Removal efficiency of 66 pharmaceuticals during wastewater treatment process in Japan.

Both biological treatment processes including conventional activated sludge (CAS) and biological nutrient removal (BNR) processes, and physico-chemical treatment processes including ozonation process and Title 22 process consisting of coagulation, sedimentation and filtration followed by UV or chlorination disinfection after the above biological processes, were compared from the viewpoint of removal efficiency. 66 pharmaceuticals including antibiotics, analgesics, psychoneurotic agents were measured with SPE-LC/MS/MS. 26 compounds out of 66 were detected in the influent ranging ng/L to microg/L order. Particularly, disopyramide, sulpiride, and dipyridamole that have been rarely detected before in the WWTP, occurred at concentration levels of more than 100 ng/L. The total concentration of the individual pharmaceuticals in the influent was efficiently removed by 80% during the biological treatment. But removal efficiencies of carbamazepine and crotamiton were less than 30%. The total concentration of the individual pharmaceuticals in the effluent from CAS process was 1.5 times higher than that from BNR process. Further, the total concentration of the individual pharmaceuticals in the discharge from WWTPs applying ozonation following activated sludge process was reduced to less than 20%. Physico-chemical treatment train called Title 22 treatment after CAS could not efficiently remove the pharmaceuticals. However, ozonation process followed by biological activated carbon process could efficiently reduce all the residual pharmaceuticals below their quantification limits.

Occurrence of 70 pharmaceutical and personal care products in Tone River basin in Japan.

The occurrence of 70 pharmaceutical and personal care products (PPCPs) was investigated in the Tone River. The river has the largest basin in Japan, and the water is utilized not only for farming, but also as a source of water supply. One day in both January and October 2006, surface waters in the river and its tributaries and effluents from sewage treatment plants (STPs) directly discharging into the Tone River were collected, the location of which ranged over 150 km along the river. The 70 PPCPs in the samples were concentrated by solid phase cartridge and were measured by LC-MS/MS using three analytical methods. Fifty-seven PPCPs were detected in one or more samples. Bezafibrate, caffeine, carbamazepine, clarithromycin, crotamiton and sulpiride were frequently detected. Mass flow profiles of some PPCPs (e.g., crotamiton) were comparable to cumulative inhabitants in the basin, suggesting that these PPCPs could be markers of population. Total load of each PPCP into the basin from upstream, the tributaries, and the STPs were calculated. The contribution of selected PPCPs from the tributaries with lower sewerage system coverage was dominant compared to those from upstream and the STPs, suggesting the installation of sewerage systems is necessary to reduce the load of PPCPs in the Tone River basin.

Increase in blood pressure with enhanced Na+, K+ -ATPase activity in stroke-prone spontaneously hypertensive rats after 4-weeks intake of rapeseed oil as the sole dietary fat.

Twenty stroke-prone spontaneously hypertensive rats were divided into 2 groups of 10 animals each, and fed a defatted diet and orally administered rapeseed (canola) oil or soybean oil at 10 (w/w)% of the consumed diet once a day for 4 weeks. At the 4th week of administration, the systolic blood pressure in the canola oil group was higher (235 +/- 2 mmHg, mean +/- S.E.M., N=10) than that in the soybean oil group (225 +/- 4 mmHg, N=10, P<0.05). In isolated, perfused mesenteric bed from these rats, the increase in perfusion pressure by norepinephrine, ATP, arachidonic acid, endothelin-1, angiotensin II or serotonin showed no between-group differences. There were also no between-group differences in the production of thromboxane A2 and prostaglandin 12 in the outflow by arachidonic acid injection. On the other hand, in the isolated aortic ring from the canola oil group, developed tension in potassium-free solution was enhanced with activation of Na+, K+ -ATPase. These results suggest that canola oil intake as the sole dietary fat increases systolic blood pressure of stroke-prone spontaneously hypertensive rats. The changes in vascular responsiveness to vasoconstrictors and production of prostanoids are unlikely to have relevance to the elevation of blood pressure. However, altered Na+, K+ -ATPase activity may play a role in the promotion of blood pressure elevation.

