Long-term effects of prenatal progesterone exposure: neurophysiological development and hospital admissions in twins up to 8 years of age.

OBJECTIVES: To perform a neurophysiological follow-up at 48 or 60 months of age in children exposed prenatally to progesterone compared with a placebo and evaluate their medical histories up to 8 years of age. METHODS: In this study, Danish participants of the PREDICT study, including 989 surviving children from 498 twin pregnancies, were followed-up. PREDICT was a placebo-controlled randomized clinical trial examining the effect of progesterone for prevention of preterm delivery in unselected twin pregnancies. Medical histories of the children were reviewed and neurophysiological development was evaluated by the parent-completed Ages and Stages Questionnaire (ASQ) at either 48 or 60 months after the estimated date of delivery. We used the method of generalized estimating equation to account for the correlation within twins. RESULTS: A total of 492 children had been exposed prenatally to progesterone and 497 to placebo. There was no difference in the number of admissions to or length of stay in hospital between the treatment groups, and we found no overall difference in the rates of diagnoses made. However, the odds ratios (ORs) for a diagnosis concerning the heart was 1.66 (95% CI, 0.81-3.37), favoring placebo, among all children, 2.38 (95% CI, 1.07-5.30) in dichorionic twins and 8.19 (95% CI, 1.02-65.6) in all children when excluding diagnoses made at outpatient clinic visits. ASQ scores were available for 437 children (progesterone, n = 225; placebo, n = 212). Mean ASQ score was slightly higher in the progesterone group compared with the placebo group (P = 0.03). In dichorionic twins, the risk of having a low ASQ score (< 10(th) centile) was decreased in the progesterone group (OR, 0.34 (95% CI, 0.14-0.86)). CONCLUSION: Second- and third-trimester exposure of the fetus to progesterone does not seem to have long-term harmful effects during childhood, but future studies should focus on cardiac disease in the child. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Influence of chorionicity on perinatal outcome in a large cohort of Danish twin pregnancies.

OBJECTIVE: To assess outcome in twin pregnancies according to chorionicity. METHODS: A cohort was retrieved from local ultrasound databases at 14 obstetric departments in Denmark, comprising all twin pregnancies with two live fetuses scanned between weeks 11 and 14 in the period 1 January 2004 to 31 December 2006. Outcome data were retrieved from the National Board of Health. RESULTS: Among 2038 twin pregnancies, 1757 (86.2%) were dichorionic (DC) and 281 (13.8%) were monochorionic diamniotic (MC). In MC pregnancies, the rate of spontaneous fetal loss in both second and third trimesters was more than threefold higher than the comparable rate in DC pregnancies: 6.0% vs. 1.9% for at least one fetus in the second trimester (P < 0.001) and 2.1% vs. 0.7% in the third trimester (P = 0.03). In 98.4% of DC pregnancies and in 91.1% of MC pregnancies, at least one infant was liveborn. Amongst pregnancies with two live fetuses at 24 weeks, the proportion with two live infants at 28 days after delivery was 97.5% and 95.1%, respectively. CONCLUSIONS: The increased incidence of fetal loss in MC pregnancies compared with DC pregnancies predominantly occurs before 24 weeks' gestation. After this stage, although the risk of intrauterine fetal death is still higher in MC than in DC pregnancies, if both fetuses are alive at 24 weeks, the chance of a woman having two live infants 1 month after delivery is similar in MC and DC pregnancies.

Stool testing for pulmonary TB diagnosis in adults.

BACKGROUND: Mycobacterium tuberculosis is acid-fast and able to survive in the gastrointestinal tract. Thus, bacteria can be found in stool if sputum is swallowed. In this study, the accuracy of different diagnostic stool methods (microscopy, polymerase chain reaction PCR and culture) among adults with pulmonary TB (PTB) were assessed and compared with sputum culture.METHODS: Embase and PubMed were searched to identify studies with data on stool testing among patients with clinically presumed or microbiologically verified PTB.RESULTS: Thirteen relevant studies were included. A pooled sensitivity of one or more of the three TB identifying methods was 79.1% (95% CI 61.5-92.5). The sensitivity of stool microscopy, PCR and culture was respectively 41.1% (95%CI 24.9-58.2), 89.7% (95% CI 81.4-95.9) and 38.0% (95% CI 26.2-50.6). The heterogeneity of the studies included was high.CONCLUSION: Our review findings indicate that the analysis of stool specimens as part of PTB diagnostics is useful. PCR methods were particularly helpful in detecting a substantial proportion of patients with PTB.

