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Udgivelsesdato: 2010-Jul

SummaryLow-dose acetylsalicylic acid (ASA) has been shown to be beneficial in patients with acute myocardial infarction and unstable angina pectoris. Oral administration of ASA is difficult in the acute phase of these syndromes. In this study we evaluated the effect of 25 mg, 50 mg or 100 mg of ASA given as an intravenous bolus injection on platelet function and fibrinolysis in healthy males and related this to plasma concentrations of ASA. No adverse effects were found. A complete inhibition of serum thromboxane B2 synthesis was demonstrated 5 min after injection of 100 mg ASA intravenously. ASA disappeared from the circulation within 60 min after bolus injection and at this time thromboxane B2 synthesis was inhibited dose-dependently by 71%, 90% and 100% for doses of 25 mg, 50 mg and 100 mg, respectively. Inhibition of thromboxane B2 synthesis after 100 mg of intravenous ASA was still 96.5% at 24 h and 93.4% at 48 h after the injection. The bleeding time measured at 30 min after ASA administration was significantly prolonged on the average by 70 s, 144 s and 211 s after 25 mg, 50 mg and 100 mg of ASA, respectively. Minor, but significant changes were found in tissue plasminogen activator antigen and in plasminogen activator inhibitor within the first hour after injection of low dose ASA, but similar changes were found after injection of saline. No change in tissue plasminogen activator activity was found. We conclude, that intravenous administration of low dose ASA is safe and easy, and that almost immediate, complete blockage of serum thromboxane B2 synthesis can be obtained after a single intravenous bolus injection of 100 mg.

Superficial thrombophlebitis is a common disease. Recently, a relatively high incidence of concomitant venous thromboembolism has been found. Graduated compressing stockings and low-molecular heparin subcutaneously in weight-based therapeutic doses for 10-30 days are considered the best treatment. Non-steroidal-anti-inflammatory drugs or local treatment with heparinoid may reduce the pain. A new Cochrane analysis concludes that the existing studies do not demonstrate strong recommendations for any treatment. Ongoing trials will add to our knowledge about optimal treatment of ST.

The pathogenesis of deep vein thrombosis (DVT) involves vascular changes or injury, stasis and alterations in the blood composition. The risk increases with age; however, important risk factors are cancer, surgery, immobilisation and hormone therapy. DVT most often appears in the crural veins. The diagnosis is based on ultrasound, d-dimer and clinical examination. Correct treatment requires gradient compression hosiery, low-molecular heparins and anticoagulant therapy. Duration of treatment depends on the individual risk of recurrence.

Bleeding is the main adverse effect when using oral anticoagulants (OACs). The risk of major bleeding with vitamin K antagonists (VKAs) is dependent on the quality of anticoagulation control and estimated to be ∼1.3/100 patients/year in patients with INR 2.0–3.0.1,2 Multiple limitations of VKAs stimulated the development of non-vitamin K antagonist oral anticoagulants (NOACs) acting directly on coagulation factors, including factor FIIa (thrombin) and FXa. Pharmacological properties of the NOACs relevant for bleeding are summarized in the supplement including Supplementary material online, Table S1 and their main effects are summarized in Supplementary material online, Table S2 . The risk of bleeding in patients managed with NOACs was properly assessed in the four landmark Phase III trials in patients with atrial fibrillation (AF; Table 1 ). Major bleeding was the principal safety outcome in RE-LY,3,4 ARISTOTLE,5 and ENGAGE AF.6 In ROCKET-AF, the primary safety endpoint was the composite of major and non-major clinically relevant bleeding.7 The risk of major bleeding was significantly reduced with dabigatran 110 mg b.i.d., apixaban and both doses of edoxaban3–6 while the bleeding rates for dabigatran 150 mg b.i.d. and rivaroxaban were similar to those with warfarin ( Table 1 ). View this table: Table 1 Risk of bleeding with non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation (rates per 100 patients-years) Gastrointestinal (GI) bleeding accounts for ∼90% of major extracranial haemorrhages in patients with AF receiving VKAs.8 With the NOACs, dabigatran 150 mg b.i.d., rivaroxaban, and edoxaban 60 mg o.d. significantly increased rates of GI bleeding (∼1.5-fold) compared with warfarin.3,6,7 While rivaroxaban increases upper and lower GI bleeding …