Blood coagulation and osmolar tolerance of erythrocytes in stroke-prone spontaneously hypertensive rats given rapeseed oil or soybean oil as the only dietary fat.

The life-span of stroke-prone spontaneously hypertensive rats (SHRSP) has been reported to become shorter by ingestion of some vegetable oils, including rapeseed oil, when given as the sole dietary fat. The present study was undertaken to examine if the ingestion of rapeseed (canola) oil affects blood coagulating time and erythrocyte membranes. Namely, SHRSP were orally given canola oil or soybean oil as the only dietary fat (10% of diet) for 4 weeks. After the 4-week feeding, activated partial thromboplastin time (APTT) in the canola oil group (19.9+/-0.5 s, N=8) was significantly shorter than that in the soybean oil group (21.6+/-0.6 s, N=8, P<0. 05), though there were no between-group differences in plasma Ca(2+), platelet density and platelet aggregation. Erythrocytes from the canola oil group were less tolerant to low osmotic pressure than those from soybean oil group; the EC(50) values for NaCl concentration to cause hemolysis were 0.42+/-0.004 and 0.40+/-0.005% in the canola oil and the soybean oil groups, respectively (N=10, P<0.01). The canola oil-induced shortening of blood coagulation time and increased fragility in erythrocyte membranes may have relevance to the promotion of strokes in SHRSP.

Stereocontrol in solid-phase radical reactions: radical addition to oxime ether anchored to polymer support

A high degree of stereocontrol in solid-phase radical reactions was achieved by using triethylborane and diethylzinc as a radical initiator at low reaction temperature. Alkyl radical addition to Oppolzer's camphorsultam derivatives of oxime ether anchored to polymer support proceeded smoothly to give the alpha-amino acid derivatives with excellent diastereoselectivities.

The phenomenon of "one-trial tolerance" to the anxiolytic effect of chlordiazepoxide in the elevated plus-maze is abolished by the introduction of a motivational conflict situation.

A single exposure to the elevated plus-maze test of anxiety reduces or abolishes the anxiolytic efficacy of benzodiazepines. The present study was designed to examine whether this phenomenon of "one-trial tolerance" resulted from a motivational deficit on trial 2. We hypothesized that whereas there is a motivational conflict on trial 1 in relation to the open arms (exploration drive X natural fear of open spaces), there is no "reason" for an animal to explore it on trial 2. A motivational conflict was introduced on trial 2 by rendering the enclosed arms of the apparatus aversive on trial 1. Thus, every time rats entered the enclosed arms, an aversive situation (light and hot air blow) was produced until they left the arm. On trial 2, rats did not receive this aversive stimulation. Chlordiazepoxide significantly enhanced the percent open arm time as well as the percent open arm entries on trial 2 in rats that had been submitted to the aversive stimulation in the enclosed arms on trial 1, but was not effective in rats which had been exposed to the apparatus in the absence of the aversive stimulation on trial 1. In addition, there was no difference in the percent open arm time and entries on trial 2 between saline-treated rats submitted to the aversive or non-aversive condition on trial 1. The aversive condition on trial 1 did not modify the number of total arm entries on trial 2, either. The results suggest that the anxiolytic effect of chlordiazepoxide in the elevated plus-maze depends on the presence of a motivational conflict situation.

Age-related changes in adenosine 5'-triphosphate-induced constriction of isolated, perfused mesenteric arteries of rats.

