A review of the toxicology of the antibiotic MICOTIL 300.

MICOTIL 300 is a new macrolide antibiotic for the treatment of Bovine Respiratory Disease complex. As with other macrolides used in human and veterinary medicine, overdoses of MICOTIL do not produce pathognomonic lesions. The toxicity dose response varies among laboratory animal and domestic livestock species. However, clinical evidence of MICOTIL toxicity due to large doses is generally a manifestation of the positive chronotropic and negative inotropic cardiovascular effects. No adverse environmental effects are expected from the use of MICOTIL in cattle.

A 40-week male fertility study of the anticancer agent sulofenur (LY186641) administered orally to rats.

Sulofenur was evaluated for fertility effects on rats. Five-week old male rats (20/group) received 0, 5, 30, or 60 mg Sulofenur/kg/day for 14 weeks. Fertility was evaluated five times. Treated males were mated with untreated females at 10 weeks. Half the males from each group were necropsied after the 14-week treatment period and the remainder were mated four additional times during a 26-week posttreatment period. Following each mating, females were killed on gestation-day 20 and examined for evidence of pregnancy. Six weeks after mating trial 5, the remaining males were necropsied. Testes and epididymides were collected, weighed, and examined microscopically. All rats mated in each mating trial, and all control and low-dose animals were fertile. A significant reduction in fertility occurred in the middle- and high-dose males. This was consistent with testicular hypospermatogenesis in these groups. Fertility recovered in the high-dose group following cessation of treatment, but remained reduced in the middle-dose group. Preimplantation and postimplantation loss in mating trial 1 were higher in the middle- and high-dose groups. Abnormal fetuses were present in the high-dose group in mating trial 3, but not in mating trials 4 or 5. In conclusion, male rats given doses of 30 and 60 mg/kg/day of Sulofenur showed hypospermatogenesis and decreased fertility. Spermatogenesis and fertility recovered in the high-dose group. A dose of 5 mg/kg/day did not produce any effect on testes or fertility.

Maintenance of unimplanted fertilized ova in sprayed rats. IV. Effects of duration of ovarian hormone deprivation and progesterone therapy prior to the deprivation.

Studies were carried out in the spayed-rat delayed-implantation model to determine whether progesterone treatment prior to an ovarian hormone deprivation during the pre-implantation period would influence the incidence of subsequent delayed ovo-implantation induced with progesterone plus estrone. Implantation was rarely induced with 4 mg progesterone plus 1 microgram estrone/day after 5 to 11 days of ovarian hormone deprivation in rats that were spayed on Day 3, if progesterone treatment were not given before ovarian hormone deprivation. In contrast to this, implantation was fairly consistently induced with 4 mg progesterone plus 1 microgram estrone/day after 3, 5, 7, or 11 days of ovarian hormone deprivation in rats that were spayed on Day 3 and received 4 mg progesterone/day before the deprivation period (i.e., on Days 2 through 3, 2 through 6, or 2 through 8). The post-implantation viability of the embryos of the dams undergoing the longer periods of ovarian hormone deprivation, however, was reduced.

Relationship between progesterone suppression and pregnancy in rats.

Four luteolytic agents were administered to groups of pregnant rats to examine the quantitative relationship between serum progesterone levels and the maintenance of pregnancy. Each agent inhibited progesterone in a dose-dependent manner, however only three, azastene, thiosemicarbazone and dihydrotestosterone, adversely affected pregnancy. A statistical analysis of the data suggests that, regardless of the mechanism of action of a particular luteolytic agent, a treatment-induced depression of serum progesterone to concentrations less than 45% of that of the controls on day 11 of pregnancy is incompatible with pregnancy maintenance.

Effects of differing absolute and relative doses of progesterone and estrone on implantation and fetal survival in ovariectomized rats.

Rats were inseminated, then ovariectomized and treated with different doses of progesterone (P) and estrone (E), to determine the minimal and optimal daily doses of P and E required for implantation and fetal survival in ovariectomized rats. The minimal daily dose of P and E required for an optimal rate of implantation and fetal survival in ovariectomized rats was between 0.4 and 4.0 mg of P, and 0.1 and 1.0 microgram of E. The daily 5.0 micrograms E dose was too high to realize implantation or fetal survival when it was injected with P beginning on the day after insemination. If, however, 7 days of daily P treatment preceded the daily 5.0 micrograms E, combined with 20 mg P, delayed implantation was realized but subsequent fetal survival was not. High P doses alone did not substitute for combining E with lower P doses.

