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D W Hahn

Publications and source records attributed to D W Hahn.

At least 37 records · Page 2Linked to original sources
PubMed1990

Pharmacologic and pharmacokinetic characteristics of norgestimate and its metabolites.

Biotransformation, pharmacologic, and pharmacokinetic studies of norgestimate and its metabolites indicate that 17-deacetyl norgestimate, along with the parent drug, contributes to the biologic response. The postulated metabolic pathway, which is based on the identification of urinary products had indicated that three metabolites of norgestimate, 17-deacetyl norgestimate, 3-keto norgestimate, and levonorgestrel, might participate in the response. The pharmacologic evaluation of these metabolites demonstrates that only 17-deacetyl norgestimate has a pharmacologic profile consistent with that of norgestimate, and significant concentrations of this metabolite have been measured in the serum of women after the administration of norgestimate. These studies indicate that 17-deacetyl norgestimate contributes to the pharmacologic response to norgestimate.

Animals↗
PubMed1990

Progestational and androgenic receptor binding affinities and in vivo activities of norgestimate and other progestins.

The progestational and androgenic in vitro receptor binding affinity and the in vivo activity of norgestimate was compared with that of its metabolites and other progestins. The relative binding affinities (RBAs) of norgestimate and its 17-deacetylated metabolite for rabbit uterine progestin receptors were similar to that of progesterone (P); those of 3-keto norgestimate and levonorgestrel were about five times that of P; those of gestodene and 3-keto desogestrel were about nine times that of P. The RBAs of norgestimate, P, and 3-keto norgestimate for rat prostatic androgen receptors were from 0.003 to 0.025 times that of dihydrotestosterone (DHT); those of 3-keto desogestrel, gestodene, and levonorgestrel were from 0.118 to 0.220 times that of DHT. The order of receptor level selectivity represented by the ratio of androgen:progestin IC50 values (with a greater ratio value reflecting a better selectivity) was norgestimate greater than P = 3-keto norgestimate greater than 17-deacetylated norgestimate greater than 3-keto desogestrel greater than gestodene greater than levonorgestrel. In vivo studies demonstrated similar profiles for norgestimate and its 17-deacetylated metabolite. These latter two steroids were equally potent as progestins in stimulating rabbit endometrium, and compared with the other progestins, both steroids exhibited minimal androgenicity as measured by the stimulation of rat prostate growth. In conclusion, these studies, as well as previous preclinical and clinical studies, provide evidence of the selectivity of norgestimate based on minimal androgenicity, indicating an improvement over other progestins used in oral contraceptives.

Animals↗
PubMed1990

Relative binding affinity of norgestimate and other progestins for human sex hormone-binding globulin.

The relative binding affinity of norgestimate for human sex hormone-binding globulin was compared with that of its metabolites and other progestins by measuring their abilities to displace [3H]testosterone from this carrier protein in vitro. Norgestimate and its 17-deacetylated and 3-keto metabolites did not significantly displace [3H]testosterone from sex hormone-binding globulin at concentrations up to 10,000 nM, whereas gestodene, levonorgestrel, and 3-keto desogestrel displaced [3H]testosterone from sex hormone-binding globulin with IC50 concentrations of 23.1, 53.4, and 91.0 nM, respectively. Since it is believed that a progestin may exert androgenic effects by displacing testosterone from sex hormone-binding globulin, thereby increasing circulating levels of free, active testosterone, these data are consistent with the results of preclinical and clinical studies demonstrating the selective progestational activity of norgestimate.

Binding, Competitive↗
PubMed1989

Profile of an oxytocin antagonist, RWJ 22164 for treatment of preterm labor in laboratory models of uterine contractility.

An oxytocin antagonist, 1-deamino-[D-TYR(Oethyl)2,THR4,ORN8]oxytocin (RWJ 22164; dTVT), has recently been characterized in models of uterine contractility. Studies were undertaken to characterize the action of dTVT further on both oxytocin- and vasopressin-induced increases in uterine contractility both in vitro and in situ models and in a model of preterm labor. In these studies, dTVT was found to be a specific competitive inhibitor of both oxytocin- and vasopressin-induced contractions of both pregnant and nonpregnant guinea pig uterus in vitro. In situ, the intravenous administration of dTVT induced a dose-dependent inhibition of oxytocin- and vasopressin-induced contractions in a guinea pig model which measures uterine activity as changes in uterine perfusion pressure. Further studies demonstrated that the intravenous infusion of dTVT delays ongoing labor.

