Anticoagulation with low-molecular-weight heparin in patients with heart diseases.

Low-molecular-weight heparins (LMWH) were investigated in different cardiac diseases requiring anticoagulation. In case of short term usage advantages over intravenous unfractionated heparin (UFH) are of relevance, such as simple subcutaneous application, possibility for outpatient treatment and predictable effect on anticoagulation enabling abstention of laboratory monitoring in most cases. Thromboprophylaxis in acute medically ill patients and therapy of non-ST-elevation acute coronary syndromes (NSTE-ACS) are important indications, in which significant advantages for special LMWH as compared to Placebo or UFH were shown. A significant effect versus Placebo was demonstrated for the LMWH Dalteparin in prolonged anticoagulation until revascularisation procedure in NSTE-ACS. Promising results from trials were also published concerning use of LMWH Dalteparin and Enoxaparin in TEE-guided cardioversion. Findings from cohort trials are available for temporary or long term switch from oral anticoagulation to LMWH. Due to limited data, determination of individual benefit-to-risk ratio is of special importance to select suitable anticoagulation regimen in this case. Further investigations as a basis of general recommendations on standard dosing regimen are outstanding for use of each LMWH in percutaneous coronary interventions, as combination with Glycoprotein IIb/IIIa-inhibitors, in acute myocardial infarction and in artificial heart valves. In cardiology, most studies were performed with Dalteparin and Enoxaparin, suggesting these to be used in established cardiac indications as well as in further investigations.

Anticoagulation with the low-molecular-weight heparin dalteparin (Fragmin) in atrial fibrillation and TEE-guided cardioversion.

BACKGROUND: Cardioversion (CV) in atrial fibrillation can cause arterial embolism. Effective anticoagulation clearly reduces the risk. In practice, in every third case anticoagulation is not in line with the recommendations. Simplification can be achieved, and time gained, by transesophageal echocardiography (TEE) due to the shorter anticoagulation period prior to CV, and by use of low-molecular-weight heparin (LMWH) for anticoagulation. As yet little data is available on LMWH in cardioversion. The aim of this cohort study was to investigate the administration of a LMWH in this indication under everyday clinical conditions. METHODS: 125 patients treated as inpatients for atrial fibrillation or -flutter received the LMWH Fragmin (dalteparin 2 x 100 anti-Xa units/kg, maximum dosage 2 x 10,000 anti-Xa units subcutaneously). In the presence of a relevant indication, TEE-guided CV was performed. The application of dalteparin was terminated as soon as effective anticoagulation had been achieved from phenprocoumon or once anticoagulation was no longer indicated. RESULTS: 125 patients with atrial fibrillation or -flutter received dalteparin for a median of 11 days (range of 3-41 days). TEE was performed in 39 patients. Five patients revealed a thrombus in the left atrial appendage in the TEE, and one patient died from suspected cerebral embolism over the further course. In the remaining 124 patients, no thromboembolic event was established. Successfully cardioverted were 26 of 34 patients (76%) who had no thrombus in the TEE. Serious adverse effects did not ensue. CONCLUSION: Simple, well tolerated and effective anticoagulation is possible with dalteparin in TEE-guided CV. Due to the methodic limitations of a cohort study and the low incidence of emboli, the efficacy of dalteparin in this indication needs to be further confirmed by prospective and randomized studies.

[Diagnosis and treatment of streptococcal myositis]. / Diagnose und Therapie der Streptokokkenmyositis.

HISTORY AND CLINICAL FINDINGS: Case 1: Following an influenza a 40-year-old patient was treated by intramuscular injections for backache. 24 hours later he was admitted to a hospital with massive pain in both lower extremities and a markedly reduced general condition. Case 2: Two days after a knee joint arthroscopy a 57-year-old man developed strong pain in the extremity treated by application of diclofenac. On the following day the patient was admitted to a university hospital in a septic state with a swollen, cold and blurry changed extremity. INVESTIGATIONS: The myoglobin concentration was dramatically increased in both cases (> 15 000 mg/l). CRP values were elevated. The progressive septic state with acute renal failure was verified by elevation of creatinine concentration and decrease of leukocyte values in the second case (from 10/nl to 2,5/nl) shortly after admission. DIAGNOSIS, TREATMENT AND COURSE: Both the patients died for septic shock. Case 1 died shortly after admission before surgical intervention. The second patient developed rapid progression of the myositis including the trunk despite radical surgical treatment (hip joint exarticulation). CONCLUSION: In cases of sudden and painful swelling of an extremity of unknown origin or following intramuscular injection streptococcal myositis has to be taken into account. Only an immediate surgical intervention up to amputation of the affected extremity can stop the fatal course.

The farnesyl protein transferase inhibitor BZA-5B blocks farnesylation of nuclear lamins and p21ras but does not affect their function or localization.