Atmospheric chemistry of n-butanol: kinetics, mechanisms, and products of Cl atom and OH radical initiated oxidation in the presence and absence of NO(x).

Smog chamber/FTIR techniques were used to determine rate constants of k(Cl+n-butanol) = (2.21 +/- 0.38) x 10(-10) and k(OH+n-butanol) = (8.86 +/- 0.85) x 10(-12) cm(3) molecule(-1) s(-1) in 700 Torr of N(2)/O(2) diluent at 296 +/- 2K. The sole primary product identified from the Cl atom initiated oxidation of n-butanol in the absence of NO was butyraldehyde (38 +/- 2%, molar yield). The primary products of the Cl atom initiated oxidation of n-butanol in the presence of NO were (molar yield) butyraldehyde (38 +/- 2%), propionaldehyde (23 +/- 3%), acetaldehyde (12 +/- 4%), and formaldehyde (33 +/- 3%). The substantially lower yields of propionaldehyde, acetaldehyde, and formaldehyde as primary products in experiments conducted in the absence of NO suggests that chemical activation is important in the atmospheric chemistry of CH(3)CH(2)CH(O)CH(2)OH and CH(3)CH(O)CH(2)CH(2)OH alkoxy radicals. The primary products of the OH radical initiated oxidation of n-butanol in the presence of NO were (molar yields) butyraldehyde (44 +/- 4%), propionaldehyde (19 +/- 2%), and acetaldehyde (12 +/- 3%). In all cases, the product yields were independent of oxygen concentration over the partial pressure range of 10-600 Torr. The yields of propionaldehyde, acetaldehyde, and formaldehyde quoted above were not corrected for secondary formation via oxidation of higher aldehydes and should be treated as upper limits. The reactions of Cl atoms and OH radicals with n-butanol proceed 38 +/- 2 and 44 +/- 4%, respectively, via attack on the alpha-position to give an alpha-hydroxy alkyl radical which reacts with O(2) to give butyraldehyde. The results are discussed with respect to the atmospheric chemistry of n-butanol.

Integrin signalling regulates the expansion of neuroepithelial progenitors and neurogenesis via Wnt7a and Decorin.

Development of the cerebral cortex requires regulation of proliferation and differentiation of neural stem cells and a diverse range of progenitors. Recent work suggests a role for extracellular matrix (ECM) and the major family of ECM receptors, the integrins. Here we show that enhancing integrin beta-1 signalling, by expressing a constitutively active integrin beta-1 (CA*ß1) in the embryonic chick mesencephalon, enhances neurogenesis and increases the number of mitotic cells dividing away from the ventricular surface, analogous to sub-apical progenitors in mouse. Only non-integrin-expressing neighbouring cells (lacking CA*ß1) contributed to the increased neurogenesis. Transcriptome analysis reveals upregulation of Wnt7a within the CA*ß1 cells and upregulation of the ECM protein Decorin in the neighbouring non-expressing cells. Experiments using inhibitors in explant models and genetic knock-downs in vivo reveal an integrin-Wnt7a-Decorin pathway that promotes proliferation and differentiation of neuroepithelial cells, and identify Decorin as a novel neurogenic factor in the central nervous system.

Blockade of leukotriene production by a single oral dose of MK-0591 in active ulcerative colitis.