In isolated mesenteric arteries of rats, dose-dependent increase in perfusion pressure by adenosine 5'-triphosphate (ATP, 0.1 approximately 3000 nmole) diminished with age. ATP responses of both 4- and 32-week-old rats were enhanced by indomethacin (5 microM), and further by the combination of indomethacin and N(G)-nitro-L-arginine methyl ester (L-NAME, 5 microM). The enhancement with each of the treatments was less in 32-week-old rats than that in 4-week-old rats, and there was no enhancement in 75-week-old rats. The ATP response was enhanced by removing the endothelium only in 4-week-old rats. The constrictions in response to ATP (1000 nmole) in both 4- and 32-week-old rats were equally enhanced by reactive blue 2 (30 micromole) and were inhibited by pyridoxal-phosphate-6-azophenyl-2',4-disulphonic acid (PPADS, 30 microM) and alpha, beta-methylene ATP (alpha, beta-mATP, 100 nmole) to a similar extent. The increased tone which was produced by the perfusion with physiological solution containing 100 mM potassium chloride was greater in older animals. This age-related change in the vascular tone disappeared when the responses were potentiated by L-NAME. These results demonstrate that in rat mesenteric arteries, ATP-induced constriction decreases with age. The age-related decline of vasoconstriction is not likely to arise from the changes in the contractility of smooth muscle, from the counterbalancing regulation by the endothelium, or from the cooperation of P2 purinoceptor subtypes. The density of purinoceptors and some post-receptor signal transduction mechanisms in the vascular smooth muscle cells may change with age. The enhanced ATP response might have special physiological significance in rats during development.

Formaldehyde treatment suppresses ruminal degradation of phytate in soyabean meal and rapeseed meal.

Most of the P in oilseed meal is in the form of phytate P, and phytate forms complexes with protein. Phytate P has been considered to be absorbed easily in ruminants because of phytate degradation in the rumen. Treatment of oilseed meals with formaldehyde improves the nutritional value of protein through suppressing its ruminal degradation. The present experiment was conducted to study the effects of formaldehyde treatment on phytate degradation in the rumen. The ruminal degradation of phytate in formaldehyde-treated soyabean meal or rapeseed meal was determined by a nylon-bag technique in sheep. Soyabean meal and rapeseed meal were treated with formaldehyde at levels of 3, 5 or 10 g/kg. Treatment with formaldehyde suppressed phytate and protein degradation in both the oilseed meals. Compared with the regular soyabean meal, the regular rapeseed meal showed lower degradability of phytate in the rumen. These results suggest that treatment with formaldehyde suppresses ruminal degradation of phytate in oilseed meal. Thus, the absorption of P from oilseed meal is probably decreased by this treatment in ruminants.

Differences in responses to norepinephrine and adenosine triphosphate in isolated, perfused mesenteric vascular beds between normotensive and spontaneously hypertensive rats.

The responses to norepinephrine and adenosine 5' triphosphate (ATP) of isolated, perfused mesenteric vascular beds were compared between spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. Norepinephrine (0.01-100 nmol) dose-dependently increased perfusion pressure in the intact bed and the arteries, but not in the veins. The maximal responses in SHRs were larger than those in WKY rats. ATP (0.1-3,000 nmol) increased perfusion pressure in all preparations. The responses of the intact bed and the veins were larger in SHRs, whereas there was no strain difference in the arteries. Indomethacin (5 x 10(-6) M) enlarged the norepinephrine responses of both strains only in the intact beds and did not affect the ATP responses, except the veins in SHRs, where it was reduced. N(G)-nitro-L-arginine methyl ester (5 x 10(-6) M), in combination with indomethacin, potentiated the responses, except the arterial response to high doses of norepinephrine in SHRs, which was not affected. Endothelium denudation in the arteries produced similar changes to those after the combined treatment. UK14,304-induced and ADPbetaS-induced decreases in perfusion pressure at increased tone were similar between the strains. Thus neither the vasodilation induced by the stimulation of alpha2-adrenoceptors nor of P2y receptors seems to affect the response to norepinephrine or to ATP, respectively. These results demonstrate that the intact mesenteric vascular bed of SHRs shows potentiated responses not only to norepinephrine, but also to ATP, as compared with WKY rats, and that the critical regions for determining the strain differences for norepinephrine are overall arteries, and that for ATP are the vessels downstream from arterioles. In the intact beds, neither regulation by endogenous prostanoids nor that by endothelium-derived relaxing factors (EDRFs) is implicated in the strain difference. However, these two types of regulation differ markedly between different kinds of vessels.

