RESUMO
The amphiphilic novenamines described in this report have been shown previously to be specific inhibitors of human immunodeficiency virus type 1 reverse transcriptase-associated ribonuclease, which they inhibit when they are in the micellar state but not when they are monomeric. These compounds also inhibit the bacterial enzyme DNA gyrase, which is essential for DNA replication. Hence, the present studies were initiated to determine whether the molecular species inhibiting the gyrase reaction was the monomeric or the micellar form. For this purpose, the rate of DNA replication was measured in a toluenized Escherichia coli cell system in the presence of increasing concentrations of novenamines. The resulting concentration-response curves proved anomalous, suggesting the involvement of micelles or some other, noncovalently aggregated forms of the inhibitors. The results were analyzed in terms of a variety of kinetic schemes and were found to be most consistent with the model where novenamines inhibit replicative DNA synthesis predominantly as cooperative dimers and, to a lesser extent, as monomers, but not as highly aggregated micelles. Based on this analysis and the knowledge that novobiocin and all novenamine-containing analogs are powerful gyrase inhibitors, we conclude that the target of the cooperative, dimeric inhibition is the gyrase, whereas the monomers of the novenamines inhibit another enzyme species involved in the bacterial DNA replication process.
Assuntos
DNA/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Novobiocina/análogos & derivados , DNA/sangue , Relação Dose-Resposta a Droga , Novobiocina/farmacologiaRESUMO
The steroid specificity of the cell surface progesterone receptor in human sperm was examined with the use of progesterone, testosterone, and androstane analogues. Many compounds were shown to be more effective than progesterone at increasing intracellular free calcium concentration, e.g., 2 alpha-methyl-17beta-methoxy-5 alpha-androstan-3-one. Several testosterone analogues were demonstrated to be antagonists of progesterone, e.g., 9(11)-dehydro-2 alpha,17alpha-dimethyltestosterone. The synthetic potent progestigens, norethynodrel, cyproterone acetate, norethindrone, and megestrol acetate, were found to be only weak stimulators of the sperm cell surface receptor. Furthermore, these compounds were shown to antagonize the effect of progesterone to elevate intracellular free calcium concentration in sperm. It is known that progesterone and some of its analogues bind to the intracellular progesterone nuclear receptor via the alpha-face of the steroid molecule. In stark contrast, it was concluded from the analysis of the steroid analogues examined on human sperm in this study that intimate contact exists between the effective progesterone analogues and the sperm cell surface progesterone receptor across the beta-face of the steroid C/D-ring "upper" edge (C11, C12, and C17). Positioning of the C21 methyl group is also critical for efficacy, and recognition of the steroid A-ring seems not to be involved.
Assuntos
Progesterona/farmacologia , Receptores de Progesterona/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Masculino , Receptores de Progesterona/agonistas , Receptores de Progesterona/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
The synthesis and biological activity of a series of seco-oxysterol analogs designed to be inhibitors of transcription of the gene for 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGR) are described. The compound possessing the most significant activity, [1 alpha (E),4 beta]-3-[2-(4- hydroxy-1-methylcyclohexyl)ethenyl]-alpha,alpha-dimethylbenzenepentan ol (4, U-88156), inhibited (IC50 = 10 microM) the expression of beta-galactosidase (beta-gal) in a transfected human HepG2 cell line wherein the beta-gal gene was driven by a 5 kB segment of the promoter for hamster HMGR. Furthermore, using wild-type HepG2 cells, it was shown that 10 microM 4 reduced HMGR mRNA levels by 73% while stimulating LDL-receptor activity by 47%. In the same system, the related oxysterol, 25-hydroxycholesterol (1), at 10 microM lowered both HMGR mRNA levels and LDL-receptor activity by 58% and 64%, respectively. Overall HMGR activity in wild-type HepG2 cells was inhibited 30% by 4 at 10 microM. These findings collectively demonstrate that a seco-oxysterol analog is capable of regulating HMGR gene expression and that this regulation can occur without a concomitant attenuation of the level of LDL-receptor activity.