Effects of 2(p-biphenyl) propionic acid on the life span of the corpus luteum of pseudopregnant and cyclic rats.

A potent prostaglandin synthesis inhibitor (cyclooxygenase inhibitor), 2(p-biphenyl) propionic acid (BPPA), was administered subcutaneously at the dose of 1 mg twice daily to pseudopregnant and cyclic rats. It was found to prolong the duration of pseudopregnancy by about 10 days and to have little or no effect on estrous cycle length. It did not block ovulation and had little effect on ovulation rate in cyclic rats. BPPA was given to pseudopregnant rats in two trials (one in October-December and the other in March-May) to determine its effect on ovarian weight and plasma progesterone concentration on Days 14, 15 and 16 (Day 0=day of induction of pseudopregnancy). BPPA significantly (P less than 0.001) increased plasma progesterone concentration and reduced ovarian weight. The present data support the hypothesis that prostaglandins cause the normal functional demise of the corpora lutea of pseudopregnancy in the intact rat, and that depressing their synthesis will prolong the functional life span of the corpora lutea.

Effects of the interaction of the ovary with an androstane nitrile on the uterus of the rat.

The compound 17 cyano-5,16 androstadien-3 beta-ol-acetate (cyanoacetate) was considered as a promising candidate for use as a contraceptive agent, since it was reported to specifically inhibit the ovarian conversion of pregnenolone to progesterone. A preliminary study in rats indicated that this compound had unique properties that interfered with the interpretation of results concerning the decidual response. It appeared to interact with the ovaries of the animal to cause an increase in uterine weight. Because of these observations, a multiple factorial study was designed to determine whether this compound was, in fact, more uterotrophic in intact, than in spayed, psuedopregnant rats. The study demonstrated that the presence of the ovary resulted in a significantly greater uterine weight, while 2 mg progesterone daily for 10 days had no significant effect on uterine weight. Cyanoacetate (10 mg/day for 10 days) was found to increase uterine weight significantly in intact, but not spayed, psuedopregnant rats. Neither cyanoacetate (10 mg/day) nor progesterone (2 mg/day) affected ovarian weight. The data suggest that cyanoacetate is converted by the ovary from a compound with little uterotrophic activity to a material with substantial uterotrophic activity.

The effects of a number of non-steroidal anti-inflammatory compounds on parturition in the rat.

A method was developed for assessing non-steroidal anti-inflammatory compounds for their potency in blocking parturition, and prolonging gestation, in the rat. This consisted of injecting compounds into groups of 10 to 13 rat dams twice daily from Day 18 through Day 22 of pregnancy, and comparing the treated dams with appropriate controls on Day 23. The rate of blocked parturition appeared to be positively related to dose of non-steroidal anti-inflammatory agent and, therefore, this model and end-point appeared to be useful for assessing different non-steroidal anti-inflammatory compounds for potency. Among the twenty-seven non-steroidal anti-inflammatory agents evaluated by this method were: ibuprofen, phenylbutazone, tolmetin, flufenamic acid, 2(p-biphenyl) acetic acid, mefenamic acid, aspirin, fenoprofen calcium, flumazole, ketoprofen, naproxen, isoxicam, indomethacin, 2(p-biphenyl) propionic acid, 2(2'-fluoro-4-biphenyl) propionic acid, flurbiprofen, sudoxicam and piroxicam. Piroxicam, sudoxicam, flurbiprofen, 2(p-biphenyl) propionic acid and 2(2'-fluoro-4-biphenyl) propionic acid showed the greatest potency. The relationship between structure and activity and between the blocking of parturition and the inhibition of prostaglandin synthesis are discussed.

Maintenance of unimplanted fertilized ova in spayed rats: effects of cortisone acetate therapy during the period of embryonic diapause.

Rat dams were ovariectomized on day 3 of pregnancy and treated with corn oil (0.25 ml/day), progesterone (4 mg/day), cortisone acetate (2 or 10 mg/day), cortisone acetate (10 mg/day) plus progesterone (4 mg/day) or progesterone (4 mg/day) plus oestrone (1 microgram/day) from days 2 to 8 or 14, followed by 6 to 11 days of treatment with progesterone (4 mg/day) plus oestrone (1 microgram/day). Implantation of ova at the normal time was realized in the animals treated from day 2 with progesterone plus oestrone. Implantation of ova was only realized subsequent to progesterone plus oestrone in the dams treated with progesterone alone, cortisone acetate alone, or progesterone plus cortisone acetate, except for one animal in the latter group. Implantation of ova was not usually realized even after progesterone plus oestrone treatment in the dams treated with corn oil. Even though cortisone acetate maintained unimplanted ova in spayed rats in much the same manner as does progesterone, it was not equivalent to progesterone in efficacy or action.

