The potential effects of linalool on enantioselective skin permeation of norgestrel / 药学学报

The purpose of this study is to investigate the enantioselectivity of norgestrel (NG) transdermal permeation and the potential influence of linalool and lipids on the enantioselectivity. In vitro skin permeation studies of NG across the excised rat skins were performed with Valia-Chien diffusion cells, and the permeation samples were analyzed by enantioselective HPLC. The possible enantioselective permeation of NG across intact rat back skin and lipids extracted rat back skin and the influence of linalool were evaluated. The skin permeation rate of dl-NG was two times higher than that of l-NG when donor solutions (EtOH/H2O 2 : 8, v/v) containing l-NG or dl-NG. It may be mainly attributed to the solubility discrepancy between enantiomer and racemate. The enantioselective permeation of dl-NG across intact rat skin was observed when the donor solutions containing dl-linalool. The permeation flux of l-NG was 22% higher than that of d-NG. But interestingly, the enantioselective permeation of dl-NG disappeared under the same experimental condition except that the lipid extracted rat skin was used. Attenuated total reflection-fourier transform infrared spectroscopy analysis of stratum corneum showed that the wave number for asymmetric CH2 stretching vibrations of lipids treated with dl-linalool was greater than that of the control. The results indicated that the enantioselective permeation of NG may be contributed by the interaction between dl-linalool and lipids. More than half of lipids were composed of ceramides. The stereospecific interaction maybe existed among chiral enhancer (linalool), lipids (ceramides) and/or chiral drugs (NG).

A clinical study of transdermal contraceptive patch in Thai adolescence women.

OBJECTIVE: To study cycle control, compliance and safety of a transdermal contraceptive patch in adolescent Thai women. MATERIAL AND METHOD: Fifty-eight healthy women were assigned to receive 3 cycles of contraceptive patch (ethinyl estradiol 20 microg and norelgestromin 150 microg/day). All participants aged 16-20 years were invited to participate from the family planning clinic at King Chulalongkorn Memorial Hospital. Data were collected on adverse effects, perceived advantages and disadvantages, body weight, blood pressure, patch detachments and compliance. Data were analyzed using mean, percentage and student's t-test. RESULTS: The participants' average age was 19.4 years, height 158.8 cm, weight 51.8 kg, BMI 20.8 Kg/m2. The most location of patch application was the abdomen and the most adverse event was breast tenderness (31.0%) followed by application site reaction, nausea vomiting and headache respectively. The breast symptom was mild in severity. The participants reported decrease in dysmenorrhea and shorter duration of bleeding. There were no significant changes in body weight and blood pressure. The improvement of their facial acne was reported. There were no pregnancies during use and the adhesion of the contraceptive patch is excellent. Partial patch detachment was reported in only 6.9%. No completed patch detachment was found. CONCLUSION: The present study found an overall positive impression of a new transdermal contraceptive patch. The good compliance and few side effects were demonstrated. The adhesive patch contraceptive was excellent.

A clinical study of transdermal contraceptive patch in Thai women.

OBJECTIVE: To study cycle control, compliance and safety of a transdermal contraceptive patch in Thai women. MATERIAL AND METHOD: Sixty-nine healthy women were assigned to receive 3 cycles of contraceptive patch (ethinyl estradiol 20 microg and norelgestromin 150 miccrog/day). All participants aged 18-45 years were invited to participate at the family planning clinic at King Chulalongkorn Memorial Hospital. Adverse effects, perceived advantages, and disadvantages were collected. RESULTS: The participants averaged 22.4 years old, height 158.9 cm, weight 52.5 kg, BMI 20.7. The most common location of patch application was abdomen and the most adverse event was application site reaction (29%) followed by breast tenderness, nausea vomiting, and headache. The breast symptom was mild in severity. The participants reported decrease in dysmenorrhea and shorter duration of bleeding. Only 1.1% had breakthrough bleeding. There were no significant changes in body weight and blood pressure. Improvement of their facial acne was reported. There were no pregnancies during the use and the adhesion of contraceptive patch was excellent, partial patch detachment was reported at only 14.4%. No complete patch detachment was found. CONCLUSION: The study found an overall positive impression of new transdermal contraceptive patch. Good compliance and few side effects were demonstrated. The adhesive of the contraceptive patch was excellent.