Assuntos
Hidroximetilglutaril-CoA Redutases/genética , Esteróis/farmacologia , Transcrição Gênica/efeitos dos fármacos , Animais , Cricetinae , Desenho de Fármacos , Regulação Enzimológica da Expressão Gênica , Humanos , Oxigênio/química , Regiões Promotoras Genéticas , Receptores de LDL/metabolismo , Esteróis/síntese química , Células Tumorais CultivadasRESUMO
25R)-26-Hydroxycholesterol, 25-hydroxycholesterol, and 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one, all extraordinarily potent suppressors of sterol synthesis and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity in mammalian cells, have been studied with respect to their effects on the metabolism of low density lipoproteins (LDL) by human hepatocarcinoma (HepG2) cells. The three oxysterols differed markedly in their effects on LDL metabolism, as measured by the combination of cell-associated plus degraded 125I-LDL. The 26-hydroxysterol, at concentrations from 0.1 microM to 75 microM, lowered LDL metabolism. In contrast, the 25-hydroxysterol and the 15-ketosterol, at concentrations from 0.05 microM to 2.5 microM, caused an increase in LDL metabolism. At higher concentrations of these oxysterols, LDL metabolism was suppressed. However, upon increasing the concentration of the 15-ketosterol further to 75 microM, an extraordinary 9-fold increase in LDL metabolism was observed. In contrast to their effects on LDL metabolism, the 25-hydroxysterol and the 15-ketosterol caused simple concentration-dependent decreases in the levels of HMG-CoA reductase activity under the same conditions.
Assuntos
Colestenonas/farmacologia , Hidroxicolesteróis/farmacologia , Hidroximetilglutaril-CoA Redutases/metabolismo , Lipoproteínas LDL/metabolismo , Carcinoma Hepatocelular , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Cinética , Neoplasias Hepáticas , Estrutura Molecular , Células Tumorais CultivadasRESUMO
Spontaneously hypercholesterolemic (SH) cynomolgus monkeys were identified that have average plasma cholesterol of 202 mg/dl, while that in normal monkeys is 119 mg/dl. The LDL from these SH monkeys have lower affinity for fibroblast LDL receptors in vitro. The amount of LDL2 (1.030 mean value of d 1.063 g/ml) required to displace 50% of [125I]LDL was 3.8 micrograms/ml for normal LDL2 and 6.6 micrograms/ml for SH-LDL2. The binding affinity of LDL1 (1.019 mean value of d 1.030 g/ml) was the same in normal and SH animals. LDL turnover experiments showed that the SH monkeys were comprised of two populations. Normal LDL2 was cleared much slower in two of the SH monkeys than in normocholesterolemic animals, suggesting that these two animals have an LDL receptor defect. However, LDL2 isolated from these two SH monkeys was cleared normally in normal monkeys. LDL2 isolated from two other SH monkeys is cleared slower than is normal LDL2 in normal animals, suggesting that these animals have an LDL defect. Thus, the hypercholesterolemia of these SH monkeys is associated with defective LDL catabolism; two animals appear to have functionally defective LDL receptors, and two animals appear to have functionally defective LDL.
Assuntos
Hipercolesterolemia/veterinária , Lipoproteínas LDL/metabolismo , Macaca fascicularis , Doenças dos Macacos/metabolismo , Receptores de LDL/metabolismo , Animais , Apolipoproteínas B/sangue , Apolipoproteínas E/sangue , Ligação Competitiva , Células Cultivadas , Colesterol/sangue , Fibroblastos/metabolismo , Humanos , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Cinética , Lipoproteínas LDL/sangue , Lipoproteínas LDL/isolamento & purificação , Doenças dos Macacos/genéticaRESUMO
A series of novel lipophilic polyamines was synthesized by the sodium cyanoborohydride-mediated reductive amination of various ketones and aldehydes with the polyamine tris(2-aminoethyl)amine. Two of these compounds, N,N-bis[2-(cyclododecylamino)ethyl]-N'-benzyl-1,2-ethanediamine trihydrochloride (36.3HCl) and N,N-bis[2-(cyclododecylmethylamino)ethyl]-N',N'-dimethyl-1,2-ethan ediamine (23), are 29 and 24 times more potent than colestipol hydrochloride, respectively, for lowering animal serum cholesterol levels.
