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Biomedical subjects

L J Lerner

Publications and source records attributed to L J Lerner.

At least 19 recordsLinked to original sources
PubMed1990

Development of antiestrogens and their use in breast cancer: eighth Cain memorial award lecture.

This paper describes the laboratory discovery and clinical testing of the first nonsteroidal antiestrogen, MER-25 (ethamoxytriphetol). The compound blocks estrogen action in all species tested and has only slight but transient estrogenic effects. No other antisteroidal actions are noted. MER-25 is antiestrogenic in primates and was investigated in the clinics in a wide range of gynecological conditions, including breast and endometrial cancer. Unfortunately toxic side effects (hallucinations, etc.) precluded further investigation. A derivative of triphenylethylene, clomiphene, has some partial agonist (estrogen-like) actions in laboratory animals and following clinical evaluation is now an established agent for the induction of ovulation in subfertile women. Although clomiphene is active in advanced breast cancer, it was not developed further. In the late 1960s a related compound, tamoxifen, was evaluated to treat a number of estrogen-responsive disorders but was successfully introduced in the 1970s for the treatment of advanced breast cancer. Although there was only modest initial interest in the palliative use of tamoxifen, an enormous increase in basic and applied studies with antiestrogens resulted in a definition of the target site-specific and tumoristatic actions of tamoxifen. Close cooperation between laboratory and clinical evaluation has guided the subsequent development of tamoxifen which is now available to treat all stages of breast cancer. Long-term adjuvant tamoxifen therapy, a concept developed in the laboratory, is currently the treatment strategy of choice. The considerable success of tamoxifen has focused attention on new antiestrogens with different pharmacological properties for other potential clinical applications.

Antineoplastic Agents↗
PubMed1989

Development of novel embryotoxic compounds for interceptive fertility control in the dog.

Studies in pregnant rats, hamsters and guinea-pigs with a series of 2-phenyltriazole isoindoles and isoquinolines and related compounds have demonstrated that these agents are potent abortifacients. These compounds were very effective when administered around the time of implantation and less effective even at higher doses when administered several days before or after implantation. Most of the members of these series of compounds are effective with a single injection although the dosage can be 5 or more times as large as that needed for each of 5 daily injections. The least soluble compounds, L-14105 and L-12717 (Lotrifen), have the longest duration due to slow clearance from the injection site and were the most potent abortifacients. Experiments in beagle and mongrel dogs treated with L-10492, L-10503, L-11204 and Lotrifen during various stages of gestation indicated that all were most efficacious when administered around Day 20 of pregnancy. Lotrifen was the most potent. High abortifacient potency and slow release from the injection depot permitted treatment of bitches during any of the first 15 days after mating with a dosage low enough to reduce unwanted side effects to acceptable levels. Toxic manifestations in all species generally were related to the gastrointestinal tract and consisted of reduced feeding, anorexia and loss in body weight, vomiting by non-rodents, congestion of the intestines and in some animals there was blood loss from this tract. The mechanism of activity has not been defined, but the abortifacient activity is primarily limited to the early post-implantation period.

Abortifacient Agents↗
PubMed1984

Peritoneal fluid and serum steroids in infertility patients.

Peritoneal fluid and serum were collected from 78 patients at the time of laparoscopy. Twenty-two were fertile controls (CTL), and 56 were infertility patients, who were subdivided into three main groups: endometriosis (EMS), pelvic adhesions (ADH), and ovarian dysfunction (OvDF). Based on control group data, biochemical criteria indicative of the presence of a stigma, S(+), were established: (1) serum progesterone (P) greater than or equal to 2 ng/ml, (2) peritoneal fluid P greater than or equal to 50 ng/ml, and (3) peritoneal fluid/serum ratio of P greater than or equal to 3. Direct visualization by laparoscopy showed that 21% CTL, 75% EMS, 69% ADH, and 56% OvDF subjects had luteinized unruptured follicle (LUF) syndrome. Biochemical criteria, however, demonstrated only 7% CTL, 37% EMS, 23% ADH, and 56% OvDF subjects had LUF. Peritoneal fluid estradiol (E2) and P concentrations and total content were significantly lower in LUF than in non-LUF patients, whereas serum E2 and P concentrations were not different between the two groups. Values for testosterone and androstenedione in peritoneal fluid and serum were similar between these two groups. Endometrial dating in LUF versus non-LUF patients were also similar. The usual indicators of ovulation, i.e., serum P, endometrial dating, and basal body temperature, failed to identify LUF. The diagnosis of LUF can be best made by P assay of peritoneal fluid and serum.