BACKGROUND: 5-Lipoxygenase products of arachidonic acid metabolism are thought to play a central role in the secondary amplification of the inflammatory response in a number of human inflammatory diseases, such as ulcerative colitis. MK-0591 (3-(1((4-chlorophenyl)methyl)-3((1,1-dimethyl-ethyl)thio)-5(quinolin+ ++-2ylmethyl-oxy)-1H-indol-2yl)-2,2-dimethyl-propanoate) exerts its effect by binding to the 5-lipoxygenase activating protein, thereby inhibiting the translocation and activation of 5-lipoxygenase. METHODS: Concentrations of leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) in rectal dialysis fluid, ex vivo biosynthesis of LTB4 in whole blood, and urinary excretion of leukotriene E4 (LTE4) from 16 patients with mild to moderately active distally located ulcerative colitis were measured by use of radioimmunoassays in a double-blind, placebo-controlled parallel-design study before and after oral administration of a 250 mg dose of MK-0591 or placebo. RESULTS: The mean LTB4 concentration in rectal dialysis fluid was lowered after MK-0591 by > 90% (p < 0.05) from 4 to 8 hours, with a maximum inhibition of 97.5% +/- 3.4% (mean +/- SD) at 20 to 24 hours after dosing, whereas PGE2 was unchanged. In whole blood, MK-0591 decreased ex vivo biosynthesis of LTB4 (p < 0.01), with a maximum inhibition of 96.4% +/- 2.1% at 4 hours after dosing. Urinary excretion of LTE4 was reduced by more than 85% (p < 0.001) from 4 to 48 hours. No adverse events were observed. CONCLUSION: These findings show that a single oral 250 mg dose of MK-0591 results in nearly complete blockade of systemic leukotriene production and LTB4 formation in the target tissue of inflammation (the rectum). Controlled multiple-dose trials to assess the clinical efficacy of this novel 5-lipoxygenase-activating protein inhibitor seem to be worthwhile.

Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF: implications for the mechanism of IGFBP-4 proteolysis by PAPP-A.

Pregnancy-associated plasma protein-A (PAPP-A) has recently been identified as the proteinase responsible for cleavage of insulin-like growth factor binding protein (IGFBP)-4, an inhibitor of IGF action, in several biological fluids. Cleavage of IGFBP-4 by PAPP-A is believed to occur only in the presence of IGF. We here report that in addition to IGFBP-4, PAPP-A also cleaves IGFBP-5. Cleavage occurs at one site, between Ser-143 and Lys-144 of IGFBP-5. In the presence of IGF, IGFBP-4 and -5 are cleaved with similar rates by PAPP-A. Interestingly, cleavage of IGFBP-5 by PAPP-A does not require the presence of IGF, but is slightly inhibited by IGF. These findings have implications for the mechanism of proteolysis of IGFBP-4 by PAPP-A, suggesting that IGFBP-4 binds IGF, which then becomes a PAPP-A substrate. Using highly purified, recombinant proteins, we establish that (1) PAPP-A cleavage of IGFBP-4 can occur in the absence of IGF, although the rate of hydrolysis is very slow, and (2) IGF is unable to bind to PAPP-A. We thus conclude that IGF enhances proteolysis by binding to IGFBP-4, not by interaction with PAPP-A, which could not previously be ruled out.

Clinical pharmacokinetics of drugs used in the treatment of gastrointestinal diseases (Part II).

Part I of this article, which appeared in the previous issue of the Journal, covered the following agents: histamine H2-receptor antagonists (cimetidine, ranitidine, famotidine, nizatidine); muscarinic-M1-receptor antagonists (pirenzepine); proton pump inhibitors (omeprazole); site-protective agents (colloidal bismuth subcitrate, sucralfate); antacids and prostaglandin analogues; antiemetics and prokinetics (metoclopramide, domperidone, cisapride); and antispasmodics. In Part II, we consider the anti-inflammatory salicylates, nonspecific antidiarrhoeal agents, laxatives and cathartics.

Clinical pharmacokinetics of drugs used in the treatment of gastrointestinal diseases (Part I).