Assuntos
Anticolesterolemiantes/síntese química , Ácidos e Sais Biliares/metabolismo , Poliaminas/síntese química , Animais , Anticolesterolemiantes/metabolismo , Anticolesterolemiantes/farmacologia , LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Colestipol/farmacologia , Coturnix/sangue , Estrutura Molecular , Poliaminas/metabolismo , Poliaminas/farmacologia , Relação Estrutura-AtividadeRESUMO
Diabetes is associated with altered cholesterol metabolism that may contribute to cardiovascular complications. Treatment of rats with pioglitazone hydrochloride, a novel antidiabetic compound that improves the general response of target cells to insulin, significantly lowered cholesterol levels in rats fed a hypercholesterolemic diet and produced a significant reduction in cholesterol absorption. Drug treatment was ineffective in rats that were not given dietary cholesterol. To determine whether these effects of pioglitazone hydrochloride might be related to the known ability of this compound to improve the response to circulating insulin, similar studies were conducted in streptozocin-induced diabetic rats with and without insulin replacement. Diabetic rats absorbed a greater percentage of dietary cholesterol than control rats. Treatment of insulin-deficient diabetic rats with pioglitazone alone did not affect cholesterol absorption; however, the combination of insulin and pioglitazone was synergistic to lower absorption of cholesterol and circulating cholesterol and triglycerides. Treatment of either normal rats or diabetic rats receiving insulin with pioglitazone hydrochloride produced a twofold decrease in the ratio of total cholesterol to high-density lipoprotein cholesterol. These results suggest that treatments that improve insulin sensitivity may also have a positive impact on coronary artery disease associated with diabetes.
Assuntos
Colesterol na Dieta/metabolismo , Colesterol/metabolismo , Diabetes Mellitus Experimental/metabolismo , Hipoglicemiantes/farmacologia , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/enzimologia , Tiazóis/farmacologia , Tiazolidinedionas , Animais , Colesterol/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Insulina/uso terapêutico , Masculino , Microssomos/enzimologia , NADH Desidrogenase/metabolismo , Pioglitazona , Ratos , Ratos Endogâmicos , Valores de Referência , Esterol O-Aciltransferase/metabolismoRESUMO
A novel series of 6,7-dihydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-5,8-dione inhibitors of the enzyme acyl-CoA:cholesterol O-acyltransferase is described. A number of these derivatives were found to be potent modulators of serum lipoprotein levels in cholesterol-fed rats. Further evaluation of one of the most effective analogues confirmed that it was significantly blocking the absorption of cholesterol from the gut.
Assuntos
Anticolesterolemiantes/síntese química , Pirimidinonas/síntese química , Esterol O-Aciltransferase/antagonistas & inibidores , Animais , Anticolesterolemiantes/farmacologia , Fenômenos Químicos , Química , Colesterol/sangue , Colesterol/metabolismo , Masculino , Pirimidinonas/farmacologia , Ratos , Ratos Endogâmicos , Relação Estrutura-AtividadeRESUMO
Apolipoprotein (apo) B-100, the protein constituent of low density lipoproteins (LDL), is the determinant responsible for LDL binding to the apoB,E(LDL) receptor on cells. The current study was designed to identify the region(s) of apoB-100 that interact with the apoB,E(LDL) receptor. Apolipoprotein B-100 was fragmented by thrombin digestion, and the isolated fragments (T2, T3, T4) were recombined with cholesterol-induced canine high density lipoproteins (HDLc). Before the recombination, the receptor binding activity of apoE of the HDLc was abolished by reductive methylation and extensive trypsin treatment. This treatment permitted almost complete replacement of the small residual apoE fragments by the large apoB fragments. Recombinant apoB particles were isolated by ultracentrifugation and tested for binding to receptors on cultured human fibroblasts. The recombinant particles had chemical and physical properties similar to those of native HDLc. Recombinants of both the whole thrombolytic digest and of isolated fragments displayed specific binding to the apoB,E (LDL) receptor. Anti-apoB,E(LDL) receptor antibodies abolished 90% of the binding, and there was almost no specific binding to receptor-negative fibroblasts or to cells in which the receptors had been down-regulated. The binding of apoB-100 recombinants to the receptor also demonstrated calcium dependency; in addition, the surface binding of the recombinants was released by polyanionic compounds. All these recombinants had binding affinities comparable to one another but less than that of native LDL. Although T2, T3 and T4 recombinants can all bind specifically to the apoB,E(LDL) receptor, it remains to be established whether their activity represents physiologically relevant binding. Nevertheless, the present findings illustrate the potential of the recombinant method using HDLc lipids to reconstitute biological activity.
