RESUMEN
This investigation describes the synthesis of a biodegradable hydrogel composed of a core surrounded by four concentric sheaths containing dextran, copolymers of polylactide and epsilon-caprolactone. The hydrogel was impregnated with iron (II) d-gluconate dihydrate, which causes complete spermiostasis due to lipid peroxidation, ascorbic acid to increase the viscosity of the cervical mucus and mixtures of polyamino and polycarboxylic acids to sustain vaginal pH close to 4.5. The combined effects of the agents in the daily eluates of the hydrogel were efficacious up to 16 days, within 30 s, as shown by sperm penetration tests. For in vivo studies, rabbits were chosen as the experimental model because they are easy to handle and the female is always in estrus. The anterior vagina of estrous female rabbits was instilled with the hydrogel, and then inseminated with the semen from a fertile male. Postinsemination flush from the female rabbits showed that all of the sperm were dead. These observations demonstrate the potential for the development of a biocompatible, nonhormonal, intravaginal contraceptive device.
Asunto(s)
Ácido Ascórbico/farmacología , Moco del Cuello Uterino/efectos de los fármacos , Anticonceptivos Femeninos/farmacología , Compuestos Ferrosos/farmacología , Hidrogeles/química , Motilidad Espermática/efectos de los fármacos , Administración Intravaginal , Mezclas Anfólitas/química , Animales , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/química , Anticonceptivos Femeninos/administración & dosificación , Dextranos/química , Femenino , Compuestos Ferrosos/administración & dosificación , Compuestos Ferrosos/química , Humanos , Concentración de Iones de Hidrógeno , Masculino , Poliésteres/química , Conejos , Interacciones Espermatozoide-Óvulo/efectos de los fármacosRESUMEN
Adult female dogs were immunized with 0.5 mg bovine luteinizing hormone receptor (LH-R) encapsulated in a silastic subdermal implant and subsequently with four intramuscular booster injections of 0.1 mg LH-R each. Circulating LH-R antibody was detected in the sera 3 weeks post-implant. The appearance of LH-R antibody was associated with a decline in the serum progesterone concentrations to a range of 0-0.5 ng/ml until day 365 in the immunized dogs in comparison with a range of 5-10 ng in the control animals, suggesting a lack of ovulation and corpus luteum function in immunized dogs. The immunized dogs did not show signs of 'standing heat' and failed to ovulate when induced by LH-RH challenge. Serum oestradiol levels, however, remained in the range of 30-40 pg/ml in both the immunized and the control dogs. With the decline in the antibody titres, the hormonal profile and vaginal cytology returned to a fertile state and the dogs exhibited signs of 'standing heat', as well as vaginal bleeding. Dogs immunized with LH-R did not show any serious metabolic, local or systemic adverse effects. The hypothalamic--pituitary gonadal axis remained intact as indicated by little difference in pituitary LH levels between control and immunized animals, and by the release of LH by LH-RH challenge. These studies demonstrate that active immunization of female dogs with LH-R could immunomodulate ovarian function to cause a reversible state of infertility. It may be postulated that, due to extensive interspecies homology, a recombinant LH receptor-based immunocontraceptive vaccine may also be effective in other vertebrates.
