Walter H. Reinhart

Drug-Induced Bronchospasm: Analysis of 187 Spontaneously Reported Cases

Background: The Swiss Drug Monitoring Center (SANZ) uses a systematic approach to the collection of spontaneously reported individual cases on suspected adverse drug reactions (ADRs). Spontaneous reporting schemes are designed to detect new, rare and unexpected ADRs and to act as an early warning system but there is a tendency to overreport severe reactions. Objectives: The aim of the study was to determine drug-induced episodes of bronchospasm, their seriousness and predisposing risk factors. An ADR is classified as serious if the reaction results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity. Results: From 1986 to 1995 SANZ received 8,191 case reports of suspected ADRs. In 187 cases (2%) bronchospasm was reported. In 55% of these cases the reaction was regarded as serious. Analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) were reported most frequently and were involved in 24% of the cases of which 64.5% were classified as serious. In three cases a lethal outcome was reported after intravenous administration of metamizol. Anti-infectious agents were implicated in 18% (52% serious), cardiovascular drugs in 11% (50% serious), drug formulation agents in 9% (41% serious), vaccines and immunoglobulins in 5.5% (50% serious), and plasma volume expanders in 5.5% (80% serious). Other drug groups were involved in 27% of the cases. About 50% of patients experiencing bronchospasm after NSAIDs, pharmaceutical formulation agents, vaccines and immunoglobulins had predisposing risk factors such as asthma, atopy or drug allergy. In other drug groups a predisposing factor was identified in 27% or less. Conclusion: Drug-induced bronchospasm is frequently reported with NSAIDs, anti-infective agents, cardiovascular drugs and excipients with a high proportion of serious reactions.

Effect of brief secondhand smoke exposure on endothelial function and circulating markers of inflammation.

OBJECTIVE In contrast to the well defined detrimental consequences of long-term secondhand smoke (SHS) exposure, little is known about the acute effects of passive smoking on endothelial function and inflammation. The aim of the present study was to assess the acute effects of short-term SHS exposure on endothelial function and circulating markers of inflammation. METHODS Peripheral microvascular endothelial function assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) index, circulating markers of endothelial function (von Willebrand factor antigen, Thrombomodulin, E-selectin) and circulating inflammatory markers (high sensitivity C-reactive protein (hsCRP), Interleukin-6 (IL-6)) were measured in eighteen male, non-smoking volunteers before and 12h after a 1-h SHS exposure. RESULTS Twelve hours after passive smoking, average RH-PAT index was significantly lower than before SHS exposure (1.54±0.49 vs 2.01±0.55 (mean±SD), p=0.01) indicating deterioration of peripheral microvascular endothelial function. von Willebrand factor antigen as a marker of endothelial activation was significantly increased after SHS exposure (93.0±25.5% vs 78.4±17.9%, p=0.03). Levels of Thrombomodulin, E-selectin, hsCRP, and IL-6 were unaffected by SHS exposure. CONCLUSION Short-term SHS exposure leads to a measurable disturbance of endothelial function. However, 1h of passive smoking appears to be too short to elicit a significant inflammatory response.

Studies on metabolically depleted erythrocytes

Erythrocytes kept outside the blood circulation undergo progressive changes in metabolism, shape and function, which was the topic of this study. For that purpose, blood anticoagulated with either heparin, citrate or EDTA was incubated at temperatures of 5°C, 22°C or 37°C for 0 h, 24 h and 48 h, respectively. A temperature- and time-dependent decrease of glucose and ATP and increase of lactate and LDH were observed. An erythrocyte swelling and echinocytic shape transformation, which was also time- and temperature-dependent, was seen. Density-separated young and old erythrocytes behaved similarly. The degree of echinocytic shape transformation correlated with the increase in blood viscosity at high shear rate. Echinocytosis was partially reversible when erythrocytes were suspended in buffer containing 0.2% albumin. This phenomenon is specific for albumin, since molecules with a similar molecular weight (dextran 70, heat shock protein, protein C) had no effect. These finding may have an impact on blood banking and transfusion medicine.

Interaction of injectable neurotropic drugs with the red cell membrane.

