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Biomedical subjects

D W Hahn

Publications and source records attributed to D W Hahn.

At least 55 records · Page 3Linked to original sources
PubMed1985

The affinity of norgestimate for uterine progestogen receptors and its direct action on the uterus.

Norgestimate is a new orally active progestational agent. Studies were conducted to demonstrate that norgestimate is active pharmacologically without requiring biotransformation to an active metabolite. In in vitro studies, norgestimate exhibited a relatively high affinity for the rabbit uterine progestogen receptor. To demonstrate that norgestimate was not being degraded to a biologically active entity, which was binding to receptor sites in the cytosol preparation, the stability of 14C-norgestimate in the preparation was determined. Following the incubation of 14C-norgestimate with the cytosol fraction used in the receptor assay, the labeled material was extracted and analyzed by reverse phase high performance liquid chromatography. 14C-Norgestimate was recovered from these incubation mixtures, confirming that norgestimate was available to bind to the progestogen receptor. In in vivo studies, norgestimate stimulated the endometrium in immature rabbits when applied directly to the uterus, again suggesting that bio-transformation to an active metabolite is not required for expression of norgestimate's pharmacological activity. These in vitro and in vivo studies, when considered with previously reported studies, show that norgestimate is a unique progestogen.

Animals↗
PubMed1985

Effect of androgens and gonadotropins on progesterone secretion of chicken granulosa cells.

A culture system has been used to study the effect of PMSG in vivo pretreatment and androgens on the in vitro secretion of progesterone from avian granulosa cells. PMSG in vivo pretreated cells secreted greater amounts of progesterone than did cells obtained from untreated hens. Testosterone and 5-alpha-dihydrotestosterone significantly increased basal progesterone secretion in PMSG pretreated cells as well as in granulosa cells harvested from non-treated hens. Testosterone or 5 alpha-dihydrotestosterone in combination with FSH or LH were additive and never resulted in a synergistic stimulation of progesterone secretion.

Animals↗
PubMed1985

Development of an animal model for quantitatively evaluating effects of drugs on endometriosis.

The present study was conducted to induce endometriosis in an experimental animal model in which the condition and its response to pharmacologic agents could be quantified. Endometriosis was induced in New Zealand White rabbits by transplanting endometrial sections into various sites throughout the peritoneum. After 7 weeks, the mean implant weight increased in concomitant controls from 10.3 to 89.0 mg. In the next 8 weeks, endometrial implant weight increased to 163.6 mg. Daily subcutaneous administration of a luteinizing hormone-releasing hormone agonist, histrelin, or oral administration of danazol, reduced the ectopic implant weight within 8 weeks to 21.7 and 46.0 mg, respectively. In a group of animals that were bilaterally ovariectomized, implant weight decreased significantly in the same 8-week period to 22.4 mg. Furthermore, histologic analysis of the endometriomas showed that ovariectomy, histrelin, or danazol treatment reduced the number of endometrial glands and atrophied the stroma. We conclude that this animal model represents an excellent method for quantitative evaluation of potential therapeutic agents for endometriosis.

Animals↗
PubMed1985

In vitro and in vivo comparisons of antiandrogenic potencies of two histamine H2-receptor antagonists, cimetidine and etintidine--HCl.

The antiandrogenic potency of cimetidine was compared to that of a new histamine H2-receptor antagonist, etintidine-HCl (ORF 16753-02). Although both compounds displaced [3H]dihydrotestosterone from androgen receptors in vitro and inhibited androgen-stimulated growth of the accessory sex organs of male rats in vivo, etintidine-HCl was significantly less antiandrogenic than cimetidine in the analysis of androgen receptor binding and in the inhibition of seminal vesicle weights. Because etintidine-HCl has been shown previously to have more potent gastric antisecretory activity than cimetidine, its lower antiandrogenic activity suggests that etintidine-HCl has a much wider therapeutic ratio and that its use clinically will result in fewer antiandrogenic side effects.