Assuntos
Apolipoproteínas B/metabolismo , Fibrinólise , Receptores de Superfície Celular/metabolismo , Receptores de Lipoproteínas , Apolipoproteína B-100 , Apolipoproteínas E/metabolismo , Ligação Competitiva , Fibroblastos/metabolismo , Humanos , Hiperlipoproteinemia Tipo II/sangue , Lipoproteínas HDL/metabolismo , Microscopia EletrônicaRESUMO
Transformation of the rabbit uterine progesterone receptor following binding to several synthetic steroids was studied. Cytosolic receptors were prepared with and without 10 mM sodium molybdate. Following incubation with the 3H-ligands the cytosols were chromatographed on phosphocellulose minicolumns. The rank order of the compounds to promote transformation in the absence of molybdate was: medroxyprogesterone acetate (MPA) greater than 17 alpha, 21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione (R5020) greater than progesterone much greater than deoxycorticosterone (DOC) much greater than 20 alpha-hydroxyprogesterone (20 alpha OH-P). The rank order was the same in the presence of molybdate, but the amount of transformation was reduced by 35-90%. Molybdate inhibited transformation to a greater extent when the receptor was bound to progesterone, DOC and 20 alpha OH-P than when bound to MPA or R5020. The antiprogestin, 11 beta-[4-(dimethylamino)phenyl]-17 beta-hydroxy-17-(1-propynyl)-4,9-estradiene-3-one (RU38486, synthesized by The Upjohn Company and designated U-66990), promoted approximately twice as much receptor transformation as did progesterone. MPA, R5020 and U-66990 all dissociated from the progesterone receptor much more slowly than did progesterone. In all cases dissociation was faster in the presence of molybdate than in its absence. These data demonstrate that potent progestins (MPA and R5020) promote a greater amount of receptor transformation than does progesterone, and that steroids with little progestin bioactivity (DOC and 20 alpha OH-P) promote very little transformation. In addition, the antiprogestin activity of U-66990 cannot be attributed to a lack of progesterone receptor transformation nor to a rapid rate of dissociation from the receptor.
Assuntos
Progestinas/farmacologia , Receptores de Progesterona/metabolismo , Animais , Desoxicorticosterona/farmacologia , Estrenos/farmacologia , Feminino , Hidroxiprogesteronas/farmacologia , Medroxiprogesterona/análogos & derivados , Medroxiprogesterona/farmacologia , Acetato de Medroxiprogesterona , Mifepristona , Molibdênio/farmacologia , Progestinas/antagonistas & inibidores , Progestinas/metabolismo , Promegestona/farmacologia , Conformação Proteica , Coelhos , Receptores de Progesterona/efeitos dos fármacosRESUMO
Succinate esters and many other carboxylic acid esters utilized as water-soluble prodrugs have limited utility due to their aqueous solution instability. In an earlier study, a strategy for the design of solution-stable 21-carboxylic acid esters of corticosteroids was developed from a consideration of various physical organic factors which influence ester hydrolysis. Several 21-esters of methylprednisolone were synthesized, and their stability in aqueous solution was monitored to demonstrate the feasibility of the approach. In this study, the bioconversion of representative examples of 21-esters of methylprednisolone exhibiting shelf lives of greater than or equal to 2 years at 25 degrees C was monitored to evaluate their utility as prodrugs in comparison to a commercially marketed sodium succinate ester. Ester hydrolysis studies conducted in human and rhesus monkey serum suggest that derivatives having an anionic solubilizing moiety (sulfonate or carboxylate) are not hydrolyzed in serum, while compounds having a cationic (tertiary amino) solubilizing moiety are hydrolyzed rapidly by serum esterases. In vivo pharmacokinetic studies in rhesus monkeys were also conducted to compare the bioconversion rates and overall bioavailability of several solution-stable prodrugs with the 21-succinate ester. Derivatives having solution stability exceeding 2 years at 25 degrees C with a faster bioconversion rate and an overall bioavailability equal to or higher than that of the succinate ester have been identified. Relative bioavailability appears to be highly sensitive to the charge of the solubilizing pro-moiety and pro-moiety chain length.
