[Treatment of Chronic Functional Constipation during Pregnancy and Lactation]. / Behandlung der chronischen funktionellen Obstipation in der Schwangerschaft und Stillperiode.

Natural fibres (bulk-forming agents), docusate sodium (stool-softener), mineral oils (lubricant laxatives), macrogol (polyethylene glycol, PEG), sugars and sugar alcohols (osmotic laxatives) and anthraquinones and diphenolic laxatives (stimulant laxatives) seem to be safe medicaments regarding teratogenicity and lactation. The US Food and Drug Administration (FDA) risk categories for these substances taken during pregnancy and lactation are often the result of the lack of studies than of evidence-based information. So risk categories do not help in the decision-making for the right laxative. Alternative solutions such as proposals of the American College of Gastroenterology's Committee on FDA related matters, (ACG-FDA) and the Motherisk Programme try to improve decision-making. For newer compounds such as chloride-channel-activators and procinetics no data regarding safe use in pregnancy and during breast-feeding are available as yet. We suggest the use of macrogol and lactulose as the first-line therapy in treating chronic constipation during pregnancy. Macrogol shows some advantages, such as faster onset of bowel action and fewer flatulences. If this treatment does not work or starts but then stops working, we recommend in the second and third trimenon a second-line treatment with diphenolic laxatives such as bisacodyl and and sodium picosulfate. During pregnancy the decision on the application of these laxatives is largely determined by the side-effects of tenesmus associated with preterm births. During lactation we recommend macrogol (preferable to lactulose due to the lack of data), lactulose, bisacodyl and sodium picosulfate, according to the nature of the conditions.

Computerized in vivo classification of methylene blue stained fallopian tube mucosal damage: preliminary results.

OBJECTIVE: Fertiloscopy is a simple minimal invasive method which allows salpingoscopy and microsalpingoscopy in order to examine the mucosa of the fallopian tubes of patients with unexplained infertility. Infectious tubal damage is a common cause of tubal infertility. In 1998 it was demonstrated that nuclear staining of cellular nuclei during microsalpingoscopy with methylene blue provides a simple in vivo method to evaluate cellular damage of the tubal epithelium. The purpose of this study was to introduce and statistically test a new computerized method to objectively evaluate the extent of tubal damage. DESIGN OF RETROSPECTIVE STUDY: Cooperation of two Departments of Gynecology and Obstetrics (Krankenanstalt Rudolfstiftung, Vienna, Austria and CRES Center, Hôpital Natecia, Lyon, France) with the University of Art and Design, Linz, Austria and University Hospital, Vienna, Austria. MATERIALS AND METHODS: Microsalpingoscopic images from ten female patients, aged between 18 and 45 years with primary infertility, showing stained nuclei in damaged intrafallopian tubal epithelium were provided by Antoine Watrelot, CRES Center, Hôpital Natecia, Lyon, France. These images were evaluated by an experienced medical expert staff examiner and a computerized standard method called cross-correlation and template matching. The obtained numbers of nuclear stainings were statistically evaluated. RESULTS: Computerized evaluation of nuclear staining of damaged intrafallopian epithelial cells in female patients with infertility obtains similar but more reproducible results compared to manual evaluation (p = 0.007). CONCLUSION: Normalized cross-correlation can be used to measure tubal damage diagnosed by in vivo methylene blue dyeing during microsalpingoscopy and might facilitate the decision for in vitro fertilisation in patients with unclear unexplained infertility in further studies.

How to make hypericin water-soluble.