Animals↗
PubMed1988

Inhibition of pregnancy before and after implantation in rats with monoclonal antibody against progesterone.

A monoclonal antibody against progesterone completely blocked pregnancy when rats were injected intraperitoneally at 0.53 mumol/kg/day on days 1 and 2, or on day 11 of a first pregnancy. The antibody was equally effective when injected again during a second pregnancy. There was no evidence for anti-idiotypic antibody production even when the injection of a heterologous (mouse) antibody was repeated in a second pregnancy.

Animals↗
PubMed1988

Evaluation of the anaphylactoid activity of a new LHRH antagonist.

ORF 23541 [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Pal(3)3,Ser4,Nic-Lys5,D-Nic-Lys 6, Leu7, I-Lys8, Pro9,D-Ala10NH2; "Nal-Lys antagonist"] was identified as a potent LHRH antagonist without significant anaphylactoid activity. It blocked ovulation in proestrus rats when administered subcutaneously with an ED50 of 5.8 micrograms/kg. Much higher doses of ORF 23541 than of other antagonists were required to induce a cutaneous anaphylactoid-like reaction. Intradermal administration of ORF 23541 caused an 8.75 x 8.75 mm wheal response with estimated doses of 10.9 and 13.7 micrograms in rats and guinea pigs, respectively. These doses were at least 10 times greater than that required of other LHRH antagonists for the same response. ORF 23541 also did not alter pulmonary function in guinea pigs or dogs when administered intravenously at doses up to 10 mg. These results indicate that ORF 23541 represents a new generation of LHRH antagonists with an improved safety margin.

Anaphylaxis↗
PubMed1987

Anaphylactoid and anti-ovulatory activities of LHRH antagonists in rats.

Studies were conducted with LHRH antagonists examining the relationship of structure to anaphylactoid-like activity and the relationship of anaphylactoid-like activity to anti-ovulatory activity in rats. Substitution of basic amino acids appeared to enhance the anaphylactoid-like activity of these peptides but other complex structural characteristics may also be involved. Anaphylactoid and anti-ovulatory activities were clearly independent and potent LHRH antagonists with minimal anaphylactoid-like activity were identified.

Amino Acid Sequence↗
PubMed1987

Sensitivity differences in reproductive/endocrine organs to chronically administered LHRH agonists in female rats.

The acute and chronic effects of two LHRH agonists on reproductive endocrine target organs were examined in female rats. Animals were injected twice daily with [(ImBzl)-D-His6,Pro9-NEt]LHRH (histrelin) or [D-Trp6,Pro9-NEt]LHRH for 1, 3, 5, 7, 11 or 28 days at 1, 10, 100 or 1000 micrograms/kg/day beginning in the luteal phase. The responses observed with the two agonists were similar. An initial stimulatory phase was observed on the first day of treatment with substantial increases in serum LH and progesterone levels. A significant diminution of hormone response was seen by day 3. Only 1000 micrograms/kg abolished the pituitary LH response at later treatment periods. Estrous cyclicity, ovarian and uterine weight, and progesterone and estradiol levels were inhibited in a time and dose dependent manner. The results demonstrate target organ sensitivity differences. In contrast to the relatively high doses needed to inhibit the pituitary response and decrease ovarian weight, doses as low as 1 microgram/kg were sufficient to decrease uterine weight. If these findings extrapolate to humans, it may be that conditions in which the desired therapeutic action is suppression of uterine tissue, may be treated with lower doses of LHRH agonists than conditions requiring complete gonadal suppression.

Adrenal Glands↗
PubMed1987

A comparison of the potencies and activities of progestogens used in contraceptives.

The potencies and activities of six progestational agents, norethindrone, levonorgestrel, desogestrel, medroxyprogesterone acetate (MPA), progesterone (P) and norgestimate have been evaluated using standard laboratory bioassays. The endocrine activities measured are those most closely related to the clinically important actions of contraceptives. Relative potencies varied with parameter measured, route of administration and species showing clearly that each progestogen is a distinct pharmacological entity. The order of potency using oral administration for either ovulation inhibition or endometrial stimulation in rabbits was desogestrel greater than levonorgestrel greater than MPA greater than norgestimate greater than norethindrone. Levonorgestrel was more androgenic than desogestrel, and P, norethindrone, norgestimate and MPA were essentially devoid of androgen activity. This profile demonstrates clear differences in the potencies and activities of these progestogens and in their selectivity for target organs.