Androgen Antagonists↗
PubMed1984

Evaluation of drugs for arrest of premature labor in a new animal model.

Reported are pharmacologic data from a new animal model used for evaluating drugs from several therapeutic classes for their potential use in the treatment of premature labor. This model measures the spontaneous delivery time between the first and second rat pups in a term pregnancy. In control animals, this averaged 16.3 +/- 4.2 minutes. Ethanol (3.5 gm/kg) and the beta-agonists ritodrine (12.5 mg/kg) and albuterol (0.25 mg/kg) significantly delayed delivery of the second pup. The calcium blockers nifedipine, verapamil, and diltiazem were the most active of all compounds tested in this model. The nonsteroidal anti-inflammatory agents indomethacin and naproxen were inactive at doses as high as 5 and 25 mg/kg, respectively. Metiamide, an H2-antagonist, and dimenhydrinate, an H1-antagonist, were inactive.

Albuterol↗
PubMed1984

Smooth muscle contraction as a model to study the mediator role of endogenous lipoxygenase products of arachidonic acid.

In the lung, the contraction of smooth muscle, or bronchospasm, is generally caused by an immunologic insult resulting in mast cell degranulation and the release of histamine, slow reacting substances, and other mediators of inflammation (1). Although the immediate response is bronchospasm, continued activation of this sequence of events results in a chronic inflammatory disease. In the uterus, numerous conditions can result in smooth muscle contraction. One major pathophysiological syndrome associated with increased uterine tone and severe rhythmic contraction is primary dysmenorrhea (2). In this disease state, prostaglandins have been shown to play a major role in these contractions (3,4), and inhibitors of cyclooxygenase have proven beneficial in clinical practice (5). Both dysmenorrhea and cervical ripening have been likened to inflammatory reactions due to varying degrees of vasodilation, invasion by inflammatory cells, proliferation of fibroblasts and smooth muscle contraction (6,7). Metabolism of arachidonic acid (AA) via cyclooxygenase to prostaglandins and thromboxanes and via lipoxygenase to hydroxyeicosatetraenoic acids (HETEs) and leukotrienes is an integral part of both the acute and chronic inflammatory reaction in the lung or uterus. The material reviewed here examines the effect of endogenous leukotrienes on both the lung and uterus and suggests that other smooth muscles and pathophysiological states may be more involved with the lipoxygenase pathway of AA metabolism than previously believed.

Animals↗
PubMed1984

Antifertility activity and general pharmacological properties of ORF 13811: a synthetic analog of zoapatanol.

ORF 13811, a synthetic analog of zoapatanol, was evaluated in a variety of in vivo and in vitro biological test systems to determine antifertility and uterotonic activity as well as its general pharmacological profile. ORF 13811 is a potent antifertility agent after oral administration in a number of animal species including mice, rats, guinea pigs, dogs and baboons. The single oral ED50 for contragestational activity in the pregnant guinea pig (day 22), mouse (day 16) and rat (day 16) is in the range of 6 to 10 mg/kg. In pregnant beagle dogs, a dose-related contragestational effect was obtained within several days after oral administration of ORF 13811 in the dosage range of 10 to 30 mg/kg. ORF 13811, when administered to pregnant baboons, caused dose-related vaginal bleeding and evacuation of uterine contents within 3 days following treatment with oral doses of 40 to 60 mg/kg. Serum progesterone levels were decreased in baboons and the degree of reduction correlated with contragestational activity. ORF 13811 was also effective in inhibiting implantation in mice, rats and hamsters, but required higher dose levels than those of the post-implantive treatments. In vitro uterotonic properties of ORF 13811 were demonstrated by its ability to induce contraction of uterine strips obtained from female guinea pigs at two different reproductive stages (day 15 of the estrous cycle and day 22 of pregnancy). In these preparations ORF 13811 was approximately 1/30 to 1/50th as potent as PGF2 alpha. In a series of pharmacological tests, ORF 13811 was found to possess slight sedative properties but was devoid of activity on pulmonary, gastrointestinal, and immune systems as well as in a number of biochemical tests, data not reported here. However, in cardiovascular studies, ORF 13811 appears to possess a vasoconstrictor profile in the dog, monkey and baboon as indicated by an increase in mean arterial blood pressure as well as total peripheral and regional vascular resistances. The in vitro pharmacological profile of ORF 13811 was examined in myocardial tissue and vascular smooth muscle test systems and compared to PGF2 alpha. ORF 13811 was found to contract rat aortic strips, 15 times less potent than PGF2 alpha. The compound had no direct effect on isolated guinea pig atria or papillary muscle. In summary, ORF 13811 is a potent orally active antifertility agent characterized primarily as a contractor of uterine and vascular smooth muscle.