ATP-induced, P2U purinoceptor-mediated constriction of isolated, perfused mesenteric beds of the rat.

alpha,beta-Methylene ATP (alpha, beta-mATP), ATP and UTP dose dependently increased the perfusion pressure of rat mesenteric arteries with a potency order of alpha, beta-mATP >> ATP > UTP. In the veins, while alpha, beta-mATP did not affect the pressure, both ATP and UTP equi-potently increased it. The arterial ATP response was attenuated to some degree by suramin (100 microM), but markedly and to a similar extent by pyridoxal-phosphate-6-azophenyl-2',4-disulphonic acid (PPADS 30 microM) and alpha, beta-mATP (100 nmol). The venous response was not affected by PPADS or alpha, beta-mATP, but was slightly attenuated by suramin. Thus, ATP seems to elicit arterial constriction predominantly by stimulating P2X, but venous constriction by stimulating P2U purinoceptors.

Changes in the regulation by endothelium of norepinephrine response in isolated, perfused mesenteric vascular bed of rats at different ages.

Age-related changes of norepinephrine response were studied in isolated perfused mesenteric arteries and veins of rats at 4, 32 and 75 weeks of age. Norepinephrine (0.1-100 nmole) significantly and dose-dependently increased perfusion pressure of the arteries, whereas it only slightly changed that of the veins. The arterial response increased, but the venous response decreased with age. Indomethacin at 5 x 10(-6) M did not change the arterial response at any of the ages. The combination of indomethacin and NG-nitro-L-arginine methyl ester (L-NAME) at 5 x 10(-6) M, and endothelium denudation similarly augmented the response in 4-week-old rats, but neither of these affected the responses in 32- and 75-week-old rats. At raised tone by 100 mM potassium chloride, acetylcholine-induced decrease in perfusion pressure and inhibition of the response by L-NAME were attenuated gradually with age. The raised tone in 75-week-old rats was higher than that in either 4- or 32-week-old rats, but the difference disappeared in the presence of L-NAME. These results demonstrate that the arterial portion is predominant in norepinephrine response and the arterial and venous responses change oppositely with age. It is also suggested that neither prostanoids nor endothelial nitric oxide regulate the arterial response in mature animals, while only in 4-week-old rats, nitric oxide may counteractively regulate the response. Additionally, the roles of nitric oxide in the regulation of transient norepinephrine response, in the regulation of the potassium-induced tonic contracture, and in the vasodilation through muscarinic receptor stimulation seem to change somewhat differently with age.

Age-related differences and roles of endothelial nitric oxide and prostanoids in angiotensin II responses of isolated, perfused mesenteric arteries and veins of rats.