Perspectives of contraceptive choices for men.

Apart from condoms and vasectomy, which have several limitations of their own, no other methods of contraception are available to men. Various chemical, hormonal, vas based and herbal contraceptives have been examined and few of them have reached the stage of clinical testing. Promising leads have been obtained from testosterone buciclate/undecanoate, alone or in combination with levonorgestrel butanoate or cyproterone acetate, RISUG, an injectable intravasal contraceptive and a few herbal products, particularly the seed products of Carica papaya. It is feasible that an ideal male contraceptive, that meets out all the essential criteria will be made available to the community in the near future.

Norelgestromin/ethinyl estradiol transdermal system.

The transdermal contraceptive patch is an innovative contraceptive technology. The failure rate is quite low and has high continuation rate. The side effects and complications are not different from other hormonal contraceptives. This contraceptive method should be an alternative birth control technique for women.

Bioequivalence study of postcoital emergency contraceptions containing levonorgestrel.

OBJECTIVE: The progestogen-only method of emergency contraception, levonorgestrel, is one of the effectiveness in preventing expected pregnancies. The comparative bioavailability was carried out on levonorgestrel tablets (0.75 mg) from two different sources (Hungarian and Thai made). METHOD: Eighteen healthy female volunteers were given a single oral dose of 0.75 mg tablets in a crossover design. Serum levonorgestrel concentration was determined by radio-immunoassay. The pharmacokinetic analysis of serum levonorgestrel concentration from each treatment was established. The comparative bioavailability of the two products was determined by the analysis of variance (ANOVA) for two way crossover design. RESULTS: The results found that the mean peak (X +/- SD) serum concentration (Cmax) of the Thai-made pill and Hungarian-pill were 1.18 +/- 0.12 and 1.14 +/- 0.10 ng/ml, respectively. The 90% confidence intervalfor the difference of log Cmax mean was 99.54-120.78%. The time to peak serum concentration (Tmax) of the Thai-made pill and Hungarian-pill were 1.56 +/- 0.73 and 1.58 +/- 0.67 hrs, respectively. The different time of peak serum levonorgestrel concentration was 1.27%. The mean area under the curve (AUC) of Thai-made pill and Hungarian-pill were 2.14 +/- 0.21 and 2.09 +/- 0.16 ng.h/ml, respectively. The 90% confidence interval for the difference of log AUC mean was 103.27 - 121.89%. CONCLUSION: The present study revealed that the 90% confidence interval for the difference of log Cmax mean and log AUC mean were in the criteria of acceptance, which should be within 80-125%. So, the authors can conclude that the Thai-made pill was bioequivalent to the Hungarian-pill.

Effect of oral contraceptives on respiratory function.

The present study was carried out to assess the lung functions in oral contraceptive administered women. Lung function tests were carried out with Spirometer (Vitallograph Compact II). A significant increase in vital capacity (VC) was observed in these women as compared to normal control. There was also a significant decrease in forced expiratory volume in 1 sec./vital capacity (FEV1/VC%) and forced expiratory volume in 1 sec./forced vital capacity (FEV1/FVC%) among oral contraceptive administered women as compared to controls. Further, a significant increase in peak expiratory flow rate (PEF), reduction in forced expiratory flow rate (FEF75-85%) and FEF75% were observed among oral contraceptive administered women as compared to controls. The increase in VC and PEF might be due to the synthetic form of progesterone (progestins) present in oral contraceptive pills which causes hyperventilatory changes. Synthetic progesterone during luteal phase of menstrual cycle might increase the static and dynamic volumes of lung i.e. VC and PEF. But FEF75% showed a decrease which might be due to the lower neuromuscular coordination during breathing.

Current status of fertility control methods in India.

