Investigation of Deteriorated Dissolution of Amorphous Itraconazole: Description of Incompatibility with Magnesium Stearate and Possible Solutions.

Disadvantageous crystallization phenomenon of amorphous itraconazole (ITR) occurring in the course of dissolution process was investigated in this work. A perfectly amorphous form (solid dispersion) of the drug was generated by the electroblowing method (with vinylpyrrolidone-vinyl acetate copolymer), and the obtained fibers were formulated into tablets. Incomplete dissolution of the tablets was noticed under the circumstances of the standard dissolution test, after which a precipitated material could be filtered. The filtrate consisted of ITR and stearic acid since no magnesium content was detectable in it. In parallel with dissolution, ITR forms an insoluble associate, stabilized by hydrogen bonding, with stearic acid deriving from magnesium stearate. This is why dissolution curves do not have the plateaus at 100%. Two ways are viable to tackle this issue: change the lubricant (with sodium stearyl fumarate >95% dissolution can be accomplished) or alter the polymer in the solid dispersion to a type being able to form hydrogen bonds with ITR (e.g., hydroxypropyl methylcellulose). This work draws attention to one possible phenomenon that can lead to a deterioration of originally good dissolution of an amorphous solid dispersion.

Assessment of heat provocation tests on the human gingiva: the effect of periodontal disease and smoking.

UNLABELLED: Periodontal inflammation is associated with morphological changes in the blood vessels which may influence the regulation of gingival blood flow (GBF). Our aim was to adapt the heat provocation test to the human gingiva to assess vascular reactivity in periodontal inflammation. METHOD: GBF was recorded by Laser Doppler Flowmetry before and after heat provocation in healthy volunteers (n = 50). Heat was generated either by warm saline or a halogen lamp. The latter method was also utilized for a heat test in non-smoking and smoking patients with periodontal inflammation. The circulatory parameters were correlated to the inflammatory marker, i.e. gingival crevicular fluid (GCF) production measured by Periotron. RESULTS: Local application of heat caused a rapid, significant and transient increase in GBF regardless of the method used. The increase in the speed and not in the concentration of moving blood cells was responsible for increased GBF. Higher GCF values were correlated with increased peak flow, flux pulse amplitude and faster restoration of GBF after the test in non-smokers, but not in smokers. CONCLUSIONS: The heat test could be a valuable tool to check the vascular reactivity of gingival vessels. Moderate periodontal inflammation may facilitate gingival vascular responsiveness which can be suppressed by smoking.

New practical synthesis of Tamsulosin.

The medicine called Tamsulosin was produced 25 years ago and since then almost 10 new synthesis route has been known. Each process shows the researchers' workstyle, every year, which mainly differs in the way of separating the enantiomers. The applied reaction steps also reflect the development over the past 25 years and the new synthesis is influenced by the antecedents. The key-intermediate used in our new method is a racemic secondary amine derivative, which is unknown in the literature before and for resolving it, we worked out a quite advantegeous process. By using an optically active secondary amine, side reactions can be avoided.

Adjuvant chemotherapy following surgery in the management of uterine sarcomas.

OBJECTIVE: The aim of this study was to investigate the use of imaging tools in the diagnosis of uterine sarcomas, and to evaluate the effect of the adjuvant chemotherapy for uterine sarcomas. PATIENTS AND METHODS: The data of 29 patients with uterine sarcomas who received cytostatic polychemotherapy between 1990 and 2000 at the Oncological Division of the Ist Department of Obstetrics and Gynecology, Semmelweis University were evaluated by the authors. Symptoms leading to diagnosis and methods of diagnosis were examined. Vascular changes shown by two-dimensional, color and pulsed Doppler ultrasonography were observed. For staging the currently accepted FIGO method was adopted. Most of the patients underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH & BSO). In each case we administered adjuvant combination chemotherapy according to the CYVADIC-protocol. The effect of adjuvant chemotherapy was evaluated. RESULTS: Six patients had Stage I, ten had Stage II, 11 had Stage III, and two had Stage IV disease. The mean age of the patients was 53.6 years with a range of 22 to 77 years. Histopathologic distribution included nine leiomyosarcomas (LMS), 13 mixed mesodermal sarcomas (MMS), and seven endometrial stromal sarcomas (ESS). Although most patients experienced neutropenia following cytotoxic chemotherapy, other non-hematologic adverse effects were easy to control. The average progression-free interval was 22.14 months, in which no significant difference was found between the histologic types. Different stages showed highly varied responses: surprisingly, patients in Stage IV with lung metastases were documented to have the longest progression-free survival. The three-year survival rate for all stages was demonstrated in 34.4% of cases. Patients with progressive disease had an average survival period of 4.4 months. CONCLUSIONS: These findings suggest that adjuvant cytostatic therapy for patients with distant metastasis confined to a single organ may produce better results than expected.

