The determination of the urinary ratio of alphaCTX to betaCTX could be useful for monitoring the effect of bisphosphonate treatment in restoring bone quality in patients with Paget's disease.

Cyclosporine is a potent immunosuppressive agent, however, its use is limited by nephrotoxicity. Increased production of the potent vasoconstrictor thromboxane A2 contributes to cyclosporine nephrotoxicity in animal models, but the role of thromboxane in human cyclosporine nephrotoxicity has not been established. We therefore studied cyclosporine-treated renal allograft recipients who had evidence of toxicity manifested by decreased renal function. We measured GFR and PAH clearance (CPAH) before, during, and one week after a 48-hour intravenous infusion of the thromboxane synthase inhibitor CGS 13080. At baseline, the urinary excretion of TXB2 and 2,3-dinor-TXB2 was elevated in the study patients compared to healthy subjects. CGS 13080 infusion caused selective and nearly complete inhibition of thromboxane metabolite excretion in all patients. Mean CPAH improved 33% from 223 +/- 45 to 298 +/- 59 ml/min/m2 (P = 0.055) during infusion, while mean GFR improved 9% from 50.1 +/- 3.9 at baseline to 54.6 +/- 4.5 ml/min/1.73 m2 (P = 0.111). The effect on GFR occurred primarily in those patients taking calcium channel blockers. The mean increase in GFR in these 5 patients was 10.0 +/- 2.8 versus -1.0 +/- 2.8 ml/min/m2 in the remainder. We conclude that thromboxane synthase inhibitors may be useful in attenuating the nephrotoxic effects of cyclosporine following renal transplantation.

No abstract

No abstract

No abstract

The objectives of this study were to investigate the effects of KISS1 94-121 fragment on the contractility of nonpregnant and pregnant rat uteri, and to determine the uterine and myometrial expressions of Kiss1r. Uterine muscle strips were obtained from non-pregnant Sprague-Dawley rats in oestrous phase and from pregnant rats on gestational days 5, 15, 18, 20 or 22. The in vitro contractility measurements were carried out in an isolated organ bath in the presence of KISS1 94-121. Experiments with 5-day pregnant tissues were also performed in the presence of kisspeptin-234 trifluoroacetate. The mRNA and protein expressions of Kiss1r were measured by RT-PCR and Western blot analysis, while localizations of receptors were defined by fluorescent immunohistochemistry. KISS1 94-121 induced a dose-dependent relaxation both in non-pregnant and pregnant intact and endometrium-denuded uteri. A gradual decrease was found in the uterine expressions of Kiss1r mRNA and protein towards the end of the gestational period, and it was further confirmed by the immunohistochemical results. The significant majority of Kiss1r is found in the myometrium, however the few endometrial Kiss1r also influences the uterine contractions. The relaxing effect of kisspeptin is continuously reduced towards the end of gestational period in parallel with the reduction of Kiss1r expression. Our results suggest a putative role of kisspeptin in the maintenance of uterine quiescence that may have significance in miscarriage or preterm contractions.

Aquaporins (AQPs) are expressed in the uterus, playing a physiological role during pregnancy. An osmotic pathway—through AQP5—may modify the transient potential vanilloid 4 (TRPV4) function and uterine contraction. Our aim was to determine the role of TRPV4 antagonist citral in the regulation of pregnant uterine contraction. In vitro uterine contractions were evoked by KCl and the response was modified with citral. The expressions of TRPV4 and AQP5 were measured by RT-PCR and Western blot techniques. The lengths of gestational periods were determined in normal and LPS-induced preterm births after citral treatment, in vivo. Citral significantly decreased the uterine contraction on day 22 of pregnancy. AQP5 expression significantly increased after citral incubation; however, TRPV4 expression did not show significant changes. After citral pretreatment, the gestational period was extended both in normal and LPS-induced preterm births. Our results suppose that the downregulation of AQP5 may initiate hypertonic stress, activating TRPV4 the uterine contraction on the last day of the gestational period. The putative cooperation between AQP5 and TRPV4 may open a novel target to treat or prevent preterm birth.

The pharmacokinetics and pharmacodynamics of biochemical effect of a selective thromboxane synthase inhibitor, CGS 12970, were studied in healthy male volunteers after a dosing scheme of either 200 mg once daily or 100 mg twice a day for 6 days. The peak plasma concentration appeared 1 to 2 hours after administration, followed by a biexponential decline with half life values of about 1 and 7 hours, respectively. The mean oral clearance was 16 L/hr. Biochemically, the capacity of the platelets to form thromboxane A2 ex vivo (serum) was inhibited greater than 90% at both doses. In contrast to the short plasma half-life, the suppression of ex vivo serum thromboxane production was maintained greater than 70% to 80% at 48 hours after dosing. Inhibition of the thromboxane production in vivo (urine) was also substantial, but incomplete at both doses (200 mg daily; thromboxane B2, 75%; 2,3-dinor-thromboxane B2, 83%; 11-dehydrothromboxane B2, 90%). The urinary excretion, however, returned to the predose level at the end of a 1-week follow-up period after the last dosing. In conclusion, CGS 12970 is an orally active, reversible inhibitor of thromboxane synthase with a prolonged duration of action in humans.