Animals↗
PubMed1984

Comparative effect of estriol and equine conjugated estrogens on the uterus and the vagina.

Estriol has been reported to act selectively on the vagina and cervix without causing endometrial proliferations. Studies comparing this effect of estriol to that of equine conjugated estrogens after intravaginal administration have not been reported. In this study, intravaginally administered Ortho- Gynest which contains estriol, and Premarin which contains equine conjugated estrogens, were evaluated for their ability to stimulate vaginal maturation and uterine growth in rats. Approximately 15 times more conjugated estrogens than estriol was needed to induce the same degree of vaginal cornification in castrated rats. In contrast, estriol was less potent than the conjugated estrogens in causing uterine growth in immature rats after subcutaneous administration in sesame oil and in mature rats after intravaginal administration in cream preparations. In studies evaluating the vaginal irritation potential of estriol vaginal cream, the irritation exhibited by treated rabbits was found to be comparable to that of sham-treated control rabbits. Estriol was well-tolerated in an oral acute safety study in rats.

Administration, Topical↗
PubMed1984

Potency and activity variation of LHRH analogs in different models and species.

The LHRH agonist [D-His(Bzl)6, Pro9-NHEt]LHRH was estimated to be 3.4, 4.4 and 9.2 times more potent than LHRH as a stimulator of ovulation in Nembutal-anesthetized, androgen-sterilized and diestrus rats, respectively; and 57 times more potent than LHRH as a stimulator of uterine growth in immature mice. Higher doses of agonist were required to induce ovulation in diestrus hamsters and mice than were needed in diestrus rats. Rats and hamsters also exhibited different sensitivities to an antagonist of LHRH. The LHRH antagonist [N-Ac delta 3-Pro1, D-pF-Phe2,D-Trp3,6]LHRH was active but higher doses were required to inhibit ovulation in hamsters than were needed in rats. In addition, treatment at 1500 hr on the day of proestrus in rats, in contrast to treatment at 1000 hr in hamsters, caused the greatest inhibition of ovulation. It is clear from these data, that the estimated in vivo potencies of analogs of LHRH are greatly influenced by species and animal model, as well as route of administration and biopharmaceutic factors previously reported.

Animals↗
PubMed1983

Involvement of lipoxygenase products in myometrial contractions.

Studies with an in situ preparation of guinea pig uterus suggest the possible involvement of the lipoxygenase pathway of arachidonic acid (AA) metabolism in myometrial contractions. Female guinea pigs were sensitized to ovalbumin (OA) on day one of their estrous cycle. On day 14, these pigs were anesthetized and the uterus was cannulated for measuring contractions. OA challenge, with histamine antagonism (methapyrilene) resulted in uterine contractions which significantly raised myometrial tonus, presumably due to AA metabolites. Pretreatment with high doses of indomethacin resulted in only 60% inhibition of the OA induced contraction, suggesting the remaining contraction was due to something other than cyclooxygenase products. In the presence of indomethacin and methapyrilene, the addition of AA to increase available substrate caused increased myometrial tone following antigen challenge. This increase in uterine tone was inhibited in a dose dependent fashion by FPL-55712 demonstrating that leukotrienes can contract the uterus and that antigen challenge may provide a means for studying leukotriene involvement in uterine pathophysiology.