Approximately 48.2% of couples of 15 to 49 years of age practice family planning methods in India. Female sterilization accounts for 34.2%, with male sterilization declining from 3.4% in 1992-93 to 1.9% in 1998-99. Use of the condom increased to 3.1% from 2.4%. There is an urgent need for research to develop new contraceptive modalities especially for men and also for women and to make existing methods more safe, affordable and acceptable. Current efforts in India to develop a male contraceptive are mainly directed towards (i) development of antispermatogenic agents to suppress sperm production, (ii) prevention of sperm maturation, (iii) prevention of sperm transport through vas deferens or rendering these sperm infertile and (iv) prevention of sperm deposition. Research work in the field of prevention of sperm transport through vas deferens has made significant advances. Styrene maleic anhydride (SMA) disturbed the electrical charge of spermatozoa leading to acrosome rupture and consequent loss in fertilizing ability of sperm. A multicentre phase-III clinical trial using SMA is continuing and it is hoped that the SMA approach would be available in the near future as an indigenously developed injectable intra-vasal male contraceptive. The safety and efficacy of available oral contraceptives were evaluated. An indigenously developed oral contraceptive 'Centchorman', which is a nonsteroidal, weakly estrogenic but potently antiestrogenic, was found to be safe and effective and is now being marketed in India since 1991 as a 'once a week' pill. Cyclofem and Mesigyna have been recommended as injectable contraceptives with proper counselling and service delivery by Indian studies. It has been recommended that these injectable contraceptives be added to the existing range of contraceptive methods available in the National Family Planning Programme. Based on the Indian studies CuT 200 was also recommended. Studies have indicated the advantage of intrauterine devices (IUD); they are long acting, relatively easily removed and fertility returns rapidly after their removal. Recent studies have recommended CuT 200 for use up to 5 years. The combination of some plant products i.e. Embelia ribes, Borax and Piper longum has been found to be safe and effective as a female contraceptive and the results of phase-I clinical trials are encouraging. Research work is going on in the country in various areas with special reference to hormonal contraceptive - a three monthly injectable contraceptive, immuno-contraceptives, antiprogestins, etc.

Efecto del norgestomet inyectado sobre el folículo dominante persistente y la formación del cuerpo lúteo en vacas sincronizadas con implantes de norgestomet / Effect of injected norgestomet on persistent dominant follicles and corpora lutea formation in estrus synchronized bovine females

Se evaluó el efecto de la inyección im de 3 mg de norgestomet (NG) en la inducción de atresia del folículo dominante persistente (FDP) y la formación del cuerpo lúteo (Cl) que se desarrolla después de inducir la ovulación del FDP con hCG, en vacas sincronizadas con implantes de norgestomet. Se utilizaron 11 vaquillas y 20 vacas Holstein previamente sincronizados con doble inyección de PGF2a. El día 7 del ciclo (día 0 del experimento), se les insertó un implante sc de 3 mg de norgestomet (iNG) y recibieron PGF2a; posteriormente se asignaron al azar a los siguientes tratamientos: para el tratamiento hCG (n = 8) el día tres se aplicaron 2 500 UI de hCG im; para el tratamiento hCG + NG (n = 8) el día tres se aplicaron 2 500 UI de hCG im y el día cinco recibieron 3 mg de norgestomet im; para el tratamiento NG (n = 8) el día cinco recibieron 3 mg im de norgestomet. Al grupo testigo (n = 7) se le aplicó solución salina im el día tres y el día cinco, 5 ml de aceite vegetal. El iNG se retiró nueve días después de su inserción. Diariamente, a partir de la inserción del iNG y hasta la presentación del estro, se realizaron ultrasonografías de los ovarios y se tomaron muestras sanguíneas, en las cuales se determinaron las concentraciones de progesterona. La proporción de animales en los cuales se eliminó el FDP y se promovió un recambio folicular fue similar (0.05 < P < 0.1) entre los tratamientos hCG (5/8), hCG + NG (7/8) y NG (6/7), pero fue diferente (P < 0.05) al grupo testigo, en el cual no se eliminó ningún FDP (0/7). El porcentaje de concepción fue similar (P > 0.05) entre las vacas que ovularon un folículo nuevo (66.6 por ciento; 12/18) y aquellas que ovularon el FDP (53.8 por ciento; 7/13). En el grupo hCG + NG el tratamiento con norgestomet después de la inyección de hCG evitó el desarrollo del Cl, ya que sólo una vaca de seis que ovularon tuvo niveles > 1 ng/ml de progesterona al retirar el iNG, mientras que en el grupo hCG los cinco5 animales que ovularon tuvieron niveles > 1ng/ml de progesterona (P < 0.05). Se concluye que la inyección de 3 mg de norgestomet el día cinco posterior a la inserción del iNG provocó la atresia del FDP y evitó el desarrollo del cuerpo lúteo inducido con hCG.