A retrospective study of 27 ovarian tumors of low malignant potential.

INTRODUCTION: This study was undertaken to retrospectively review the fertility-sparing surgical treatment and long-term outcome of 27 patients with ovarian tumors of low malignant potential treated at the 1st Department of Obstetrics and Gynecology of Semmelweis University Faculty of Medicine between 1990 and 2000. MATERIALS AND METHODS: Between 1990 and 2000, 163 patients with epithelial ovarian tumors were diagnosed and treated. Of these, 27 patients were diagnosed as having low malignant potential (LMP) ovarian tumors. The authors evalutated the effect of histopathologic parameters (histologic type, grade of nuclear atypia, tumor size and tumor growth on the ovarian surface) and clinical parameters (age at diagnosis, stage of disease, and treatment modalities) on prognosis in this group of patients with a long observation time. We reviewed our experience to assess the safety of conservative surgical management of patients younger than age 40 with early stage disease, and to determine the long-term outcome of low malignant potential ovarian tumors. Medical records were reviewed on all 27 patients to determine age, gravidity, size of tumor, bilaterality, sites of extraovarian involvement, stage of disease and the operative procedure. Follow-up information was obtained from hospital records, and in some cases, by direct patient contact. Statistical comparisions were made by the chi2 test. RESULTS: The incidence of LMP tumors in our patient population was 16.5%. The patients ranged in age from 15 to 82 years (median, 45 years). The lesions were staged according to FIGO. The stage distribution was Stage IA in 20 patients, Stage IB in one patient, Stage IC in one patient, Stage IIA in one patient, Stage IIB in one patient, Stage IIC in one patient and Stage IIIA in two patients. The ovarian tumors ranged in size from 3 to 19 cm (median 9 cm) and 15% of the tumors were bilateral. All patients with LMP ovarian tumors were treated with primary surgery; those who were older than 40 (14 patients) were treated with total trans-abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH and BSO), while patients younger than 40 with early stage disease (12 patients) who wished to retain their fertility potential were treated with fertility-sparing surgery, namely unilateral salpingo-oophorectomy (USO). One patient who was younger than 40 with a Stage IIIA LMP ovarian tumor was also treated with TAH and BSO. Follow-up information was available for all 27 patients with LMP ovarian tumors. Only those patients with a minimum of two years of follow-up were included. Follow-up information from two to ten years (median, 6 years; mean, 6.5 years) revealed that all 27 patients were alive. During the period of follow-up one patient who initially had stage IIIA disease developed recurrent tumor. Fifty percent of patients who underwent conservative fertility-sparing surgical treatment (6/12) subsequently conceived. CONCLUSIONS: This study confirms the excellent prognosis for patients with low malignant potential ovarian tumors. Conservative fertility-saving surgical treatment can be offered to young patients (< 40 years) with early stage (stage I-II) disease who wish to retain their fertility potential. Up to 50% of women in this study who underwent conservative surgery subsequently conceived. The long-term outcome of LMP ovarian tumors is extremely favorable, even when long-term follow-up is extended to ten years.

Outcome of pregnancies after cold-knife conization of the uterine cervix during pregnancy.