Animals↗
PubMed1983

Scanning electron microscopy of human spermatozoa after incubation with the spermicide nonoxynol-9.

The most frequently utilized spermicide in vaginal contraceptives is No-9. Schill and Wolff used TEM to demonstrate the focal effects of No-9 on human sperm and reported that No-9 damaged cell membranes and acrosomal membrane complexes. The present study by SEM was made to assess the extent of membrane damage due to the direct action of No-9 during an incubation period of only 5 minutes. SEM revealed that No-9 caused loosening and detachment of acrosomal, neck, and midpiece membranes of all sperm even at the lowest concentration tested (0.05%). The severity of membrane alterations observed in any of these regions would render sperm immotile and unable to penetrate the ovum. The fact that these alterations are produced within 5 minutes after exposure to No-9 attests to the effectiveness of No-9 as a vaginal contraceptive.

Adult↗
PubMed1982

The effect of porcine follicular fluid on ovulation, mating and pregnancy in the rat.

We have examined the effects of charcoal-treated, greater than 10,000 MW porcine follicular fluid (PFF retentate) treatment on ovulation, cyclicity, mating and pregnancy in the rat. Rats treated i.p. with PFF retentate twice on the day of metestrus and once on the day of diestrus exhibited a dose-related reduction in the mean number of ova when oviducts were checked on the afternoon of expected estrus. However, oviducts checked on the morning of expected metestrus contained a normal number of ova. To study the effects of PFF retentate on cyclicity, mating and subsequent pregnancy, rats were treated (0.2 ml, i.p.) two, three or four times a day beginning on the day of metestrus until proestrus cytology was exhibited. PFF retentate treatment resulted in a dose-related delay in the appearance of proestrus cytology and a reduction in the number of embryonic implants following cohabitation with males on the night of proestrus. However, PFF retentate had no effect on the number of implants, when given post-coitally. These results show that administration of PFF retentate to female rats delays ovulation, alters the estrous cycle and reduces the mean number of embryonic implants in a dose-related manner.

Animals↗
PubMed1982

Effects of suprofen and other prostaglandin synthetase inhibitors in a new animal model for myometrial hyperactivity.

An in situ model for studying factors related to dysmenorrhea and for evaluating drugs for their inhibitory effects on uterine contractility induced by arachidonic acid and prostaglandins has been developed. Intravenous administration of arachidonic acid and PGF2 alpha to guinea pigs during the late stage of the estrous cycle, induced dose related uterine contractions and an elevation in uterine basal pressure similar to that seen in patients with dysmenorrhea. Pretreatment with prostaglandin synthetase inhibitors inhibited the response to arachidonic acid. The order of relative potency was suprofen (1) greater than indomethacin (0.65) greater than naproxen (0.52) greater than ibuprofen (0.43) greater than aspirin (0.31). The effectiveness or maximal response for suprofen was significantly greater than that of the other compounds tested. Simultaneous administration of suprofen with PGF2 alpha also blocked induction of uterine contractions, suggesting the possibility that suprofen also antagonizes PGF2 alpha receptor binding. Bradykinin also induced uterine contractions, an effect blocked by pretreatment with suprofen. Finally, histochemical studies demonstrated stimulation of uterine catecholamine levels (norepinephrine) by arachidonic acid, PGF2 alpha and bradykinin. These effects were blocked by suprofen. These data suggest that suprofen, an analgesic prostaglandin synthetase inhibitor, may be of use in the clinical treatment of uterine contractions associated with primary dysmenorrhea.

Animals↗
PubMed1981

Antifertility and endocrine activities of gossypol in rodents.