We examined whether or not cyclo-oxygenase products of arachidonic acid and endothelium-derived relaxing factor (nitric oxide, NO) regulate the vascular response to angiotensin II differently with aging or development. For this purpose angiotensin II responses of isolated, perfused rat mesenteric vascular beds were compared between rats aged 4 weeks and 32 weeks. Angiotensin II increased perfusion pressure in arteries and veins of both rats aged 4 weeks and 32 weeks. In the arteries of rats aged 32 weeks the increase was slight, and less than that in rats aged 4 weeks. In contrast, the veins showed similar increases in perfusion pressure in rats aged 4 weeks and 32 weeks. Indomethacin, an inhibitor of cyclo-oxygenase, at 5 x 10(-6) M depressed the increase in perfusion pressure only in the arteries of rats aged 32 weeks. NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, applied at 5 x 10(-6) M in the presence of indomethacin enlarged the perfusion pressure increase in the arteries of both rats aged 4 weeks and 32 weeks, while it failed to modify that in the veins. After removal of the endothelium from the blood vessels, the perfusion pressure responses in arteries were increased in both rats aged 4 weeks and 32 weeks, whereas those in veins were not affected. Regardless of the endothelium being intact or removed, the increase in arterial perfusion pressure of rats aged 32 weeks all but disappeared with 5 x 10(-6) M furegrelate, an inhibitor of thromboxane A2 synthase, and with a combined application of furegrelate and 10(-6) M SQ29,548, a blocker of thromboxane A2/prostaglandin H2 receptors. These results indicate the following: in rat mesenteric vascular beds the angiotensin II response in the arteries appears to diminish with aging or development, whereas that in the veins does not change. The NO released from the endothelium regulates the arterial response but vasodilating prostanoids have no role in the response. Moreover, in the arteries of rats aged 32 weeks, vasoconstricting prostanoids, such as prostaglandin H2 and thromboxane A2, seem to play a role in angiotensin II-induced vasoconstriction. With aging or development, and depending on the type of blood vessel, NO and prostanoids appear to modify the angiotensin II response differently.

The dithiane Ro 44-5912 enhances vinblastine sensitivity of drug resistant and parental KB lines in vivo.

The multidrug resistance modifying activity of a dithiane analogue of tiapamil, Ro 44-5912, was examined in vivo. Results of acute toxicity studies in mice indicated that lethal toxicity occurred with doses greater than 1 mmol/kg of body weight. In a preliminary pharmacokinetic investigation, Ro 44-5912 appeared to have a longer half-life in mice than did its (R) enantiomer Ro 44-5911 (3.15 +/- 0.02 h versus 2.15 +/- 0.14 h) as measured by total radiolabel in plasma. In non-tumour bearing mice, Ro 44-5912 enhanced the toxicity of vinblastine in a manner that was dependent on the dose of both drugs. Vinblastine did not have a significant effect on tumour growth when given to nude mice bearing the parental cell line KB-3-1 at a dose of 1.5 mg/kg once per week for 3 weeks. Combination treatment with Ro 44-5912 markedly enhanced the antitumour activity of vinblastine. Similar results were seen when KB-3-1 tumours were treated with the combination of vinblastine plus cyclosporin A. Another tiapamil analogue, Ro 11-2933, had no enhancing activity with this tumour when used at an equitoxic combination dose. Ro 44-5912 also significantly enhanced vinblastine activity with P-glycoprotein-expressing KB-8-5 tumours. In three independent experiments, Ro 44-5912 enhanced the growth inhibiting activity of vinblastine by a mean of approximately 40%. Neither Ro-11-2933 nor cyclosporin A, at the maximal tolerated doses in combination with vinblastine, led to significant inhibition of KB-8-5 tumour growth compared to treatment with the two vehicles alone. These results show that Ro 44-5912 is an active modulator of drug resistance in vivo.

Detection of O6-methylguanine, O4-methylthymine and O4-ethylthymine in human liver and peripheral blood leukocyte DNA.

O6-Methylguanine, O4-methylthymine and O4-ethylthymine were determined by a recently developed, highly sensitive and specific method (PREPI, pre-fractionation, 32P-post-labeling and immunoprecipitation) in human liver DNA obtained from 15 autopsy specimens and in 15 peripheral blood leukocyte DNA samples obtained from healthy volunteers. All the cases had no obvious history of recent occupational or therapeutic exposure to alkylating agents. In the human liver DNA O6-methylguanine was detected in 13 cases at levels of 1.1-6.7 adducts/10(7) guanine; two cases were below the detection limit of approximately 1.1 x 10(-8). O4-Methylthymine and O4-ethylthymine were detected in all the liver samples at levels of 0.1-14 adducts and 0.5-140 adducts/10(7) thymine respectively. The mean value of the ratio of O6-methylguanine to O4-methylthymine was about 6. Among the three DNA adducts measured there was no significant correlation between any two combinations of adducts. In peripheral leukocytes of healthy volunteers O6-methylguanine was detected at 0.7-4.6 adducts/10(8) guanine, this being approximately 3-6% of that in livers. Neither O4-methylthymine nor O4-ethylthymine was above the detection limits. These results suggest that humans are exposed to exogenous and/or endogenous methylating and ethylating agents in daily life.