OBJECTIVE: To determine the incidence of cervical intraepithelial neoplasia (CIN) in pregnancy and to determine the outcome of pregnancies in women treated by cold knife conization during pregnancy. METHODS: The authors retrospectively studied the cases of 19,807 pregnant patients, who presented to the 1st Department of Obstetrics and Gynecology Semmelweis University Faculty of Medicine between January 1, 1993 and December 31, 1997. Of these, there were 1,513 spontaneous abortions, 6,170 artificial abortions and 12,124 deliveries. Cytological evidence of a high-grade squamous intraepithelial lesion (LGSIL) was found in 48 pregnant patients. A low-grade squamous intraepithelial lesion (LGSIL) was found in 55 pregnant patients. All pregnant patients with HGSIL including those with satisfactory and nonsatisfactory colposcopical examinations underwent diagnostic cold knife conization during pregnancy in the second trimester. A gynecologic pathologist (Dr. Zs. Csapó) reviewed the histopathological sections. RESULTS: Overall, 44 patients had CIN, three patients had microinvasive carcinoma (FIGO stage I/A1), and one patient had neither CIN nor invasive carcinoma in the HGSIL group. Among the 48 pregnant patients with HGSIL, there were two spontaneous abortions occurring during the 21st and the 22nd gestational weeks respectively, so the pregnancy loss rate was 4.2%. Forty patients (83%) delivered at term and six patients (12.5%) at preterm. Twenty-four patients (52%) delivered vaginally and 22 (48%) by cesarean section. Comparing this data with the control group consisting of pregnant patients who had LGSIL, the difference between the two group as regards the total number of adverse pregnancy outcome cases was not significant. In the three patients with microinvasive cervical carcinoma (FIGO stage I/A1), elctive cesarean section was performed, followed by an immediate abdominal hysterectomy at term. CONCLUSION: The incidence of CIN in pregnancy was 0.22%. The incidence of microinvasive cervical carcinoma was 0.015%. Pregnant patients with CIN who underwent cold knife conization during pregnancy were not at increased risk of adverse pregnancy outcome, however they were at increased risk of cesarean delivery.

Assessment of myometrial and cervical invasion of endometrial cancer by transvaginal sonography.

INTRODUCTION: The aim of this study was to determine the efficiency of transvaginal ultrasonography in the assessment of myometrial invasion and cervical involvement (preoperative staging) of endometrial cancer. MATERIALS AND METHODS: Transvaginal ultrasonography was performed on 52 women to classify endometrial cancer with respect to myometrial invasion and cervical involvement according to the International Federation of Gynaecologists and Obstetricians recommendations for surgical staging of endometrial cancer. Endometrial cancer was diagnosed on the basis of dilatation and curettage and the degree of invasion was evaluated preoperatively by transvaginal ultrasonography. Ultrasonographic findings were compared to the surgical staging and histopathology of the surgical specimen. RESULTS: Myometrial invasion evaluated by transvaginal sonography was accurate in 46 of 52 cases (accuracy 88%, sensitivity 86%, specificity 90%, positive predictive value 92%, negative predictive value 83%). Tumor extension to the cervix was properly diagnosed in seven of ten women in which it was present. CONCLUSION: Transvaginal ultrasonography is a reliable method for assessing myometrial invasion and cervical involvement. This non-invasive method should be included as an important tool in the establishment of individualized treatment programs for women with endometrial cancer.

Differences in thermostability of thymidine kinase isoenzymes in normal ovary and ovarian carcinoma.

UNLABELLED: Thymidine kinase 1 (TK 1 EC. 2.7.1.21) the most specific and cell-cycle regulated salvage enzyme for pyrimidine nucleoside supply of DNA synthesis is a promising target to rationally designed chemo- and other therapies. The present study was undertaken to compare the heat stability of TK isoenzymes of both normal ovarian and epithelial ovarian cancer cells. Tissue extracts of epithelial ovarian carcinomas (N = 7) and normal ovaries (N = 9) were analyzed for thymidine kinase activity using the polyethyleneimine-cellulose disc radioassay. The TK activity in extracts of ovarian carcinomas was 12-fold higher than in extracts of normal ovaries. The TK activity of ovarian carcinomas decreased significantly even after 30 minutes incubation at 37 degrees C while, the enzyme activity of normal ovarian extracts was more stable and decreased to the same extent after 120 minutes. The half-life time of the enzyme activity was 82 min in the normal but only 36 minutes in the cancer tissue extract at 37 degrees C. CONCLUSION: The TK activity of malignant ovarian cells was much higher but more unstable (t1/2 = 36 minutes) than the enzyme isolated from healthy ovaries (t1/2 = 82 minutes). This profound difference in thermostability might provide the molecular background for hyperthermia combined with chemotherapy as a promising treatment for ovarian malignancies.

[Ovarian carcinoma of low malignant potential treated at the 1(st) Department of Obstetrics and Gynecology Semmelweis University Faculty of Medicine, between 1990 and 2000] / Az alacsony malignitású petefészek-daganatok kezelésével szerzett tapasztalataink Klinikánk 10 éves beteganyagában (1990-2000).