Androgens↗
PubMed1987

Evaluation of 1-deamino-[D-Tyr(Oethyl)2, Thr4, Orn8] vasotocin, an oxytocin antagonist, in animal models of uterine contractility and preterm labor: a new tocolytic agent.

We attempted to characterize the ability of a new oxytocin derivative, 1-deamino[D-Tyr(Oethyl)2,Thr4,Orn8] vasotocin (ORF 22164), to antagonize the action of oxytocin in several in vitro and in vivo animal models of uterine hyperactivity. In these studies, the derivative was found to be a specific competitive inhibitor of oxytocin-induced contractions of pregnant guinea pig uterus in vitro. In addition, its intravenous administration induced a dose-dependent inhibition of oxytocin-induced uterine contractions in situ. Finally, like ritodrine, the drug induced a dose-dependent delay of ongoing labor in rats. These results suggest that 1-deamino-[D-Tyr(Oethyl)2,Thr4,Orn8] vasotocin, unlike ritodrine, is a potent and specific antagonist of oxytocin-induced uterine contractions and thus may have potential clinical utility in the treatment of preterm labor.

Animals↗
PubMed1987

Characterizing pituitary response to a gonadotropin-releasing hormone (GnRH) antagonist in monkeys: tonic follicle-stimulating hormone/luteinizing hormone secretion versus acute GnRH challenge tests before, during, and after treatment.

Pituitary sensitivity to a gonadotropin-releasing hormone (GnRH) challenge test before, during, and after GnRH antagonist administration was compared in four ovariectomized female monkeys receiving GnRH antagonist intramuscularly (IM) at increasing doses of 0.3, 1.0, and 3.0 mg/kg/day over 9 days. Three days before and 3 days after treatment, monkeys received vehicle alone. On experiment days 4, 7, 10, 13, and 16, 100 micrograms of GnRH was administered intravenously (IV) and blood drawn at 0 and 30 minutes. Before treatment, tonic follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were 248 +/- 105 and 178 +/- 31 ng/ml, respectively; after 0.3 mg/kg/day of GnRH antagonist, FSH and LH decreased to 30 +/- 6 and 41 +/- 4 ng/ml, respectively. After treatment with either 1 mg/kg/day or 3 mg/kg/day of GnRH antagonist, both gonadotropins were undetectable in serum. Monkeys with lower initial levels of gonadotropins were suppressed by 48 hours after GnRH antagonist, while those with higher tonic gonadotropins were suppressed 6 days later (FSH: r = 0.992; LH: r = 0.833). The data show that initial physiologic status is predictive of the rapidity of the suppression response induced by a GnRH antagonist and that, after achieving pituitary suppression, responsivity to an IV GnRH challenge test may be restored before normal tonic FSH/LH secretion is regained.

Animals↗
PubMed1986

Role of adrenal androgens in prostate regression in rats treated with an antiandrogen and an LHRH agonist.

Histrelin, a potent luteinizing hormone releasing hormone (LHRH) agonist, and flutamide, an antiandrogen, were administered to intact and adrenalectomized rats to determine the role of adrenal androgens in the additive effects of the two drugs on prostate regression. Each compound, given separately, was effective in decreasing prostate weights in intact rats. When given together, additive effects were demonstrated by even greater atrophy of the prostates. It has previously been proposed that this additive effect may be primarily attributed to the ability of the antiandrogen to block the action of adrenal androgens. However, in adrenalectomized rats, the combination of histrelin and flutamide still produced a greater reduction in prostate weights than did either drug alone, indicating that the role of adrenal androgens in this effect is negligible. This experiment also was repeated with castrate, androgen-supplemented rats, and the additive effects previously described were not observed. In a final experiment, prostatic atrophy in castrate rats was not enhanced by either adrenalectomy or flutamide treatment. Thus, the additive effects of histrelin and flutamide appear to focus on testicular rather than adrenal androgens.

Adrenal Cortex↗
PubMed1986

Experimental evidence for failure to implant as a mechanism of infertility associated with endometriosis.

The effect of endometriosis on pregnancy, from ovulation through day 14 of pregnancy, was studied in an animal model previously developed and validated with the use of the rabbit. Endometrial tissue was implanted surgically in rabbits and allowed to grow for 11 weeks without hormonal supplementation. The animals were artificially inseminated with semen from bucks with established fertility and human chorionic gonadotropin was administered to induce ovulation. The animals were put to death 1, 4, 8, or 14 days later. The number of corpora lutea and fertilized ova was not affected through day 4. However, on days 8 and 14, a significant reduction in the number of normal fetuses was observed. In a second experiment peritoneal fluid from animals with endometriosis was transferred to normal rabbits 1 day before artificial insemination. A significant reduction in the number of normal fetuses was observed. These studies suggest that failure of nidation due to the maternal environment may be a major factor in infertility associated with endometriosis.