Isolation and characterization of a novel hair follicle-specific gene, Hacl-1.

We have isolated a hair-follicle-specific gene, termed hacl-1, from a cDNA library of ICR mouse skin. Hacl-1 is expressed specifically in skin, and its mRNA level is correlated with the active state of hair follicles in developmental and regenerative processes of hair. Its mRNA is approximately 1 kilobase pairs (kb). Its cDNA was completely co-linear with the genomic clone, indicating that the hacl-1 gene is composed of one exon. The hacl-1 gene has an open reading frame of 579 base pairs (bp). The deduced amino acid sequence showed six direct repeats of a decapeptide on the C-terminal side. The repetitive unit contains a CQP motif, which is present in repetitive peptide sequences of some hair- and epidermal-cell-specific proteins. In situ hybridization with a 3' untranslated region of the hacl-1 cDNA as a probe showed that hacl-1 was expressed specifically in the keratogenous zone of the cortical cells of the hair shaft. No other components of hair follicles or epidermis showed a positive signal. Thus, hacl-1 is a novel, hair-follicle-specific gene.

A highly sensitive and specific method for quantitation of O-alkylated DNA adducts and its application to the analysis of human tissue DNA.

Formation and accumulation of O6-alkylguanine and O4-alkylthymine in human tissues is possibly the most relevant marker for cancer risk. Because humans are chronically exposed to diverse kinds of chemicals and eventual DNA structural modifications are supposed to be a complex mixture of adducts at very low levels, it is essential to use an assay with extremely high sensitivity and specificity. We have established a quantitation method, called PREPI, for O6-methylguanine, O4-methylthymine, and O4-ethylthymine by the combination of prefractionation by HPLC, 32P-postlabeling, and immunoprecipitation. The detection limit was about 1 fmole for all three adducts, enabling us to analyze about 1 x 10(-8) levels as a molar ratio to normal counterpart using 100 micrograms of DNA. In a pilot experiment, we analyzed 11 peripheral blood samples from healthy volunteers. O6-Methylguanine was detected in all the cases with a mean value of 2.0 +/- 1.3 x 10(-8) (range, 0.78-4.6 x 10(-8)). Neither O4-methylthymine nor O4-ethylthymine was above the detection limit of 0.8 x 10(-8) as a ratio to thymine.

Highly sensitive, specific detection of O6-methylguanine, O4-methylthymine, and O4-ethylthymine by the combination of high-performance liquid chromatography prefractionation, 32P postlabeling, and immunoprecipitation.