UNLABELLED: Hypericin, isolated from Hypericum perforatum, is an effective photodynamic substance as demonstrated by various studies. Practical forms of applications of hypericin solutions for systemic use and introduction into body cavities are, however, lacking. We developed an aqueous solution of hypericin non-covalently bound to polyvinylpyrrolidone (PVP). PVP is a poly-N-vinylamide of various degrees of polymerization and forms of intermolecular crosslinks suitable for diagnostic and therapeutic applications. We used PVP (molecular weights of PVP between 10 kD and 40 kD) as a complex forming agent to prepare hypericin for photodynamic therapy and diagnostics. In pure water, hypericin forms aggregates which are non-soluble and non-fluorescent. The hypericin-PVP complex binds more than 1000 mg of hypericin in presence of 100 g PVP or less and is soluble in 1 liter of pure water. Aqueous complex solutions of hypericin-PVP display a characteristic absorption spectrum and fluorescence emission band around 600 nm wavelength. Varying concentrations of hypericin do not cause a blue- or red-shift in the absorption maximum at 595 nm. Excitation at 200 nm to 500 nm leads to emission at 590 nm; a property conducive to diagnostic investigations both in vitro and in vivo. Furthermore, hypericin-PVP exhibits high photostability in the presence of oxygen and broad band light which ensures reproducible photodynamic therapy and diagnosis. CONCLUSION: Hypericin forms liquid molecular chromophore complexes in water when bound to PVP thus allowing investigations in biological media.

Hypericin--the facts about a controversial agent.

Hypericin is a naturally occurring substance found in the common St. John's Wort (Hypericum species) and can also be synthesized from the anthraquinone derivative emodin. As the main component of Hypericum perforatum, it has traditionally been used throughout the history of folk medicine. In the last three decades, hypericin has also become the subject of intensive biochemical research and is proving to be a multifunctional agent in drug and medicinal applications. Recent studies report antidepressive, antineoplastic, antitumor and antiviral (human immunodeficiency and hepatitis C virus) activities of hypericin; intriguing information even if confirmation of data is incomplete and mechanisms of these activities still remain largely unexplained. In other contemporary studies, screening hypericin for inhibitory effects on various pharmaceutically important enzymes such as MAO (monoaminoxidase), PKC (protein kinase C), dopamine-beta-hydroxylase, reverse transcriptase, telomerase and CYP (cytochrome P450), has yielded results supporting therapeutic potential. Research of hypericin and its effect on GABA-activated (gamma amino butyric acid) currents and NMDA (N-methyl-D-aspartat) receptors also indicate the therapeutic potential of this substance whereby new insights in stroke research (apoplexy) are expected. Also in the relatively newly established fields of medical photochemistry and photobiology, intensive research reveals hypericin to be a promising novel therapeutic and diagnostic agent in treatment and detection of cancer (photodynamic activation of free radical production). Hypericin is not new to the research community, but it is achieving a new and promising status as an effective agent in medical diagnostic and therapeutic applications. New, although controversial data, over the recent years dictate further research, re-evaluation and discussion of this substance. Our up-to-date summary of hypericin, its activities and potentials, is aimed to contribute to this process.

Photodynamic action of meta-tetrahydroxyphenylchlorin (mTHPC) on an ovarian cancer cell line.

Meta-tetrahydroxyphenylchlorin (mTHPC) exhibits significant cytotoxicity against a variety of human cells in culture in combination with light, but also in dark reaction. The ovarian cancer cell line SK-OV3 was incubated with various concentrations of mTHPC and in comparison with Taxol and Cisplatin: then the effect on cell growth was determined. mTHPC exhibited an IC50 of 0.9 muM after 24 hours incubation (IC50 of 1.25 after 2 hours), whereas Cisplatin and Taxol, which, have been used as first line agents for the treatment of ovarian carcinomas, inhibited cell proliferation with an IC50 concentration of 4.6 muM and 78 nM after 24 hours incubation, respectively. Incubation of SK-OV3 cells with mTHPC for 5 days resulted in cytostatic cytotoxicity at a concentration of 0.5 muM. The photodynamic effect of mTHPC depends/among other parameters/on the concentration of the dye present. In combination with light (approximately 15 J/cm2) a linear relationship between the dose of mTHPC and the amount of necrotic cells was observable. Higher concentrations of mTHPC caused necrosis of the ovarian tumor cells. The intracellular concentration of mTHPC showed a linear increase up to 28.6 nM (incubation concentration). In summary, these studies demonstrated that mTHPC exhibits potent antiproliferative activity by inducing necrosis after application of light. MTHPC might be a promising agent with cytostatic and photodynamic properties for the treatment of metastasing ovarian carcinomas. A sensitive PCR method was not able to show the induction of apoptosis in the SK-OV3 ovarian cell line. Using propidium staining, it could be proved that the cell death was caused by necrosis and not through apoptosis after irradiation with light.

