(+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N- hydroxyureidyl)methylphenyl]-5-(3,4, 5-trimethoxyphenyl)tetrahydrofuran (CMI-392), a potent dual 5-lipoxygenase inhibitor and platelet-activating factor receptor antagonist.

By incorporating an N-hydroxyurea functionality onto diaryltetrahydrofurans, a novel series of compounds was investigated as dual 5-lipoxygenese (5-LO) inhibitor and platelet-activating factor (PAF) receptor antagonist. These dual functional compounds were evaluated in vitro for 5-LO inhibition in RBL cell extracts and human whole blood, and PAF receptor antagonism in a receptor binding assay. PAF-induced hemoconcentration and arachidonic acid- and TPA-induced ear edema in mice were used to determine in vivo activities. The structure-activity relationship analysis to define a preclinical lead is presented. (+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl- N-h ydroxyureidyl)methylphenyl]-5-(3,4, 5-trimethoxyphenyl)tetrahydrofuran (40, CMI-392) was selected for further study. In the arachidonic acid-induced mouse ear edema model, 40 was more potent than either zileuton (a 5-LO inhibitor) or BN 50739 (a PAF receptor antagonist), and it demonstrated the same inhibitory effect as a physical combination of the latter two agents. These results suggest that a single compound which both inhibits leukotriene synthesis and blocks PAF receptor binding may provide therapeutic advantages over single-acting agents. The clinical development of compound 40 is in progress.

A procedure for successful nonsurgical embryo transfer in swine.

The current study was undertaken to develop a successful procedure for the nonsurgical transfer of pig embryos. A total of 663 embryos were surgically collected on Day 4 or 5 from 55 donors, of which 542 embryos of acceptable quality were nonsurgically transferred to 46 recipients. Nonsurgical recipient gilts were sedated 15 min prior to transfer with 20 mg im acepromazine maleate. A disposable insemination spirette with an attached 3-way stopcock was manipulated into the cervix of each gilt. Embryos were expelled from a tomcat catheter into the spirette, and 10 to 12 ml of Whitten's medium were used to flush embryos through the spirette into the reproductive tract. Sixteen (34.8%) recipient gilts did not return to estrus before Day 36, and 10 (21.7%) gilts farrowed with an average litter size of 4.3 +/- 0.7. Embryos were collected from an additional 20 donors and were surgically transferred to an additional 19 recipients. Surgical transfers conducted at the same time as the nonsurgical transfers resulted in 12 (63.2%) gilts farrowing and 7.1 +/- 0.6 pigs were born per litter. In conclusion, a procedure has been developed for nonsurgical transfer of swine embryos which simplifies the process of embryo transfer and which may increase the potential for utilization of embryo transfer technologies by swine producers.

Effects of adrenalectomy and glucocorticoids on puberty in gilts reared in confinement.

The effect of adrenal function and flumethasone (FM, a synthetic glucocorticoid) on induction of puberty in crossbred gilts raised in confinement was examined in two experiments. In Exp. 1, gilts were adrenalectomized (Adx) or subjected to sham adrenalectomy (Sham) between 140 and 160 d of age. Twenty days later indwelling jugular catheters were implanted in Adx, Sham and another group of intact gilts designated as Controls, and the gilts were moved from confinement to outdoor pens and checked daily for estrus with a mature boar. Fewer (P less than .05) Adx (1/11) than Sham (9/14) gilts showed estrus and ovulated by 205 d of age. Response of Control gilts (6/14) was not different from the other groups. Although Adx gilts received 40 mg cortisone acetate and 10 mg deoxycorticosterone acetate daily throughout the experiment, mean plasma glucocorticoids were lower (P less than .05) in Adx (24 +/- 4.7 ng/ml) than in either Sham (47 +/- 8.1 ng/ml) or Control (44 +/- 6.1 ng/ml) gilts. Experiment 2 was conducted to determine whether FM given to Adx gilts immediately after surgery could have inhibited estrus and ovulation. Intact gilts received a total of 27.5 (FM1) or 17.5 (FM2) mg FM over 4 d between 150 and 160 d of age before relocation and boar exposure 20 d later. Control gilts received no injections. Nine of 13 FM-treated but none of the Control gilts showed estrus. It is concluded from these results that the adrenal glands may facilitate the onset of puberty in gilts through increases in glucocorticoid production, but that this is not required for puberty to occur.

Lifespan of corpora lutea induced in estrous-synchronized cycling and anestrous ewes.

The effect of pretreatment with flurogestone acetate (FA) on the lifespan of corpora lutea induced with pregnant mare serum gonadotropin (PMS) was examined in cycling and anestrous ewes. Cycling ewes received one of three treatments: 750 IU PMS 2 d before expected estrus (P), FA-impregnated vaginal sponges for 16 d (F), and FA sponges for 16 d and 750 IU PMS 2 d before sponge removal (FP). A fourth group served as controls (C). When compared with d 12 means within treatment, plasma progesterone means were lower (P less than .05) on d 16 in control ewes, on d 15 in P and F ewes, and on d 14 in FP ewes. Only 44% of ewes receiving FA treatment alone exhibited estrus (P less than .05) compared with 100% of untreated ewes. The FP treatment increased ovulation rate compared with controls (P less than .01). The decrease in luteal lifespan observed in cycling ewes suggests a possibility of asynchrony between the uterus and embryo, which could result in failure of an embryo to prevent luteal regression, thus resulting in reduced fertility. None of the seasonally anestrous ewes that received PMS alone and only 55% of those treated with FA sponges for 8 d before PMS injection exhibited estrus. Ewes pretreated with FA exhibited higher plasma progesterone concentrations on d 10 through 16 after PMS injection. There were no differences in luteal lifespan as measured by peripheral plasma progesterone patterns. Although FA treatment did not alter luteal lifespan in anestrous ewes, the increased plasma progesterone concentrations observed with FA treatment suggest that progestogen pretreatment may be essential for optimal luteal function.

Control of estrus in gilts with a progestogen.

Two trials were conducted to evaluate the effectiveness of a synthetic progestogen, allyl trenbolone, for control of estrus and ovulation in gilts. Estrus was effectively synchronized with 33 of 38 gilts exhibiting estrus 2 to 7 days after last progestogen feeding. There was no effect on fertilization rate in gilts free of ovarian abnormalities. Ovulation rate was higher in gilts fed the progestogen in both Trial 1 (P less than .01) and Trial 2 (P less than .10). Progestogen treatment caused an increase (P less than .01) in the incidence of cystic follicles which resulted in a decrease (P less than .01) in conception rate in Trial 1.