Assessment of the progestagenic and oestrogenic activity of compounds by their effect on implantation in rats with diapausing embryos.

The oestrogenic, progestagenic and mixed oestrogenic--progestagenic activities of various compounds were assessed by their effects on implantation and its delay in the ovariectomized rat. Progesterone, norgestrel and 17 alpha-(2-butynyl)-17 beta-hydroxyestra-4,9,11-trien-3-one (R3852-3) were investigated. Progesterone and norgestrel proved to be progestagens with little or no inherent oestrogenic activity, while R3852-3 appeared to have both progestagenic and oestrogenic activity. The oestrogenic activity of R3852-3 was verified by using an Allen--Doisy type of assay system.

Studies on the effects of pharmacologic doses of cortisone acetate and several nonsteroidal anti-inflammatory compounds on ovo-implantation, early pregnancy, and the deciduomal response in the rat.

Cortisone acetate (10 mg/day), alone or in combination with progesterone (4 mg/day); progesterone (4 mg/day); progesterone (4 mg/day) plus estrone (1 microng/day); indomethacin (0.75 mg/day); phenylbutazone (20 mg/day); flufenamic acid (10 mg/day); and Compound 83161 (tetrazolo less than 1,5-alpha greater than s-triazolo less than 3,4-c greater than quinoxoline) (8 mg/day and 12 mg/day) were each given to intact rats during early pregnancy (days 1 and/or 2 through day 8). Only cortisone acetate treatment caused a true delay in ovo-implantation. Both progesterone treatment beginning on day 1 and cortisone acetate treatment beginning on day 1 or 2 caused an increased postimplantation fetal death rate. Compound 83161, at doses causing signs of general toxicity (12 mg/day), caused a marginal inhibition of implantation. Treatment with indomethacin, phenylbutazone, or flufenamic acid caused some inhibition of the traumatic deciduomal response in spayed rats treated with progesterone, while treatment with cortisone acetate and Compound 83161 did not.

PIP: The effects of pharmacologic doses of cortisone acetate and various nonsteroidal antiinflammatory compounds on ovo-implantation, early pregnancy, and the deciduomal response in rats were investigated. The animals received either 10 mg/day cortisone acetate, alone or in combination with 4 mg/day progesterone, 4 mg/day progesterone plus 1 mcg/day estrone, .75 mg/day indomethacin, 20 mg/day phenylbutazone, 10 mg/day flufenamic acid, or 8 or 12 mg/day Compound 83161 (tetrazolo-(1,5)-s-triazolo(3,4-c)quinoxoline) on Days 1 or 2 through 8 of pregnancy. Treatment with progesterone, beginning on Day 1, and with cortisone acetate, beginning on Day 1 or 2, increased the postimplantation fetal death rate, though only cortisone acetate produced a true delay in ovo-implantation. The highest dose of Compound 83161 had a marginal effect on implantation. Spayed rats treated with progesterone plus either indomethacin, phenylbutazone, or flufenamic acid exhibited some inhibition of the traumatic deciduomal response, though this effect was not observed with cortisone acetate and Compound 83161.

The effects of 5-bromo-2-thienyl-ethyl-ketone thiosenicarbazone on ovarian cyclicity and ovulation in the rat.

Pseudopregnant and cyclic rats were injected for 5 to 26 days with daily doses of 5 and/or 3 mg of 5-bromo-2-thienyl-ethyl-ketone thiosemicarbazone (70026) starting on Day 0 (the day of oestrus). The vaginal smear cytology, record of ovulation and ability to breed and conceive were compared with the results for corn oil-injected controls. Both doses of 70026 were found to cause a reappearance of pro-oestrous and/or oestrous vaginal smears within 4 to 6 days in the pseudopregnant rats, but ovulations did not occur. The 5-mg dose of 70026 inhibited ovulation and interrupted the oestrous cycle in cyclic rats, even though the daily 3-mg dose seemed to have little effect on ovulation, ovarian cyclicity, breeding or conception. In spite of the absence of an ovulation accompanying the induced pro-oestrous and/or oestrous vaginal smears in the pseudopregnant rats, the pattern of the vaginal smears suggested the occurrence of a 'delayed pseudopregnancy' in most of the pseudopregnant rats treated daily with 3 mg, but in few of those treated with 5 mg, 70026.