Cyproterone synthesis, recognition and controlled release by molecularly imprinted nanoparticle.

In this study, we used novel synthetic conditions of precipitation polymerization to obtain nanosized cyproterone molecularly imprinted polymers for application in the design of new drug delivery systems. The scanning electron microscopy images and Brunauer-Emmett-Teller analysis showed that molecularly imprinted polymer (MIP) prepared by acetonitrile exhibited particles at the nanoscale with a high degree of monodispersity, specific surface area of 246 m(2) g(-1), and pore volume of 1.24 cm(3) g(-1). In addition, drug release, binding properties, and dynamic light scattering of molecularly imprinted polymers were studied. Selectivity of MIPs was evaluated by comparing several substances with similar molecular structures to that of cyproterone. Controlled release of cyproterone from nanoparticles was investigated through in vitro dissolution tests and by measuring the absorbance by HPLC-UV. The pH dissolution media employed in controlled release studies were 1.0 at 37 °C for 5 h and then at pH 6.8 using the pH change method. Results show that MIPs have a better ability to control the cyproterone release in a physiological medium compared to the non molecularly imprinted polymers (NMIPs).

Preterm birth prevention by 17 alpha-hydroxyprogesterone caproate vs. daily nursing surveillance.

OBJECTIVE: To compare the incidence of spontaneous recurrent preterm delivery (SPTD) between women receiving 17 alpha-hydroxyprogesterone caproate (17P) and women receiving daily perinatal nursing surveillance (dPNS) with home uterine activity monitoring. STUDY DESIGN: Women enrolled for dPNS or weekly nursing visits with 17P injection were eligible. Included were singletons with previous SPTD, without preterm labor (PTL), cerclage or vaginal bleeding and < 27 weeks at enrollment. 17P and dPNS patients were matched 1:1 by race, marital status, tobacco use and number of SPTDs. Primary study outcome was incidence of spontaneous PTD. RESULTS: Data from 342 matched pairs were compared. Diagnosis of PTL (39.2% vs. 60.8%) and tocolytic use (12.9% vs. 49.7%) was decreased with 17P vs. dPNS (p < 0.001). The incidences of spontaneous PTD at < 32, 35 and 37 weeks were similar between the groups. CONCLUSION: There was no difference in recurrent SPTD between women treated with 17P and those receiving dPNS.

Progestins for the prevention of spontaneous preterm birth: review and implications of recent studies.

Progesterone plays a central role in the mechanisms of parturition in many species. Despite remarkable advances in our understanding of this hormone's mechanism of action, its roles in human pregnancy maintenance and parturition are not fully appreciated. Proper scientific hypothesis testing of progestins to prevent preterm birth has been limited because of the issues that can plague interventional trials in obstetrics, including patient selection, choice of outcome and power. The largest studies enrolling patients with a history of prior preterm birth alone to prevent recurrence appear contradictory. In contrast, consistent evidence from one multinational trial and a secondary analysis of another suggests cervical length may serve to identify potential responders to this therapy. Finally, the safety of progestin administration is a legitimate concern and a meta-analysis justifies the need for further investigation of safety issues. This review presents recent findings regarding progestin therapy from both clinical and laboratory data and considers unresolved issues for use of these agents.

Prodrugs of gestodene for matrix-type transdermal drug delivery systems.

PURPOSE: The aim of this study was to enhance the transdermal absorption of the highly active progestin gestodene from matrix type transdermal delivery systems (TDDS) by formation of prodrugs with improved matrix solubility. METHODS: Gestodene esters were synthesized via acylation of the drug with the respective carboxylic anhydrides. Subsequently TDDS were produced using the solvent cast method. Selected formulations were examined with in vitro diffusion experiments using skin of nude mice. RESULTS: One prodrug, gestodene caproate proved to be an oil at ambient temperature and showed a very high solubilty of over 10.5% in the TDDS matrix. Within in vitro penetration studies using those systems the prodrug exhibited a significantly higher transdermal penetration rate than gestodene from reference systems. Furthermore, the prodrug was hydrolyzed to the parent drug to a high extent during the passage of the skin. CONCLUSIONS: Designing prodrugs to the requirements of matrix TDDS is an efficient way of enhancing the transdermal drug flux rate.

[Influence of anti-androgen therapy for prostatic hypertrophy on lipid metabolism].