Impact of hysteroscopy on disease-free survival in clinically stage I endometrial cancer patients.

Recent data strongly suggest tumor cell dissemination of endometrial carcinoma cells in the course of fluid hysteroscopy. In patients who had endometrial cancer which was (except for peritoneal cytology) confined to the uterus, the disease-free survival (DFS) of 135 patients who underwent hysteroscopy prior to staging laparotomy was compared with the DFS of 127 patients without hysteroscopy. After a median follow-up of 23 months, 10 patients experienced tumor recurrence. Although there was a trend towards a higher incidence of positive peritoneal cytology at laparotomy in patients who underwent hysteroscopy, this difference did not achieve statistical significance (P = 0.47). For 5 years, the DFS was 92.4% in patients with hysteroscopy and 84.7% in patients without hysteroscopy before laparotomy (log-rank, P = 0.782). Our data therefore suggest a similar short-term DFS in endometrial cancer patients with and without hysteroscopy prior to laparotomy.

5-aminolevulinic acid-mediated photodynamic therapy of intraepithelial neoplasia and human papillomavirus of the uterine cervix--a new experimental approach.

The aim of this study was to treat patients for ectocervical dysplasia [cervical intraepithelial neoplasia (CIN) grades 1 and 2] and associated human papilloma virus (HPV) infections with photodynamic therapy (PDT). In 20 patients, 5-aminolevulinic acid (5-ALA, 12% w/v) was applied topically with a cervical cap 8 h prior to illumination. A thermal light source (150 W halogen lamp) emitting a broadband red light (total energy: 100 J/cm2, fluence rate: 90 mW/cm2) was used for superficial illumination of the portio. In addition, an Nd:YAG pumped dye laser (652 nm) was used to illuminate the cervical canal (total energy: 50 J/cm2, fluence rate: 300 mW/cm2). Preliminary results of follow-ups at 1, 3, 6, and 9 months posttherapy showed a cytological improvement in the grading of the PAP smears in 19 patients and the eradication of cervical HPV in 80%. These results demonstrate that ectocervical dysplasia and associated HPV infections can be treated by PDT.

Antagonistic effects of combination photosensitization by hypericin, meso-tetrahydroxyphenylchlorin (mTHPC) and photofrin II on Staphylococcus aureus.

Photodynamic therapy involves the application of a photosensitizer activated by visible light to generate cytotoxic reactive oxygen. In addition to clinical investigations, in vitro studies concerning photodynamic potency of sensitizers as well as quantification of illumination procedures are necessary. In our investigation, the objective was to evaluate not only the effects of photosensitizer and light on Gram-positive Staphylococcus aureus, but also to investigate possible synergistic or antagonistic effects of these sensitizers. Therefore, we used hypericin, Photofrin II, porfimer sodium and meso-tetrahydroxyphenylchlorin (mTHPC) alone, as well as in combination. Log-phase cells of S. aureus exhibited a marked sensitivity to white thermal light irradiation in the presence of Photofrin II and mTHPC. However, hypericin caused a rather stimulated growth expressed in increased optical density (OD) and increase of total cell count (TCC) of the culture. Combination sensitization of S. aureus by Photofrin II and mTHPC with hypericin likewise caused a stimulation of bacterial growth. No synergistic effects were obtained by combination of Photofrin II and mTHPC; photoresponse of S. aureus was rather decreased by using combined porphyrins. In comparison, TCC and colony-forming units (CFU) were suppressed in the presence of mTHPC after an illumination procedure as well as in dark reactions. These effects were also obtained in the combination photosensitization by mTHPC and Photofrin II. In the presence the of hypericin, photodynamic effects of mTHPC and Photofrin II were inhibited. It was finally concluded that hypericin in our model is not a proper sensitizer for combination photo-sensitization due to antagonistic effects on photodynamic activity of mTHPC and Photofrin II.