The authors analyzed the epidemiologic and histological characteristics and the management of ovarian carcinoma of low malignant potential (LMP) at a university hospital between 1990 and 2000. The authors carried out a retrospective study reviewing hospital charts. Based on the records experience with 29 such tumors is peresented. Of these 20 (74%) were of the serous variety, 7 (26%) were mucinous. LMP tumors accounted for 16% of proliferating epithelial ovarian tumors. They occured at a mean age of 45 years. The LMP tumors were bilateral in 12% of the cases. The majority of patients (87%) with LMP tumors presented with early stage disease. Tumor markers such as CA-125 were not always elevated as in invasive ovarian carcinoma. Laboratory investigations have not demonstrated that these tumors represent an intermediate step between benign ovarian tumors and carcinoma. The recommended therapy is surgical, consisting of total abdominal hysterectomy, bilateral salpingo-oophorectomy, peritoneal washings, and tumor debulking. Conservative surgery consisting of unilateral salpingo-oophorectomy is considered to be an appropriate treatment for young women with early stage LMP ovarian tumors who wish to retain their fertility potential. 50 percent of women who underwent conservative surgery subsequently conceived in this study. There were no recurrences in the study group, so the authors conclude that the long term outcome of LMP tumors is extremely favorable.

[Current status of the management of patients with malignant ovarian cancer in Hungary]. / A rosszindulatú petefészek-daganatos betegek ellátásának aktuális helyzete hazánkban.

The authors analyzed data of patients suffering from ovarian cancer in a one year period (1.1.1994-31. 12.1994) in Hungary. Data of 584 patients of 95 gynecological wards were found to be appropriate for detailed evaluation. With respect to the latest international classification staging of the disease was controlled in every case by histological results and all available clinical data. Data were analyzed with special emphasis on the type of medical department involved, and the implied methods and diagnostic procedures in the establishment of diagnosis of ovarian cancer. Comparison was made of age and stage distribution of cervical, endometrial and ovarian cancer cases in Hungary. Therapeutic approaches of ovarian cancer are discussed, as well as the operative procedures, with special emphasis of the size of residual tumor, and different types of cytostatic chemotherapy. Actual situation of treatment is evaluated, taking into account the possibilities of operative and pharmacological interventions. The authors propose the proper staging and grading establishment of ovarian cancer cases with respect to the international recommendations and protocols in order to achieve a high level of treatment.

[Management of patients with endometrial cancer in Hungary]. / A méhtestrákos betegek ellátásának helyzete hazánkban.

The authors made an investigation of patients suffering from endometrial cancer during a one year period in Hungary. Out of the data of 105 gynecological wards from the 1051 patients 1043 cases were evaluated. Staging was controlled having the histological results and the clinical data on every sheet, fitting the requirements of the latest international classification, and taking into account the grading of histological differentiation. They evaluated the place and the way of diagnosis and the distribution of the methods leading to definitive diagnosis. The different examinations to state a definitive diagnosis were reported. Distributions of age and stages were compared with the published Hungarian cases. Actual situation of management was criticized, studying the present possibilities of operative, irradiative and chemical treatment. They suggest more particular determination of staging and grading of patients suffering from endometrial cancer in order to provide uniform treatment that fits the international requirements.

[Management of cervical cancer patients in Hungary]. / A méhnyakrákos betegek kezelése hazánkban.

The authors made an exact investigation of the treatment of patients suffering from cervical cancer during one year period. Out of the data of 101 gynecological wards 1700 cases were evaluated. The authors evaluated the different ways of treatment with respect to the international requirements on the base of hystological results. They elaborated the operative methods in every stage of cervical cancers, with more details on radical hysterectomy and regional lymphadenectomy. The authors suggest that patients suffering from cervical cancer should be treated by standardized principles based on international scientific experiences.

[Management of cervical cancer patients in Hungary. (Detection)]. / A méhnyakrákos betegek ellátásának aktuális helyzete hazánkban (A felismerés).

The authors made an exact investigation of the patients suffering from cervical cancer during a one-year period. Out of the data of more than 1800 patients of 101 gynaecological wards, 17,006 cases were evaluated. The present publication deals with the issue of diagnosis. Staging was controlled by data sheets, having the histological diagnosis at hand and with due respect to the most recent international staging. The way of diagnosing cervical cancer and the distribution of examinations guaranteeing definite diagnosis were investigated. The different diagnostic methods were evaluated on the basis of the expansion of the different medical interventions. The authors report on the medical interventions performed in the interest of making a definite diagnosis. Comparisons are made, on the basis of age and staging, with the earlier Hungarian and international results and findings. Finally, the authors propose that all the gynaecological examination should, at the same time, be cancer screening, and a proposal is made on the methods of doing it.