Management of perioperative treatment with anticoagulants and antiplatelet drugs is a complex medical problem. Careful preoperative evaluation of the risk of bleeding and thromboembolism with and without of antithrombotic therapy is the key prerequisite to secure safe outcome of elective, invasive procedures performed on patients treated with antithrombotic agents. In emergency cases, knowledge of the pharmacokinetics and pharmacodynamics of antithrombotic drugs and of the effect of antidotes and blood-derived, recombinant, and other haemostatic products is important.

The presence of significant effects beyond what may be achieved by reducing consultation blood pressure, particularly in stroke prevention, has been indicated by several clinical hypertension trials, including LIFE, ASCOT, NORDIL, ACCESS and now also MOSES. New data suggest that apparent pressure equality could be a beta-blocker-induced diminished white coat effect; despite this, the evidence points towards the presence, however not a major one, of meaningful preventive effects unrelated to pressure reduction.

Our goal was to investigate the use of venous thromboprophylaxis in Danish hospital departments of internal medicine, neurology and intensive care.All 242 Danish departments/wards received a two-page survey form to complete. Two reminders were sent.Eighty-two percent responded. Ninety percent use thromboprophylaxis, but only 69% of intensive care wards, 36% of neurological wards, and 22% of internal medicine wards have established general guidelines for its use. There is no difference between hospitals in larger cities and those in smaller cities. The most usual indication was prolonged bed rest.Compared with the scientific documentation, the use of thromboprophylaxis in Danish medical wards must be considered insufficient.

Aims To investigate the prognostic value of T-wave abnormalities in patients with nonST-segment elevation acute coronary syndromes (NSTE-ACS), and whether such ECG changes may predict benefit from an early coronary angiography. Although STsegment changes are considered the most important ECG feature in NSTE-ACS, T-wave abnormalities are the most common ECG finding. We hypothesize that a new quantitative approach to T-wave analysis could improve the prognostic value of this ECG abnormality. Methods and results Quantitative T-wave analysis was performed on the admission ECG in 1609 patients with NSTE-ACS. Nine different categories of T-wave abnormality were analysed for their prognostic value concerning clinical outcome in patients not randomized to early coronary angiography. Also, the presence of one category (i.e. T-wave abnormality in � 6 leads) was analysed for its predictive value concerning benefit from early coronary angiography. The combined study endpoint was death or myocardial infarction at 1 year follow-up. Patients with � 6 leads with abnormal T-waves and concomitant ST-segment depression had a higher risk when not receiving early coronary angiography (24 vs. 12%, respectively; P ¼ 0.003), but could be brought to the same level of risk as the remaining patients with this treatment. For noninvasively treated patients five different categories of T-wave abnormality were significantly associated with an adverse outcome. Conclusion New quantitative T-wave analysis of the admission ECG gives additional predictive information concerning clinical outcome and identifies patients who benefit from early coronary angiography.

Aims The FRISC II trial demonstrated that, for patients with unstable coronary artery disease, an early invasive strategy following acute treatment with dalteparin and aspirin, was superior to a more conservative approach. We evaluated whether it is beneficial to extend treatment with dalteparin to patients eligible for revascularization but for whom these procedures are performed after the initial hospital stay. Methods and Results As a subanalysis of FRISC II, the efficacy and clinical safety of extended dalteparin treatment (5000 or 7500IU.12h−1 to day 90) compared with placebo was assessed in 1601 patients randomized to a non-invasive group who underwent revascularization only when necessary because of recurring symptoms, (re)infarction, or severe ischaemia. By day 90, 440 patients had undergone revascularization: 267 of these procedures occurred during the double-blind period. All patients initially received acute treatment (5–7 days from day 1) with dalteparin (120IU/kg−1 12h−1). The incidence of death and/or myocardial infarction was monitored until revascularization or day 45 and until revascularization or day 90. There was a significant difference in the estimated probability of death and/or myocardial infarction until revascularization or day 90 in favour of dalteparin (log-rank test, P =0·0415) and there was a significant reduction in death and/or myocardial infarction in favour of extended dalteparin treatment at day 45, with a 57% relative risk reduction ( P =0·0004). At day 90 the relative risk reduction was 29%. The safety profile of extended dalteparin treatment was similar to that of acute usage. Conclusion Extended dalteparin treatment for up to 45 days is effective and safe as a bridging therapy for patients with unstable coronary artery disease awaiting revascularization. Copyright 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved .

