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.

[The importance of a gynecological teenager consulting hour by the example of "First Love"]. / Die Bedeutung einer gynäkologischen Teenagersprechstunde am Beispiel von "First Love".

There are worldwide deficits in sexual and contraceptive education of teenagers and the effects on their contraceptive behaviour. It is worthwhile to offer services tailored to the needs of adolescent girls. This can be demonstrated by the experience of 10 years work of 'First Love', a gynaecological out-patient department for teenagers at Rudolfstiftung Hospital, Vienna. Together with the girls and their partners, individual concepts for safe, responsible and satisfying sexuality are developed. A multidisciplinary team, easy access, the possibility of remaining anonymous and free-of-charge consultations are the major principles in this work. There are also a lot of preventive health care issues: as young girls experience their first gynaecological examination as painless and less embarrassing than expected, they will agree to routine check-ups in their future life.

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.

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.

A significant correlation between melatonin deficiency and endometrial cancer.

Endometrial cancer is the most common pelvic genital cancer in women. Its incidence is increasing. Unlike the successful screening method for cervical cancer, there is no such equivalent procedure for the early diagnosis of endometrial cancer. Screening procedures currently being tested are too insensitive and nonspecific while diagnostics are either too complex or invasive. In Austria, a multicenter study was begun to search for parameters appropriate for a screening program. 138 women were selected based on anamnestic, serologic and cytologic risk factors. 68 women were diagnosed with endometrial cancer, 70 patients had abnormal bleeding. There were no significant differences in age and menopausal status. Secondary diseases including diabetes mellitus, hypertonia and adipositas were evenly distributed in both groups. In addition to the routine hormone analyses, we tested the patients' plasma for differences in melatonin levels. We found a significant correlation (p < 0.001) between melatonin plasma levels and the presence of endometrial cancer. The mean plasma melatonin value was 6.1 pg/ml in the cancer-positive group and 33.2 pg/ml in the cancer-negative control group resulting in a 6-fold difference between the two groups. We conclude that decreasing melatonin plasma levels may be an indicator of endometrial cancer and that this may therefore be used as a reliable screening parameter.

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.

The clinical effect of uterine hyperflexion and cervical elongation in cases of pelviscopic hysterectomy.

In a retrospective study of women who had undergone pelviscopic hysterectomies in the last 2 years, we focused on postoperative cyclic spotting. Preoperatively, a regular, cyclic menstruation and a premenopausal sexual hormone constellation were common to all patients. In the first group (n = 29), spotting occurred only in association with two uterine anatomical varieties: uterine hyperflexion and cervical elongation. The second group (n = 18), in which intraoperative internal electrocoagulation of the residual cervical envelope was performed, no spotting occurred despite the presence of uterine hyperflexion and cervical elongation. This procedure prevents the occurrence of postoperative spotting in cases of uterine anatomical varieties.

[Laparoscopic interventions in gynecology]. / Laparoskopische Eingriffe in der Gynäkologie.

Gynecological surgery is performed in a difficult anatomical area of vital organs close to the pelvic wall. It requires precise hemostasis to prevent blood loss and postoperative complications. Both blood loss and complications are reduced by pelviscopic operation techniques. Patients who undergo gynecological pelviscopic operations often experience in comparison to laparotomy less fever, require less postoperative analgesia and are able to tolerate a full diet within 24 hours of surgery. Very often they have a faster recovery and a shorter hospital stay than patients undergoing traditional abdominal or transvaginal operations. The endoscopic operative technique lays the foundation for minimal invasive surgery. The mainly organ-resecting gynecological laparotomy, aiming to avoid recurrence, is increasingly being replaced by pelviscopic organ preservative techniques. Meanwhile we tend to perform many hysterectomies laparoscopically assisted (LAVH). It avoids laparotomy in casesa of adhesions and high uterine tissue mass and seems to lower intraoperative risks such as infection by strong operative restriction of the vaginal approach. CISH (classic intrafascial S*E*M*M* hysterectomy, S*E*M*M denoting "serrated edge macro-morcellated") even leaves the pelvic floor intact. Furthermore, we perform pelviscopic operations in cases of endometriosis, benign tumors of the ovaries, ectopic pregnancies and genital malformations (i.e., Vecchietti genitoplasty in the MRK-syndrome).

Pelvic promontory fixation of the vaginal vault in sixty-two patients with prolapse after hysterectomy.

During a 20 year study period from 1969 to 1991, 62 patients underwent abdominal colpopexy between a prolapsed vaginal vault and the cartilage of the promontory. A simple surgical operation technique introduced in 1954 was modified and tested on these women. Hysterectomy, either transabdominal or vaginal, had previously been performed upon all of these patients. In some instances, short lyodura loops were used to suspend the vagina. In all operations, the suspension was covered with peritoneum of the lumbosacral area. Functional and cosmetic results were excellent and urinary stress incontinence could often be improved. It is suggested that this type of procedure is indicated in subtotal and total prolapse of the vagina after hysterectomy in patients who desire to preserve sexual function.

[Resection of cervical glands in pelviscopic hysterectomy]. / Zur Resektion zervikaler Drüsen bei der pelviskopischen Hysterektomie.

A case of pelviscopic hysterectomy with uterine hyperflexion and cervical elongation is presented. In this case we were forced to extirpate the cervical fascia because of uterine hemorrhage by laparotomy after the cervical tissue punch had been performed. The histological findings were supravaginal cervical glands. Complete removal of cervical glandular tissue may be undetermined by hyperflected uteri and cervical elongation.