Postcoital Contraceptive Pills

Postcoital contraception or emergency contraception(EC), commonly known as the "morning after pills", prevents pregnancy after unprotected intercourse. A comprehensive definition of EC is as follows : "specific contraceptive methods that can be used as emergency measures to prevent pregnancy after unproteted intercourse". Both drugs and certain devices can be used for emergency contraception. The best-studied regimen(Yuzpe) consists of an ordinary combination of oral contraceptives containing ethinyl estradiol and norgestrel. Conventional clinical guidelines recommend a first dose within 72 hours after unprotected intercourse and a second dose 12 hours thereafter. These drugs are most effective when taken as soon as possible after the intercourse. The Yuzpe regimen reduced the risk of unintended pregnancy by at least 75% in clinical trials. The most common side effects of the Yuzpe method are nausea and vomiting. Levonorgestrel is the synthetic progesterone. The major benefits of levonorgestrel are the decreased side effects and greater contraceptive efficacy than Yuzpe regimen. Mifepristone (RU486) is a synthetic steroid that prevents progesterone from binding to the progesterone receptors and glucocorticoid receptors. It has been used extensively in Europe as an abortifacient and also has been used as an effective EC. Its common side effect is a delay in the onset of menses, leading to anxiety for the user. The intrauterine contraceptive device(IUCD) is the only method of emergency contraception available to women presenting beyond 72 h and within 5 days from unprotected intercourse. EC is not protective against infections such as STD(sexually transmitted diseases). There are many situations where EC is indicated, including condom rupture or slip, unplanned unprotected intercourse, incidental misuse of regular contraceptive methods, and sexual assault. Emergency contraceptive pills can prevent ovulation, but an alternative major mechanism of action is to prevent uterine implantation of the embryo at the endometrial level. A 3-week follow-up visit should be scheduled to assess the result and to counsel for regular contraception. EC provides a second chance at preventing undesired pregnancies. but it should not be used as a routine birth control method, because it is actually less effective and needs a higher dose at preventing pregnancies than most types of oral contraceptives. Widespread and appropriate use of EC will provide a promising means to reduce the incidence of unplanned pregnancy and to contribute to the women's health.

Variación de la actividad de la enzima butirilcolinesterasa en usuarias de anticonceptivos hormonales / Enzyme butilcholinesterase activity variation in hormonal contraception users

OBJETIVO: Evaluar la actividad de la enzima butirilcolinesterasa en mujeres usuarias de dos anticonceptivos hormonales, norgestrel etinilestradiol y acetato de medroxiprogesterona, utilizando como marcador hepático indirecto la fosfatasa alcalina. MATERIAL Y MÉTODOS: Mujeres que asistían al programa de Planificación Familiar del C. S. "7 de Octubre" - El Agustino, continuadoras en los métodos de anticoncepción hormonal (mayor de seis meses). Se extrajo sangre en ayunas y realizó la medición sérica de la actividad enzimática. RESULTADOS: Las usuarias de ambos tipos de anticonceptivos tuvieron aumento significativo de la actividad butirilcolinesterasa respecto al grupo control, observándose en las usuarias de medroxiprogesterona 30 por ciento más con cifras elevadas. El 12 por ciento de usuarias de norgestrel etinilestradiol y el 18 por ciento de medroxiprogesterona tuvo valores fuera del promedio ñ2 DE. La actividad de fosfatasa alcalina tuvo aumento significativo de 8 por ciento sólo en usuarias de medroxiprogesterona. CONCLUSIONES: El uso del anticonceptivo acetato de medroxiprogesterona originó mayor variación de la actividad butirilcolinesterasa y por más tiempo que el del norgestrel etinilestradiol.

Comparison of norgestrel- versus cyproterone acetate-containing hormone replacement therapy on lipid-lipoprotein metabolism.

