A. Szczeklik

Clinical patterns of hypersensitivity to nonsteroidal anti-inflammatory drugs and their pathogenesis

Abstract Clinical observations coupled with challenge tests using 16 different nonsteroidal anti-inflammatory drugs were carried out in 123 patients with a history of allergy to analgesics. Several different patterns of hypersensitivity could be distinguished. Our clinical and experimental data suggest that in the largest group of patients studied the idiosyncrasy to aspirin-like drugs was not of immunologic type but was due to the suppression of prostaglandin generation in tissues of the patients. The adverse reactions to aspirin-like drugs were manifested as asthmatic attacks or urticaria/angioedema. In another group, the hypersensitivity was limited to pyrazoline drugs and was not related to inhibition of prostaglandin biosynthesis. This type of hypersensitivity, resulting in anaphylactic shock and urticaria, seems to have an immunologic background. In a patient with lupus erythematosus the hypersensitive reactions to analgesics were related neither to their chemical structure nor to their known biochemical activities. In a small group of patients the hypersensitivity to aspirin could possibly be attributed to the minute amounts of impurities present in some commercial products.

Circulatory and anti-platelet effects of intravenous prostacyclin in healthy men

Summary Intravenous infusion of prostacylin (2 - 50 ng/kg/min) into six healthy men caused vasodilation of the skin vessels of head, neck and palms, a lowering of diastolic blood pressure with little effect on systolic blood pressure, an increase in heart rate and a rise in venous oxygen pressure. Prostacyclin infusions also resulted in suppression of platelet aggregability to ADP, as well as a dispersion of circulating platelet aggregates. Template bleeding time became prolonged, while partial thromboplastine time, prothrombine time and euglobulin lysis time remained all unchanged. These effects of prostacyclin were transient and disappeared briefly after termination of the hormone infusion. During infusion of a high dose of prostacyclin (50 ng/kg/min) signs of collapse appeared and waned shortly after withrowal of the prostacyclin infusion. No other serious immediate or remote side effects were observed. It is concluded that vasodilatory and anti-platelet actions of prostacyclin, now proved in men, are of the potential therapeutic interest in thrombo-embolic diseases.

Aspirin-induced Asthma

Abstract Eighteen patients with asthma and aspirin hypersensitivity have been challenged with increasing doses of aspirin, fenoprofen, ibuprofen, and dextropropoxyphene. Low doses of the first three drugs induced bronchoconstriction in all the patients as evidenced by fall in peak expiratory flow and appearance of clinical symptoms. There were no reactions to therapeutic doses of dextropropoxyphene. Aspirin, fenoprofen, and ibuprofen, but not dextropropoxyphene, inhibited prostaglandin synthetase activity in three different microsomal preparations, i.e., in bovine seminal vesicles, in rabbit brain and, in rabbit kidney medulla. Expected in vivo antienzymic potency of a drug, calculated from experiments using rabbit brain microsomes, corresponded roughly with its potency to induce bronchoconstriction in the challenge tests. An individual pattern of sensitivity to threshold doses of prostaglandin, synthetase inhibitors was demonstrated for each patient. The results obtained suggest that precipitation of asthmatic attacks by nonsteroidal anti-inflammatory drugs is mediated through inhibition of prostaglandin biosynthesis. The degree of enzymic inhibition, which is sufficient to precipitate bronchoconstriction, is an individual hallmark. Knowing the threshold dose for any of prostaglandin synthetase inhibitors in a patient, one can predict the threshold doses for the rest of aspirin-like drugs in this particular patient.

