[Bioavailability of 17 beta-estradiol after transdermal administration--dependence on the patch system]. / Bioverfügbarkeit von 17 beta-Oestradiol nach transdermaler Applikation--Abhängigkeit vom Pflastersystem.

The objective of this study was to compare the pharmacokinetics of serum estradiol concentrations after application of two different transdermal estradiol delivery systems. Ten postmenopausal women (E2 < or = 30 pg/ml; follicle-stimulating hormone > or = 30 mIE/ml) were prospectively randomized to a crossover treatment protocol separated by a 7-day wash out period. The absorption of estradiol was measured after application of a patch either containing 4.0 mg of E2 in a reservoir system or 1.8 mg of E2 in a specially designed matrix system. Although the increase of serum estradiol concentrations after application of the patches with the matrix system was slightly delayed, mean E2 levels over the whole observation period of 80 hours were significantly higher than those achieved with the reservoir system (difference of mean values: 5.1 pg/ml; p < 0.05). This observation was most striking at the end of the observation period and after removal of the patches. Yet, fluctuations of hormone concentrations were greater with the matrix system patches, and the areas under the E2 concentration-time curves were slightly but not significantly increased as compared to these of the patches with the reservoir system (3211 +/- 584 vs. 2556 +/- 249 pg/ml x h). In conclusion, both transdermal estradiol delivery systems are well suited for postmenopausal hormone substitution providing stable serum estradiol concentrations at about 50 pg/ml, with the matrix system possibly increasing the life span of the patch and thus the recommended application period.

Retrospective study on laxative use and melanosis coli as risk factors for colorectal neoplasma.

In a retrospective study a cohort of 2,277 patients was defined by colonoscopy. Among other factors it was tested whether in these patients laxative use or the endoscopically diagnosed presence of melanosis coli were risk factors related to colorectal neoplasma. In comparison to patients taking no laxatives there was no significant increase in colorectal cancer rate either in laxative users or in patients with melanosis coli. However, there was a statistically significant association between the occurrence of colorectal adenomas and laxative use (relative risk of all patients exposed to laxatives = 1.72; of patients exposed to laxatives without melanosis coli = 1.47). The relative risk of adenoma development in patients with melanosis coli was 2.19. Taking into account that polyps can be diagnosed in the dark mucosa of melanosis coli patients more easily, even this relative risk of 2.19 seems to be related to a generally enhanced risk of laxative intake rather than to a special group of (anthranoid containing) laxatives.

Good clinical practice and phytotherapy.

The GCP Guideline of the European Community on the performance of clinical trials became obligatory in June 1991. As the GCP standards have mainly been set for innovative drugs, there is a certain danger that these criteria could not be fulfilled by medicines used in phytotherapy. As regards, the chances and risks of the European guideline, especially for herbal medicines, the differences between chemically-defined and herbal drugs, as well as the extent, to which herbal medicines might be concerned by the guideline, have to be taken into account. Herbal medicines are different from chemically defined medicines in their character as well as in their medicinal use. They always contain a mixture of numerous substances. Data on preclinical investigations are often incomplete, whereas, on the other hand, physicians and patients have a long-term experience in applying these medicines. They are, in general, well-tolerated and therefore suitable for the treatment of chronic diseases. Due to a characteristic taste and smell, the production of placebos is often impossible. The GCP directive also contains basic elements concerning chemically defined drugs as well as herbal medicines in a similar way.

Diamine oxidase activities in the large bowel mucosa of ulcerative colitis patients.

The term colitis suggests mucosal inflammation as the key event. However, it may be that the disease starts with mucosal hyperproliferation, and inflammation of the impaired mucosa is a succeeding event. Therefore we studied the activity of the intestinal diamine oxidase (DAO) in ulcerative colitis (UC). This enzyme was shown to have a mucosal antiproliferative function. Biopsy specimens of 30 patients having a normal rectosigmoidal mucosa showed a DAO activity of 22.8 nmol/min g. In 12 UC patients the DAO activity was 2.7 nmol/min g (p = 0.01). In 3 patients where UC was in remission the DAO activity was 103, 107 and 208 nmol/min g, indicating an antiproliferative rebound effect. Together with the strongly reduced monoamine oxidase (MAO) activity, the decrease in DAO activity indicates that the large bowel in UC is unable to produce a proliferation terminating substance (probably gamma-aminobutyrate) derived from polyamine metabolism by oxidative deamination (DAO) or by the interconversion pathway (MAO).