Asunto(s)
Perros/fisiología , Ovario/fisiología , Ovulación/inmunología , Progesterona/sangre , Receptores de HL/inmunología , Adyuvantes Inmunológicos , Animales , Anticuerpos/sangre , Cuerpo Lúteo/inmunología , Perros/sangre , Perros/inmunología , Implantes de Medicamentos , Estradiol/sangre , Femenino , Hormona Liberadora de Gonadotropina , Inmunización/veterinaria , Inyecciones Intramusculares/veterinaria , Hormona Luteinizante/sangre , Ovario/inmunología , Ovulación/fisiología , Receptores de HL/administración & dosificaciónRESUMEN
CONTEXT: Noninvasive magnetotherapeutic approaches to bone healing have been successful in past clinical studies. OBJECTIVE: To determine the effectiveness of low-amplitude, extremely low frequency magnetic fields on patients with knee pain due to osteoarthritis. DESIGN: Placebo-controlled, randomized, double-blind clinical study. SETTING: 4 outpatient clinics. PARTICIPANTS: 176 patients were randomly assigned to 1 of 2 groups, the placebo group (magnet off) or the active group (magnet on). INTERVENTION: 6-minute exposure to each magnetic field signal using 8 exposure sessions for each treatment session, the number of treatment sessions totaling 8 during a 2-week period, yielded patients being exposed to uniform magnetic fields for 48 minutes per treatment session 8 times in 2 weeks. The magnetic fields used in this study were generated by a Jacobson Resonator, which consists of two 18-inch diameter (46-cm diameter) coils connected in series, in turn connected to a function generator via an attenuator to obtain the specific amplitude and frequency. The range of magnetic field amplitudes used was from 2.74 x 10(-7) to 3.4 x 10(-8) G, with corresponding frequencies of 7.7 to 0.976 Hz. OUTCOME MEASURES: Each subject rated his or her pain level from 1 (minimal) to 10 (maximal) before and after each treatment and 2 weeks after treatment. Subjects also recorded their pain intensity in a diary while outside the treatment environment for 2 weeks after the last treatment session (session 8) twice daily: upon awakening (within 15 minutes) and upon retiring (just before going to bed at night). RESULTS: Reduction in pain after a treatment session was significantly (P < .001) greater in the magnet-on group (46%) compared to the magnet-off group (8%). CONCLUSION: Low-amplitude, extremely low frequency magnetic fields are safe and effective for treating patients with chronic knee pain due to osteoarthritis.
Asunto(s)
Campos Electromagnéticos , Magnetismo/uso terapéutico , Osteoartritis de la Rodilla/terapia , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Osteoartritis de la Rodilla/complicaciones , Osteoartritis de la Rodilla/fisiopatología , Dolor/etiología , Dolor/fisiopatología , Manejo del Dolor , Dimensión del Dolor/métodos , Dimensión del Dolor/estadística & datos numéricosRESUMEN
We describe a patient with onset of puberty at the age of 5 yr. characterized by accelerated growth, enlargement of genitalia, pubarche, and serum hormone levels compatible with noncentral precocious puberty. Exon 11 of the LH receptor gene was amplified from genomic DNA by PCR and directly sequenced. We identified a heterozygous C to T base change at nucleotide position 1126, exchanging codon 373 from Ala to Val in the first transmembrane domain. The LH receptor sequence of the parents was normal. The mutated receptor displayed an up to 7.5-fold increase in basal cAMP production compared to that of the wild-type receptor in transiently transfected COS-7 cells. Treatment of the patient with ketoconazole resulted in inconsistent suppression of serum testosterone levels. At the age of 9.1 yr, central activation of the hypothalamic-pituitary-gonadal axis occurred. Additional treatment with a GnRH agonist led to complete suppression of testosterone secretion. This is the first description of constitutive activation of the LH receptor in the first transmembrane segment. It suggests the involvement of the first transmembrane helix in signal transduction and provides further insight into the structural organization of the seven transmembrane domains of the glycoprotein hormone receptor proteins.
Asunto(s)
Mutación , Pubertad Precoz/genética , Receptores de HL/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Células COS , Niño , Gonadotropina Coriónica/farmacología , AMP Cíclico/biosíntesis , ADN/análisis , Exones , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Pubertad Precoz/tratamiento farmacológico , Receptores de HL/química , Receptores de HL/metabolismo , Análisis de Secuencia , Homología de Secuencia , Transfección , Pamoato de Triptorelina/uso terapéuticoRESUMEN
Safety, contraceptive efficacy, and acceptability of norethindrone, encapsulated in biodegradable poly-dl-lactide-co-glycolide injectable microspheres (NET-90), was evaluated for 12 months in one hundred women. Fifty-one volunteers received 65 mg, and 49 received 100 mg of NET-90, at three month intervals, intramuscularly in the gluteal region. The mean NET levels at 3-month intervals for the 65 and 100 mg groups were, respectively, 0.32 +/- 0.16 ng/ml and 0.49 +/- 0.25 ng/ml. No local or systemic side-effects were observed in either group. Body weight, blood pressure, and laboratory parameters, namely hemoglobin, hematocrit, lipid profile, sequential multichannel autoanalyzer computer profiles (SMAC), as well as PAP smear, remained within normal limits throughout the study in both groups. There was no pregnancy in the 65 mg group; however, one volunteer became pregnant in the 100 mg group. In the 65 mg group, 52.9% of menstrual cycles were normal, 34.5% were amenorrheic, and 12.6% showed prolonged bleeding. In the 100 mg group, 40.6% of the cycles were normal, 52.3% were amenorrheic, and 7.1% had episodes of prolonged bleeding. A total of 40.3% and 36.6% of the cycles showed increased spotting in the 65 and 100 mg group, respectively. Our observations indicate that NET-90 microsphere injectables can provide a safe, efficacious, and acceptable method of contraception.