We have evaluated bleeding during and after hip replacement in 186 patients in relation to preoperative intake of nonsteroidal anti-inflammatory drugs (NSAID) combined with low molecular weight heparin. NSAID was associated with increased preoperative bleeding and blood transfusion requirements.

In the PLATO trial ticagrelor was superior to clopidogrel in reducing ischemic outcome and death in patients with acute coronary syndromes (ACS). Ticagrelor is a direct-acting P2Y12 receptor antagonist that is rapidly absorbed and partly metabolized to the major metabolite AR-C124910XX (ARC). ARC is

Microvascular thrombosis plays a significant role in the pathophysiology of ischaemic reperfusion injury. A fish oil-supplemented diet containing n-3 polyunsaturated fatty acids (PUFA) reduces thromboxane A(2) (TxA(2)) synthesis and, thus, vasoconstriction and platelet aggregation. The aim of this study was to elucidate whether n-3 PUFA in a porcine model of ischaemia and reperfusion injury 1) inhibit accumulation of platelets and fibrinogen in ischaemia-reperfusion injured tissue, 2) prolong the bleeding time, and 3) inhibit TxA(2) synthesis. Nine pigs were fed a standard diet supplemented with 7 g n-3 PUFA/day for 3 weeks. Nine pigs on the standard diet served as controls. Unilateral myocutaneous flaps were exposed to ischaemia for a period of 6 hours. Contralateral flaps were nonischaemic. Tissue contents of radioactive-labelled platelets and fibrinogen were measured after 4 hours of reperfusion. Platelet count, serum TxB(2), and the cutaneous bleeding time were measured before and after 3 weeks of diet. In the fish oil group, the accumulation of platelets was significantly reduced in all the myocutaneous flaps, except in the ischaemic skin part, when compared to control animals. Fibrinogen was significantly reduced in nonischaemic flaps, but not in ischaemic flaps. After the feeding period, the level of TxB(2) was significantly lowered in the fish oil group (p0.01). No difference in the bleeding time was observed. Thus, dietary supplementation with n-3 PUFA inhibits the formation of microvasculatory thrombosis in this model.

GDF-15 level in acute coronary syndrome and its relations to cardiovascular risk factors, disease manifestations, treatments and outcome - results from the PLATO-study

Ischaemic events following planned discontinuation of study treatment with ticagrelor or clopidogrel in the PLATO study

Two major hypotheses to explain the pathogenesis of atherosclerotic disease — the thrombogenic and the lipid hypothesis — have dominated in the past century. The thrombogenic theory was postulated by Rokitansky, who in 1844 described intimai thickening resulting from fibrin deposition with subsequent organization by fibroblast and lipid accumulation. He deduced that the deposit derived from the arterial blood, reviving the idea of dyscrasia, which had been popular in antiquity [1]. The lipid theory was proposed by Virchow in 1856, who observed that the intimai thickening in atherosclerosis was located in the subendothelial layer, and therefore could not be derived from surface deposits [2]. Both theories have been integrated into one single multifactorial theory that involves the common step — endothelial dysfunction as a reponse to injury — developed by Ross [3]. One or more risk factors (hyperlipidemia, smoking, obesity, hypertension, diabetes etc.) plus local factors such as shear stress or injury are hypothesized to contribute to the development of endothelial lesions.

