ACE-inhibition with perindopril in essential hypertensive patients with concomitant diseases. The Perindopril Therapeutic Safety Collaborative Research Group.

PURPOSE: Many hypertensive patients have other, usually long-term diseases. Antihypertensive therapy may interfere with these diseases and their therapies. In the present study, the possible interactions of the ACE-inhibitor perindopril with several of the most common long-term diseases was evaluated. PATIENTS AND METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, the effect of perindopril was evaluated in 490 patients with mild essential hypertension and any one of the following concomitant diseases: hyperlipidemia, type II diabetes mellitus, ischemic heart disease, cardiac arrhythmia, peripheral arterial occlusive disease, nephropathy with proteinuria, chronic obstructive pulmonary disease, or degenerative joint disease treated with nonsteroidal anti-inflammatory drugs (NSAIDs). After a 3-week single-blind placebo run-in, the patients received either perindopril (4 mg/d) or matching placebo for 6 weeks. RESULTS: Blood pressure was effectively reduced by perindopril irrespective of the associated disease. The rate of spontaneously reported side effects was low. Treatment with perindopril was free from adverse interactions with the concomitant diseases and therapies. Moreover, favorable actions could be observed in patients with ischemic heart disease (reduction of maximal ST-segment depression during peak exercise and decrease in the number of angina attacks), in patients with proteinuria (decrease in albuminuria in patients with normal serum creatinine levels), and in patients with NSAID-treatment (increase in prostaglandin E2 concentration in gastric mucosa suggesting gastric cytoprotection). CONCLUSION: This trial shows that ACE-inhibition with perindopril represents a simple, safe, and effective short-term therapeutic option for the large proportion of patients with mild essential hypertension and concomitant diseases and therapies.

[Premedication with H1- and H2-receptor antagonists for intravenous urography using contrast media]. / Prämedikation mit H1- und H2-Rezeptorantagonisten vor intravenöser Kontrastmitteldarstellung der ableitenden Harnwege.

Intravenous urography using Telebrix was performed on 500 patients. Two hundred patients (group I) received no pre-medication; 300 patients (group II) were premedicated with H1 and H2 receptor antagonists. All patients were examined for signs of contrast reactions, blood pressure, pulse rate and plasma histamine levels. These were measured before and three minutes after the administration of the antihistamine substances and/or the contrast medium, and also at the end of the examination. Following the administration of H1 and H2 receptor antagonists, a slight, transient and insignificant rise in plasma histamine could be demonstrated. Both groups showed a significant rise in plasma histamine levels after the injection of the contrast medium. Although the pre-medicated group contained a higher percentage of high risk patients, there were significantly fewer patients with contrast reactions. Pre-medication with H1 and H2 receptor antagonists in high risk patients is therefore advisable.

Effects of preservative-free heparin on plasma histamine concentration and on hemodynamics in patients undergoing aortocoronary bypass surgery.

Several reports, dealing with typical cardiovascular reactions immediately after injection of heparin during cardiac surgery, have been presented. A possible reason for these reactions is a short-lasting elevation of plasma histamine concentration following heparin injection. As most types of heparin contain antibacterial preservatives such as benzyl alcohol, which can cause adverse reactions, both substances, heparin itself and the preservative, can theoretically be responsible for this reaction. Therefore, this study was carried out in order to measure the effects of preservative-free heparin on plasma-histamine levels and on hemodynamic parameters. It became evident that preservative-free heparin also entails characteristical hemodynamic effects, such as a decrease in arterial mean pressure and peripheral vascular resistance as well as an increase in cardiac output. A significant increase in plasma-histamine concentration could be shown 20-120 seconds after injection of heparin. We conclude that benzyl alcohol is not the major reason for the hemodynamic effects and elevation of plasma-histamine concentration, following heparin injection, but we cannot exclude that benzyl alcohol does in fact play a minor role. The results of this study suggest that the cardiovascular reactions and the elevation of plasma histamine concentration following heparin injection are heparin-specific phenomena.

[Histamine in the urogenital tract]. / Histamin im Urogenitaltrakt.

Tissue histamine determination in the urogenital tract showed that there are significant differences concerning tissue histamine content between intraoperative and postmortem tissue samples. The difference appeared to be most significant in the case of renal pelvis samples, where the decrease was about 90% in the autopsie material compared to intraoperative tissues. In comparing tissue histamine content in special organs of different animal species we discovered considerable differences; e.g. in the ureter of the dog we measured 30 micrograms/g tissue - where as against the values in man amounted to only 6 micrograms/g tissue. The physiological meaning of the different tissue histamine levels is unknown.

