Synergistic effects of DL111-IT combined with mifepristone on termination of early pregnancy in rhesus monkeys.

The objectives of this study were to determine the synergistic effects of DL111-IT in combination with mifepristone (RU486) on termination of early pregnancy in rhesus monkeys. Pregnancy was confirmed by tactile sensation of pregnant uterus via anus with finger and ultrasound examination. Pregnancy termination was obtained with vaginal bleeding and abortion materials including fetuses and placentae after treatment. With multiple doses of DL111-IT or RU486 given alone between d24 and d50 of gestation, pregnancy arrests were obtained in 40% (2/5) of monkeys treated with DL111-IT intramuscularly (im) (25 mg x kg(-1) x d(-1) x 3 days), in 20% (1/5) of monkeys treated with 9 mg x kg(-1) x d(-1) x 2 days, and 4.5 mg x kg(-1) on day 3 with RU486 intragastrically (ig). DL111-IT (25 mg x kg(-1) on day 1, im) in combination with RU486 (the same treatment as above) resulted in 100% (10/10) termination of pregnancy and uterine bleeding lasted 6.6 +/- 1.3 days. RU486 (as above treatment) in combination with misoprostal (Miso, 109 microg x kg(-1) on day 3, ig) showed 71.4% (5/7) termination of pregnancy, and uterine bleeding lasted 12.9 +/- 9.6 days. The synergistic effect of DL111-IT plus RU486 enhances termination of early pregnancy and significantly shortens the bleeding time than RU486 plus Miso does in rhesus monkeys.

Termination of early pregnancy in the mouse, rat and hamster with DL111-IT and RU486.

The effectiveness of DL111-IT and RU486 given alone and in combination for terminating early pregnancy was tested in the rat, mouse, and hamster. In the mouse and rat, the combination of RU486 and DL111-IT is much more effective in terminating pregnancy than either of the two compounds used alone (single or multiple treatment). A low-effective dose of DL111-IT in combination with a non-effective or a sub-effective dose of RU486, exerted additive or synergistic effects resulting in resorption of embryos and termination of pregnancy. The serum progesterone concentrations were significantly suppressed by these combinations when pregnancy was terminated. In the hamster, single treatment with DL111-IT plus RU486 exhibited a strong effect on interrupting early pregnancy. The ED50 of RU486 in combination of a non-effective dose of DL111-IT was decreased to 163-fold lower dose than RU486 given alone. It is concluded that in mouse, rat, and hamster, the synergistic action between DL111-IT and RU486 not only greatly enhances efficacy in terminating pregnancy but also reduces substantially the dose required to produce this effect.

[Heart morphologic state in retired fighter pilots].

Objective. To study the heart morphology in the retired fighter pilots, and to provide clinical evidence for protection combined G-loads (+ Gz), heat, noise, hypoxic and vibration stress induced cardiac structural damage. Method. Parameters of heart morphology were studied using Doppler echocardiography in 40 retired fighter pilots with 40 veteran cadres as control. Result. LVDd, LVDs, LADs, LVEDV, LVPWs and LVM in pilot group were somewhat higher than those in control group (NS); while IVSs and LVMI in pilot group were slightly lower than those in control group (NS); LVESV, aortic valve area, internal diameter of the ring and sinus in pilot group were significantly higher than those in control group (P < 0.05). Conclusion. Analysis of the results revealed no pathomorphologic damage of the heart. It suggest that all the variations can be regarded as adaptive changes due to the effects of the combined environmental factors experienced in long time flying.

Effect of DL111-IT on progesterone biosynthesis and viability of rat luteal cells in vitro.

AIM: To study the influence of DL111-IT on progesterone biosynthesis of cultured luteal cells (LC). METHODS: LC viability was assessed with trypan blue dye exclusion and progesterone concentration was measured with radioimmunoassay. RESULTS: DL111-IT decreased the viability of LC after 24-h incubation, its ED50 being 7.7 (95% confidence limits: 7.1-8.5) mg.L-1. DL111-IT inhibited basal secretion of progesterone in a concentration-dependent manner, and 3 mg.L-1 decreased progesterone concentration by 25% vs control. DL111-IT 3 mg.L-1 also inhibited the stimulatory effect of forskolin (cAMP activator) 10 mumol.L-1 and pregnenolone [converted to progesterone by 3 beta-hydroxysteroid dehydrogenase-isomerase complex (3 beta-HSD)] 10 mumol.L-1 on progesterone production in cultured LC, and their inhibitory rates were 43% and 155%, respectively. At the same concentration, DL111-IT did not influence hCG-induced progesterone production. CONCLUSION: DL111-IT inhibited progesterone synthesis by suppressing the conversion of pregnenolone to progesterone (inactivating 3 beta-HSD) and suppressed the activity of cAMP. DL111-IT 6-24 mg.L-1 decreased the viability of LC.