The normal red blood cell (RBC) shape is a biconcave discocyte. An intercalation of a drug in the outer half of the membrane lipid bilayer leads to echinocytosis, an intercalation in the inner half to stomatocytosis. We have used the shape transforming capacity of RBCs as a model to analyse the membrane interaction potential of various neurotropic drugs. Chlorpromazine, clomipramine, citalopram, clonazepam, and diazepam induced a reversible stomatocytosis, phenytoin induced echinocytosis, while the anticonvulsants levetiracetam, valproic acid and phenobarbital had no effect. This diversity of RBC shape transformations suggests that the pharmacological action is not linked to the membrane interaction. We conclude that this simple RBC shape transformation assay could be a useful tool to screen for potential drug interactions with cell membranes.

Reactivation of herpesvirus infections after vaccinations

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Severe Toxic Laryngo-Tracheo-Bronchitis in a Drunken Man

Accessible online at: http://BioMedNet.com/karger A 54-year-old alcoholic was admitted after he had, in search of alcohol, accidentally ingested and partially aspirated fluid which he remembered to taste of detergent. The chemical analysis of the left-over liquid showed a slightly alkaline (pH 8.3) detergent solution (water content 90%) with common detergents (ethoxylated and propoxylated fatty alcohols), salts (alkali chlorides, alkali citrate 3–4%), solvents (isopropanol !0.1%), ethers of ethylene glycol (!1%), flavoring additives as well as the preserving and antimicrobial agent 2-hydroxybenzoic acid phenylmethyl ester (!0.1%). No nitrogen containing substances were detected. On physical examination a respiratory rate of 22/min with wheezing and prolonged expiration was noticed. The chest X-ray revealed an opacity in the left lower lobe (fig. 1). A bronchoscopy was performed and showed very severe inflammation of the larynx (fig. 2a) and the tracheobronchial tree (fig. 2b). Esophagoscopy was without signs of inflammation, indicating that the esophageal epithelium was less vulnerable to this detergent. The diagnosis of toxic laryngo-tracheo-bronchitis and aspiration pneumonia in the left lower lobe was made. Treatment with inhalational and oral corticosteroids (50 mg prednisone) and antibiotics (amoxicillin-clavulanate) was begun. Over the next 2 weeks the patient recovered slowly. The lung function test on day 25 showed a mildly restrictive pattern without obstruction. The patient was discharged on day 33 for pulmonary rehabilitation. Further follow-up was uneventful.

Incidence and time frame of life-threatening arrhythmias in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

BACKGROUND Life-threatening arrhythmias may complicate the hospital course of patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). The optimal duration of electrocardiographic monitoring in such patients is not well established. We aimed to determine the incidence and the time of occurrence of life-threatening arrhythmias in STEMI patients undergoing PPCI. METHODS Data of 382 consecutive patients with STEMI undergoing PPCI were analysed regarding the occurrence of ventricular fibrillation (VF), sustained ventricular tachycardia (sVT) or bradycardia necessitating temporary or permanent pacing. RESULTS Of these patients, 55% had inferior STEMI, 41% anterior and 4% lateral STEMI. The infarct-related arteries were the right in 41%, the left anterior descending in 41%, the left circumflex in 16%, the left main stem in 1% and a vein graft in <1%. During hospitalisation, 27 (7.0%) patients developed 29 life-threatening arrhythmias (incidence 7.6%): 19 episodes occurred during PPCI (VF n = 11, bradycardia n = 8), 9 episodes during the first 24 hours after PPCI (VF n = 7, sVT n = 2), and 1 sVT episode in a hypokalemic patient on the 4th post-procedural day. A total of 17 patients (4.5%) died within the first 30 days, and 3 of these died during the PPCI procedure. CONCLUSIONS Life-threatening arrhythmias occur in a considerable proportion of STEMI patients undergoing PPCI during hospitalisation. Most of these arrhythmias occur during the PPCI procedure. Post-procedural life-threatening arrhythmias are virtually limited to the first 24 hours after PPCI. Thus, routine electrocardiographic monitoring beyond the first 24 hours after PPCI might not be required in most patients with uncomplicated STEMI.