Gastric mucosal reactions in patients with food allergy.

The aim of our study was to determine whether patients suffering from food allergy show any pathologic reactions on the mucosa of the gastrointestinal (GI) tract after allergen contact. For this reason, we included in the study 30 patients whose food-allergic history had been proven through double-blind challenge tests; 20 healthy volunteers also were included as controls. The patients and volunteers underwent standard laboratory investigations and allergy tests with PRICK and RAST. To observe possible mucosal reactions, we applied the proposed allergens via endoscope to the gastric mucosa. Macroscopic reactions were observed blindly by two independent physicians. Biopsies were taken from the challenged areas for histological and histochemical analysis. The examinations included the estimations of tissue histamine concentrations and of mast cell and lymphocyte counts. In all 30 patients, macroscopic reactions (swelling, erosions, bleedings) were observed. Patients with food allergy had, in contrast to healthy volunteers, elevated lymphocyte counts, tissue histamine concentrations, and mast cell counts. After provocation, tissue histamine concentrations and mast cell counts fell significantly. Skin and RAST tests showed positive results in only 46.7% and 50.0%, respectively, of food-allergic patients. We conclude, first, that through intragastric provocation under endoscopic control (IPEC), food-allergic reactions on the mucosa of the GI tract can be verified and, second, that the liberation of tissue histamine seems to play an important role in the establishment of food-allergic reactions on the mucosa.

[Hypertension and gastrointestinal diseases]. / Bluthochdruck und Magen-Darm-Erkrankungen.

Essential hypertension and gastrointestinal disease are two of the most common diagnoses made in the doctor's office. Since they may occur simultaneously, the differential therapeutic aspects of the respective therapies are of importance for every general practitioner. However, complex interactions between hypertension and gastrointestinal diseases often make the choice of the most suitable drug difficult. The present article provides an overview of the most common therapeutic regimens, identifies possible interactions, and should help the doctor to select the optimal treatment for the individual patient.

Intragastral provocation under endoscopic control (IPEC) in food allergy: mast cell and histamine changes in gastric mucosa.

In fourteen patients with food allergy, intragastral provocation under endoscopical control (IPEC) was performed. In all patients positive immediate-type reactions of the gastric mucosa were observed consisting of oedema, erythema and petechial bleeding. Microscopically, mast cell degranulation was observed and measured by mast cell counts using the o-phthaldialdehyde technique. Concomitantly, tissue histamine content in gastric mucosa decreased significantly after allergen provocation, while there was no change in normal volunteers. Plasma histamine concentration increased in most patients; the increases were most evident in four patients showing mild systemic reactions (urticaria and bronchospasm). The technique described might prove to be useful in establishing the diagnosis in doubtful cases of food allergy.

[Acute stomach lesions and changes in histamine level of various organs in immobilization stress]. / Akute Magenläsionen und Veränderungen des Histamingehaltes verschiedener Organe beim Immobilisationsstress.

In the glandular part of the stomach, the histamine content was significantly increased during stress by immobilization. Following 8 hours of restraint these alterations were observed only in lung tissue, but not in other organs investigated. Although the maximum of stress ulcer formation did not correspond with the maximum increase in gastric histamine content as far as the time course is concerned, a role of histamine in stress ulcer disease cannot be excluded.

Histamine1--histamine2 antagonism: effect of combined clemastine and cimetidine pretreatment on allergen and histamine-induced reactions of the guinea pig lung in vivo and in vitro.

In a preliminary study high doses of the H1-antagonist clemastine (clem) and the H2-antagonist cimetidine (cim) were used in order to detect the side effects of both drugs on allergic reactions. After pretreatment with clem or clem/cim different guinea pigs were challenged with either OA or histamine. Bronchial obstruction was measured by body plethysmography using a new parameter ('compressed air'). Pretreatment with clem/cim in high doses protected guinea pigs against OA-induced bronchial obstruction much more effectively than H1-receptor antagonism alone; lower cim doses produced insignificant effects. In histamine-challenged animals cim showed no protective effects. In vitro clem/cim caused a marked reduction of histamine release measured in perfused lungs from 16.9 +/- 4.2 ng/ml (eight control cases) to 2.8 +/- 1.7 ng/ml (n = 8). Our preliminary data suggest that high doses of clem/cim can protect sensitized guinea pigs against allergen-induced bronchial obstruction by inhibiting histamine release.

The role of histamine in the cardiovascular effects of atracurium.