Multiple endometrial stromal nodules with sparse cysts and glands in the lung--a nodular variation of endometriosis that may mimic metastases of sarcoma.

We report an unusual case of a nodular variation of pulmonary endometriosis. To our knowledge, there is no previous report on a morphological investigation of this entity. The etiology of this rare condition is still a matter of discussion. The well-circumscribed nodular mass is composed of cells identical to, or closely resembling, those of endometrial stroma containing sparse cysts and glands. Immunohistochemically, the cells showed an extensive co-expression of cytokeratin AE1/AE3 and vimentin and were highly positive for progesterone receptor (PRICA) and estrogen receptor (ERICA). Cells lining the cysts and glands as a monolayer were reactive for Ber-Ep4, cytokeratin Pan and cytokeratin AE1/AE3 and negative to all other markers used including PRICA and ERICA. The differential diagnosis of this entity included fibrous tumor of the pleura and metastatic low-grade-endometrial-stromal-sarcoma. The morphological findings are correlated with immunohistochemical studies and results of cell image analysis. This study details the clinicopathological features of the nodular variation of pulmonary endometriosis.

Endometrial cancer: accuracy of the finding of a well differentiated tumor at dilatation and curettage compared to the findings at subsequent hysterectomy.

The objective of this study was to examine the accuracy of the finding of a histologically well differentiated endometrial carcinoma at dilatation and curettage (D & C) prior to hysterectomy. A retrospective multicentric chart review of 137 endometrial cancer patients was conducted, including all patients in whom a well differentiated endometrial carcinoma had been diagnosed by D & C. Histopathologic grading as determined by D & C was compared with the grading established at the final histologic examination after hysterectomy. Seventy-eight percent of all cases in which a well differentiated tumor was diagnosed with D & C were confirmed as well differentiated endometrial carcinomas, whereas 20.4% had to be upgraded as moderately differentiated tumors after evaluation of the hysterectomy specimen. In one case in which a uterine adenocarcinoma was diagnosed by D & C, a well differentiated adenocarcinoma was found to be combined with a carcinosarcoma in the hysterectomy specimen. In order to avoid false findings of a well differentiated tumor, the histologic grade should be confirmed by intraoperative frozen section examination. This is especially important in cases in which surgical staging was not planned initially.

[Experimental investigations and clinical use of photodynamic therapy (PDT) in the Rudolf Foundation Hospital]. / Experimentelle Forschung und klinische Anwendung der photodynamischen Therapie an der Krankenanstalt Rudolfstiftung.

This article addresses experimental investigations and the clinical use of PDT in the Rudolfstiftung Hospital, Vienna. We investigated mesotetrahydroxyphenylchlorine (mTHPC) and the photosensitizer hematoporphyrin derivative alone or in combination to prove photodynamic antibacterial effects on Staphylococcus aureus (wild type). mTHPC showed antibacterial toxicity in the dark; hematoporphyrin derivative showed suppressive growth effects only after white-light illumination. Photodynamic activity by the combination of both dyes was obtained in a roughly additive manner. Furthermore, we observed the development of resistance of erythromycin after the illumination procedure with hematoporphyrin derivative. Wild-type S. aureus developed no resistance to the other antibiotics tested. Furthermore, long-term follow-up examinations proved mTHPC-mediated PDT as a possible adjuvant intraoperative therapy in cases of relapses of gynecologic carcinomas. PDT is a tissue-selective and simple intervention. It shows few side effects, and, therefore, it reduces the overall burden of tumor patients. In another clinical investigation, we used 5-aminolevulinic acid-based PDT to treat intraepithelial neoplasia and human papillomavirus of the uterine cervix. 33 of 38 (86,8%) patients with superficial cervical intraepithelial neoplasia grades I and II were treated successfully with PDT. Eradication of human papillomavirus infections was successfully performed in 80% of the cases.

Does the in-vitro efficiency of meso-tetrahydroxy-phenyl-chlorin depend on pre-treatment of sensitizer?