Asunto(s)
Anticonceptivos Femeninos/farmacología , Sistemas de Liberación de Medicamentos/normas , Noretindrona/farmacología , Congéneres de la Progesterona/farmacología , Adulto , Cápsulas , Femenino , Humanos , Inyecciones Intravenosas , Estudios Longitudinales , Trastornos de la Menstruación/inducido químicamente , Embarazo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Safety, contraceptive efficacy and biodegradability of subdermal norethindrone (NET)-cholesterol implants (Anuelle) were investigated in 19 healthy, sexually active women. Mean serum NET levels in women with four and five pellets, containing 174 mg and 266.5 mg NET, showed a "burst-effect" of 3.17 and 3.71 ng/ml, respectively, within 24 h post implantation. Subsequently, for the four- and five-pellet groups, respectively, the levels declined from 0.75 to 0.40 ng/ml and 1.05 to 0.61 ng/ml during the months 12-15, from 0.40 to 0.11 ng/ml and 0.61 to 0.25 ng/ml up to month 36. The serum NET levels were undetectable at 36 months and beyond, indicating complete biodegradability of NET pellets. Serum E2 levels remained within normal limits (> 50 pg/ml), whereas serum P indicated anovulatory cycles in 78% of the four-pellet group and 99% of the five-pellet group. FSH and LH levels were subnormal and acyclic. Plasma lipids showed reduced total and LDL cholesterol and triglycerides. HDL cholesterol remained unchanged. Drug-related adverse effects were essentially limited to irregular bleeding. There were no pregnancies in either group.
PIP: The results of a clinical study of 15 women suggest that Anuelle norethindrone (NET) biodegradable subdermal implants provide a promising alternative to both the pill and non-biodegradable implants. Study subjects were randomly assigned to receive either four pellets (174 mg NET) or five pellets (266.5 mg NET). An initial burst effect in 24-hour postimplantation serum NET levels was observed in both groups (to 3.17 +or- 0.39 ng/ml in the four-pellet group and to 3.71 +or- 0.37 ng/ml in the five-pellet group), followed by a decline, then sustained levels, and finally undetectability at 36-38 months. Menstrual cycles were normal in 65% of women in the four-pellet group and 47% of those in the five-pellet group; no subject dropped out due to abnormal vaginal bleeding patterns. The incidence of ovulation was 22% in the four-pellet group and 1% in the five-pellet group; no pregnancies occurred in either group in 24 months of observation. Plasma lipids showed reduced total and low density lipoprotein cholesterol and triglycerides. No major adverse local or systemic side effects were noted. Acceptability was good in terms of cosmetics, convenience of implantation, biodegradability, and ease of removal (if required) and most study participants expressed the desire to use NET implants as their contraceptive method of choice.
Asunto(s)
Noretindrona/sangre , Congéneres de la Progesterona/sangre , Adolescente , Adulto , Biodegradación Ambiental , Implantes de Medicamentos , Femenino , Hormonas Esteroides Gonadales/sangre , Hormonas Esteroides Gonadales/metabolismo , Gonadotropinas Hipofisarias/sangre , Gonadotropinas Hipofisarias/metabolismo , Humanos , Lipoproteínas/sangre , Lipoproteínas/metabolismo , Menstruación/efectos de los fármacos , Noretindrona/administración & dosificación , Noretindrona/efectos adversos , Aceptación de la Atención de Salud , Congéneres de la Progesterona/efectos adversos , Congéneres de la Progesterona/metabolismoRESUMEN
OBJECTIVE: To evaluate the contraceptive efficacy, pharmacokinetics, and safety of two formulations of Annuelle (Endocon, Inc., South Walpole, MA) biodegradable norethindrone (NET) SC pellet implants. DESIGN: Prospective observational study. SETTING: Two clinical sites in the United States. PATIENT(S): Thirty-nine healthy, fertile, sexually active women. INTERVENTION(S): Nineteen women received a four-pellet system containing 174 mg NET; 20 women received a five-pellet system containing 266.5 mg NET. MAIN OUTCOME MEASURE(S): Contraceptive efficacy, median serum NET levels, adverse events. RESULT(S): No pregnancies were observed in 293 woman-months in the four-pellet group or in 375 woman-months in the five-pellet group. An initial burst in median serum NET levels occurred in the first 24 hours postinsertion followed by a steady decline over the next 3 years. Norethindrone levels varied considerably among women. The main side effect was bleeding abnormalities, which persisted in half the participants for up to 2 years. No serious adverse events were reported that were related to the pellets. Pellet insertion and removal generally were uncomplicated. CONCLUSION(S): Annuelle shows potential as an effective, safe contraceptive with distinct advantages over other long-acting agents, because it is biodegradable but can be removed if problems arise or if fertility is desired.