Early alterations of rat intestinal diamine oxidase activity by azoxymethane, an intestinal carcinogen.

Some mutagenic hydrazino compounds are also diamine oxidase inhibitors. Therefore, this interrelationship was studied for the intestinal carcinogen azoxymethane. In vitro, azoxymethane was a very weak inhibitor of rat intestinal diamine oxidase activity. In vivo, after subcutaneous injection of a single dose of azoxymethane, diamine oxidase activity was increased in the duodenum but was mainly inhibited in the colon. Intestinal diamine oxidase activity may then be influenced by regulatory processes induced by azoxymethane rather than by a direct effect.

The histamine-diamine oxidase system and mucosal proliferation under the influence of aminoguanidine and seventy percent resection of the rat small intestine.

We have suggested previously that the histamine-diamine oxidase system is involved in cell proliferation. Therefore, the diamine oxidase activity and the histamine content were studied during mucosal proliferation induced by 70% resection of the small intestine of the rat with and without aminoguanidine (AG), a specific inhibitor of diamine oxidase (DAO). The DAO activity underwent a marked alteration during the period of mucosal proliferation, probably as an expression of an antiproliferative regulation mechanism. The histamine content decreased in the proliferating mucosa. No influence of AG on mucosal proliferation could be found, which might be due to a compensatory activity of the interconversion pathway.

Large bowel tumors and diamine oxidase (DAO) activity in patients: a new approach for risk group identification.

In the intestinal mucosa, diamine oxidase (DAO) seems to be involved in a feed-back regulation mechanism for the termination of proliferation. Therefore, we studied the DAO activity in large bowel tumors and in the non-affected mucosa of these patients in comparison with patients having a normal large mucosa. The DAO activity in the tumor tissue itself was diminished by 85% as compared to the surrounding mucosa. Comparing the colonic mucosa of normal and tumor bearing individuals, the DAO activity in cancer patients was diminished by 22%, while it was elevated by 64% in patients with polyps (biphasic response of the DAO activity). Histologically proven hyperproliferative mucosal alterations were indicated by a reduced DAO activity with 75% sensitivity and 42% specificity. It remains open whether this limited specificity may indicate a more sensitive reaction of the DAO activity to proliferative mucosal alterations than the histological examinations.

The intestinal diamine oxidase activity under the influence of adaptive proliferation of the intestinal mucosa--a proliferation terminating principle?

Under clinical conditions, intestinal mucosal hyperproliferation together with a reduced diamine oxidase (DAO) activity was found in inflammatory and neoplastic diseases. Therefore, we studied the influence on DAO activity of a regulated mucosal proliferation as obtained following partial small bowel resection in a rat model. A statistically significant, more than 4-fold elevation of the enzymic activity was observed during the first days after partial resection. At the peak of mucosal proliferation (8th. postoperative day) the DAO activity was significantly reduced by about 50% of the initial value. We suggest that the DAO may be involved in a negative feed-back control mechanism of mucosal proliferation.

[Evaluating endoscopy]. / Bewertung der Endoskopie.

Endoscopy is a safe technique with a sensitivity and specificity superior to those of conventional diagnostic procedures, which it has consequently replaced. In doing so, it has also altered many diagnostic and therapeutic concepts. Moreover, endoscopy has positively influenced the previously unaffected course of certain diseases, e.g. upper G. I. bleeding. Endoscopy benefits both the patient and the physician. Although no complete cost-benefit analysis is available, preliminary reports have been favourable. These aspects indicate that endoscopy is highly valuable in a clinical setting. It must be pointed out, however, that endoscopy as a whole has not yet been fully analyzed in any single given clinical study.

Large bowel tumor promotion by diamine oxidase inhibition: animal model and clinical aspects.