Antiandrogen therapy has an important role in the treatment of patients with benign prostatic hypertrophy who lack indication for surgery. Herein, the effects on lipid metabolism of administration of antiandrogen agents for benign prostatic hypertrophy are reported. Eighty patients with benign prostatic hypertrophy were each treated with the antiandrogen agents, chlormadinone acetate, allylestrenol, gestonolone caproate and oxendolone for 12 months. The levels of total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), alpha-lipoprotein, apoprotein, and maronediardehyde (MDA) were measured every 4 weeks after initiation of antiandrogen treatment. In the chlormadinone acetate group, the TG level was significantly decreased between 3 and 6 months after treatment (p < 0.05). In the oxendolone group, the alpha-lipoprotein level was also elevated between 3 and 6 months and between 6 to 12 months after treatment (p < 0.05). The MDA level was also significantly elevated 6 and 12 months after treatment. However, the levels of the other lipids were within the normal range. In conclusion, the changes in the levels of plasma lipoprotein, apoprotein and MDA resulting from antiandrogen therapy were unlikely to be a cause of ischemic coronary disease.

[Pharmacological combinations in the treatment of benign prostatic hypertrophy]. / Associations pharmacologiques dans le traitement de l'hypertrophie prostatique bénigne.

In the development of the obstructive symptomatology of benign prostatic hypertrophy (BPH), two components may be identified, mechanical and dynamic. In the mechanical component, the interaction of a stromal and a epithelial compartment determines prostatic mass growth. The dynamic component involves smooth muscle tone in the prostate and urethra. The consideration that prostatic disease is not only epithelial in origin, but also stromal, leads to the association of an antiandrogen (which acts on the epithelial component) and an antiestrogen (active on the stromal component) in the medical therapy of BPH. In 1985 we carried out a randomized study on 256 BPH patients treated with Cyproterone acetate (CPA) plus Tamoxifen (TAM). Recently, we performed a multicenter double blind study on BPH patients treated with the association CPA plus Serenoa Repens. A statistically significant difference in prostate volume reduction between the groups treated with the combinations and those with the monotherapies was observed. The development of new compounds, such as 5 alpha reductase and aromatase inhibitors, consents to introduce a combination therapy with less side effects. A second pharmacological association may be obtained with drugs acting on the mechanical and others acting on the dynamic (alpha blockers) component of BPH. This combination may associate the early symptomatic effect of alpha blockers with the long term results of a 5 alpha reductase inhibitor, antiestrogen or aromatase inhibitor.

[Antiandrogen therapy of benign prostatic hyperplasia--review of the agents evaluation of the clinical results].

Various non-surgical therapeutic modalities such as balloon dilation of the prostatic urethra, hyperthermia of the prostate and medication with antiandrogens and/or adrenergic blockade have been attempted for the patients with benign prostatic hyperplasia (BPH) especially in an early stage or in a poor operative risk. The observation that androgen deprivation induces shrinkage of the hyperplastic prostate represents the basis for the treatment of BPH with antiandrogen. Although several antiandrogens are now in clinical use in our country, there still remain problems to be solved. We reviewed the mechanism of action and the clinical results of antiandrogens in the treatment of BPH. The improvement following antiandrogen therapy occurred among the patients with symptomatic BPH, in 50-80% subjectively and in 40-50% objectively. The therapy appeared to be more effective in an early stage of the disease. However, the limitation of the duration of the effects and unfavorable side effects should also be noticed. The progestational agents such as gestonorone caproate, chlormadinone acetate and allylestrenol suppress more or less sexual function by interference of the pituitary-gonadal axis. Besides, coincidental prostate cancer must be excluded since antiandrogen therapy might hinder the natural course of the cancer.

Active specific immunotherapy of renal cell carcinoma patients: a prospective randomized study of hormono-immuno-versus hormonotherapy. Preliminary report of immunological and clinical aspects.

Early results of a prospective, randomized trial of active, specific immunotherapy adjunctive to nephrectomy in all stages of RCC are presented. Forty-three patients with median followup of 30 m, who were randomly allocated to either immuno-hormonotherapy arm (IMT), or hormonotherapy alone (HT), are evaluated in terms of progression-free interval (PFI) and overall survival by life table method. Immunotherapy consisted of autologous irradiated tumor cells (AITC), admixed with bacillus Calmette-Guérin (Glaxo) administered by the intradermal and endolymphatic route. Clinical results of this study show only a trend for advantage of the experimental (IMT) arm over the control (HT) arm, this trend did not reach statistical significance level: prolongation of disease free period in stages I-III with localized disease (p less than 0.1) and prolongation of survival in patients with metastatic disease (p less than 0.07). A correlation was established between induction of cutaneous delayed hypersensitivity (DTH) to AITC and prolonged PFI and survival: patients with positive DTH had a significantly better course of disease than those who could not be converted to positivity after repeated immunizations. Positive in vitro leukocyte migration inhibition against autologous tumor preparations correlates well with positive in vivo cutaneous DTH. Some immunological aspects of active immunization with autologous tumor cells are discussed.

Growth patterns and hormonal sensitivity of primary tumor, abdominal metastasis and ascitic fluid from human epithelial ovarian carcinomas in the tumor colony-forming assay.