To compare the effects on the lipid profile of estradiol valerate with norgestrel to a regimen of estradiol valerate with cyproterone acetate. Sixty-four healthy women in their perimenopause or early postmenopause, aged between 40-55 years, were randomized to one of the two 21-day sequential regimens: estradiol valerate 2 mg/day for 21 days and combined with either norgestrel 0.5 mg/day or cyproterone acetate 1 mg/day from day 12 to 21, with 7 days of drug-free interval, for 12 cycles. Lipid profiles were followed at baseline, 6 and 12 cycles. Sixty-one subjects completed the study, 30 in the norgestrel group and 31 in the cyproterone group. During 12 cycles of study, serum HDL cholesterol levels decreased significantly in the norgestrel group (p < 0.01) and were unchanged in the cyproterone group. The levels were significantly lower in the norgestrel group than in the cyproterone group (p < 0.05). No differences were found between groups as regards LDL cholesterol and total cholesterol levels. Triglyceride levels decreased significantly in the norgestrel group (p < 0.01), remained unchanged in the cyproterone group and the levels were significantly different between groups (p < 0.01). In conclusion, the study demonstrated that sequential regimen of estradiol valerate with norgestrel produced less favorable HDL cholesterol but more favorable triglyceride levels than the regimen of estradiol valerate with cyproterone acetate.

Interferencia endometrial de los estrógenos sintéticos en la regulación de la fertilidad / Endometrial interference of synthesis estrogens in fertility regulation

Inicialmente la actividad antiovulatoria de algunos preparados estrógeno/progestacional, era la acción requerida para controlar la fertilidad. A la fecha se ha conseguido una notable reducción en la dosis de ambos componentes hormonales, ofreciendo menos efectos colaterales, con una eficacia anticonceptiva aceptable. Actualmente se dispone de una variedad de esas combinaciones, en donde el estrógeno sintético concentra de 80 a 20 µg/tableta y la prescripción se inicia o el 1er. día o el 5o. día del ciclo menstrual. Al analizar el plasma y el endometrio simultáneamente obtenida de usuarias crónicas que incluían en la tableta dosis de 30 o 50 µg del estrógeno sintético, se observó un perfil de 17B-estradiol como el de la maduración folicular de los ciclos ovulatorios sólo en las mujeres que tomaban la dosis más baja. Sin embargo, este fenómeno de ciclicidad no se obtuvo a nivel local; paralelamente la progesterona circulante en ambos grupos nunca fue > 5.0 ng/ml. La observación indica que se debe buscar un periodo crítico local durante el ciclo menstrual ovulatorio, con mucho menores dosis hormonales para controlar la fertilidad

O lugar dos implantes subdérmicos na anticoncepçäo no Brasil / The place of subdermal contraceptive implants in Brazil

Os implantes subdérmicos contraceptivos foram inseridos em 3382 mulhres brasileiras, que aceitaram participar do estudo brasileiro do Norplant, em vinte e uma clínicas de planejamento familiar do brasil. A eficácia anticoncepcional foi alta em todos os anos estudados, com uma taxa de gravidez de 0,21 por cento ao final do primeiro ano de uso e que chegou a 1,5 por cento ao final dos cinco anos. Näo houve diferença na taxa de gravidez entre as mulheres que usaram os implantes durante seis e sete anos após a inserçäo. Entre ascausas de interrupçäo de uso, o sangramento aumentado foi a mais importante, com uma taxa de 7,85 por cento e 12,92 por cento, respectivamente, ao final do primeiro e do segundo anos de uso. Poucas mulheres interromperam devido esta causa após o segundo ano de uso e a taxa de descontinuaçäo aos cinco anos, devido sangramento aumentado, foi de 16,12 por cento. Nenhuma mulher apresentou hemorragia durante o estudo. Remoçöes dos implantes devido às outras causas médicas ocorreram com frequência bastante inferior a näo foram observados efeitos secundários que colocassem em risco a saúde das usuárias. A aceitabilidade do norplant foi boa, tendo em vista a alta taxa de continuaçäo de 72,78 por cento ao final do primeiro ano e 27,30 por cento ao final do quinto, a despeito de importante campanha contra o método, realizada no Brasil, durante o segundo ano da pesquisa. Aos sessenta meses de observaçäo, as mulheres sem filhos ou com no máximo um filho, tiveram uma taxa de continuaçäo menor que as outras (20,70 por cento contra 32,80 por cento entre as mulheres com tres ou mais filhos). Elas descontinuaram mais por desejo de filho (36,58 por cento contra 9,48 por cento) e devido às causas médicas (31,09 por cento contra 22,41 por cento). Já as mulheres com menos de 25 anos continuaram menos o uso dos implantes que aquelas com mais idade (25,95 por cento entre as mulheres com idade inferior a 20 anos contra 32,27 por cento entre as mulheres com trinta ou mais anos de idade). Elas descontinuaram mais por desejo de filho (31,04 por cento contra 7,88 por cento). E as mulheres com menor peso descontinuaram mais que as outras devido sangramento aumentado, chegando a 27,08 por cento entre aquelas com menos de 50 quilogramas e 13,98 por cento entre as mulheres com setenta ou mais quilogramas.