The efficiency of a new photosensitizer of the second generation, meso-tetra-hydroxyphenyl-chlorin (mTHPC), which has a strong absorption at 652 nm, was investigated by oxygen consumption measurements and membrane integrity testing. The experiments proved a great increase in the efficiency of mTHPC after preincubation at 37 degrees C for 24 hours. From these findings it can be assumed that tumor cells can be treated in an optimal way with PDT after a longer delay following drug administration.

Clinical effect of meso-tetrahydroxyphenylchlorine based photodynamic therapy in recurrent carcinoma of the ovary: preliminary results.

This article addresses the use of meso-tetrahydroxyphenylchlorin-based photodynamic therapy (m-THPC-PDT) to treat recurrent gynaecologic malignancies of the ovary. Photodynamic therapy is an experimental approach in the treatment of neoplasms and results indicate it is a highly tissue selective, relatively simple intervention with few side effects, therefore reducing the overall burden on the patient. Of the three patients involved in the initial study, two were treated solely with photodynamic therapy by laparoscopy, and one underwent additional palliative debulking surgery of metastatic tumours. After a post-operative period of more than two years all three women remained free of relapses.

Elevated serum melatonin levels during human late pregnancy and labour.

Melatonin (MLT) shows an influence on gonadal steroid genesis, and has soporific effects. Serum MLT levels were examined during late pregnancy and 4 days after delivery in 25 women. Circulating levels of melatonin were analysed as integrated values (areas under the curve [AUC]) over 24 hours, 5 to 2 days before and 4 days after delivery. Antepartum AUCs were significantly increased compared with postpartum AUCs. Additionally, MLT levels were measured every 2 hours in a subgroup of 11 women during spontaneous labour between 08.00 and 12.00 h at a time when physiological serum MLT levels were low. Increased MLT levels were determined and compared to MLT levels measured in a previous evaluation of the antepartum AUCs. Elevated serum MLT levels during late-pregnancy and labour may influence the concentration of receptors of gonadal steroids in the gravid uterus at term and the psychic perception of painful uterine contractions during labour.

[Sarcoma botryoides in the pediatric vagina--a soft tissue sarcoma with good prognosis]. / Das Sarcoma Botryoides der kindlichen Vagina--Ein Weichteilsarkom mit guten Heilungschancen.

Although rare, sarcoma botryoides of the vagina in infants is a highly aggressive soft tissue tumour. Former opinions suggesting exenterative surgery and radiation to improve the dismal outcome in these young children, are outdated. Due to balanced therapies (topical tumourectomy, chemotherapy and radiation adjusted to tumour stage) cure of these sarcomas may be expected dependent on tumour stage, localisation and response to chemotherapy. The rate of complete remissions has increased in recent years. We report on an eighteen-month old girl with complete remission of tumour stage IIA who had been treated according to the CWS 91 protocol. Diagnosis and treatment were performed in March 1994 at the age of six months. We observed the patient in complete remission for 8 months (till September 1995).

A new approach to cancer therapy due to appropriate uptake and retention kinetics of meta-tetrahydroxy-phenylchlorin in a human fibroblast cell line.

Studies have shown that meta-tetrahydroxy-phenylchlorin is an efficient tumor targeting agent for laser photodynamic therapy. The effectiveness of this approach for cancer treatment depends on drug concentration, incubation time and extracellular protein. We studied uptake and retention kinetics of mTHPC in a human fibroblast cell line. Our results clearly demonstrate a difference in the amount of extracellular mTHPC at an incubation temperature of 37 degrees C compared to 20 degrees C and 4 degrees C. pH-values were always constant and not responsible for the increase. Furthermore, both absorption and fluorescence of mTHPC increase when incubated at normal human body temperature. Incubation of human fibroblast cells with mTHPC (10 micg/mL) showed that intracellular mTHPC increases in a linear manner reaching saturation after 24 hours and declining until 48 hours with concommitant increase of supernatant mTHPC. Therefore, we believe that tumor cells can be treated optimally with PDT following a delay > 24 hours after drug administration with a minimum of damage to surrounding normal tissues.