Synergistic effects on pregnancy-termination activity of DL111-IT in combination with mifepristone.

AIM: To clarify the role of DL111-IT when combined with mifepristone (Mif) on termination of early pregnancy. METHODS: Progesterone receptors (PR) was measured using radioligand assay (RA), and peroxidase-antiperoxidase (PAP) immuno-histochemistry. Decidual cells (DC) were estimated using cell culture and histological examination (HE) (including fetus). RESULTS: DL111-IT 100 mg.kg-1 i.m., Mif 5 mg.kg-1 i.g., DL111-IT 16 mg.kg-1 i.m. + Mif 1.5 mg.kg-1 i.g. and tea seed oil (TSO) 2 mL.kg-1 i.m. on d 7 of pregnancy in rats, DC and fetus of treated groups were found to be degenerated at 24 h after treatment, at 48 h after treatment, PAP labeling index (%) of uterus PR of 4 groups were 22 +/- 4, 18.7 +/- 2.9, 10.3 +/- 1.2, 52 +/- 15, respectively. Rats i.m. DL111-IT 100 mg.kg-1 24 h after treatment, the quantity of PR decreased by 47% vs that of TSO. The affinity of PR with Mif and progesterone did not change. Cultured human DC were exposed to DL111-IT and Mif 0-50 mg.L-1, alone or combinatively, for 24 h. LD50 (mg.L-1) were: DL111-IT 18.1 (15.1-21.4), Mif 25.0 (23.1-26.9), DL111-IT 5.0 plus Mif 3.5 (1.8-6.5) or Mif 5.0 plus DL111-IT 4.6 (1.1-7.3), respectively. CONCLUSION: DL111-IT enhanced action of Mif on DC, reduced quantity of PR, so the 2 drugs had the synergistic action in termination of early pregnancy.

The binding of plasminogen fragments to cultured human umbilical vein endothelial cells.

Glu-plasminogen, kringle 1-5, kringle 1-3, and miniplasminogen exhibited strong binding to human umbilical vein endothelial cells (HUVEC). On the other hand, no significant binding was obtained with microplasminogen and kringle 4. Kringle 1-5 and miniplasminogen, which both contained kringle 5, specifically inhibited the binding of plasminogen to HUVEC while kringle 1-3 did not. The results implied plasminogen molecule contained at least two binding sites, with which it interacted HUVEC. The stronger binding site was located in kringle 5 and the weaker one was in kringle 1-3. Kringle 4 and the active site domain exhibited no significant binding to HUVEC. The interaction of plasminogen with HUVEC is mainly through binding site on kringle 5.

Embryotoxicity and teratogenicity of DL111-IT, an early pregnancy-terminating agent, in the subsequent gestation following administration in rats.

DL 111-IT is a new non-hormonal early pregnancy-terminating agent. The subsequent embryotoxic and teratogenic effects of DL111-IT were studied in the rats whose first pregnancy had been terminated by the agent. The secondary pregnancy of the treated rats were allowed to initiate at 30-, 45-, and 90-day intervals, respectively, after the termination of the first pregnancy. The toxicities primed with DL111-IT, such as resorbed embryos and nephrohydrosis fetuses, were found to be 8.0% and 8.5%, respectively, in the rats with pregnancy at 30-day interval. This is significantly different from 4.0% resorbed embryos and 2.4% nephrohydrosis fetuses in vehicle control (P less than 0.05). However, the rate of resorbed embryos decreased to 7.0% or 6.0% in the rats with pregnancy at 45- or 90-day intervals, respectively. No other significant embryotoxicity and teratogenicity were observed in those rats initiating their pregnancy 45 days later after first-pregnancy termination by DL111-IT. Thus, DL111-IT appears to have very low subsequent toxicity in the course of rat pregnancy cycles.

[Parenteral magnesium sulfate exerts no central anticonvulsant action].

It was said that parenteral magnesium (MS) had a central anticonvulsant action responsible for controlling seizures in eclampsia of pregnancy. The present study was carried out to examine this statement. In conscious rabbits, MS 214 mg.kg-1 iv quickly relieved them from convulsion induced by sc pentylenetetrazol, yet spikes of high frequency in electrocorticogram burst inceasingly. Judging from electrocorticogram changes, MS 220 mg.kg-1 iv did not raise the electroshock seizure threshold. In mice, MS 430 mg.kg-1 did not significantly increase the LD50 of ip pentylenetetrazol. However, in anesthetized rats, MS 250 mg.kg-1 ip lowered the hypertensive response to angiotensin amide and norepinephrine. These results indicated that parenterally administered MS exerted no demonstrable central anticonvulsant action, and its benefits gained in the treatment of eclampsia of pregnancy might derive from its peripheral action, such as reduction of vascular response to pressor substances.