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4-[[(p-Chlorophenoxy)acetyl]amino]-5-chloro-2-methoxy-N-[2-(diethylamino)ethyl]benzamide (cloxacepride, 1), exhibited substantial oral antiallergic potential in a reaginic PCA test in rats over a wide range of antigenic challenge times. Available reference compounds with oral activity, such as doxantrazole and 7-(2-hydroxyethoxy)-9-oxoxanthene-2-carboxylic acid (AH 7725, 4), were active only when administered 15 min before challenge: 4, in particular, was not consistent in effect. Oral ED50 values for cloxacepride of 46-49 mg/kg were comparable to that of theophylline and to an intravenous injection of 2 mg/kg of disodium chromoglycate (DSCG) followed by immediate challenge. Following oral ED50 doses, 1 showed slower onset and longer duration of action than theophylline. The absence of inhibition of systemic anaphylaxis and of antihistaminic activity suggests specific effect or reaginic antigen antibody reactions. Structure-activity relationships of various chemical modifications were investigated and discussed in terms of essential substituents.

Between the different forms of multiple hairs the circumscribed occurence of compound hairs is a rare nevoid hair-abnormality. It is caused by merging of several follicles in the middle or upper corium. The deep parts and the papillae are independent units. The pathogenesis, clinical relevance and therapy of compound hairs are discussed on the basis of an own observation.

White sponge nevus of the mucosa is a rare, mostly verifiable hereditary ectodermal dysplasia of the mucous membranes. Because associated symptoms of the skin are missing, it is classified as a distinctive disease among the congenital leukokeratoses. In the most cases the symptomless mucosal lesions are detected by dentological examination though they are present at birth or appear in the first years of life. On the basis of three own observations clinical appearance, histopathology, electronmicroscopy and differential diagnosis are discussed.

The binding of the fluorescent probe 4,4'-bis[8-(phenylamino)naphthalene-1-sulfonate] (bis-ANS) to human alpha- and gamma-thrombins was investigated. Bis-ANS binds in a 1:1 complex to both forms of the enzyme, with Kd = 14.8 +/- 2.2 microM and 5.8 +/- 1.0 microM for alpha- and gamma-thrombin, respectively, at pH 7.0 [25 mM tris(hydroxymethyl)aminomethane, 0.15 M NaC1]. Fluorescence changes upon complexation included a considerable (approximately 30-nm) blue shift in the fluorescence emission maximum as well as a dramatic increase in the fluorescence emission intensity: a 70-fold enhancement was observed with alpha-thrombin vs. a approximately 220-fold enhancement with gamma-thrombin. Proflavin was not displaced upon bis-ANS binding. The unknown thrombin effectors ATP, Ca(II)ATP, Co(III)ATP, phosphate, and pyrophosphate bound with enhancement of the fluorescence of the bis-ANS-alpha-thrombin complex. The two inhibitors benzamidine and p-chlorobenzylamine as well as heparin caused decreases in bis-ANS-thrombin fluorescence: valerylamidine had no effect on the fluorescence of the bis-ANS-thrombin complex. Kinetic measurements with two chromogenic substrates, S-2238 and S-2160, indicated that bis-ANS acts as a partial noncompetitive inhibitor of thrombin amidase activity. The kinetic evidence combined with the ligand binding results suggests that bis-ANS does not overlap the catalytic site. The fluorophore ANS complexed with equal affinity to both alpha- and gamma-thrombins (Kd = 24 +/- 4 microM); however, the gamma-thrombin-ANS complex emission at 470 nm was enhanced 26% more than that for the alpha form.

Ethyl-2(p-chlorophenoxy)-2-methylpropionate (clofibrate) related compounds were synthesized from substituted aryloxy acetic acids (III) either by esterification with selected alcohols (3,3,5-trimethylcyclohexanol and oxyalkyltheophyllines), by introduction into heterocyclic ring system (triazine type) or by amidation (aminotriazines and p-aminobenzoates). Lipid lowering effect was tested in normolipemic and hyperlipemic rats against clofibrate as reference. Some of these derivatives show high activity at low dosage, even under hyperlipemic conditions, whereas clofibrate is only slightly effective. From pharmacological results it can be suggested that the nature of acid group substituent is the main factor for efficacy, while the role of alpha-substituent is important for differentiation of activity against cholesterol and/or triglyceride.

In 30 patients with cancer of the large bowel, 24 (80%) had detectable levels of methane in their breath, compared with 25 (39%) of 64 patients with non-malignant large-bowel disease and 83 (40%) of 208 subjects without large-bowel disease. These findings suggest that there may be a difference in anaerobic intestinal flora between patients with cancer of the large bowel and those without the disease. This difference may antedate the development of the tumour or, alternatively, result from the tumour.