Avaliaçäo da exposiçäo ocupacional a hormônios sexuais / Occupational exposure evaluation the sex hormones

O objetivo desse artigo é revisar os principais efeitos sobre a saúde do trabahador, em indústrias formuladoras de contraceptivos orais, que utilizam como matéria-prima ativa uma estrogênio(etinil estradio), associado a um progestogênio (norgestrel e levonorgestrel), visando ao estabelecimento de um programa básico de controle.

Implantes anticonceptivos NORPLANT R: opinión de mujeres dominicanas que usaron el método

Con el objetivo de conocer directamente de las mujeres cuál ha sido su experiencia de uso y cuáles habían sido los problemas principales desde su punto de vista, se entrevistó a 309 mujeres que usaban o habían usado los implantes anticonceptivos NORPLANT R. Setenta; sin embargo, cuando se les interrogó específicamente sobre si habían observado cambios en su ciclo menstrual, el 70% respondió afirmativamente. Las características preferidas del método fueron la forma de uso y su eficacia; y la característica que menos le gustó fue el sangrado excesivo

Microbial transformation of 13-ethyl-3-methoxy-8,14-seco-gona-1,3,5(10),9(11)-tetraene-14, 17-dione to its 17-beta hydroxy derivative by Pichia farinosa in pilot plant fermentors.

Parameters for microbial transformation of 13-ethyl-3-methoxy-8, 14-seco-gona-1,3,5 (10), 9(11)-tetraene-14,17-dione to its 17 beta-hydroxy derivative by P. farinosa have been standardised in pilot plant fermentors. The yield of the pure crystalline compound was 80%.

Seguimiento a largo plazo de mujeres tratadas con implantes anticonceptivos de Levonorgestrel Norplant / Long-term follow up of women treated with contraceptive implants of norplant levonorgestrel

Este trabajo describe el seguimiento a largo plazo de 376 mujeres que recibieron los implantes Norplant durante el período comprendido entre octubre de 1974 y mayo de 1979. En ciento diez de estos casos, se reemplazaron los implantes luego de diferentes plazos de uso del primer set. Los niveles promedios de levonorgestrel plasmático declinaron en forma paulatina a través de ocho años de uso continuo de las cápsulas Norplant (r=937). Los valores fueron 0,35 ng/ml, 0,29 ng/ml y 0,22 ng/ml durante el primer, quinto y octavo año de tratamiento, respectivamente. Luego de la extracción de Norplant y su reemplazo con un segundo set de implantes, los niveles de levonogestrel plasmático fueron similares a aquellos observados después de la primera inserción, tanto cuando se colocaron en el mismo lugar que el primer set como cuando se ubicaron en un área diferente. Se estableció que la vida media del levonorgestrel en plasma después del retiro de los implantes es de 42 ñ 16 h (x ñ D. S) y que sólo quedaban cantidades mínimas en circulación después de 96 h. Durante 18.530 meses-mujer de uso del primer set de implantes se produjeron diecinueve embarazos, once de ellos entre el sexto y octavo año de tratamiento. El índice de Pearl para los primeros cinco años de uso de implantes Norplant fue 0,63. En los 5.020 meses-mujer observadas durante el tratamiento con un segundo set de cápsulas no se ha producido ningún embarazo. Cincuenta y seis mujeres (14,9%) de las 376 usuarias del primer implante, y doce (10,9%) de las 110 mujeres que aceptaron el reemplazo de los implantes se retiraron del estudio por razones médicas, principalmente efectos secundarios asociados frecuentemente con la contracepción hormonal..