Drug treatment of gastrointestinal diseases, which was previously limited to the use of antacids, anticholinergics, antispasmodics, cathartics and laxatives, has changed markedly over the past decade. Histamine H2-receptor antagonists (e.g. cimetidine, ranitidine and more recently famotidine and nizatidine) have revolutionised the treatment of peptic acid disorders, but their role is currently challenged by muscarinic-M1-receptor antagonists (e.g. pirenzepine), proton pump inhibitors (e.g. omeprazole), prostaglandin analogues and site-protective drugs (e.g. colloidal bismuth subcitrate and sucralfate). Newer antiemetics with prokinetic properties (e.g. metoclopramide, domperidone and cisapride) have also been introduced in the management of gastrointestinal motility disturbances, and new anti-inflammatory salicylates (e.g. olsalazine and mesalazine) have been developed for the treatment of chronic inflammatory bowel diseases. Finally, diphenoxylate and loperamide have gained wide clinical application as nonspecific antidiarrhoeal agents. The basic pharmacokinetic properties of the above agents are briefly reviewed with the main emphasis on the newer and more important drugs in current use. Furthermore, the effects of age and disease on pharmacokinetics, in addition to drug interaction potentials and pharmacokinetic-pharmacodynamic relationships, are discussed. The anti-inflammatory salicylates, nonspecific antidiarrhoeal agents, laxatives and cathartics will be dealt with in Part II.

Effect of 10 mg and 20 mg omeprazole daily on duodenal ulcer: double-blind comparative trial.

One-hundred and seventy-one patients with endoscopically proven duodenal ulcers were allocated at random to double-blind treatment with 10 or 20 mg of omeprazole in the morning for up to 4 weeks. Patients completed the study if ulcer healing and pain relief had occurred at 2 weeks. A total of 155 patients completed the trial. Patients treated with 20 mg of omeprazole daily responded significantly more rapidly than those treated with 10 mg of omeprazole daily (P less than 0.001; Cochran-Mantel-Haenszel test covering both time points), cumulative healing rates at 2 and 4 weeks were 74% (58/78) and 91% (71/78), respectively. The corresponding rates in the group treated with 10 mg daily were 48% (39/81) and 75% (58/77). Pain relief was again more pronounced during treatment with the larger dose (P less than 0.05; stratified Wilcoxon test). No major clinical or biochemical side effects were noted. An omeprazole dose of 20 mg daily is preferable to a lower dose for the treatment of duodenal ulcer disease in the short term.

Bronchodilating effect of terbutaline powder in acute severe bronchial obstruction.

The bronchodilating effect of terbutaline dry powder inhaled via Turbuhaler was compared with terbutaline inhaled via a conventional, chlorofluorocarbon (CFC) inhaler and Nebuhaler (750 ml spacer) in 68 consecutive patients attending the emergency department with acute severe bronchial obstruction. The study was of an open, randomized, parallel group design with one study day. Patients were treated with 2.5 mg of terbutaline 15 min apart, either as dry powder via Turbuhaler or with a CFC inhaler in conjunction with Nebuhaler. Data from 62 patients were analyzed. The mean baseline FEV1 values were 0.81 L (SD, 0.64; range, 0.14 to 2.74 L) in the Turbuhaler group (n = 33), and 0.90 L (SD, 0.90; range, 0.27 to 2.60 L) in the Nebuhaler group (n = 29). The mean increases in FEV1 from baseline were 0.40 L (SD, 0.40; range, 0.06 to 2.36 L) and 0.21 L (SD, 0.25; range, -0.05 to 0.95 L) 10 min after the last inhalation via Turbuhaler and Nebuhaler, respectively. The difference between mean values of the increase in FEV1 after terbutaline treatment with Turbuhaler and the CFC inhaler and Nebuhaler was statistically significant (p = 0.0004, ANOVA). This study showed that inhalation of terbutaline via Turbuhaler produced a significantly greater increase in FEV1 compared with the same dose of terbutaline administered via the CFC inhaler and Nebuhaler in patients attending the emergency department with acute severe bronchial obstruction.

A proposal for a practical treatment guideline designed for the initial two-hours of the management of patients with acute severe asthma and COPD using the principles of evidence-based medicine.

We have proposed a clinical treatment guideline for the management of acute, severe asthma and chronic obstructive pulmonarydisease (COPD) using the principles of evidence-based medicine. The content is based upon practical clinical issues in need of consensus. A previous study has shown that this particular area is in serious need of quality control. Based on a strict 2 h time schedule with a unified treatment plan for both asthma and COPD, it is possible to secure for the patients a well-documented medical therapy promoting decision-making and clarification of the patient within this time limit. A summary of the statements is presented in a one-page, user-friendly format in order to cope with the clinician's need of having access to published evidence quickly and easily. A website (www.phanareth.dk or a website provided by Respiratory Medicine) has been established providing regular updates. A strategy for the implementation and the evaluation process has been planned after the publication of this paper. We believe this approach to be an important step towards an increase in the quality of guidelines and also a tool to make "guideline writers" aware of the responsibility of making their recommendations work.