Reversible male antifertility activity was obtained with orally administered gossypol acetic acid in rats at 20 mg/kg/day and in hamsters at 10 mg/kg/day but not in mice at dosages up to 40 mg/kg/day. An increased number of degenerating spermatocytes was found in the testicular tubular lumens of rats. Pigment-laden cells containing an intracytoplasmic lipofuscin-like material were noted in the testis and epididymal interstitium in rats and mice. Gossypol was also tested in the female for effects on ovulation and pregnancy. Gossypol did not inhibit ovulation in the rat at dosages up to 80 mg/kg/day but did cause 90% inhibition of pregnancy in mice treated with 80 mg/kg/day during the first two weeks of pregnancy. In several standard endocrine bioassays, gossypol did not demonstrate estrogenic, antiestrogenic, androgenic or antiandrogenic activities, but it did potentiate the androgenicity of methyltestosterone.

Animals↗
PubMed1981

Antifertility activity of Montanoa tomentosa (Zoapatle).

According to folklore medicine, the Mexican plant zoapatle (Montanoa tomentosa) possesses antifertility activity in women. We report here the effect of various isolated preparations from this plant on early pregnancy in several rodent species including the mouse, rat, hamster, and guinea pig. When an aqueous extract of the leaves similar to the tea utilized in folklore medicine was administered orally during early stages of pregnancy, no antifertility activity could be detected. Day 22 pregnant guinea pigs, however, provided an animal model which allowed conservation of test materials and which showed the antifertilty activity of the plant extracts. Purer fractions derived from the plant were more potent in this assay system when administered either intraperitoneally or orally. As the purity of the extracts (and hence the quantity of active ingredient administered) increased, we were able to demonstrate inhibition of implantation in rats and mice when administered on days 1-6 and in hamsters when administered on days 4-6 of gestation. Preliminary data indicate the plant extracts are not estrogenic. It is concluded that zoapatle plant extracts possess unique antifertility activity.

Animals↗
PubMed1981

Postcoital, Vaginal, spermicidal potency of formulations: the Macaca arctoides (stumptailed macaque) as animal model.

The Macaca arctoides (stumptailed macaque) was found to be a good animal model for determining the postcoital spermicidal activity of vaginal preparations. The stumptailed macaque is easy to handle, so formulations can be inserted correctly into the vagina just before coitus. The male mates rapidly, and the entire test can be completed within 5 to 10 minutes, minimizing all extraneous factors other than those inherent to the reproductive tract and the coital act. Data from postcoital breeding experiments were found to be reliable and consistent when results of six primate mating tests for a single dose level of a test formulation were averaged. Dose-response curves can be prepared from these average results, and the relative in vivo effectiveness of the spermicides can be determined. The Sander-Cramer test proved to be a good assay with which to quantitate the in vitro spermicidal potency of formulations. The spermicidal preparations tested immobilized human and primate spermatozoa in vitro to the same extent with the exception of one formulation (possibly due to the vehicle in which the active ingredient was incorporated). The relative spermicidal effectiveness of preparations differs with in vitro and postcoital testing. Because the latter is a more realistic indicator of the contraceptive potency of a formulation, it is recommended that postcoital primate experiments be performed with newly developed vaginal spermicides before extensive animal breeding experiments clinical trials are initiated.

Animals↗
PubMed1981

The importance of biopharmaceutic considerations in biological assays of LHRH and its analogs.

The choice of vehicle, route of administration and actual biological end-point utilized to measure the potency of LHRH analogs can have marked effects on the results of such studies. The activities of LHRH and an analog (D-TRP6,Pro9-NEt-LHRH) suspended in two vehicles were evaluated in two different biological tests including induction of ovulation in androgen sterilized rats and stimulation of uterine growth in immature mice. Our data clearly demonstrate that variables inherent in bioassays used to study LHRH analogs must be controlled if valid conclusions are to be made regarding the relative pharmacological activity and potency of these peptides.

Androgens↗