Treatment of steroid-dependent bronchial asthma with cyclosporin

The treatment of chronic severe asthma is unsatisfactory for many patients. The aim of the study was to determine the effects of treatment of steroid-dependent asthma with cyclosporin. We performed a double-blind, placebo-controlled, randomized, parallel group trial on the effect of cyclosporin on pulmonary function, asthma severity and tapering of prednisone in 34 steroid-dependent asthmatics (mean oral prednisone dose: 16 mg.day-1). The study consisted of: 1) baseline period (12 weeks); 2) experimental period divided into two parts: Part I (12 weeks) cyclosporin or placebo treatment; Part II (22 weeks) cyclosporin or placebo treatment and oral prednisone reduction; and 3) follow-up observation (8 weeks). Asthma symptoms score, pulmonary function tests (daily peak expiratory flow (PEF) and bi-weekly forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and maximal mid-expiratory flow (MEF50), biochemical profile and blood cyclosporin levels were monitored throughout the study. Following cyclosporin administration, a slight beneficial effect on some subjective parameters of asthma severity was observed. At the same time, no beneficial effect on pulmonary function was noted. The time trends analysis of mean daily prednisone doses between the treatment groups revealed a statistically significant difference indicating that, during prednisone reduction, cyclosporin seemed to be slightly more efficient than placebo in reducing the requirement for systemic corticosteroid, even though the steroid reduction was accompanied by slight impairment of some pulmonary function. However, there was no significant difference in the final dose reduction between the treatment groups. These data and the known toxicity of the drug suggest a limited place for cyclosporin treatment in steroid-dependent bronchial asthma.

Pulmonary and anti-platelet effects of intravenous and inhaled prostacyclin in man

Abstract Prostacyclin in aerosol was inhaled by three healthy volunteers (0.3 – 30 μg) and by twelve patients with bronchial asthma (200 or 400 μg). Essentially, no changes in pulmonary function were noticed. Intravenous infusion of prostacyclin (2 – 20 ng/kg/min) into six healthy volunteers also remained without effects on respiratory indices studied. Inhaled prostacyclin impaired platelet aggregability to ADP, dispersed circulating platelet aggregates and produced vasodilation comparable to those observed following intravenous administration of the hormone. We suggest that aerosols of prostacyclin might be used in future in treatment of arterial thrombo-embolism.

Anti-platelet action of intravenous infusion of prostacyclin in man.

Abstract Sodium salt of prostacyclin in 0.1 M Tris buffer pH 9.0 was infused intravenously at doses of 2, 5, 10, 20 and 50 ng/kg/min into six healthy men, aged 26–46 years. Begining with a dose of 5 ng/kg/min prostacyclin caused a dose-dependent inhibition of ADP-induced platelet aggregation in plasma and dissipation of circulating platelet aggregates in blood. At a dose of 20 ng/kg/min template bleeding time and concomitant blood loss were doubled. Prostacyclin did not influence partial thromboplastin time, prothrombin time and euglobulin lysis time. The anti-platelet action of prostacyclin was accompanied by a moderate fall in diastolic blood pressure, increase in heart rate, vasodilation in the regions of face, neck and palms, as well as by arterialization of venous blood. All of the pharmacological effects of prostacyclin disappeared briefly after termination of the infusion. This is the first report on antiplatelet action of prostacyclin in man and it is concluded that prostacyclin may be a valuble drug in the treatment of thromboembolic diseases.

Aspirin-induced asthma: Hypersensitivity to fenoprofen and ibuprofen in relation to their inhibitory action on prostaglandin generation by different microsomal enzymic preparations

Abstract Eighteen patients with asthma and aspirin hypersensitivity have been challenged with increasing doses of aspirin, fenoprofen, ibuprofen, and dextropropoxyphene. Low doses of the first three drugs induced bronchoconstriction in all the patients as evidenced by fall in peak expiratory flow and appearance of clinical symptoms. There were no reactions to therapeutic doses of dextropropoxyphene. Aspirin, fenoprofen, and ibuprofen, but not dextropropoxyphene, inhibited prostaglandin synthetase activity in three different microsomal preparations, i.e., in bovine seminal vesicles, in rabbit brain and, in rabbit kidney medulla. Expected in vivo antienzymic potency of a drug, calculated from experiments using rabbit brain microsomes, corresponded roughly with its potency to induce bronchoconstriction in the challenge tests. An individual pattern of sensitivity to threshold doses of prostaglandin, synthetase inhibitors was demonstrated for each patient. The results obtained suggest that precipitation of asthmatic attacks by nonsteroidal anti-inflammatory drugs is mediated through inhibition of prostaglandin biosynthesis. The degree of enzymic inhibition, which is sufficient to precipitate bronchoconstriction, is an individual hallmark. Knowing the threshold dose for any of prostaglandin synthetase inhibitors in a patient, one can predict the threshold doses for the rest of aspirin-like drugs in this particular patient.