The human tumor colony forming assay was used to evaluate the response of ovarian carcinoma cells from primary tumors, ascitic fluids and metastasis to hormonal treatment. In 12/35 patients a sufficient colony formation (greater than 30 colonies/dish) was obtained in order to perform a simultaneous drug testing. The plating efficiency of the metastatic samples (0.12%) was significantly higher (P less than 0.053) than those from the primary tumor (0.076%) or those that were derived from the ascitic fluid (0.082%). Colonies from the metastatic tissues could be evaluated 2-4 days earlier than those from primary tumors. These discrepancies may be due to a heterogeneity in the clonable tumor cell compartment of primary tumor and metastasis. The antiproliferative properties of the antiestrogen tamoxifen and the progestin gestoneron were studied. In 9/12 cases a significant, dose-dependent reduction of colony formation (greater than 70-90% of the controls) was observed after continuous exposure to 1 mumole tamoxifen. No correlation between the dose response and the content of steroid receptors was found. Even estrogen receptor negative tumor samples showed a maximal antiproliferative effect of tamoxifen.

In vitro responsiveness of ovarian epithelial carcinomas to endocrine therapy.

As previously reported, ovarian epithelial carcinomas may respond to endocrine therapy. We examined the direct effect of progesterone, medroxyprogesteroneacetate, gestoneron, 17-beta-estradiol, tamoxifen, 4-OH-tamoxifen, or N-desmethyltamoxifen on the proliferative capacity of ovarian carcinoma cells by means of the colony assay described by Hamburger and Salmon. The growth rate of 25 tested tumors (ascitic fluid, primary tumor, metastases) was 68%. The plating efficiency was 0.078%. Beside the drug testing estrogen and progesterone receptor levels were determined. The inhibition of colony survival was slightest with 17-beta-estradiol, more pronounced with medroxyprogesteroneacetate, gestoneron, N-desmethyltamoxifen, and progesterone, and greatest with 4-OH-tamoxifen and tamoxifen. Significant and dose-dependent inhibition of greater than 70% was observed with tamoxifen and 4-OH-tamoxifen in 80% of the tested tumors. There was no significant correlation between the in vitro responsiveness and the level of hormonal act not only via an estrogen receptor but also via an antiestrogen-binding site.

Pilot study with adjuvant hormone therapy in FIGO stage I endometrial carcinoma with myometrial invasion.

A pilot study with adjuvant hormone therapy in FIGO stage I endometrial carcinoma with myometrial invasion was carried out. All patients received total abdominal hysterectomy and bilateral salpingo-oophorectomy plus complementary radium therapy on the vaginal stump. After the conventional treatment, patients were randomly allocated to adjuvant hormone therapy or no further treatment. Hormone therapy consisted of gestonorone caproate (17 alpha-hydroxy-19-norpregn-4-en 3, 20 dione caproate) administered i.m. at the dose of 200 mg/week for 1 year. Of the 62 patients who entered the study, 51 were considered evaluable (24 with adjuvant hormone therapy and 27 with no further treatment). Five patients had a relapse: four of these were in the group with no further treatment. Actuarial relapse-free survival analysis at 5 years was 95.7% in the group of adjuvant-treated patients and 82.8% in the control group. Although there is no statistical significance, adjuvant therapy appears to result in an increase in relapse-free survival in the group of patients with deep myometrial invasion and undifferentiated carcinoma. Further studies are necessary to assess the effectiveness of hormone adjuvant treatment in FIGO stage I endometrial carcinoma with myometrial invasion.

Use of progestogens as an adjuvant to surgery in the treatment of stage I adenocarcinoma of the uterine corpus.

Fifty-nine patients with proven stage I adenocarcinoma of the uterine corpus were treated by total abdominal hysterectomy and bilateral salpingo-oophorectomy, followed by gestronal hexanoate intramuscularly for 3 months and then medroxyprogesterone acetate orally for a prolonged period. In the 7-year period of study, there were no vaginal recurrences, but one patient suffered a recurrence in the inguinal lymph nodes and pelvis. Undesirable side effects did not occur. These results compare favourably with other reported studies in which surgery and radiotherapy were used.

Cyclic GMP in urine to monitor the response to ovarian cancer to therapy.

Guanosine 3':5'-phosphate (cycle GMP) in urine has been used to monitor the response of patients with ovarian cancer to treatment. Changes in the cyclic GMP level appear to correlate well with clinical status in that the disappearance of clinically detectable tumour is associated with a drop in the level whereas a tumour recurrence is associated with an elevation. Serially measured cyclic GMP is valuable for detecting a recurrence of tumour growth in patients in clinical remission and can predate any clinical signs by as much as 10 months. In patients who show no response to treatment, cyclic GMP levels in urine are elevated in the majority of specimens collected.