We have investigated the effect of a bolus injection of atracurium 0.6 mg kg-1 on the cardiovascular system in 16 patients undergoing aortocoronary bypass surgery. H1- and H2-receptor antagonists were administered to eight patients before the neuromuscular blocker. A standard anaesthetic was used comprising fentanyl, flunitrazepam, etomidate and enflurane. After administration of atracurium, haemodynamic changes and plasma histamine concentrations were measured at frequent intervals. In the first group, who received only atracurium, a brief but marked decrease in SVR and MAP occurred, accompanied by an increase in Cl, together with a marked increase in plasma concentration of histamine. In the second group, who received H1- and H2-receptor block, there was no decrease in MAP and only a small increase in plasma histamine concentration. However, there were significant changes in SVR and Cl similar to those in atracurium group.

Mediator studies in skin blister fluid from patients with dual skin reactions after intradermal allergen injection.

Skin blister fluid (SBF) samples obtained after allergen skin testing in a total of 26 patients with late cutaneous reactions (LCRs) were examined for the presence of various vasoactive mediators. Histamine was predominant during the early phase of the wheal and flare reaction(206 +/- 40 ng/ml) and decreased with the development of the LCR toward normal SBF levels (around 20 ng/ml). Kallikrein activity was measurable in low amounts (around 5 ng/ml) in three out of 13 SBF samples taken 30 min after skin testing and in five of 13 SBF samples taken 6 hr after allergen testing. The thromboxane B2 content of SBF showed an increase with the development of LCR (control skin 976 +/- 483 ng/ml; allergen-tested skin 30 min after allergen injection, 1465 +/- 1566 ng/ml; allergen-tested skin 6 hr after antigen injection, 1775 +/- 731 ng/ml). SBF obtained from normal skin as well as from allergen-tested skin showed significant platelet-activating property as measured in an in vitro serotonin-release assay from washed human platelets. It is concluded that during the development of late-phase reactions a complex interaction of various mediator systems takes place.

[Clarifying the pathophysiologic mechanism of food allergy]. / Untersuchungen zur Klärung des pathophysiologischen Mechanismus der Nahrungsmittelallergie.

Various lymphocyte populations, dendritic cells and macrophages contribute to the intake of antigen. The transportation of antigen in the intestinal wall is possible with the help of receptive endocytosis, including extracellular protein in fluid droplets, bacterial and vegetable toxins, as well as certain viruses, which seem to be able to penetrate the cell membrane and enter directly into the cell. Own investigations: After endoscope controlled allergy-irritation of the gastro-intestinal tract, 20 people used in the clinical test showed acute signs of mucosal reaction with inflammation and swelling of the mucous membrane as well as haemorrhagic lesions. A histamine release from the mastcell was proved.

[Plasma histamine level in the pulmonary vein immediately following the bolus injection of high-dose heparin in the right atrium. A study carried out during aortocoronary bypass surgery]. / Plasmahistaminspiegel in der Vena pulmonalis unmittelbar nach Bolusinjektion einer hohen Heparindosis in den rechten Vorhof. Eine Untersuchung während aortokoronaren Bypass-Operationen.

This study demonstrates a very rapid and short-lasting elevation of plasma histamine concentrations after heparin injection prior to cannulation for extracorporeal circulation during cardiac surgery. Plasma histamine concentrations increased significantly for less than 1 min following bolus injection of heparin into the right atrium. Blood samples were taken from the distal pulmonary vascular bed, i.e. the pulmonary vein. The design of the study enabled us to observe the development of plasma histamine concentrations within very short time intervals and to detect the high peak plasma histamine concentration that may occur, primarily in the pulmonary outstream vessels. Therefore, the histamine found here could originate from intrathoracically located mast cells. It is more likely, however, that the histamine was administered together with the heparin in complex binding, due to purification problems. The amount of histamine found in this study was sufficient to produce mild to severe circulatory effects in all patients receiving a high dose of heparin.

Action of FPL 52694 on gastric acid secretion in the healthy human stomach.

In a double blind crossover experiment in 16 healthy male volunteers, the effects of oral FPL 52694 and a matching placebo upon pentagastrin stimulated gastric acid secretion, gastric mucosal histamine content, and gastric mucosal mast cell count were compared. There was a significant increase in acid secretion, and a fall in tissue histamine and the mast cell count after treatment with the placebo. All these changes were inhibited by FPL 52694, and there was a significant difference between the effects of this compound and the placebo in all three parameters. It is concluded that FPL 52694 caused significant inhibition of acid secretion, and that the likely mechanism of action is by stabilisation of mast cells and inhibition of histamine release.