 0.019, 0.014, 0.018, and 0.047, respectively, greater than calculated for the outer monolayer of SPMVPL. Selective quenching of DPH by trinitrophenyl groups was also utilized to examine the effects of n-alkanols on the individual monolayer structure of SPMVPL. n-Alkanols fluidized the hydrocarbon region of bulk SPMVPL and the potencies of n-alkanols up to 1-nonanon increased with carbon chain length. It appears that the potencies in bilayer fluidization increase by 1 order of magnitude as the carbon chain length increases by two carbon atoms. The cut-off phenomenon was reached at 1-decanol, where further increase in hydrocarbon length resulted in a decrease in pharmacological activity. The n-alkanols had greater fluidizing effects on the outer monolayer as compared to the inner monolayer of SPMVPL, even though these selective effects tended to become weaker as the carbon chain length increased. Thus, it has been proven that n-alkanols exhibit selective rather than nonselective fludizing effects within transbilayer domains of SPMVPL.

Release characteristics of five different types of hydrophilic albumin microspheres (HAM) containing different ratios of methotrexate-albumin (MTX-HSA) conjugates to free MTX: 1 : 0 (HAMC), 3 :1 (HAMC 3F), 1 :1 (HAMCF), 1:3 (HAMCF3) and 0 : 1 (HAMF) were investigated in the absence or presence of protease using dissolution tester. In all the HAMs studied except HAMC, the MTX was released bi-exponentially in the absence of protease; an initial fast release period up to approximately 6h, and thereafter the release rate was very much slower. The fast release of MTX from the HAMs (such as HAMC3F, HAMCF, HAMCF3 and HAMF) at the initial phase in probably due to the release of "physically associated" MTX from the core of the HAMs. The initial rate constants were 7.2, 8.7, 8.5 and 5.9 times greater than the second rate constants for HAMF, HAMCF3, HAMCF and HAMC3F, respectively. MTX release from HAMC was very slow and mono-phasic. It was at most 2.2% of the total entrapped amount by 24 h. The protease accelerated the release of MTX from the HAMs. The percentages of MTX released from HAMs up to 24 h were 100, 89.0, 75.0, 66.0 and 61.0% for HAMF, HAMCF3, HAMCF, HAMC3F and HAMC, respectively in the presence of protease and the corresponding values in the absence of protease were 30.2 19.0, 10.0, 6.5 and 2.2%, respectively. In vitro release of MTX in the presence of protease varied according to the ratios of MTX-HSA conjugates to MTX; the data set from HAMF, HAMCF3 and HAMCF fits better to monophasic first-order profile more adequately than to zero-order profile, that of HAMC3 monophasic first-order, and that of HAMC to bi-phasic zero-order. Above results suggested that zero-order release rate can be achieved by adjusting the ratio of MTX-HSA conjugates to MTX in the preparation of HAMs such as HAMC3F.as HAMC3F.

Anti-inflammatory glucocorticoid (GC) derivatives have been clinically used in immune-malfunctional diseases for their immunosuppressive activity. However, there is still a lack of knowledge on the relationship between anti-inflammatory and immunosuppressive activities. In order to compare immunosuppressive activities with the known anti-inflammatory activities of the GC derivatives, eight clinically used GC derivatives including hydrocortisone, prednislone, 6$\alpha$-methyl prednisolone, triamcinolone, dexamethasone, betamethasone, triamcinolone acetonide and fluocinolone acetonide were selected, and lymphoblastosis inhibition and plaque-forming cell (PFC) response in mice were studied as immunological parameters. In Con A-induced lymphoblatosis inhibition invitro, all derivatives showed potent inhibition $IC_{50}$ values of the derivaties except methyl prednisolone and triamcinolone were less than $10^{-7}$M and good dose dependency was obtained. This result was well correlated with that of their anti-inflammatory potencies obtained. This result was well correlated with that of their anti-inflammatory potencies and their receptor binding affinities. However, in PFC response, consistent result were not obtained. Total numbers of PFCs per spleen were decreased by some derivatives, but numbers of PFCs per $10^6$ cells were not decreased by systemic administration of but numbers of PFCs per $10^6$ cells were not decreased by systemic administration of GC at the dose of 0.05 mg/mouse. Furthermore, at the dose of 0.1 mg/mouse, numbers of PFCs per $10^6$ cells were found to be increased, although total PFCs per spleen were decreased.

The stabilizing effects of $\alpha$-$\beta$-$\gamma$- and dimethyl-$\beta$-cyclodextrins $(\alpha$-, $\beta$-, $\gamma$- and DM-$\beta-$-CyDs) on the degradation of hydrocortisone 17-butyrate (HC-17B) in aqueous solution was investigated. Hc-17B underwent a facile hydroxide ion-catalyzed rearrangement to the less active 21-butyrate ester by the apparent first-order kinetics, and maximum stability of HC-17B was obtained at around pH 4.0. The stability of HC-17B was increased by inclusion complexation with $\alpha$-, $\gamma$- and DM-$\beta$-CyD in the pH range of 2.0-8.0 examined, whereas $\beta$-CyD accelerated the degradation of HC-17B at the pH higher than 5.0. The effects of ionic strength, solvent, temperature and CyD concentration were also investigated. Stability constants and apparent degradation rate constants of HC-17B-$\gamma$-CyD and HC-17B-DM-$\beta$-CyD complexes were determined kinetically on the basis of 1:1 complexation. The results suggested that the inclusion complexation with $\gamma$-CyD or DM-$\beta$-CyD was most useful means to enhance the stability of the steroid.

Malonic acid amides were synthesized using different amino acids and their esters. THe synthesized compounds were evaluated for their sedative activity on rats. Potentiating effect of all the compounds on pentobarbitone induced sleep on rats was observed. Plasma protein binding studies were also carried out and it was observed that the synthesized compounds have low plasma protein binding as compared to barbiturates.

In the preceding paper, we reported the synthessis and biological properties of cephalosporins having quinoliniumthiomethyls at the C-3 position and demonstrated that quinoliniumthiomethylcephalosporins exhibited an extended antibacterial spectrum including antipseudomonal activity, especially strong antiGram-positive activity. With the aim of elaboration to optimize the antibacterial potency of the quaternary ammonium cephalosporins, we have studied the modification of substituents in the pyrrolidine ring of cefepime 1 which is characterized by its potent activity.