The safety and pharmacokinetics of NM441, a prodrug of a new thiazeto-quinoline carboxylic acid derivative, NM394, were evaluated in healthy male volunteers given the drug orally in single doses of 20, 50, 100, 200, and 400 mg, and multiple doses of 300 mg twice daily for 6.5 days. No remarkable abnormalities were observed in symptoms, physical tests, laboratory tests, electrocardiogram (ECG), electroencephalogram (EEG), or equilibrium test. The mean plasma concentrations of active metabolite NM394 peaked between 0.5 and 1.0 hours, and the maximum concentrations were 0.68, 1.09, and 1.88 micrograms/mL at doses of 100, 200, and 400 mg, respectively. The mean half-lives were 7.7 to 8.9 hours and were not affected by dose. The mean urinary excretion rates of NM394 were 46.0, 38.3, and 30.6% of the doses within 48 hours, respectively, and other metabolites were excreted in urine by 7% of the doses. The mean salivary concentrations of NM394 were approximately 20% of the plasma concentrations. The mean fecal excretion rates of NM394 and NM441 were 52.9 and 4.2%, respectively within 72 hours after dosing of 400 mg. The Cmax, AUC, and urinary excretion rates were not altered by food intake, whereas the Tmax was prolonged slightly. In the multiple-dose study, the steady state of plasma concentration of NM394 was achieved on day 3 or 4, and further accumulation did not occur thereafter. The mean urinary excretion rate of NM394 was 49.0% during and 48 hours after the multiple administration. The acceptable safety and tolerance and defined pharmacokinetic characteristics of NM441 support further testing.

Aims To investigate the pharmacokinetics and safety profile of JTP-4819, (-)-(2S)-1-benzylaminocarbonyl-[(2S)-2-glycoloylpyrrolidinyl]-2-pyrrolidinecarboxamide, a novel specific orally active prolyl endopeptidase (PEP) inhibitor. Methods JTP-4819 was given orally to 28 healthy male volunteers at single doses of 30 mg (n=6), 60 mg (n=6), 120 mg (n=6) and placebo (n=3) and multiple doses of 60 mg three times daily (n=5) and placebo (n=2) for 7 days to investigate its safety and pharmacokinetics following a preliminary safety evaluation of 3, 10 and 30 mg doses in six healthy volunteers. With the single dose of 60 mg, a cross-over study was conducted to examine the effect of food on the bioavailability of the drug. The concentrations of JTP-4819 in plasma and urine were determined by electrospray ionization-liquid chromatography/mass spectrometry (ESI-LC/MS) method. Results In the multiple-dose study, the cholinesterase activity was gradually increased and reached above the normal range on days 4 to 8 in all five subjects given JTP-4819 and gradually returned to normal range after completion of dosing. The elevation of plasma cholinesterase activity was considered to be an action of JTP-4819, but this remains to be verified. There were no other abnormal findings in objective symptoms and laboratory findings including blood pressure, heart rate, electrocardiogram, body temperature, haematology, blood chemistry and urinalysis. The C max of JTP-4819 at 30, 60 and 120 mg in fasting state were 474, 887 and 1,649 ng ml −1 , respectively, at 1 h after administration, and the t 1/2 was about 2 h.AUC increased in proportion to the given doses. The cumulative urinary recoveries within 24 h were approximately 66%. C max , AUC, t 1/2 and urinary recovery were not affected by food intake. In the multiple-dose study, there was no drug accumulation trend in plasma.Conclusions These results indicate that JTP-4819 has acceptable pharmacodynamic and pharmacokinetics profiles for clinical use without any serious adverse events as we verified in healthy young male volunteers.

The changes in the resistance of the perfused ventral rat-tail artery resulting from exposure of the tissue to ouabain-containing and/or K+-free physiological salt solution were studied. In each case, there was an increase in the vascular resistance which was not sustained. The response of the arterial wall to the above stimuli was abolished in the absence of external Ca2+. In contrast to the delayed response of the wall to either ouabain-containing or K+-free solution, an almost instantaneous rise in the resistance was observed if the two stimuli were combined, though the rate of loss of the tissue K+ was not accelerated significantly under these experimental conditions. The tension developed in K+-free solution was relieved almost instantaneously upon readmittance of external potassium.

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ABSTRACT. Pituitary folliculo-stellate (FS) cells were able to modify the effect of activin-A on gonadotropes through the paracrine factor, follistatin. The present study was aimed to examine whether a hypothalamic peptide, pituitary adenylate cyclase activating polypeptide (PACAP), could be a regulator of this paracrine interaction. Co-culture of FS cell-originated cell line TtT/GF cells with rat anterior pituitary cells showed faint inhibitory effect on the stimulatory action of activin-A on FSH secretion. When PACAP was added to the culture during the co-culture period, however, the presence of TtT/GF cells caused significant suppression of the effect of activin-A on FSH secretion. Conditioned-media (CM) from TtT/GF cells, obtained by incubation of TtT/GF cells in the presence or absence of PACAP, were next added to the cultures of anterior pituitary cells alone. CM from TtT/GF cells without PACAP treatment revealed slight, but not significant, suppressive effect on activin-induced increases in FSH secretion and the percentage of FSH cells. Meanwhile, CM from PACAP-treated TtT/GF cells attenuated both effects of activin-A. Furthermore, the inhibitory effect of the CM was neutralized when follistatin antibody was present in the culture. These results suggest that PACAP is able to regulate the paracrine action of FS cells on pituitary gonadotropes. Besides expressing direct actions on pituitary endocrine cells, PACAP may have roles as a regulator of cell-tocell interactions within the pituitary gland.KEY WORDS: activin, conditioned-media, gonadotrope, PACAP, TtT/GF cell.J. Vet. Med. Sci. 62 (7): [731][732][733][734][735][736] 2000 Gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), play important roles in the regulation of reproduction and fertility. Studies on the regulatory mechanisms of pituitary gonadotropes, the source of gonadotropins, are therefore essential to understand the physiology, pathology, as well as to develop remedies, of reproductive functions and disorders. Hypothalamic gonadotropin-releasing hormone (GnRH) and gonadal steroid hormones are classically known regulators of the gonadotrope functions, and today the inhibin, activin and follistatin have also obtained recognition as the regulators [7]. Activin not only stimulates the secretion of FSH [22,37] but also enlarges the population of FSH gonadotropes in primary cultures of rat anterior pituitary cells [17,18]. Our previous study demonstrated that the latter effect of activin-A (one of three forms of dimeric activin; -A, -AB and -B) was negatively controlled by pituitary folliculo-stellate (FS) cells through a paracrine factor, follistatin [16]. This and other studies concerning interactions of activin and follistatin in various tissues [3,6,23] have led us to the understanding that the balance of these two factors are important in the regulation of various biological functions. In the anterior pituitary gland, follistatin expression has been shown to vary under different conditions [8,12]. Although hypothal...