Acute effects of short-term exposure to second-hand smoke on induced platelet aggregation

Passive smoking may increase cardiovascular events by yet insufficiently understood mechanisms. We, therefore, tested the hypothesis that passive smoking could affect platelet aggregation. Fourteen healthy non-smoking males were exposed to second-hand smoke during 60 min in a room with smokers, who maintained the CO-concentration between 4.5-7.0 ppm throughout that period. Citrated blood was drawn before and immediately after smoke exposure (which took place between 6 and 7 p.m.). The last 7 individuals had blood taken also at 9.00 a.m. before and the day after smoke exposure. Platelet aggregation was measured (a) in flowing whole blood using the platelet function analyser PFA-100, which determines the closure time (CT) of a collagen coated membrane pore by shear-induced platelet aggregation, and (b) with a Chrono-log 700 Aggregometer, assessing platelet aggregation either by the change of impedance in diluted whole blood or light transmission in platelet-rich plasma. After short term second-hand smoke exposure we did not observe an increase in platelet aggregation with any of the instruments. We conclude that acute exposure to second-hand smoke is unlikely to increase platelet aggregability. Other mechanisms must be involved in the increased risk of cardiovascular events associated with passive smoking.

The influence of erythrocyte aggregation on induced platelet aggregation.

Red blood cells (RBCs) affect platelet aggregation in flowing blood (primary hemostasis). We tested the hypothesis that RBC aggregation could influence platelet aggregation. RBC aggregation was altered in vitro by: (i) changing plasma aggregatory properties with 3.7 g% dextran 40 (D40), 3.0 g% dextran 70 (D70) or 1.55 g% dextran 500 (D500); (ii) changing RBC aggregatory properties by incubating RBCs in 50 mU/ml neuraminidase for 60 min (reduction of the surface sialic acid content, thus reducing electrostatic repulsion) and subsequent RBC resuspension in platelet rich plasma (PRP) containing 1 g% dextran 70. RBC aggregation was assessed with the sedimentation rate (ESR). Platelet aggregation was measured: (i) in flowing whole blood with a platelet function analyzer PFA-100(R), which simulates in vivo conditions with RBCs flowing in the center and platelets along the wall, where they adhere to collagen and aggregate; and (ii) in a Chrono-log 700 Aggregometer, which measures changes of impedance by platelet aggregation in whole blood or changes in light transmission in PRP. We found that RBC aggregation increased with increasing molecular weight of dextran (ESR: 4 +/- 3 mm/h, 34 +/- 14 mm/h and 89 +/- 23 mm/hfor D40, D70 and D500, respectively, p < 0.0001) and with neuraminidase-treated RBCs (76 +/- 27 mm/h vs 27 +/- 8 mm/h, respectively, p < 0.0001). Platelet aggregation measured in whole blood under flow conditions (PFA-100) and without flow (Chronolog Aggregometer) was not affected by RBC aggregation. Our data suggest that RBC aggregation does not affect platelet aggregation in vitro and plays no role in primary hemostasis.

Viscosity of human bile sampled from the common bile duct

Cholestasis is a frequent gastroenterological problem, which is tackled by endoscopic procedures. Little is known about bile viscosity, a major determinant of its flow. We measured the viscosity of bile from the common bile duct during endoscopic retrograde cholangiography. Bile was aspirated immediately after cannulation of the papilla and deep-frozen. Viscosity was measured with a rotational viscometer at 37 degrees C and a broad range of shear rates (0.08-69.5 s(-1)). The majority of the 138 patients (64.5%) had bile viscosities between water (0.7 mPa.s) and the lower limit of plasma (1.1 mPa.s). In 20 patients (14.5%) it was above that of plasma (>1.4 mPa.s), and showed a non-Newtonian behaviour, i.e. the viscosity increased exponentially with decreasing shear rate. Cholecystectomized patients had a lower bile viscosity. Bile viscosities did not differ between patient groups with either choledocholithiasis, sludge, cholangitis, biliary pancreatitis, pancreatic carcinoma, or cholangiocarcinoma. We conclude that bile viscosity in the common bile duct is usually lower than that of plasma, in 15% it is higher and increases exponentially with decreasing flow rate, which may lead to a vicious cycle.