PIP: The contraceptive efficacy, pharmacokinetics, bleeding profiles, and safety of two formulations of the Annuelle contraceptive implant system were investigated in a prospective study conducted at two clinical sites in the US. 19 women received a four-pellet system containing 174 mg of norethindrone (NET) and 20 women received a five-pellet system containing 266.5 mg of NET. Participants were followed quarterly for up to 39 months. No pregnancies were recorded during 293 woman-months in the four-pellet group and 375 woman-months in the five-pellet group. Most women exhibited a burst in NET levels (values equal to or exceeding 2 ng/ml) 24 hours after pellet insertion, followed by a steady decline over the next 3 years. Ovulation was inhibited in most participants in both groups at 9 months after insertion, and this protective effect persisted as long as 2 years in 16 of the 39 subjects. More than 80% of women in both groups had at least one clinically important bleeding pattern (e.g., frequent, irregular, or prolonged bleeding) in the first 90-day interval; this percentage dropped over time, but persisted in half the participants for up to 2 years. Serum levels of total cholesterol, low density lipoproteins, and triglycerides dropped substantially after pellet insertion in both groups, while high density lipoprotein levels remained fairly constant. Overall, the Annuelle system is considered to have potential as a safe, long-acting contraceptive agent capable of being surgically removed before complete absorption. Of concern, however, is the relatively long period during which the product releases detectable amounts of NET but may no longer be a fully effective contraceptive agent.
Asunto(s)
Anticonceptivos Sintéticos Orales/sangre , Anticonceptivos Sintéticos Orales/farmacología , Noretindrona/sangre , Noretindrona/farmacología , Adolescente , Adulto , Biodegradación Ambiental , Anticonceptivos Sintéticos Orales/efectos adversos , Relación Dosis-Respuesta a Droga , Implantes de Medicamentos , Estradiol/sangre , Femenino , Humanos , Noretindrona/efectos adversos , Progesterona/sangre , Hemorragia Uterina/inducido químicamenteRESUMEN
OBJECTIVE: The primary objective of this study was to compare the safety, contraceptive efficacy, and menstrual cycle patterns in women using triphasic oral contraceptive pills, namely CTR-05, containing 50/100/150 micrograms desogestrel and 35/30/30 micrograms ethinylestradiol, and Orthonovum777 containing 500/750/1000 micrograms norethindrone and 35/35/35 micrograms ethinylestradiol. METHOD: Forty-six female volunteers, satisfying the selection criteria, were evaluated for six cycles, in an open-label, randomized study. Volunteers using CTR-05 were studied for 13 additional cycles for efficacy and safety. RESULTS: No serious adverse effects were observed in either group. The incidences of other drug-related adverse effects, such as headache and nausea, were transient in both groups. CTR-05 did not lower levels of high density lipoprotein (HDL) cholesterol. This may be attributed to the lower androgenicity of its progestin component, desogestrel. No pregnancies were reported in either group. Clinical and laboratory parameters remained within normal limits in both groups. In the CTR-05 group, the lower dose of ethinylestradiol did not affect the safety, efficacy and acceptability of the product. CONCLUSION: Desogestrel, with little estrogenic activity and only minimal androgenic activity, leads to lipoprotein changes, resulting in a favorable cardiovascular profile, as well as minimal androgen-related effects, such as hirsutism and acne.