Treatment of acute severe asthma and chronic obstructive pulmonary disease in Danish hospitals. Do national recommendations improve on the quality of the treatment?

Studies have demonstrated suboptimal treatment of acute severe asthma and chronic obstructive pulmonary disease (COPD). We examined the quality of treatment in Denmark and the effect of intervention, by publication of recommendations for standardised treatment. All 70 hospitals in Denmark with emergency facilities participated in a telephone questionnaire, examining treatment behaviours among house officers. The survey was repeated 3 years later, after publication of national recommendations for treatment of acute exacerbations of asthma and COPD. The response rate in both surveys was 100%. An insufficient handling of nebulisers, a huge variation in the delivered dose of bronchodilators and a suboptimal use of corticosteroids was found. A significant trend towards more liberate use of oxygen was seen in both asthma (3.2 l min(-1) versus 4.8 l min(-1), P<0.001) and COPD (1.5 l min(-1) versus 1.9 l min(-1), P = 0.047). Further, a huge difference in treatment behaviours was revealed from this survey The knowledge among house officers of basic principles of treatment was insufficient. Treatment behaviour was only moderately affected by national publication of detailed recommendations for treatment. This study indicates a need for implementing tools for quality control.

Early clinical investigation of Viozan (sibenadet HCl), a novel D2 dopamine receptor, beta2-adrenoceptor agonist for the treatment of chronic obstructive pulmonary disease symptoms.

Viozan, (Sibenadet HCl, AR-C68397AA) is a dual D2 dopamine receptor, beta2-adrenoceptor agonist that combines bronchodilator activity with the sensory afferent modulating effects associated with D2-receptor agonism. Investigation in animal models of key chronic obstructive pulmonary disease (COPD) symptoms has demonstrated that sibenadet effectively inhibits sensory nerve activity, thereby reducing reflex cough, mucus production and tachypnoea. The results of the early clinical evaluation of this novel agent are reported. An initial proof of concept study (Study 1) aimed to determine the clinical potential of this novel agent by assessing the effects of three doses of sibenadet therapy relative to placebo, with two commonly used bronchodilators, intended to provide a benchmark against which sibenadet activity could be judged. In all, 701 patients were randomized to one of three sibenadet dose groups (400, 600 or 1000 microg ex valve), salbutamol 200 microg, ipratropium bromide (IB) 40 microg or placebo, all three times daily via pressurized metered dose inhaler (pMDI) for 4 weeks. Once the results of Study 1 had been evaluated, a dose-ranging, study (Study 2) involving 872 patients randomized to receive sibenadet (45, 270, or 495 microg ex actuator), or placebo all three times daily via pMDI, for 6 weeks commenced. Both studies were preceded by a 2-week baseline phase and followed by a 2-week follow up period.The primary efficacy variable identified changes in key COPD symptoms over the treatment period (compared with baseline data) as determined by the novel Breathlessness, Cough and Sputum Scale (BCSS). In addition, data on lung function, health-related quality of life and adverse events were collected. Patients receiving sibenadet therapy three times daily exhibited statistically significantly greater improvements in BCSS total score than those receiving placebo or bronchodilator therapy alone. A clear dose-response was evident in Study 2. Symptom improvement in this study was also accompanied by improved lung function and health-related quality of life. Sibenadet therapy was well tolerated with an adverse events profile comparable to current bronchodilator therapy. These data were viewed as extremely encouraging, warranting further, large-scale clinical investigation.

The role of the novel D2/beta2-agonist, Viozan (sibenadet HCl), in the treatment of symptoms of chronic obstructive pulmonary disease: results of a large-scale clinical investigation.