In a placebo-controlled study, the safety and efficacy of the selective alpha 1-adrenoceptor-blocking agent doxazosin 4 mg once daily in the symptomatic treatment of benign prostatic hyperplasia (BPH) were evaluated. One hundred patients were primarily included in a 9-weeks study, and after this 75 patients accepted to continue in the present 20 weeks extension. Of the patients in the doxazosin-group (DG) 61% reported overall improvement against 53% in the placebo-group (PG)--(p = 0.56). In the DG, 49% of obstructive symptoms were improved compared to 27% in the PG (p0.01), and a reduction of 60% of irritative symptoms was found in the DG against 36% in the PG (p0.01). Daytime frequency was reduced by median 1.5 in the DG and remained unchanged in the PG (p0.01). Nocturia was reduced by median 1 and 0.5 respectively (p = 0.06). Maximum urinary flow rate (MFR) was improved by median 1.5 ml/s in the DG, while it deteriorated by median 0.5 ml/s in the PG (p0.05), Considering postvoid residual urine volume, cystometry variables (first sensation and bladder capacity), changes in sexual function and adverse events there was no difference between the two groups. In conclusion, doxazosin 4 mg once daily in long-term treatment of patients with BPH reduces both obstructive and irritative symptoms, daytime voiding frequency and although only slightly, significantly augments MFR without interference with sexual function and without other serious adverse effects.

The diagnosis of pulmonary embolism (PE) remains one of the most difficult in clinical medicine, and the diagnostic value of lung scintigraphy has been questioned. To evaluate the observer variation in the interpretation of ventilation-perfusion lung scanning in the diagnosis of PE, 87 lung scintigrams from consecutive patients with phlebography-proven deep venous thrombosis and without clinical signs of PE were randomly mixed with 50 reference lung scintigrams from patients with PE symptoms. The scintigrams were reevaluated blind by two experienced clinical physiologists. Each observer evaluated each lung scintigram twice and recorded whether the lung scan was normal or abnormal. If it was abnormal, the location and number of segment defects were registered. The intraobserver agreement, including number and location of segments, ranged from 0.77 to 0.85 and for the diagnosis of PE from 0.88 to 0.92 with a kappa of 0.80 – 0.84. The values for the interobserver agreement for the diagnosis of PE were 0.73 – 0.80 with a kappa of 0.56 – 0.67. It is concluded that in the interpretation of ventilation-perfusion lung scintigraphy the use of a simple scheme — deciding whether there is segmental ventilation-perfusion mismatch or not — has a good reproducibility with a high kappa for inter- and intraobserver variation and can serve as a simple routine method for diagnosing PE.

The safety and efficacy of the selective alpha 1-blocking agent doxazosin 4 mg once daily in the symptomatic treatment of benign prostatic hyperplasia were evaluated in a randomized, double-blind and placebo-controlled 9-week study of 100 patients. By patients' overall assessment of voiding difficulties, 79% in the doxazosin group (DG) and 44% in the placebo group (PG) reported improvement (p = 0.001). In the DG, improvement was noted in 63% of obstructive symptoms compared to 32% in the PG (p = 0.015), whereas improvement was noted in 76% and 45%, respectively, of irritative symptoms (p = 0.12). Daytime frequency was reduced by 1.5 in the DG and increased by 0.3 in the PG (p = 0.001), and nocturia was reduced by 1.1 and 1.0, respectively (p = 0.12). Maximum urinary flow rate was improved by 1.5 ml/s in the DG, while it deteriorated by 0.3 ml/s in the PG (p = 0.11). Considering postvoid residual urine volume, cystometry variables (first sensation and bladder capacity) and adverse events there was no difference between the two groups. In conclusion, doxazosin 4 mg once daily is safe and effective in relieving symptoms in patients with BPH.