Asunto(s)
Anticonceptivos Orales Combinados/efectos adversos , Anticonceptivos Secuenciales Orales/efectos adversos , Desogestrel/efectos adversos , Congéneres del Estradiol/efectos adversos , Etinilestradiol/efectos adversos , Ciclo Menstrual/efectos de los fármacos , Noretindrona/efectos adversos , Congéneres de la Progesterona/efectos adversos , Adulto , HDL-Colesterol/efectos de los fármacos , Combinación de Medicamentos , Femenino , Cefalea/inducido químicamente , Humanos , Náusea/inducido químicamenteRESUMEN
A 7000 g supernatant, obtained during the purification of luteinizing hormone (LH) receptor from bovine corpora lutea homogenate, was concentrated by ultrafiltration. The filtrate, containing < 50,000 molecular weight material, exhibited LH receptor binding inhibitor (LH-RBI) activity. The filtrate was ultrafiltered sequentially through Amicon PM-10, PM-30 and UM-2 filters to yield a LH-RBI-containing fraction in the higher molecular weight range of 30,000-10,000 and a LH-RBI-containing fraction in the lower molecular weight range of 10,000-1000. The higher molecular weight LH-RBI fraction was purified on Sephadex G-25 and the lower molecular weight LH-RBI fraction was purified on Sephadex G-50. Both the high- and the low-molecular-weight LH-RBI species inhibited the binding of 125I-labeled human chorionic gonadotropin (hCG) to bovine corpora lutea and to rat Leydig cell membrane receptors. Similarly, the production of testosterone by hCG-stimulated rat Leydig cells was inhibited in a dose-response manner by both the high- and the low-molecular-weight LH-RBI species. The LH-RBI activity in the low-molecular-weight species was stable at 4 degrees C for up to 6 months and at temperatures up to 90 degrees C for 15 mins, whereas the LH-RBI activity of the high-molecular-weight species was stable at 4 degrees C for 15 months and unstable at 60 degrees C after 15 min. The 7000 g supernatant provided a much-needed source to obtain larger than previously reported quantities of LH-RBI for isolation as well as for structure and function studies.
Asunto(s)
Cuerpo Lúteo/metabolismo , Péptidos/análisis , Receptores de HL/antagonistas & inhibidores , Animales , Bovinos , Gonadotropina Coriónica/metabolismo , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular , Células Intersticiales del Testículo/metabolismo , Masculino , Peso Molecular , Péptidos/aislamiento & purificación , Unión Proteica , Ensayo de Unión Radioligante , Ratas , Receptores de HL/aislamiento & purificaciónRESUMEN
Three New Zealand white adult female rabbits, designated as A, B, and C, were immunized to produce lutropin receptor antibodies. Antisera inhibited the binding of 125I-hCG to the lutropin receptor and the production of testosterone by hCG stimulated rat Leydig cells. During the study period of, approximately 10 months after the last immunization, rabbits did not ovulate in response to an injection of 75 IU of human chorionic gonadotropin or mating as revealed by laparotomy. As the antibody titers declined, induction of ovulation and laparotomy revealed restoration of ovulation and corpus luteum formation. However, no pregnancy occurred when rabbits A and B were mated and artificially inseminated. These observations indicate that lutropin receptor antibodies can cause infertility in female rabbits.
Asunto(s)
Anticuerpos/inmunología , Ovario/fisiología , Receptores de HL/inmunología , Reproducción/inmunología , Animales , Unión Competitiva , Gonadotropina Coriónica/antagonistas & inhibidores , Gonadotropina Coriónica/metabolismo , Estradiol/biosíntesis , Femenino , Técnicas In Vitro , Inseminación Artificial/inmunología , Hormona Luteinizante/biosíntesis , Masculino , Ovario/metabolismo , Progesterona/biosíntesis , Conejos , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Testosterona/biosíntesisRESUMEN
Monoclonal antibodies (Mabs) were produced against bovine Lutropin receptor (LH-R). Antibodies were detected by an enzyme linked immunosorbant assay (ELISA). Hybridomas were subcloned to achieve monoclonality. Ascites were developed in Balb/c mice. Hybridoma supernatants were purified by ammonium sulfate precipitation and chromatography on hydroxylapatite columns. LH-R antibodies showed upto 50% inhibition of 125I-labeled hCG binding to bovine luteal cell membranes and up to 80% inhibition of testosterone production by hCG stimulated mouse Leydig cells. LH-R antibodies were predominantly IgM isotype. Purified antibodies showed a 78-kDa band, in SDS-PAGE, as the heavy chain of the immunoglobulin. LH-R antibodies were localized specifically in the thecal and luteal cells of the rat ovaries as well as in the Leydig cell of mouse testes. Injections of the LH-R antibody caused a constant estrus in normal rats. One month after the cessation of the injections the animals returned to normal estrus cycle and fertility. Pregnant mice injected with LH-R antibodies produced only 3 viable pregnancies and 10 pups, as compared to 8 pregnancies and 45 pups born to normal controls. LH-R antibodies also caused, approximately, a 50% reduction in testosterone production in normal male rats. These observations indicate a high degree of specificity of the Mab to LH-R and their potential in studies on gonadal function.