Two kinds of dosage forms of commercially available suppositories containing ketoprofen (KP), fatty suppositories (FS) and gelatin capsulated suppositories (GCS), were administered to patients immediately after anal surgery, and results obtained were compared. No difference was found in each corresponding pharmacokinetic parameter of the two dosage forms. However, when these parameters were compared with those from healthy subjects, significant differences were found in the values of peak level (C_max), peak time (T_max) and terminal phase half-life (t_1/2). C_max decreased by one half, and T_max and t_1/2 increased two and four times longer, respectively, those from healthy subjects. The absorption rate constant (k_a) in patients was significantly (p < 0.01) smaller than that in healthy subjects. However, the distribution volume/bioavailability (V_d/F), elimination rate constant (k_el), and area under the curve (AUC) differed only slightly. Consequently, the flip-flop phenomena could be seen in the time profiles of plasma KP concentration of patients. These results suggested that the rectal suppository of KP should be administered with care, especially in the patients operated on under spinal anesthesia.

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By immunizing rabbits with purified human epidermal growth factor (hEGF), which was synthesized by Escherichia coli constructed by a genetic engineering technique, high titer antiserum for hEGF was obtained. The antiserum has an excellent specificity to hEGFs {hEGF, hEGF [1-51], hEGF [1-47] and [Leu²¹] hEGF} and has almost no cross-reactivity with other biological peptides, such as mouse EGF and human platelet derived growth factor. Using radioiodinated hEGF, a radioimmunoassay (RIA) for hEGF was established by a double antibody-polyethylene glycol method. As little as 10 pg/tube of hEGF was successfully determined by the present RIA methods. The intra- and inter-assay coefficients of variation for hEGF in human plasma or serum were 2.4-4.9% and 3.7-6.2%, respectively. The hEGF levels in human body fluids determined by the present method were as follows : urine (11-100 ng/ml), serum (1.0-1.8 ng/ml), plasma (0.2-0.8 ng/ml), sperm (17-47 ng/ml), saliva (0.9-3.0 ng/ml) and tears (9.5-27 ng/ml).

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The splenic T-cells of concanavalin A (Con-A)-injected mice suppressed the in vitro Con A-induced splenic blastogenesis of normal mice. We examined electrophoretic mobilities (EPM) and surface markers of Con A-induced suppressor T-cells as a model of suppressor T-cells. The EPM of the suppressor cells with both Thy-1 and gangliotetraosyl-ceramide (asialo GM1) was lower than that of normal T-cells. The ratio of low mobility T-cells (LMT) to high mobility T-cells (HMT) correlated significantly with dose-response and time-course of Con A in the suppressor activity and with the percentages of cells carrying asialo GM1 antigen and receptor for peanut agglutinin. For in vitro induction by Con A, Lyt-2⁺ cells were reported to have suppressor activity. However, for in vivo induction by Con A, Lyt-2⁺ cells did not correlate with the suppressor activity in the dose-response and time-course experiments. By separating the Lyt-subsets, it was found that both Lyt-1⁺2⁺ and Lyt-1⁺2^- subsets were suppressor cells in the blastogenesis. The suppressor activity of in vivo Con A-induced spleen cells correlated with the LMT/HMT ratio, but not with the analysis of Lyt-phenotype. These results suggested that lymphocytes electrophoresis clearly distinguished Con A-induced suppressor T-cells with low EPM from normal T-cells.

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Two pharmacokinetic approaches (single-point Bayesian and two fixed volume of distributioniterative methods) for predicting serum lithium concentrations in patients treated with lithium carbonate for manic-depressive illness or cyclic neutropenia in Kyushu University Hospital were evaluated and compared retrospectively. Prior to these analyses, three methods (prediction using mean parameters reported by Mason et al., the Pepin method, and the Zetin method) without measuring serum concentrations were also compared. In the Bayesian analysis, the effect of population mean parameters (reported by Mason et al. and Pepin et al.), which were used as initial estimates in a fitting process, on predictive performance was also studied. Forty five patients (21 male, 24 female) were included in this study. The average number of determinations per patient was 6.3, and the sampling times ranged from 2 to 18 h after the last dose. Serum lithium concentrations were measured by atomic absorption spectrometer. The Bayesian method used a computer program (PEDA) developed previously by one of us. The prediction using the population mean values from Mason's report gave the least root mean squared error (RMSE ; a composite measure for bias and precision of prediction), and was considered to be the most precise among the methods without measuring serum concentrations. Among the methods using a single measured concentration, the Bayesian prediction was less biased and more precise than that by the two fixed volume of distribution-iterative methods. The Bayesian method reduced prediction error in serum concentration prediction compared with those obtained from population mean parameters in both cases : A high reduction of RMSE was observed when the values from Pepin method were used as initial estimates (from 0.320 to 0.219 meq/l), while, Mason's values gave less reduction (from 0.219 to 0.213 meq/l). In the Bayesian prediction of serum lithium concentration, the selection of population-based initial estimates gave no effect on predictive ability of the Bayesian method in terms of RMSE. In conclusion, the Bayesian method was robust and flexible with regard to dosing schedule, sampling time and number of blood samples, and gave the most clinically acceptable precision among the methods evaluated.