UNLABELLED: In the intestinal mucosa, diamine oxidase probably is involved in a feedback regulation mechanism for the termination of proliferation. This was proven by a considerable promotion of large bowel tumors induced by diamine oxidase inhibition in a rat model. Carcinogenesis was accompanied by characteristic alterations in mucosal diamine oxidase activity. In large bowel cancer patients similar changes in intestinal diamine oxidase activity had been observed as in the animal model. CONCLUSION: Events entailing a reduction of diamine oxidase activity are suspicious for large bowel cancer promotion under experimental and clinical conditions.

Usefulness and limitations of colonoscopy in a proctological clinic.

Colonoscopy is a superior diagnostic tool for the detection of cancer of the colon. Its limitations include that it is not always available and there is a great deal of discomfort for the patient. It should therefore be used as effectively as possible. The goal of this retrolective cohort study was to analyze the usefulness of colonoscopy, especially by relating it to the subsequent therapeutic impact. Indication-related groups included "rectal bleeding," "other symptoms suggestive of malignancy," and "follow-up." In 714 patients selected as a result of admission to the proctological unit of our surgical clinic, a carcinoma was discovered in 9% and an adenoma in 13.4%. Patients with rectal bleeding were found to benefit most from colonoscopy since active therapeutic management followed in 56% of the cases. On comparison, there was a direct therapeutic impact in only 10% of the colonoscopies performed for follow-up. Identification of additional factors such as mucosal proliferation markers may help to improve the efficiency of endoscopy by more specifically designating the populations at risk for colonic neoplasia.

Reliability and practicability of the fluorometric-fluoroenzymatic histamine determination in pathogenetic studies on peptic ulcer: detection limits and problems with specificity.

Histamine, among various "biologic-physiologic" abnormalities, is considered as a pathogenetic factor in chronic duodenal ulcer disease. The 10-30 per cent difference between its concentration in gastric and duodenal mucosa of patients compared to healthy controls, however, has to be demonstrated to be specific for the disease. It has to be shown to be neither a methodological artefact nor a common effect, concomitant factor or consequence. This study, after a series of pathogenetic trials examines systematic errors (biases) in the fluorometric-fluoroenzymatic histamine assay under the conditions of field studies including tests on specificity over a time period of 10 years. It concentrates on sensitivity (detection limits) and specificity of a standard technique described herein. A modified Shore procedure for large scale assays in human biopsies was developed including reference luminescence values for all reagents, cleaning material and glassware, reduction of OPD concentration to 0.05%, purification of n-heptan, omission of centrifugation steps in the extraction procedure and use of 2 ml 1 M HClO4 in the homogenization step to prevent losses of histamine due to adherence to the mechanical homogenizer. This assay was sensitive enough to measure histamine without difficulty in any biopsy taken. The detection limit was 3 ng/biopsy, but the smallest quantities of the amine ever obtained were 10.6 and 18.3 ng/biopsy (depending on both histamine content and biopsy weight). A series of problems had to be solved both in achieving and demonstrating specificity. It had to be defined not only for the assay in general, but also for assessing the difference in histamine content between ulcer patients and healthy controls. Exogenous more than endogenous fluorescing material interfering with the determination had to be excluded. A series of pitfalls were detected which had to be overcome in demonstrating the specificity of the assay by physicochemical and enzymatic tests. The specificity of the identification tests was more often impaired than the histamine assay itself. Fluorescing material interfering with the assay occurred in the homogenization, extraction and condensation steps, was found in water, OPD, the organic solvents, the cleaning material and in all kinds of plastic vessels. Plasticizers were shown by physicochemical characteristics including fluorescence spectra to be most likely responsible for this interfering material. Rules were developed to exclude such hazards in specificity in longterm pathobiochemical studies. Enzymatic identification test were applied to exclude endogenous fluorecing substances interfering with the standard technique. Simil

Diamine oxidase (DAO) activity and intestinal mucosa integrity: influence of suture techniques.

After various kinds of intestinal mucosal injuries, whether by disease or by experiment, the diamine oxidase activity is reduced. Therefore, we studied the effect of surgical manipulations on the intestinal mucosa and diamine oxidase activity. The reaction of the gut on the insertion of sutures was a transient increase of the enzymic activity followed by reduction as soon as the mucosa started to gain weight. After a standardized pressure injury only a reduction of the diamine oxidase activity together with an enhancement of the mass of the intestinal wall was found. A hypothesis of a feed-back regulation of the diamine oxidase activity connected with mucosal proliferation is proposed.