Androgens↗
PubMed1982

DL 111, a new non-hormonal antifertility agent: contragestational and kinetic profile in baboons.

It was previously shown that 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4 triazole (DL 111) given parenterally in single or multiple doses during the early stage of embryonal development terminates pregnancy in the mouse, the hamster, the rat, the rabbit and the dog. In the present work, the studies have been extended to the baboon. In this sub-human primate, single and/or multiple intramuscular injections of the compound terminated pregnancy when given between day 34 and 54 of gestation. The effectiveness of DL 111 was greater when earlier in gestation and the optimal mode of treatment appears to be a multiple one. DL 111 appears to act by a direct action on the conceptus, with consequent suppression of the endocrine function of the placenta, progesterone withdrawal and abortion. In all the baboons that aborted, the menstrual cycles resumed within a reasonable length of time and subsequent cycles were regular. All the animals that did not abort have given birth to normal and health term infants. Fertility appears to be unimpaired and the progeny resulting form these pregnancies did not show any abnormalities. No significant drug-related side-effects or alterations in plasma enzymes or haematological parameters were observed. Pharmacokinetic and activity relationships strongly suggest that sustained exposure of the conceptus to the drug action is indispensable for optimizing the pregnancy-terminating effect.

Abortifacient Agents↗
PubMed1982

Pregnancy termination in dogs with novel non-hormonal compounds. Studies of 2-(3-ethoxy-phenyl)-5,6-dihydro-s-triazole [5,1-a] isoquinoline (DL 204-IT).

Pregnancy termination was obtained in both Beagle and mongrel bitches after a single s.c. or i.m. injection of 2-(3-ethoxy-phenyl)-5,6-dihydro-s-triazole[5,1-a]isoquinoline (DL 204-IT) dissolved or suspended in an oily vehicle. The activity of the compound was dependent on the dose and time of pregnancy. The optimal time of treatment was found to be day 20 of gestation, at which time the smallest effective dose was 6.25 ng/kg. Pregnancy arrest normally occurs during the first stage of embryonic development (between day 25 and 30) due to the degeneration and subsequent resorption of the products of fertilization. Pregnancy termination is never accompanied by intrauterine or placental hemorrhage. After pregnancy arrest the animals return to estrus within a normal interval of time; they exhibit normal mating behaviour and their ability to conceive is not impaired. Later, pregnancies can be interrupted again by the same treatment. After subeffective doses normal parturition occurs at the expected time and the pups do not have any external malformations. High doses given every 15 days for more than one year are well tolerated and do not inhabit either the return of estrous cycle or fertility. Studies of the mechanism of action suggest that the primary site of action is the uteroplacental complex.

Abortifacient Agents↗
PubMed1981

Inhibition of superovulation and alteration of ova transportation in hamsters by prostaglandin and DL-204-IT, an anti-fertility agent.

The compound 2(3-ethoxyphenyl)-5, 6-dihydro-s-triazole- [5, 1-2] isoquinoline (DL-204-IT or L-11204) inhibited PMS-induced superovulation and reduced the number of recoverable ova in the oviducts of hamsters. PGE2 non-significantly reduced the number of ova shed but significantly decreased the number of oviductal ova. DL-204-IT was more potent than PGE2 for these effects. Administration of both compounds resulted in a complete block of ovulation. Inhibition of prostaglandin metabolism by DL-204-IT may be the cause for these effects, but no direct evidence is presently available.

Animals↗
PubMed1978

Effects of prostaglandin E2 and DL204 IT, an inhibitor of prostaglandin degradation, on ovulation and ovum transport in the hamster.

The effects of 2(3-ethoxyphenyl)-5,6-dihydro-s-triazole-[5,1-a]isoquinoline (L-11204 or DL 204 IT and PGE2 on ovulation and ova transport were studied. DI 204 IT was administered in doses of 0.2-25 mg/kg s.c. on the day of estrus. A smal reduction in ovulating follicles was observed 96 hours later, but only at the 5 mg/kg dose level. At all dose levels, however, DL 204 IT caused a dose-related reduction in the number of ova in the oviducts. PGE2 at a total dose of 2 mg/animal s.c., administered in 4 divided doses over the second and third day of the cycle did not affect ovulation or ova transport. PGE2 plus DL 204 IT (5 mg/kg), however, completely blocked ovulation in all but one animal. That animal had one ovulated follicle and a single ova was recovered from its oviduct.