Of 1078 patients admitted to the coronary care unit with acute chest pain, 293 who had possible acute myocardial infarction and symptoms of median 4 h duration were randomized to treatment with acetylsalicylic acid (ASA) 100 mg daily, 1000 mg daily or placebo for 3 months. During hospitalization, the combined incidence of cardiac death and non-fatal myocardial infarction on-treatment (withdrawals not included) was significantly lower (P less than 0.02) in the 100 mg group (7.1%) than in both the 1000 mg group (20.8%) and the placebo group (19.7%). During later time periods of treatment and at all time periods analysed according to the intention-to-treat principle (withdrawals included), data suggested the same trend, but differences were not statistically significant. Collagen-induced platelet aggregation and serum thromboxane B2 were reduced to the same degree in the two ASA groups and were normal in the placebo group. The data suggest that low-dose ASA could be cheap and safe as first-aid therapy in myocardial infarction suspects.

The systemic availability of acetylsalicylic acid (ASA) after oral ingestion of 1 g in an effervescent formulation was 16.3 +/- 2.0% and 16.9 +/- 3.2% of the ingested dose in normal women and men, respectively. The average plasma half-life of ASA in each sex was also identical at 18.5 +/- 1.4 and 18.1 +/- 1.2 min, respectively. The inhibitory effect of ASA on collagen-induced platelet aggregation in vitro on blood from both sexes was studied. The IC50 was 23.9 +/- 2.9 micrograms/ml in females and 22.5 +/- 2.7 micrograms/ml in males, which did not differ significantly. The inhibition by salicylic acid (SA) of the antiaggregatory effect of ASA was similar in both sexes with increases in IC50 to 33.5 +/- 5.1 micrograms/ml in females (p less than 0.02) and to 29.5 +/- 3.8 micrograms/ml in males (p less than 0.05). It is concluded that the observed sex-difference in the antithrombotic effect of ASA cannot be explained neither by differences between females and males in the pharmacokinetic properties of ASA after oral ingestion, nor by differences in the in vitro effect of ASA on the platelet aggregation induced by collagen.

A Multistat III Centrifugal Analyser (MCA) was used to measure platelet aggregation in vitro. It has a capacity of about 40 samples per h. In the analyser platelet-rich plasma and collagen-reagent were mixed, and the turbidity was measured as a function of time. The results were presented in arbitrary units ( arb . units), i.e. change in turbidity per min X 1000. The estimated 0.95 reference range was 50-95 arb . units, (n = 46) and the coefficient of correlation between MCA results and results obtained by conventional aggregometry ( Fibromat ) was 0.85 (P less than 0.001). The MCA method registered 50-75% reduction of platelet aggregation after intake of low dose acetylsalicylic acid (ASA) (1.2-4.0 mg/kg) during 3 days in 19 subjects. The MCA method is suitable to monitor ASA treatment routinely in order to establish an individual appropriate ASA dose during prophylactic treatment of arterial thromboembolic disease.

Abnormal sensitivity to phenprocoumon in a castrated male who was receiving substitution therapy with methyltestosterone, has been studied and compared with pharmacokinetic data obtained from six control subjects, all of whom had cardiac disorders. The concentration-effect relationship for phenprocoumon in the castrated patient was evaluated by the mathematical model described by Nagashima et al. (1969). The possible mechanisms involved in sensitization by methyltestosterone of the response to phenprocoumon are discussed. It is suggested that methyltestosterone increases the affinity of the receptor sites in the liver for phenprocoumon, an effect which has previously been attributed to other C17-alkyl-substituted androgens.

Sulfadiazine (SDZ) 800 mg and trimethoprim (TMP) 160 mg were given orally to 10 normal subjects and the concentration of SDZ and TMP in serum and urine was followed for 24 h. Both drugs showed a significant negative correlation between individual “peak” concentrations in serum and the body weight of the subject. Twelve hours after dosing the serum concentration was 12 to 25 µg/ml for SDZ and 0.3 to 1.1 µg/ml for TMP. Individual concentration ratios between SDZ and TMP in serum were 4.8 (1 h) – 145 (24 h), and in the urine the ratio was close to 6 throughout the 24 h collection period. The range of urinary concentrations was from 65 to 400 µg/ml for SDZ and from 13.8 to 93.4 µg/ml for TMP. The fraction acetylated SDZ/acetylated SDZ + SDZ was 21% during the 0–8 h period, 33% during the 8–15 h period and 41% during the 15–24 period. The average values for the notional volume of distribution, Vd, were 0.36±0.13 1/kg for SDZ and 1.39±0.25 1/kg for TMP. The average “t1/2” was 15.2±7.4 h for SDZ and 7.4±1.9 h for TMP. Individual subjects showed a significant correlation between the serum clearance of TMP and SDZ (p