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Receptores de HL/inmunología , Animales , Anticuerpos Monoclonales/aislamiento & purificación , Especificidad de Anticuerpos , Bovinos , Cromatografía por Intercambio Iónico , Cuerpo Lúteo/metabolismo , Reacciones Cruzadas , Electroforesis en Gel de Poliacrilamida , Ensayo de Inmunoadsorción Enzimática , Femenino , Hibridomas/inmunología , Isotipos de Inmunoglobulinas/análisis , Fosfatos de Inositol/biosíntesis , Masculino , Ratones , Ratones Endogámicos BALB C , Ovario/metabolismo , Ratas , Receptores de HL/biosíntesis , Transducción de Señal , Testículo/inmunologíaRESUMEN
Four baboons (Papio anubis) were actively immunized with bovine LH receptor for periods of 6-22 months. Serum antibody levels were measured by an enzyme immunoabsorbant assay (ELISA). Antibodies against the receptor were detected 2 weeks after the first injection. Antisera caused an inhibition in the binding of human chorionic gonadotropin (hCG) to its receptor as well as inhibited the production of hCG induced testosterone by rat Leydig cells in culture. Serum estradiol and progesterone levels were determined by radioimmunoassay (RIA). Progesterone levels were suppressed during the post immunization period. Two baboons experienced periods of anovulation. Serum estradiol levels were cyclic and appeared elevated. Baboons were mated with males of proven fertility; none of the immunized females conceived over eight cycles of observation. Fertility parameters returned to normal, when antibodies against LH-receptor were undetectable in the serum.
Asunto(s)
Anticuerpos/fisiología , Fertilidad/inmunología , Receptores de HL/inmunología , Animales , Células Cultivadas , Gonadotropina Coriónica/metabolismo , Reacciones Cruzadas , Ensayo de Inmunoadsorción Enzimática , Estradiol/sangre , Femenino , Inmunización , Células Intersticiales del Testículo/metabolismo , Masculino , Papio , Progesterona/sangre , Receptores de Gonadotropina/metabolismo , Testosterona/biosíntesisRESUMEN
Contraceptive efficacy of injectable norethindrone (NET) microspheres of 90 day duration was evaluated for 6 months: nine women received two injections of 65 mg each and eight received two injections of 100 mg each with 90 days between each injection. Average serum NET levels were 5 to 9 ng/mL on the day after injection and subsequently remained at 1 to 3 ng/mL. With 65 and 100 mg doses, respectively, 36% and 25% of cycles had normal bleeding patterns, 36% and 48% were amenorrheic, and the remaining 28% and 27% had prolonged bleeding. Also, 56% and 40% of cycles showed increased spotting for the 65 mg and 100 mg dose, respectively. There was no incidence of pregnancy or serious side effects. The mean serum NET concentration returned to RIA nonspecific basal levels 100 days after the second injection. Women returned to ovulatory cycles between days 100 to 115 after the second injection.
Asunto(s)
Noretindrona/administración & dosificación , Poliglactina 910 , Polímeros , Adulto , Presión Sanguínea/efectos de los fármacos , Preparaciones de Acción Retardada , Evaluación de Medicamentos , Femenino , Humanos , Lípidos/sangre , Menstruación/efectos de los fármacos , Microesferas , Noretindrona/farmacocinética , Ovulación/efectos de los fármacos , Vehículos FarmacéuticosRESUMEN
Polyhydramnios, which is caused by an excess of amniotic fluid, was diagnosed uniformly in eight patients by ultrasound examination and clinical symptoms, namely, premature uterine contraction, abdominal pain, and respiratory discomfort that resulted from excessive pressure on the diaphragm. Fetal anomalies incompatible with extrauterine existence were excluded by serum alpha-fetoprotein levels, repeated sonography, amniocentesis, and chromosomal analyses. Patients were treated with 2.2 to 3.0 mg of indomethacin/kg body weight/day. The treatment was started at an average gestational age of 24 +/- 0.5 weeks and continued for 2 to 11 weeks. All patients had significant improvement with a simultaneous reduction in amniotic fluid volume, fundal height, and umbilical perimeter. All patients were delivered satisfactorily at an average of 39 weeks' gestation. The fetuses were within the normal body weight range of 2750 to 3600 gm and showed normal development during the neonatal period of 2 to 6 months. Before delivery without indomethacin, the polyhydramnios reformed. Adverse effects or intolerance to the drug was avoided by either a reduction in the dose or cessation of indomethacin therapy. Our studies suggest that indomethacin therapy is an effective way to manage pregnancy complicated by polyhydramnios.