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The in vitro effects of diltiazem (DTZ), a coronary vasodilator, deacetyldiltiazem (D-M1), one of the metabolites of DTZ, and pentoxifylline (PTF) which is known to improve erythrocyte deformation, on the viscosity of platelet poor blood were compared. Furthermore the change in the viscosity of whole blood from patients with effort angina after intravenous administration of DTZ was examined ex vivo. The addition of DTZ into platelet poor blood at 37°C caused a rapid reduction in blood viscosity and an enhancement of erythrocyte deformability within 5 min, which then diminished in a time-dependent manner. Similar effects were also found by adding D-M1. On the other hand, the effects of PTF appeared after an incubation period of more than 60 min and were enhanced in a timedependent manner. These actions of PTF, but not those of DTZ and D-M1, paralleled the increase of erythrocyte adenosine-triphosphate content. DTZ and D-M1, but not PTF, had biphasic effects on the osmotic behavior of erythrocytes. Whole blood viscosity was reduced significantly during the period 5-30 min after intravenous administration of 10 mg of DTZ, which diminished with the elimination of plasma DTZ. In conclusion, the action mechanisms involved in the effect of DTZ and D-M1 on blood rheological properties appeared to be different from that of PTF. These effects of DTZ are clinically significant in improving the flow properties of blood in vascular diseases.

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Topical and systemic absorption of bunazosin after topical instillation was investigated in rabbits. Corneal permeability of bunazosin in vivo was increased by the addition of caprylic acid in amounts equimolar to bunazosin. Aqueous humor levels of bunazosin were significantly elevated. These results correlated well with those obtained in vitro experiments. Contrarily, the levels of plasma were not significantly affected and only slightly lowered by caprylic acid.

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The intravenous administration of 50 and 100 mg/kg of genipin (GP), gardenogenins (GAR-G), deacetylasperulosidic acid methylester genins (DAM-G), and scandoside methylester genin (SSM-G) exhibited the bile acid-independent choleretic actions. The action of DAM-G was stronger than the actions of other compounds tested. The choleretic action of SSM-G was milder, but longer lasting than those of GAR-G and DAM-G.

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The possible role of hepatic lipid peroxidation and Ca²⁺ in enhanced hepatotoxicity of aflatoxin B₁ (AFB₁) by ethanol was examined along with changes in hepatic glutathione in male rats. Hepatic glutathione (GSH) was markedly decreased (43.9%) at 12 h after AFB₁ administration in rats treated with ethanol (4.0 g/kg BW) and AFB₁ (2.0 mg/kg BW) when compared to AFB₁ alone. At 24 h after AFB₁ administration, hepatic lipid peroxide levels in subcellular fractions, particularly in microsomes, were significantly increased (76.9%) in rats treated with ethanol and AFB₁ following the decrease in hepatic GSH content. Hepatic lipid peroxide levels returned to normal values at about 48 h after AFB₁ administration. Furthermore, Ca²⁺ in whole liver (60.9%), microsomes (83.8%) and mitochondria (51.2%) were significantly increased in the rats treated with ethanol and AFB₁ as compared to those rats treated with AFB₁ alone at 48 h after toxin administration. The increase in hepatic Ca²⁺ in rats treated with ethanol and AFB₁ was a possible consequence of the increase in hepatic lipid peroxide. These findings suggest that there is a close relationship between hepatic GSH content, lipid peroxidation and intracellular accumulation of Ca²⁺. The pronounced effects on hepatic lipid peroxidation and intracellular accumulation of Ca²⁺ could play a role in ethanol-induced potentiation of AFB₁ hepatotoxicity in rats.

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Using high performance liquid chromatography with electrochemical detection, the level of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), an index of noradrenaline release, was determined in regions of the brainstem and hypothalamus of rats after acute hypotension induced by hydralazine. In hypotensive rats, an increase in MHPG concentrations was observed in the posterior hypothalamus, while no significant changes were seen for all the other regions. These results suggest that hypotension results in an enhancement of noradrenaline release in the posterior hypothalamus in rats.

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A rapid method is described for the analysis of amino acids containing in mouse brain by high performance liquid chromatography equipped with a fluorescence detector. Pre-column o-phthaladehyde-2-mercaptoethanol derivatives of the amino acids were injected onto an ODS C-18 column. 5-Amino-n-valeric acid, a non-endogenous amino acid, was used as an internal standard. Separation and elution of amino acid derivatives were achieved by varying the ratio of organic phase by a step gradient. Significant increases in γ-aminobutyric acid, glutamine and glycine levels in the brain were detected 2 h after injection of 800 mg/kg valproic acid (VPA). A high dose administration of VPA was correlated with Reye's syndrome.

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The extent of bioavailability of midazolam following sublingual and oral administration were evaluated. Three healthy volunteers received a single 15-mg dose of midazolam maleate by sublingual and oral routes on two occasions in a ossover design. Concentrations of midazolam in plasma during 4 h after each dose were measured by gasliquid chromatography with an electron-capture detector. The mean AUC_0-4 value following sublingual administration was significantly greater than that following oral administration (14889 vs 3594 ng·min/ml, p<0.05). The peak plasma concentration after sublingual dose was also singificantly higher than that after oral administration (p<0.05). The mean AUC_0-4 value of midazolam after sublingual administration was increased four times compared with that after oral administration, possibly due to avoidance of first-pass effect. Thus, the clinical effects of midazolam may likewise be enhanced by sublingual administration of midazolam.

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