Human detrusor strips were obtained from patients undergoing reimplantation of ureters because of reflux, transvesical prostatectomy, or cysto-urethrectomy en bloc because of bladder malignancy. The strips were electrically stimulated. A frequency-dependent contractant response was obtained that was potentiated by physostigmine and abolished by tetrodotoxin. The maximum response approximately equaled that of acetylcholine in a maximum concentration. In most bladder preparations from patients without known functional bladder disturbances, atropine (0.01 to 0.1 microM) had a marked inhibitory effect, and at concentrations exceeding 1 microM the blockade was complete. In strips obtained from patients undergoing transvesical prostatectomy, and who also had a cystometrically verified unstable bladder, there was a varying degree of atropine resistance, with some preparations showing a 50 per cent resistance to atropine. Prazosin, phentolamine, yohimbine, guanethidine, clonidine, and noradrenaline had no consistent effects on the electrically induced bladder contraction. Nifedipine and nimodipine caused a maximum of 65 per cent inhibition of the response. Addition of nimodipine to atropine-resistant strips when maximum atropine inhibition had been reached abolished the contractions. Omitting calcium from the bath solution rapidly abolished the electrically induced contraction. It is suggested that in the normal human bladder the contraction induced by electrical stimulation is mainly atropine sensitive. However, in the functionally disturbed bladder, part of the bladder contraction is atropine resistant, a finding that may have clinical implications.

In a double-blind cross-over study bepridil 900 mg followed by 300 mg daily for 11 days was given to 37 insulin (Type I) or non-insulin (Type II)-dependent diabetic patients. It did not modify the metabolic control of the patients as levels of glucose in blood and urine, doses of insulin and oral hypoglycaemic drugs, energy intake, and the number of hypoglycaemic attacks during therapy were unchanged. The serum concentration of C-peptide was not modified in either type of diabetic patient, and serum insulin in the Type I but not in the Type II patients was slightly higher during active drug treatment. No adverse organotoxic or arrhythmogenic effects or changes in possible atherogenic lipid fractions in serum could be demonstrated during bepridil therapy.

Out of a total of 150 patients attending an out-patient clinic for anticoagulant therapy, 12 had disorders which normally would indicate a prolonged use of an antirheumatic drug. To 6 of these patients, naproxen (1/4 g twice daily) was given while anticoagulant treatment with phenprocoumon was continued in an unchanged dosage schedule (average dose 2.1 mg/day). On the average, the prothrombin complex activity (PP%) was reduced to a stable level 10-20% below that obtained during a 2-month period before the naproxen treatment was started. No bleeding episodes or other effects were observed. Thus the simultaneous administration of naproxen caused no problems for the maintenance of a stable anticoagulant therapy.

A modification of a fluorometric assay for phenprocoumon is described. The sensitivity of the method has been increased so that the lower limit is 5 ng/ml. By an ultrafiltration technique, phenprocoumon (PPC), in therapeutic concentrations, was bound to the extent of 99.9%, both in undiluted plasma and in Krebs–Henseleit (K–H) solutions containing 4 g human serum albumin (HSA)/100 ml. An increase in the pH from 6.05 to 8.02 in phosphate buffers containing 0.2 g HSA/100 ml yielded an increase in the apparent association constant for PPC binding to HSA from 0.562–106 1/mol to 1.195–1061/mol, while the number of PPC mol bound per mol albumin remain unchainged (1.05 and 1.03 respectively). A reduced binding of PPC in undiluted plasma containing increasing concentrations of furosemide have been observed. Scatchard plots based on binding studies in K–H solutions containing 0.2 g HSA/100 ml indicate a competitive nature of the albumin binding of PPC and furosemide.