The study was carried out in 6 healthy volunteers in cross-over design. The pharmacokinetic parameters were calculated after application of 60 mg vincamine base in comparison to a sustained release formulation (vincamine ratio-pharm 30 mg) on the basis of a GC method. Summarizing it can be stated that the sustained release formulation has a flatter profile and is therefore more adapted to clinical application. The extent of absorption expressed as AUC of the serum concentration-time curve, has three times the extent of the curve with the pure substance.

Necrobiosis lipoidica confined to the face and scalp is very rare. The clinical diagnosis is complicated by the granuloma anulare like aspect and in particular by the lack of typical localization of the extremities. Histologically prominent granulomatous dermal proliferation and less marked vascular changes can often be found in the involved areas of the scalp and/or in the absence of diabetes mellitus. For the microscopic classification the large variability of necrobiosis lipoidica must be considered. In our case with an exclusive localization in the face and capillitium, diabetes mellitus was excluded. The necrobiotic type of the necrobiosis lipoidica was predominant. The identity between necrobiosis lipoidica with other chronic granulomatous diseases and the possible treatment of this benign but long-term process is briefly discussed.

Electronmicroscopical examination on skin lesions of epidermolysis bullosa dystrophica recessiva (E.b.d.r.) and epidermolysis bullosa acquisita (E.b.a.) associated with Crohn's disease have demonstrated that blistering occurs between epidermis and dermis beneath the basal lamina. The structural defect concerns the anchoring fibrils only which are missing in the junctional zone of the involved skin. All other junctional structures are intact. Beneath the basal lamina a band-like zone of a moderate electrondense, amorphous material is seen in the skin-lesions of epidermolysis bullosa acquisita, less marked in epidermolysis bullosa dystrophica. Direct immunofluorescent investigation of involved skin of E.b.a. shows a pemphigoid-like fluorescent pattern at the basal lamina with antihuman IgG-, -IgM-, beta1c/beta1a and antihuman C1q-component. In epidermolysis bullosa dystrophica, however, a fluorescent pattern at the basal lamina was found only with anti-human IgG and Anti-C3. The pathogenetic importance of the immunoglobuline-deposits at the basal lamina is discussed in regard of the loss of anchoring fibrils and the subsequent vesication in these types of epidermolytic diseases.

Pectin has been shown to minimise the fall in blood glucose seen in patients who are troubled by hypoglycaemia attacks after gastric surgery. We therefore performed 50 g glucose tolerance tests with and without 14.5 g pectin on 11 post-gastric surgery patients. After pectin, the high postprandial levels of glucose, insulin, and enteroglucagon were significantly reduced as was the fall in blood glucose between 90 and 120 minutes. These effects of pectin may reflect slower uptake of glucose from the gastrointestinal tract and provide evidence to support the use of unabsorbable carbohydrate gelling agents in treating hypoglycaemia after gastric surgery.

Rat is a likely test animal for determining the efficacy of proteinase inhibitor drugs directed toward human leukocyte elastase and cathepsin G. We therefore sought to assess and compare relevant properties of both human and rat leukocyte elastase and cathepsin G. Some differences between the pairs of proteinases from the two species were found, however both pairs of enzymes displayed comparable specificity toward various natural (plant and animal) proteinase inhibitors and also toward specific peptide substrates and a serine proteinase-specific reagent. Such overlapping specificity implies similarity of reactive center topography and sequence homology around the extended substrate/inhibitor binding regions of these proteinases. This apparent homology leads us to conclude that a pharmacologically effective inhibitor of leukocyte proteinases in the rat would probably also be effective in man.

An aminopeptidase (alpha-aminoacyl L-peptide hydrolase, EC 3.4.11.1) was purified to homogeneity from autolysates of brewer's yeast. The enzyme which is responsible for most of the yeast cell's aminopeptidase activity is a glycoprotein containing about 12% of conjugated carbohydrate and 0.02% Zn2+ and having a complex quaternary structure. The active species has a molecular weight of approx. 600000 and an isoelectric point of 4.7. The enzyme is remarkably stable, even in dilute solutions. All types of L-amino acid and peptide derivatives containing a free amino terminus are attacked, including amino acid amides and esters. As to its substrate specificity, the enzyme belongs to the so called leucine-aminopeptidases. It is strongly and specifically activated by Zn2+ and Cl- (or Br-) and inactivated by metal-chelating agents. The activation by Zn2+ seems to be mediated by a conformational transition which affects exclusively V and leads to a form of the enzyme which enhanced stability against heat. Halide anions, on the other hand, are acting as positive allosteric effectors, modulating both V and Km.