Serum lipoproteins, lipid peroxides and prostacyclin biosynthesis in patients with coronary hear diseases

Serum low-density lipoproteins (LDL) and high-density lipoproteins (HDL) were prepared by gradient ultracentrifugation and dialysis from 12 healthy subjects and 15 patients with coronary heart disease and hyperlipoproteinemia. In both lipoprotein fractions cholesterol and lipid peroxides were determined. The effect of these lipoproteins on spontaneous prostacyclin biosynthesis in rat aortic slices was studied. Serum lipoproteins were susceptible to peroxidation during the preparation procedure. LDL were more prone to peroxidation than HDL. Little lipid peroxides were formed in lipoproteins when calcium ions had been removed by EDTA, and when butylated hydroxytoluene (BHT) was present at all stages of their preparation. LDL when prepared without these precautions either from healthy subjects or from patients with coronary heart disease markedly suppressed prostacyclin generation by rat aortic slices. This inhibition was unrelated to LDL-cholesterol, but was due to LDL-lipid peroxides. Peroxide-low LDL prepared from most of the healthy subjects and patients with coronary heart disease and concomitant hyperlipoproteinemia, did not inhibit prostacyclin biosynthesis. However, in one quarter of the patients, LDL was inhibitory. Consequently, in some patients with coronary heart disease, there operate unknown mechanisms which are responsible for the inhibitory activity of LDL on prostacyclin generation.

Cyclosporin for steroid-dependent asthma

We used cyclosporin to treat 12 adult patients with severe bronchial asthma who had been on systemic steroids for an average of 16 years. During the baseline period, lasting 4‐6 months, therapy with high doses of inhaled beclamethasone, aminophylline and salbutamol was standardized and a minimum necessary dose of systemic steroids was established. After 9 months treatment with low‐dose cyclosporin (average whole‐blood trough levels of 105 ng/ml), in six patients the daily dose of oral prednisone could be reduced from mean 30 mg to mean 11 mg, while daily symptom scores and peak expiratory flows improved significantly. This was accompanied by a reduction in exacerbations of asthma. However, in six other patients attempts to taper the steroid doses were unsuccessful, and cyclosporin was stopped after 4 to 7 months. These preliminary results suggest that cyclosporin might be of benefit in some patients with steroid‐dependent asthma.

Fibrinolytic activity of prostacyclin and iloprost in patients with peripheral arterial disease

We studied the effects of prostacyclin (PGI2) and its stable analog, iloprost, on blood fibrinolytic activity in 33 patients with peripheral arterial disease. Ten subjects (group A) received three 5-hour infusions of iloprost on three consecutive days. The remaining 23 patients received three different 5-hour infusions (placebo, iloprost 2 ng/kg/min, PGI2 5 ng/kg/min). Tissue plasminogen activator (t-PA), total plasma fibrinolytic activity and euglobulin clot lysis time (ECLT) were determined in patients before and after each infusion, both in freely flowing blood samples and following 10 min venous occlusion. In patients of group A, ECLT at rest was significantly shortened after all three iloprost infusions (on average by about 5-11%). First and third infusions produced also shortening of ECLT after venostasis (by 21 and 32%). Statistically significant rise in t-PA activity (by about 68% on average) accompanied only the first infusion. In patients of the group B iloprost provoked significant fall in ECLT at rest (by about 19% on average) only. PGI2 shortened ECLT both at rest and after venous occlusion (by about 17% and 20% on average, respectively) and led to a rise in t-PA activity after venous occlusion by about 33% on average. Our results indicate that prostacyclin and its stable analog, iloprost, enhance fibrinolytic activity in man by releasing or facilitating the release of tissue plasminogen activator from the vessel wall.