During a 2-year period the diagnostic value of 99mTc-labelled-plasmin test was evaluated in 63 patients admitted with clinical signs of deep vein thrombosis (DVT). In comparison with a conventional phlebography the diagnostic sensitivity and specificity of the plasmin test was 0·97 and 0·55, respectively. The predictive value in positive cases was 0·79 and in negative 0·92. The sensitivity was highest for thrombosis in the calf and popliteal regions, while the specificity was higher for thrombosis in the femoral veins. It is concluded that the 99mTc-labelled-plasmin test is suitable for DVT-screening in groups of high-risk patients and is simple and rapid. In positive cases the DVT diagnosis must be verified by phlebography.

The binding of the potent, basic antiarrhythmic agent aprindine to serum proteins was studied in solutions of human serum albumin (HSA, lyophilized, 98% pure, KABI) and in human sera. The percentual binding in serum (90.9-96.7%) was considerably higher than in HSA solutions. The binding in serum decreased from 95-97% to 91-93% as the aprindine concentration was raised from 4 to 15 micrograms/ml. The serum binding differed significantly in sera from three normal individuals. By plotting (Formula: see text), as a function of bound drug and performing statistical analysis of the curves a striking difference between the number of primary binding sites in serum and in HSA solution was found (N1 for the HSA solution was 0.0016 and for one serum it was 0.020 "per albumin molecule".) The association constants for the primary binding sites (K1) were 4.3 X 10(6)M-1 for serum and 2.1 X 10(6)M-1 for the HSA solution. Furthermore, the analysis indicated that considerably less than one secondary binding site was present for each albumin molecule in the HSA solution. Therefore, no binding of aprindine to albumin molecules has been demonstrated and it is concluded that the entire binding of aprindine in serum as well as in 98% HSA solutions may be due to the presence of acid protein molecules. In particular, low percentual binding in HSA solutions in spite of the high association constant can be explained by a very low concentration of the binding proteins. The addition of propranolol or phenprocoumon did not cause any displacement of aprindine. In the appendix statistical problems in the analysis of the binding curves are elucidated. The experimental variance and the statistical acceptability of the binding model are discussed.

In nine patients, the synthesis rate Rsyn of the vitamin K-dependent clotting factors was calculated from changes in prothrombin-complex activity after intravenous administration of a synthesis-blocking dose of phenprocoumon (PPC). The biological half-life of PPC was between 2.70 and 7.01 days. No correlation was found between the level of the free fraction of this strongly protein-bound drug and its biological half-life. There was a positive correlation (p

In a placebo-controlled clinical trial with cross-over design the effect of alpha-adrenoceptor blockade with prazosin was studied in 18 neurological patients with detrusor hyperreflexia and bladder emptying disability. During active treatment both the distance to maximal urethral closure pressure (MUCP) and MUCP were significantly reduced. In addition, the volume at first bladder contraction was increased. The urodynamic parameters measured during voiding were unaffected. We conclude that prazosin decreases detrusor hyperreflexia but only in rare cases may benefit bladder emptying in these patients.

The antihypertensive effect of nifedipine during long-term therapy was investigated in 5 patients receiving nifedipine as the sole drug and in 10 patients who had nifedipine in combination with a beta-adrenoceptor blocking drug. Nifedipine monotherapy was problematic because of side-effects and development of resistance to therapy after a few months. In patients who received the combined therapy significant and stable blood pressure reductions were maintained during the whole observation period (12–33 months). However, the occurrence of peripheral oedema in 4 of the patients necessitated the addition of a thiazide diuretic. It is concluded that nifedipine is not a first choice drug for the long-term treatment of arterial hypertension. When given in addition to a beta-blocker it is well tolerated and powerful but fluid retention may occur and if not counteracted by a diuretic it will limit the antihypertensive potential of the drug.

Urinary excretion rates of beta 2-microglobulin and albumin were measured in 43 male printing trade workers and 43 age-matched male controls before and during exposure to toluene, 382 mg/m3, for 6 1/2 hours in a climate chamber. There were no significant changes in renal excretion rates of albumin and beta 2-microglobulin during toluene exposure indicating that no causal relationship exists between moderate exposure to organic solvents and renal injury.