Assuntos
Corticosteroides/metabolismo , Hemissuccinato de Metilprednisolona/metabolismo , Metilprednisolona/análogos & derivados , Animais , Disponibilidade Biológica , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Feminino , Meia-Vida , Humanos , Hidrólise , Cinética , Macaca mulatta , Masculino , SolubilidadeRESUMO
The binding affinities of a series of steroidal compounds for the hamster uterine progesterone receptor were determined using two sets of incubation conditions. These competitive binding conditions were designed to deduce the relative rates of ligand dissociation from the progesterone receptor. The progestin activity of these compounds was also determined in a bioassay employing the measurement of diamine oxidase in the traumatized hamster uterus. Steroids could be classified into two categories based on either an increase or decrease in relative binding affinity (RBA) with increasing time of competitive incubation. The mean (+/- SEM) progestin biopotency for the compounds having an increase in RBA was 120 +/- 18 (progesterone = 100), while the biopotency for compounds having a decrease in RBA was only 44 +/- 17. This difference was significant (P less than 0.01). Linear regression analyses revealed significant correlations between the RBAs and progestin biopotencies. Compounds showing a decrease in RBA with increasing time of incubation did not have antiprogestin activity. Kinetic studies of this type should be useful for selecting compounds with potent agonistic activity, but cannot unequivocally predict antihormonal activity.
Assuntos
Progestinas/metabolismo , Receptores de Progesterona/metabolismo , Amina Oxidase (contendo Cobre)/análise , Animais , Ligação Competitiva , Bioensaio , Cricetinae , Feminino , Cinética , Útero/efeitos dos fármacos , Útero/enzimologiaRESUMO
Polymeric controlled-release vaginal delivery systems were designed for (15S)15-methyl prostaglandin (PG)F2 alpha methyl ester (carboprost methyl). The drug was incorporated into a highly permeable reservoir membrane that was bound to a relatively nonpermeable support membrane. The rate of drug release was controlled by coating the reservoir membrane with a less permeable rate-controlling membrane. Vaginal devices were prepared with in vitro steady-state release rates from 5 to 180 microgram/hour. The release curves were characterized by an initial, transient rapid release of the drug, followed by a linear zero-order release phase. Pregnancy was terminated in rhesus monkeys following a 24-hour treatment with vaginal devices having release rates of carboprost methyl of 45 microgram/hour or greater. Successful menses induction was associated with peripheral plasma concentrations of (15S)15-methyl PGF2 alpha between 2000 and 3000 pg/ml. Peripheral plasma concentrations of progesterone declined very rapidly to less than 1.0 ng/ml in monkeys in which pregnancy was terminated. These studies demonstrate the feasibility of manufacturing controlled-release vaginal delivery systems containing carboprost methyl for use in early pregnancy termination.
Assuntos
Aborto Induzido/métodos , Carboprosta/administração & dosagem , Menstruação/efeitos dos fármacos , Prostaglandinas F Sintéticas/administração & dosagem , Aborto Induzido/veterinária , Animais , Carboprosta/sangue , Carboprosta/farmacologia , Preparações de Ação Retardada , Feminino , Cinética , Gravidez , Progesterona/sangue , VaginaRESUMO
Studies were undertaken in the rhesus monkey to determine whether development of a dominant ovarian follicle could be repeatedly arrested by the administration of a progestin on day 7 of the menstrual cycle, and then every 7 days thereafter regardless of menstrual bleeding history. Progesterone (7.5 mg), norethisterone (1.5 mg), and 17 alpha-ethinyl-17 beta-methoxy-7 alpha-methyl-4-estren-3-one (1.0 or 1.5 mg) effectively inhibited ovulation when injected intramuscularly once a week for 8 weeks. Orally administered STS 557 (17 alpha-cyanomethyl-17 beta-hydroxy-4,9-estradien-3-one, 1.0 mg) also inhibited ovulation. Two structurally related steroids (17 beta-methoxy-4-estren-3-one, 1.0 mg; and 17 beta-methoxy-7 alpha-methyl-4-estren-3-one, 1.5 mg) did not inhibit ovulation when given intramuscularly at the indicated doses. Although weekly administration of certain progestins effectively arrested follicular development and inhibited ovulation in the primate, the treatment was accompanied by disturbances in menstrual bleeding patterns.