Animals↗
PubMed1986

Multiple actions of a novel vaginal contraceptive compound, ORF 13904.

ORF 13904, a sulfonated polystyrene polymer possessing potent vaginal contraceptive activity, was tested in vitro and in vivo to investigate its mechanism of action. Observations of rabbit spermatozoa when mixed with the compound in buffered saline confirmed that the compound is not spermicidal and showed that the cells rapidly and irreversibly agglutinate. Seminal plasma did not compromise the effects of the drug, but rather enhanced them. When spermatozoa were suspended in solutions containing ORF 13904 and then washed thoroughly to remove excess drug, human spermatozoa could not penetrate bovine cervical mucus in vitro and rabbit spermatozoa could not achieve fertilization after artificial insemination in vivo, suggesting that the drug either adheres to the sperm surface or irreversibly compromises sperm function. Biochemical analysis showed that ORF 13904 is also a potent acrosin inhibitor. These experiments suggest that ORF 13904 has several mechanisms of action, including the ability to agglutinate spermatozoa, alter sperm-cervical mucus interaction, and inhibit sperm acrosin.

Acrosin↗
PubMed1985

Influence of ovarian steroids on prostaglandin- and leukotriene-induced uterine contractions.

The mammalian uterus is capable of metabolizing arachidonic acid via the lipoxygenase pathway, and the uterus responds to lipoxygenase products. We postulated that progesterone influences the production of leukotrienes in the uterus in a way similar to that in which estradiol influences prostaglandin production. Uterine contractions were measured in actively sensitized guinea pigs throughout the estrous cycle and in ovariectomized, hormonally primed, sensitized guinea pigs. Antigen challenge stimulated uterine contractions (caused by prostaglandins) that increased throughout the estrous cycle to a maximum in day 15, when estradiol is at its peak. Pretreatment with indomethacin abolished uterine contractions except on day 9 of the cycle, when progesterone levels are at their highest. Day 9 contractions were blocked by FPL 55712, a selective receptor antagonist of leukotrienes. These findings were confirmed in ovariectomized/sensitized guinea pigs. Our data suggest that endogenous synthesis of leukotrienes in the uterus may be directly related to the rise of progesterone.

Animals↗
PubMed1985

Reproductive/endocrine and anaphylactoid properties of an LHRH-antagonist, ORF 18260 [Ac-DNAL1(2), 4FDPhe2,D-Trp3,D-Arg6]-GnRH.

It has been demonstrated in a variety of experiments that ORF 18260 inhibits (ED100) spontaneous and LHRH-induced ovulation in rats (10 micrograms/kg s.c.; 10 mg/kg i.g.) and hamsters (100 micrograms/kg s.c. and 100 mg/kg i.g.). Inhibition of LHRH induced ovulation appears to be competitive in nature. In normally cycling animals, efficacy varies with time of administration. In the spontaneously ovulating rat, the most effective time is 15.00 hr of proestrus; in the hamster it is 10.00 hr. Continuous administration inhibits ovulation in rats, and ORF 18260 has contragestational activity in rats and hamsters but not in guinea pigs and mice. Prostate growth in rats is inhibited at a dose of 100 micrograms/kg (s.c.). Our studies also suggest that ORF 18260 can also induce cutaneous anaphylactoid-like reactions in rats. When compound is administered intradermally in rats, ORF 18260 causes a dose-related whealing response, noticeable from the 0.01 micrograms/rat dose level.

Administration, Oral↗
PubMed1985

ORF 13904, a new long-acting vaginal contraceptive.

A sulfonated polystyrene polymer, ORF 13904, was discovered in our laboratory to be a highly effective vaginal contraceptive in the rabbit model and to possess a unique mode of action. It was found to be non-spermicidal even at high concentrations, yet it greatly impeded sperm penetration of cervical mucus in vitro. When a gel formulation containing 5% ORF 13904 was administered to rabbits intravaginally, the mean number of fetal implants was reduced dramatically even when coitus was delayed for up to 8 hours or when multiple matings at different time intervals were permitted. The non-spermicidal qualities and extended duration of action of this compound represent major breakthroughs in the development of vaginal contraceptives.

Animals↗