To assist the attending physician who may have difficulties in deciding whether observed deviations from normal renal physiology are disease-induced or diuresis-induced we studied urinary excretion rate of proteins and protein degradation products in eight healthy male volunteers between 60 and 70 years. After a 24 hr control period in the ward the subjects received 80 mg furosemide intravenously. The 24 hr creatinine clearance was reduced from 95 +/- 9 to 83 +/- 6 ml/min. (P less than 0.05). The reduction in the 24 hr carbamide clearance from 35.8 +/- 9.4 to 33.1 +/- 6.2 ml/min. was not significant. The urinary pH was significantly increased during the first hour but after the pH showed a fall which was significant during 2-8 hours after the injection. Initially the urate excretion showed an apparent increase but from 1-8 hours after the injection significantly less urate was excreted. The 24 hr urate clearance was reduced by furosemide from 5.3 +/- 1.6 to 3.4 +/- 1.1 ml/min. (P less than 0.05) and the amount of urate excreted was reduced from 2.6 to 1.6 mmol per 24 hrs (p = 0.05). The excretion rate of beta 2-microglobulin was reduced (P less than 0.01) whereas the excretion rate of albumin was increased (P less than 0.05).

Chronic effects of organic solvents on renal function were measured by creatinine clearances and urinary excretion rates of beta 2-microglobulin and albumin. Forty-three male printing trade workers occupationally exposed to different organic solvents for 9-25 years were compared with 43 age-matched male controls. No differences were found either in creatinine clearances or average basal levels of beta 2-microglobulin and albumin excretion rates, whereas a positive relation could be demonstrated between alcohol consumption on the day before the trial and urinary excretion rate of albumin. This investigation did not reveal any adverse renal effects of moderate chronic exposure to organic solvents in a group of active trade workers.

Frost L, Johnsen SP, Pedersen L, Toft E, Husted S, Sorensen HT (Aarhus University Hospital and Aarhus University, Aarhus, Denmark). J Intern Med 2002; 252: 64–69. Objectives. A pooled analysis of randomized trials has shown that oral anticoagulation therapy reduces the risk of ischaemic stroke with 68% in patients with atrial fibrillation. We examined the effectiveness of oral anticoagulation on risk of stroke of any nature (fatal and nonfatal ischaemic and/or haemorrhagic stroke) in patients with nonvalvular atrial fibrillation or flutter living in the County of North Jutland, Denmark. Design. Cohort study. Subjects and methods. We used the Hospital Discharge Registry covering the county (490 000 inhabitants) from 1991 to 1998 to identify 2699 men and 2425 women with atrial fibrillation or flutter, aged 60–89 years. Data on prescriptions of anticoagulation were obtained from the National Health Service. We defined use of oral anticoagulation as date of prescription or reiteration plus 90 days. Patients were followed in the County Hospital Discharge Registry until a diagnosis of stroke (fatal and nonfatal ischaemic and/or haemorrhagic stroke), emigration, death or the end of 1998. We used Cox regression analyses to estimate the relative risk of stroke associated with use of oral anticoagulation compared with no use, adjusted for age, diabetes and underlying cardiovascular diseases. Results. Eight hundred and thirty-eight of 2699 men (31%) and 552 of 2425 women (23%) with atrial fibrillation had one or more recorded prescriptions of oral anticoagulation. The incidence rates of stroke were 31 per 1000 person-years of follow-up in men, and 30 per 1000 person-years of follow-up in women. The adjusted relative risks of stroke during anticoagulation were 0.6 [95% confidence interval (CI) 0.4–1.0] in men, and 1.0 (95% CI 0.7–1.6) in women compared with nonuse periods. Conclusions. The effectiveness of oral anticoagulation in clinical practice may be lesser than the efficacy of oral anticoagulation reported from randomized trials.

Activated Leukocyte Cell Adhesion Molecule (ALCAM) And Outcomes In Acute Coronary Syndromes : A Plato Biomarker Substudy