Asunto(s)
Inhibidores de la Ciclooxigenasa , Indometacina/uso terapéutico , Polihidramnios/tratamiento farmacológico , Adulto , Femenino , Humanos , Embarazo , Útero/anatomía & histologíaRESUMEN
Tests for the diagnosis of early pregnancy have been available since 1974. However, no studies have systematically verified the accuracy of routine clinical laboratories in measuring human chorionic gonadotropin (hCG) prior to the time that pregnancy is clinically evident. We have conducted such a study in association with the NICHD-funded Diabetes in Early Pregnancy Study (DIEP). The purpose of this study was to elucidate the etiology of malformations in pregnancies complicated by diabetes mellitus, which probably occurs within the first few weeks of pregnancy, and therefore uniformity of pregnancy testing was necessary among the five centers to find an association of a teratogen at the time of organogenesis. We confirmed that routine clinical laboratories, in fact, could measure accurately hCG at the time of the missed menses; however, detection was not necessarily possible prior to that time. We conclude that in order to assure accurate diagnosis of early pregnancy, tests should ordinarily be delayed until time of the missed menses. When the test is used at this time, it is a reliable tool for early pregnancy testing and thus can be used to resolve questions relating to early pregnancy pathophysiology.
PIP: This paper describes the validation procedure of early pregnancy tests within 2 days of missed menses by 6 different university clinical laboratories assaying for human chorionic gonadotropin (hCG) by radioimmunoassay (5) or radioreceptor assay (1). Test materials were known amounts of hCG added to male serum or plasma, divided into 2 aliquots, and labeled "research" or with a fictitious patient name. Concentrations of hCG were 0, 150, 300, 600, 1200, 2400 and 4800 mIU/ml. In a 2nd test, concentrations ranged from 10 to 50 mIU/ml. In the 1st verification series, there was general agreement, with only 1 center finding a false positive pregnancy. In the 2nd series, all laboratories identified correctly the serum without hCG. However, the unknown with a quantity of hCG in the range of LH cross-reactivity was called positive by 2 labs. The other 4 called the result "equivocal." All 6 laboratories had adequate agreement between "research" and pseudo-patient samples. All laboratories could detect hCG at levels compatible with those observed at the time of a missed period, less than 200 mIU/ml. Even large inter-assay variation in 1 center failed to affect the ability of that laboratory to detect low levels of hCG. 2 laboratories did not measure hCG levels above 1200 mIU accurately, not a problem in diagnosing early pregnancy, but a possible limitation in following multiple gestation or hydatidiform mole. This study demonstrates the importance of verification procedures before clinical studies that need an accurate early pregnancy diagnosis.