Animals↗
PubMed1976

Pregnancy termination in dogs with novel nonhormonal compounds.

Resorption of the products of fertilization was induced in bitches given (subcutaneously) single or multiple doses of the nonhormonal compounds L-10492 and L-10503 during the first half of gestation; also resorption or expulsion of the conceptus was induced when these compounds were given during the latter part of pregnancy. The smallest doses were required at a time immediately after implantation of the fertilized ova in the uterus. Effectiveness and appearance of side effects were dose-dependent. These consisted of decreased appetite, loss of body weight, and diarrhea (feces sometimes containing streaks of blood). Bitches which had aborted returned to estrus within normal intervals of time, exhibited normal mating behavior, and were fertile. They had normal deliveries and lactation, and the pups were normal. The mechanism of action does not involve effects on nidation and the compounds were not luteolytic, but probably involved the uteroplacental complex.

Abortifacient Agents↗
PubMed1976

Synthesis and metabolism of prostaglandins in rat placenta, uterus, and ovary during various stages of pregnancy.

1. In the rat, during days 8 to 21 of pregnancy there exists distinct patterns for prostaglandin synthesis and metabolism in the placenta, uterus, and ovaries. These patterns are different in each of the organs. 2. The ratios between PGF and PGF2alpha synthesized or metabolized changes for each of the reproductive tissues studied. 3. Day 11 of gestation represents a critical period as reflected by a highly elevated synthesis and metabolism of prostaglandins. 4. Uterine prostaglandin synthesis increases progressively during the last trimester of pregnancy being maximal on the day of parturition.

Animals↗
PubMed1975

Influence of day of pregnancy on rat placental, uterine, and ovarian prostaglandin synthesis and metabolism.

Synthesis and metabolism of prostaglandins in reproductive tissues of the gravid rat were studied from the time of post-implantation to just prior to parturition. Rat placental prostaglandin synthesis is low on day 8 of pregnancy, sharply increases on day 11, falls on day 14, and remains at a low level for the remainder of gestation. In the tissue PGE2 synthesis is 6 times greater than that of PGF2alpha on day 11. Prostaglandin metabolism in the placenta was high on day 11, low on days 8 and 14, and elevated on days 16, 18, and 21 of pregnancy. PGE1 metabolism was 8 times greater than that of PGF2alpha. Uterine prostaglandin synthesis was low until day 16, and then increased until the end of pregnancy. PGE2 synthesis was very low in this tissue in comparison to PGF2alpha synthesis. Prostaglandin metabolism in the uterus was relatively low until day 16 and then sharply increased for the remainder of gestation. This increase in metabolism was not directly proportional to uterine growth. PGE1 metabolism was 5 times higher than PGF2alpha metabolism in this organ. Ovarian prostaglandin synthesis was very low in comparison to that of the other reproductive organs. Prostaglandin metabolism in this tissue decreased from day 8 through day 18 of pregnancy. PGE1 metabolism in the ovary was twice that of PGF2alpha. These studies demonstrate patterns for synthesis and metabolism of prostaglandin in each tissue studied which may indicate inter-relationships with the physiological requirements of pregnancy.

Animals↗
PubMed1975

Effect of diftalone and other nonsteroidal anti-inflammatory agents on synthesis of prostaglandins (38560).

Diftalone and its metabolites 7, 14-Dihydroxyphthalzino (2,3-b)phthalazine-5, 12 (7H, 14H)-dione, 7-Hydroxyphthalazino (2, 3-b)phthalzine-5,12 (7H, 14H)=DIONE, AND 12 (1(2H)-oxo-2-phthalazinyl)methylbenzoic acid inhibited prostaglandin synthesis in bovine seminal vesicle microsome preparations. Diftalone was the most active of these compounds but less active than indomethacin although more active than phenylbutazone or asprin. The magnitude of the concentration of arachidonic acid influenced the velocity of the reaction in the synthesis of prostaglandins; the highest concentrations inhibited the rate of reaction. The results of the in vitro inhibition of prostaglandin synthetase studies correlated well with those obtained in the in vivo carrageenan edema inhibition studies in the rat. The relative potencies for Diftalone, indomethacin and phenylbutazone were similar with both experimental procedures.

Animals↗