Viozan (sibenadet HCl, AR-C68397AA) is a novel dual D2 dopamine receptor, beta2-adrenoceptor agonist, developed specifically to treat the key symptoms of chronic obstructive pulmonary disease (COPD), breathlessness, cough and sputum. The dual sensory nerve modulation and bronchodilator effects of sibenadet have been demonstrated in initial dose-ranging studies of patients with COPD and large-scale clinical evaluation has now been completed. Sibenadet efficacy was determined by assessing symptomatic changes, as defined by the novel assessment tool, the Breathlessness, Cough and Sputum Scale (BCSS). The findings of two placebo-controlled studies are reported. These multicentre, double-blind, placebo-controlled studies recruited over 2000 patients with stable COPD, randomized to receive sibenadet (500 microg) or placebo, pressurized metered-dose inhaler (pMDI) (three times daily) for a period of 12 or 26 weeks. Diary cards were completed daily by patients throughout the study to record BCSS scores, peak expiratory flow (PEF), study drug and rescue bronchodilator usage, changes in concomitant medication and adverse events. The primary endpoints were defined as change from baseline to the final 4 weeks of the treatment period in mean BCSS total score, and forced expiratory volume in one second (FEV1) measured 1 hour after administration of the final dose of study drug and expressed as a percentage of the predicted FEV1. In addition, clinic assessments were made to determine changes in pulmonary function, health-related quality of life, perception of treatment efficacy and adverse events. Despite initial improvements in mean daily BCSS total scores in patients receiving sibenadet, the difference in the change from baseline to the final 4 weeks of the treatment period between the two treatment groups was neither statistically significant, nor considered to be of clinical importance. Although marked bronchodilator activity was seen early on with sibenadet treatment, the duration of effect diminished as the studies progressed. Sibenadet use was not associated with any safety concerns. These studies, utilizing the novel BCSS, have clearly illustrated that, despite initial symptomatic improvement with sibenadet therapy, this clinical benefit was not sustained over the course of the study.

Clinical efficacy and safety of Turbuhaler as compared to pressurized MDIs-beta 2-agonists.

Beta 2-agonists are one of the cornerstones in the management of patients with obstructive lung diseases. The Turbuhaler containing terbutaline has been available in several countries for a few years only but has proven to have effects comparable to those of the conventional metered dose inhaler (MDI) and other powder inhalers in the treatment of obstructive lung diseases. Even in acute severe asthma, treatment with terbutaline via the Turbuhaler has proven as effective as treatment with the conventional MDI in combination with the 750ml spacer. These results indicate that the conventional MDI containing terbutaline can be exchanged by the Turbuhaler for most clinical purposes. Thereby this new method of treatment can contribute to the reduction of chlorofluorocarbon (CFC) pollution of the atmosphere. Furthermore, CFC-provoked bronchoconstriction can be avoided.

[Self-administration of adrenaline aerosol in anaphylactic reactions after insect stings]. / Selvadministrering af adrenalinaerosol ved anafylaktiske reaktioner efter insektstik.

A serious allergic reaction after an insect sting is wellknown source for concern and anxiety. Patients with known hypersensitivity to insect stings are usually equipped with an adrenaline self-injection kit by an allergologist. In Denmark a new device for self-medication of adrenaline was approved in 1994, the adrenaline aerosol spray, Adrenalin Medihaler. The article is based on former studies and experiences, related to the usage of an adrenaline aerosol spray for the treatment of anaphylactic reactions after an insect sting. We conclude that adrenaline aerosol treatment should play an important role as emergency treatment for anaphylactic reactions after insect stings, and in most cases can replace the use of adrenalin self-injection kits. Adrenaline aerosol self-treatment could have an important beneficial effect helping to avoid exacerbation of the initial symptoms after insect venom exposition, such as bronchial obstruction and laryngeal oedema.

[Allergic rhinoconjunctivitis treated with intramuscular injection of glucocorticoid]. / Allergisk rhinoconjunctivitis behandlet med intramuskulaert injiceret glukokortikoid.