Elevation of the large bowel histamine concentration by aminoguanidine induced diamine oxidase inhibition.

In inflammatory diseases of the large bowel a reduced diamine oxidase activity was found which may be related to a reduced oxidative degradation of histamine. An experimental inhibition of diamine oxidase could therefore influence the large bowel histamine concentration. The diamine oxidase inhibitor aminoguanidine was administered to rats in a single dose of 100 mg/kg orally, i.v., or i.p. A rapid increase of the concentration of the drug in the large bowel was measured (half-life = 2-5 h). During chronic amino-guanidine administration (3 times/week, 100 mg/kg orally) the large bowel histamine increased by 30% on average. This may be sufficient for a proliferative stimulus of the intestinal mucosa. Previous reports of an increase of body weight of animals and of patients under aminoguanidine treatment could not be confirmed by our study.

Proteolytic enzymes as new tumor markers in chemical carcinogenesis of intestinal tumors.

Because the role of proteolytic enzymes in carcinogenesis is not yet well understood, we studied two arylamidases cleaving Boc-(Ala)2-p-nitroanilide and Bz-Lys-p-nitroanilide in the sera of rats during azoxymethane (AOM)-induced development of bowel carcinomas. Both proteolytic activities exhibited similar patterns: During administration of the carcinogen they increased up to 2.1-fold (Boc-[Ala]2-Nan) and 1.7-fold (Bz-Lys-Nan) the activity of the control group (P less than 0.05). Subsequently they decreased, passing the normal range between weeks 16 and 20 after the first AOM treatment and then diminishing continuously with increasing manifestation of tumors. At week 24 when the last animals were sacrificed enzyme activities were only 36.5% and 43.7% of the controls (P less than 0.05). The early increase may be related to direct effects of the carcinogen. The decrease of serum activity in the further course, however, seems to be a typical event of invasive tumor growth, because a similar loss of activity was also observed in rats with benzopyrene sarcomas. We conclude that both arylamidases may become useful as nonspecific tumor markers.

[The devil's advocate--commentary on sutures]. / Advocatus diaboli-Kommentar.

The decision between hand suture or stapler was tested for the large bowel in randomized trials whereas retrospectively only in the upper gastrointestinal and respiratory tract. No clear difference was seen concerning patient's security and cost-time consumption. The stapler is more comfortable but the handsuture technique is still recommended. By the stapler anatomically very difficult anastomoses can be performed. Whether this is an advantage for the patient has to be tested because the technical progress may decrease physical function (incontinence!) and quality of life. In summary, the stapler, if applied critically, seems to be useful.

Quality of life: an important endpoint both in surgical practice and research.

Surgery asks patients to trade present discomfort and risk for future gains. Although research reports on the effectiveness of surgery have largely focused on mortality, length of hospital stay, major complications, and laboratory analyses, the principal criteria guiding surgeons' clinical decisions and patients' acceptance of treatment are most often the patients' subjective feelings and capabilities, the quality of their lives. This is true for both major and minor surgical procedures. We discuss the role of information on functional capacity, overall well-being, and quality of life in the assessment of surgical outcomes. Broadening the choice of endpoints beyond traditional, so-called "hard" variables in surgical studies has advantages for both surgeons and patients.

Diamine oxidase as a marker of intestinal integrity in acute appendicitis.

In the operative treatment of appendicitis the so called negative appendectomy is an important issue because of its increased morbidity. From the hypothesis that the intestinal diamine oxidase activity is a suitable marker of mucosal integrity, the distribution pattern of the enzyme in appendices histologically classified as inflamed or not inflamed was studied. Histologically apparent inflammation of the appendix was connected with a significant reduction of diamine oxidase activity. The determination of this enzymic activity may be a simple and sensitive test for mucosal inflammation of the appendix even at a very early state. This could reduce the rate of negative appendectomies and influence thereby risk-cost-benefit calculations.