A highly sensitive and specific method for the detection of O6-methylguanine (O6-meG), O4-methylthymine (O4-meT), and O4-ethylthymine (O4-etT) has been established by combining prefractionation by high-performance liquid chromatography (HPLC), 32P postlabeling, and immunoprecipitation by monoclonal antibodies (PREPI method). DNA was enzymatically hydrolyzed to 2'-deoxynucleoside-3'-monophosphates (3'-dNps). Each alkyl 3'dNp was separated by reverse-phase HPLC, radiolabeled at the 5' position with [gamma-32P]ATP and polynucleotide kinase. After removing 3'-phosphate for better recognition by the antibodies, the resulting alkyl nucleotides were further fractionated by HPLC and finally precipitated specifically with respective antibodies. The detection limits were 1 fmol for all the alkyl nucleotides analyzed, so that one adduct in 10(8) of its normal counterpart nucleotide can be determined using approximately 100 micrograms (O4-meT and O4-etT) or approximately 150 micrograms (O6-meG) of DNA, i.e., 3-5 x 10(7) cells corresponding to approximately 10 ml of peripheral blood or a few hundred milligrams of tissue. By the use of the PREPI method, three leukocyte and three liver DNA samples from Japanese living in the Tokyo area were analyzed with respect to O-alkyl adduct content. O6-meG was detected in all three of the leukocyte samples (O6-meG:G molar ratio, 1.1 x, 0.8 x, and 1.6 x 10(-8) as molar ratios to guanine). Neither O4-meT nor O4-etT was detected (detection limit, O4-alkylT:thymine molar ratio less than 0.5 x 10(-8)). Among the liver samples analyzed, two cases showed positive O6-meG values (4.2 x and 1.1 x 10(-7) O6-meG:guanine molar ratios). Contrary to the leukocyte DNA, O4-meT (3.9 x, 4.3 x, and 7.5 x 10(-8) as O4-meT:thymine) and O4-etT (1.9 x, 4.9 x, and 8.7 x 10(-8) as O4-etT:thymine) were detected in all the liver samples. These results indicate the validity of the PREPI method for molecular epidemiological studies on DNA alkylation products.

Pharmacology of a phosphorus-containing novel angiotensin converting enzyme inhibitor, SQ 29 852 in anesthetized dogs.

The effects of (S)-1[6-amino-2[[hydrozy(4- phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-proline (SQ 29 852), a phosphorus-containing novel angiotensin converting enzyme inhibitor (ACEI), which is synthesized aiming an ACEI with long-lasting activity and with few side effects, were studied using anesthetized dogs. SQ 29 852 was equipotent with captopril to modify blood pressure response of the animals to angiotensin I (Ang I) and bradykinin (Bdk). An intravenous infusion of SQ 29 852 at 0.1 mg/kg/min for 30 min caused a remarkable hypotension without reflex tachycardia in open-chest dogs. In these animals cardiac contractility (dP/dtmax of left ventricular pressure) appeared to be reduced by SQ 29 852 without any changes in right atrial pressure (RAP), left ventricular end-diastolic pressure (LVEDP) and aortic blood flow (AoF, cardiac output). In sodium-restricted dogs, the hypotension and renal vasodilation by SQ 29 852 (at 0.01, 0.1, and 1 mg/kg, i.v.) were slightly pronounced compared with animals fed with normal diet. It is demonstrated from these results that SQ 29 852 has comparable potency with captopril to inhibit angiotensin converting enzyme (ACE) activity and as common a pharmacological profile as ACEI. SQ 29 852 may be a favorable antihypertensive agent, if its long-lasting activity and few side effects are confirmed.

Reduction and recovery of plasma 1,5-anhydro-D-glucitol level in diabetes mellitus.

The plasma concentration of 1,5-anhydro-D-glucitol (AG) was measured in 135 newly diagnosed patients who were referred for oral glucose tolerance tests. AG concentrations in the nondiabetic patients indicated that the mean value of normal AG concentration was 21.8 micrograms/ml (SD = 5.9 micrograms/ml, range 9.6-38.8 micrograms/ml). This distribution of AG concentration was significantly different from that in patients with impaired glucose tolerance (IGT) (13.3 +/- 5.4 micrograms/ml) and definitely different from that in diabetic patients (2.1 +/- 1.8 micrograms/ml). In a standard glucagon test, it was suggested that the decrease of plasma AG was affected not only by glycemic control of the patients but also by pancreatic cell secretory activity. The reduction of AG concentration was more marked in IDDM patients than in NIDDM patients. In longitudinal studies, AG concentration was shown to be sensitive to glycemic control. However, its recovery showed a tendency toward much delay after the improvement of fasting blood glucose or HbA1 concentrations. On the other hand, AG concentration showed negligible diurnal change and no immediate change as a result of diet, oral glucose load, or acute shift of the insulin level in both normal and diabetic subjects.