Assuntos
Fertilidade/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Ovulação/efeitos dos fármacos , Progestinas/administração & dosagem , Animais , Depressão Química , Esquema de Medicação , Estradiol/sangue , Feminino , Injeções Intramusculares , Macaca mulatta , Menstruação/efeitos dos fármacos , Folículo Ovariano/fisiologia , Progesterona/sangueRESUMO
This report outlines the activity of a new thromboxane synthase inhibitor sodium, 5-(3-pyridinylmethyl)-2-benzofurancarboxylate, (U-63557A). U-63557A is a potent inhibitor of the thromboxane synthase in human platelets in vitro, as well as in rhesus monkey platelets ex vivo. A single oral dose of 3.0 mg/kg U-63557A inhibits the platelet thromboxane synthase in rhesus monkeys approximately 80% for at least 12 hrs. U-63557A has been administered to monkeys twice a day, (10 mg/kg) for 14 days, without evidence of drug tachyphylaxis or rebound. U-63557A does not inhibit thrombin-stimulated PGI2 biosynthesis in human endothelial cells, the 5-lipoxygenase in human neutrophils, or the cyclo-oxygenase in a variety of test systems. In anesthetized dogs, U-63557A injected i.v. at 0.1 to 5 mg/kg prevented the blockage of stenosed coronary arteries caused platelet aggregation. Similar effects were obtained by oral administration of 1-5 mg/kg. The thromboxane synthase inhibitor was more efficacious than cyclooxygenase inhibitors and equal to PGI2 in efficacy. Under appropriate conditions the protective effects of U-63557A could be reversed by i.v. cyclooxygenase inhibitors suggesting that its efficacy depended in part on endogenous PGI2 formation. Due to its specificity, oral activity, and extended duration of action, U-63557A is a promising compound for the evaluation of the role of thromboxane synthase in a variety of pathophysiological states.
Assuntos
Benzofuranos/metabolismo , Oxirredutases/antagonistas & inibidores , Tromboxano A2/biossíntese , Tromboxano-A Sintase/antagonistas & inibidores , Tromboxanos/biossíntese , Animais , Ácido Araquidônico , Ácidos Araquidônicos/sangue , Benzofuranos/administração & dosagem , Plaquetas/metabolismo , AMP Cíclico/sangue , Cães , Humanos , Tromboxano B2/biossínteseRESUMO
Most of the primary prostaglandins and several biologically important prostaglandin analogues were converted to 1,9-, 1,11- or 1,15-lactones, in order to investigate the biological profiles of these internal esters and to assess their potential as prodrugs for the corresponding open-chain hydroxy acids. In each case, the key lactonization step was done using Corey's "double activation" procedure (cyclization of omega-hydroxy-2-pyridinethiol esters). In general, the 1,9-lactones exhibited less than 1% of the biological activity of the parent hydroxy acids in the standard prostaglandin test systems. The 1,11- and 1,15-lactones, on the other hand, were essentially equal to the parent hydroxy acids as antifertility agents (a 4-day assay which would allow time for in vivo enzymatic lactone hydrolysis). The 1,11- and 1,15-lactones exhibited very low activity in acute or in vitro screens (e.g., rat blood pressure and gerbil colon stimulation), assays which more closely reflect the intrinsic activity of the lactones themselves. These results are consistent with the observed relative ease of enzymatic hydrolysis of the prostaglandin lactones (1,15 greater than or equal to 1,11 much greater than 1,9). Several of the lactones whose parent hydroxy acids are resistant to metabolic inactivation (e.g., 15-methyl, 16-phenoxy, and 17-phenyl) exhibited potent abortifacient activity in the hamster. These lactones, with greatly diminished activity in the blood pressure and smooth muscle assays (indicators of potential side effects), represent a therapeutically useful class of antifertility agents.