Effects and side effects of injectable depot steroid in the treatment of allergic rhinoconjunctivitis (hay fever) are described. A few controlled studies have shown injectable steroids to be superior to the effect of placebo and locally applied steroid. Over a period of 10 years from 1984-95 only 26 registered side effects were reported to the central Danish register for side effects of drugs (Laegemiddelstyrelsens Bivirkningsregister). Only eight concerned subcutaneous atrophy and in two cases the cutaneous changes persisted. Based on registration of number of treatments in the county of Funen 1996, it is estimated that the use of injectable depot steroids for treatment of hay fever accounts for about 535,000 DDD (defined daily doses corresponding to about 33,000 treatments per year). We conclude that the use of injectable corticosteroids in the treatment of hay fever is common and effective and side effects are very rare. However, injectable corticosteroids should only be used when conventional treatment is not sufficient to control symptoms.

Cytoprotection of gastroduodenal mucous membrane with analogues of prostaglandins.

Analogues of E-type prostaglandins, such as arbaprostil, enprostil, misoprostol, rioprostil, and trimoprostil, suppress gastric acid secretion and (like native E-type prostaglandins) the chemically modified analogues enhance a number of gastroduodenal mucosal defence factors. These include regulation of the thickness and the composition of the mucous layer at the epithelial surface; modulation of active bicarbonate secretion; hydrophobicity of the surface epithelium; rapid cell proliferation and differentiation after mucosal damage; maintenance of interstitial bicarbonate; and the integrity of the mucosal microcirculation. In theory, this bimodal action makes prostaglandin analogues ideal drugs for treating and preventing lesions of the gastroduodenal mucous membrane. In practice, however, these expectations remain unfulfilled. First, in doses lower than those required to decrease acid secretion, prostaglandin analogues retain cytoprotective properties but are no better than placebo in healing peptic ulcers. Second, in fully antisecretory doses some prostaglandin analogues accelerate ulcer healing compared with placebo and provide healing rates about as high cimetidine, but less than achieved with ranitidine. Third, despite the fact that high doses of some analogues are superior to placebo in alleviating pain associated with ulcer disease, these agents proved inferior to cimetidine and ranitidine in relieving pain in most comparative trials. Fourth, enprostil and misoprostol in doses which combine antisecretory with cytoprotective properties perform significantly poorer than ranitidine in preventing relapse of peptic ulcer disease. Fifth, although several uncontrolled observations have suggested a therapeutic benefit of prostaglandin analogues in gastroduodenal haemorrhage, placebo-controlled trials show no effect of arbaprostil in stopping bleeding and in preventing rebleeding.(ABSTRACT TRUNCATED AT 250 WORDS)

[Chronic inflammatory bowel disease--current status]. / Kronisk inflammatorisk tarmsygdom--status.

Chronic inflammatory bowel disease (IBD) encompasses the disease entities, ulcerative colitis (UC) and Crohn's disease (CD). An aetiologic agent has not yet been defined and the diagnosis is based, therefore, on the sum of clinical, paraclinical, radiologic, endoscopic and histopathologic features. In recent years pathogenetic studies have focused on immune mechanisms, transmissible infectious agents, the potential role of the normal intestinal flora, dietary factors, enzymatic alterations and genetic features, in addition to vascular, neuromotor, allergic and psychologic factors. The prevalence of IBD is increased in first-degree relatives of patients and there is a high rate of disease concordance among monozygotic twins. Thus abnormal genes may encode for one or several immunoregulatory factors, while bacterial wall products seem to activate colonic inflammatory cells in a non-specific way, leading to increased production of cytokines, complement-derived peptides, eicosanoids, platelet activating factor, biogenic amines, kinins, chemotactic oligopeptides, and neuropeptides. The named soluble inflammatory mediators, in addition to free oxygen radicals, are considered responsible for the secondary amplification of the inflammatory process. The corner stones in medical therapy of IBD are still corticosteroids and sulphasalazine (SAZ). The new oral salicylates, which are analogues of SAZ or "slow release" preparations of 5-aminosalicylic acid (mesalazine), have provided a therapeutic progress, because they are tolerated better than SAZ. Immunosuppressive agents, such as azathioprine and 6-mercaptopurine, reduce the requirement for corticosteroids and are effective in refractory CD, but the effect is delayed up to several months. The therapeutic action of cyclosporine A is not sustained, but often associated with side effects. Metronidazole has a beneficial effect on perineal disease.(ABSTRACT TRUNCATED AT 250 WORDS)