Asunto(s)
Gonadotropina Coriónica/sangre , Diabetes Mellitus Tipo 1/sangre , Pruebas Inmunológicas de Embarazo/métodos , Embarazo en Diabéticas/sangre , Estudios de Evaluación como Asunto , Femenino , Humanos , Embarazo , Radioinmunoensayo/métodosRESUMEN
A batch of 24 mg of luteinizing hormone-human chorionic gonadotropin (LH-hCG) receptor was isolated from bovine corpora lutea. The LH-hCG receptor showed specific binding with hCG. The receptor-hCG complex activated the regulatory Ns protein isolated from rabbit liver, which in turn stimulated adenylate cyclase to convert ATP into cAMP in vitro, attesting to the biological activity of the purified LH-hCG receptor. The LH-hCG receptor was treated with 2% sodium dodecyl sulfate (SDS) to prepare the molecular weight (Mr) 280K dimer and with 50 mM dithiothreitol (DTT) to prepare the Mr 120K monomer and subunits of Mr 85K and 38K. Oligomers of various molecular weights were recovered from gel filtration columns due to the reassociation of disulfide bonds between monomers and subunits. Hence, the receptor monomer was also dissociated into subunits of Mr 85K and 38K by reduction of -S-S-bonds with 50 mM DTT in 2% SDS and alkylation of sulfhydryl groups in the presence of 100 mM N-ethyl-maleimide. The subunits were separated by gel filtration through columns of Ultrogel AcA-44 and Sephadex G-75. The yields of the purified alkylated subunits of Mr 85K and 38K were 1.8 and 1.5 mg, respectively. Each subunit migrated as a single entity in SDS-polyacrylamide gel electrophoresis. The monomer of the receptor of Mr 120K showed specific binding with 125I-hCG, suggesting it to be the minimum molecular weight functional unit of the receptor. The Mr 85K and 38K subunits bound 125I-hCG, which could not be displaced with unlabeled hCG.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Cuerpo Lúteo/metabolismo , Receptores de Gonadotropina/aislamiento & purificación , Receptores de HL/aislamiento & purificación , Adenilil Ciclasas/metabolismo , Animales , Bovinos , Gonadotropina Coriónica/metabolismo , Activación Enzimática , Femenino , Cinética , Sustancias Macromoleculares , Peso Molecular , Receptores de Gonadotropina/metabolismo , Receptores de HL/metabolismoRESUMEN
The contraceptive efficacy of norethindrone (NET) fused pellets was evaluated over 12 months in a Phase II clinical study with three and four pellets, each pellet containing 35 mg of NET. Volunteers were healthy, fertile, sexually active women. The release rate of NET from three and four pellets, respectively, was 150.3 +/- 7.2 micrograms and 212.5 +/- 8.6 micrograms NET/day. Following the implantation of NET pellets, serum NET levels did not show any 'burst effect' and were sustained at levels between 0.4 and 0.6 ng NET/ml serum with three pellets and 0.6-0.7 ng NET/ml serum with four pellets. With three and four pellets, respectively, 40% and 27% of the women had normal menstrual cycles; 20% and 14% were amenorrheic; 27% and 37% had mid-menstrual spotting or bleeding; and 13% and 22% had prolonged episodes of bleeding. Cardiovascular, hepatic, and renal functions were normal throughout the study. Ovulation was inhibited in 85% and 92% of the cycles with three and four pellets, respectively. In women using three pellets, two pregnancies occurred, one at the 6th cycle and another at the 12th cycle. In women using four pellets, no pregnancies occurred during the entire period of study.
Asunto(s)
Anticonceptivos Femeninos , Noretindrona/administración & dosificación , Adulto , Preparaciones de Acción Retardada , Evaluación de Medicamentos , Implantes de Medicamentos , Estradiol/sangre , Femenino , Humanos , Ciclo Menstrual , Noretindrona/sangre , Ovulación/efectos de los fármacos , Progesterona/sangreRESUMEN
In order to determine the specific antigenic determinants of human follicle-stimulating hormone (hFSH), hFSH-beta peptides with amino acid residues 33-49 (V2), 95-118 (V3), 76-118 (V3 + 1/2 C2), 1-33 (V1 + C1), 22-33 (1/2C1), and 95-107 (V3 + 1/4C2) according to the nomenclature of Stewart and Stewart [Stewart, M., & Stewart, F. (1977) J. Mol. Biol. 116, 175] as well as additional peptides with the residues 93-107, 91-107, 89-107, 87-107, and 85-107 were chemically synthesized. The peptides were examined in radioimmunoassay systems of FSH, luteinizing hormone (LH), or human chorionic gonadotropin (hCG). V3 + 1/2C2 and V1 + C1 showed immunological activity, whereas the other peptides did not. Antibodies were raised in rabbits against these peptides and examined for specific binding with hFSH, LH, thyroid-stimulating hormone (TSH), and hCG. V3 + 1/2C2 as well as V1 + C1 produced antisera, which specifically bound hFSH, hLH, and hTSH, indicating that the amino acid sequences contained in hFSH-beta peptides V3 + 1/2C2 and V1 + C1 share common antigenic sites with hLH and hTSH. Antisera were produced in rabbits against hFSH-beta, against reduced and S-aminoethylated hFSH-beta (AE-FSH-beta), and against AE-FSH-beta coupled to hemocyanin. Reduced and S-aminoethylated beta-subunit of FSH-beta coupled with hemocyanin produced antisera in rabbits that specifically bound only hFSH and not hLH, hTSH, or hCG.