Assuntos
Lactonas/síntese química , Prostaglandinas Sintéticas/síntese química , Animais , Pressão Sanguínea/efeitos dos fármacos , Fenômenos Químicos , Química , Colo/efeitos dos fármacos , Cricetinae , Feminino , Fertilidade/efeitos dos fármacos , Gerbillinae , Macaca mulatta , Masculino , RatosRESUMO
A polymeric controlled release vaginal delivery system was developed for 15(S)15-methyl PGF2 alpha methyl ester. This delivery system is a reservoir-type device consisting of laminated membranes that are mounted on an inert holder. The delivery systems were designed to have in vitro steady-state release rates of 50 or 100 micrograms/hr. Included in the study were seven early pregnant (amenorrhea up to 49 days) patients who were treated with 50 micrograms/hr devices and five early pregnant patients who were treated with 100 micrograms/hr devices. Three second-trimester cases received a 50 micrograms/hr device and five received a 100 micrograms/hr device. Five of the seven early first-trimester patients given 50 micrograms/hr devices aborted completely. The plasma levels of PG in those patients were 400-600 pg/ml for up to 6 hours. In the two cases that did not abort completely, the plasma levels of drug dropped sharply after both patients had started to bleed vaginally one hour after administration of the device. All five early pregnant patients treated with 100 micrograms/hr devices aborted completely. None of the three second-trimester cases aborted within 24 hours following administration of the 50 micrograms/hr devices. Three of the five second-trimester patients aborted within 24 hours following treatment with 100 micrograms/hr devices. The plasma levels of drug reached 1-1.5 ng/ml during the first 2-5 hours and then declined, especially after rupture of the membranes. The variation of plasma levels of drug following vaginal administration of the devices in different individuals was considerably less than following vaginal suppositories. Therefore, this device seems to be close to an ideal delivery system for vaginal administration of abortifacients.
PIP: The vaginal delivery system described is a reservoir type device consisting of laminated membranes that are mounted on an inert holder which are designed to have in vitro steady state release rates of 50 or 100 mcg/hour. 7 early pregnant patients were treated with 50 mcg/hour devices and 5 early pregnant patients with 100 mcg/hour devices, 3 2nd trimester cases received a 50 mcg/hour and 5 a 100 mcg/hour device. 5 early 1st trimester patients given 50 mcg/hour devices aborted completely. The plasma levels of progesterone in those patients were 400-600 ng/ml for up to 6 hours. In 2 cases that did not abort completely plasma levels dropped sharply after they started to bleed vaginally 1 hour after administration of the device. All 5 1st trimester patients with 100 mcg/hour devices aborted completely. None of the 3 2nd trimester cases aborted within 24 hours following administration of the 50 mcg/hour devices. 3 2nd trimester patients aborted within 24 hours following treatment with 100 mcg/hour devices. Plasma levels of drug reached 1-1.5 ng/ml during the 1st 2-5 hours and then declined. This device seems to be close to an ideal delivery system since the variation of plasma levels is less than following vaginal suppositories. The major clinical indication in the future will be menses induction and the ideal release rate should be between 50-100 mcg/hour.
Assuntos
Abortivos não Esteroides , Abortivos , Carboprosta/farmacologia , Dispositivos Anticoncepcionais Femininos , Indutores da Menstruação , Prostaglandinas F Sintéticas/farmacologia , Carboprosta/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Feminino , Humanos , Injeções Intravenosas , Indutores da Menstruação/administração & dosagem , Polímeros , Gravidez , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Supositórios , VaginaRESUMO
Serum progesterone and uterine levels of diamine oxidase (DAO) activity were determined during pregnancy in hamsters. Progesterone was elevated on Day 1 of pregnancy, had a transient peak on Day 5, remained relatively constant on Days 6-10, and then increased on Days 13 and 14. Uterine DAO activity could not be detected until Day 7 of pregnancy approximately 1 1/2 days after the initiation implantation. DAO activity was associated with placental tissue, and more than 90% of the activity was localized in the maternal placenta. The temporal relationship between changes in serum concentrations of progesterone and uterine levels of DAO activity following PG administration also was studied. Serum progesterone was significantly depressed by 6 hr after treatment with PGs on Day 7 of pregnancy. However, uterine levels of DAO activity at 6 hr in the treated animals were not different from those in control animals. In contrast, both the serum progesterone concentrations and uterine levels of DAO activity were significantly lower at 24 hr after PG treatment. The effects of PG treatment on uterine DAO activity were completely blocked by concomitant administration of progesterone. However, concomitant administration of Provera only blocked the effect of one PG analog that was tested (9-deoxo-9-methylene-16,16-dimethyl-PGE2). The data indicate that changes in uterine DAO activity following treatment with the PGs used here are primarily a consequence of a decrease in peripheral progesterone (i.e. a luteolytic effect of the PG).