BZA-5B is a peptidomimetic inhibitor of protein farnesylation in mammalian cells. We have examined the specificity of this compound toward inhibition of farnesylation of p21ras and the nuclear lamin proteins, prelamin A and lamin B. We have also used the Raney nickel cleavage technique in conjunction with radio-gas liquid chromatography to assess the ability of this compound to block total protein farnesylation. These studies show that BZA-5B blocks farnesylation of the lamin proteins with an IC50 comparable to that seen for p21ras. At a concentration in excess of 25 microM, BZA-5B inhibits all protein farnesylation in CHO-K1 cells below the limits of detection. Furthermore, we found that after a 2-day exposure to high concentrations of BZA-5B, CHO-K1 cell lines exhibit no loss in sensitivity to inhibition of prenylation by this compound. Yet, despite the potent and general inhibition of protein farnesylation, BZA-5B does not interfere with a variety of cellular functions expected to be farnesylation dependent, including cell growth and viability, assembly of the nuclear lamina, membrane association of p21ras, and p21ras-dependent differentiation of PC-12 cells in response to treatment with nerve growth factor. The maintenance of farnesylation-dependent events in the presence of BZA-5B stands in marked contrast to the inhibition of the oncogenic ras-mediated transformed phenotype that has been observed with this compound and other farnesyl protein transferase inhibitors. This specificity for inhibition of ras transformation by BZA-5B is quite encouraging to its eventual development as an antimalignancy pharmaceutical.

The effects of intravenous mexiletine on spectra of the signal-averaged ECG.

This study examined the effects of intravenous mexiletine on the time-domain and spectrotemporal signal-averaged ECG (SAECG). SAECGs were recorded in 60 postmyocardial infarction (MI) patients with more than 100 premature ventricular beats per hour, before and after a constant infusion of mexiletine, 7 mg/kg, given over 1 hour. Spectrotemporal analysis was done on a fixed analyzed signal duration of QRS complex and ST segment of X, Y, and Z leads using a temporal window of rectangular type, measuring the signal content between 10-120 Hz. Intravenous mexiletine produced no significant change in the mean values of any of the time-domain variables. However, mexiletine either increased or decreased the power density spectrum (PDS) and PDS ratio (40-120 Hz/25-120 Hz) of the SAECG, and in rare cases only did it not alter the spectra of the SAECG. When PDS ratio in lead Z decreased after mexiletine, it was usually higher at baseline in comparison with that when the PDS ratio increased, or vice versa. When the treatment with mexiletine was effective, PDS increased in comparison with that when the drug was ineffective, or vice versa. Not all ranges (10-120 Hz) of spectra of the SAECG, but only certain frequency bands (25-40 Hz in lead Z, P = 0.0253; 40-55 Hz in lead Y, P = 0.0096; 55-70 Hz in X lead, P = 0.0018; and in lead Z, P = 0.0002; 70-85 Hz in lead X, P = 0.0025; and in lead Z, P = 0.0075, 85-100 Hz in lead X, P = 0.0033) were associated with mexiletine efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

Signal-averaged ECG in prediction of the short-term suppression of ventricular premature beats by Mexiletine.

We analyzed whether baseline parameters of time-domain and spectrotemporal analysis of a signal-averaged ECG or their changes during Mexiletine therapy can predict the antiarrhythmic efficacy of the drug. On 60 post-MI patients with > 100 ventricular premature beats per hour, signal-averaged ECGs were recorded before and after a constant infusion of Mexiletine (7 mg/kg) for 1 h and again after 4 days of oral Mexiletine therapy (Mexiletine SR, 360 mg twice daily). Spectrotemporal analysis was performed on a fixed analyzed signal duration of QRS-complex and ST-segment of X-, Y-, Z-leads using the temporal window of the rectangular type, measuring signals between 10-20 Hz. Intravenous and oral Mexiletine did not produce significant changes in mean values of any time-domain parameters. However, using informative variables of spectra of the signal-averaged ECG, we managed retrospectively to predict antiarrhythmic efficacy in 92% of the patients. Only certain frequency bands (from the range of the spectra at baseline, 10-120 Hz) were predictive for intravenous Mexiletine efficacy: 40-55 Hz in lead Y (P = 0.0116); 55-70 Hz in leads X and Z (P = 0.0063 and P = 0.0269, respectively); 70-85 Hz in lead Z, (P = 0.0227). When the treatment with intravenous Mexiletine was effective, the baseline power spectrum density was lower than when the drug was ineffective, and vice versa. Moreover, the efficacy of oral Mexiletine can be predicted by power density spectrum at baseline (10-25 Hz in lead Z, P = 0.0210; 70-85 Hz in lead Y, P = 0.0254) and by one of the possible (increased, decreased, unchanged) effects of intravenous Mexiletine on the spectra at frequency bands (70-85 Hz in lead X, P = 0.0432 and 40-120 Hz in lead Z, P = 0.0156). These results show the value of spectrotemporal signal-averaged ECG in selecting a subgroup of post-myocardial infarction patients that may benefit from Mexiletine therapy.

[Effect of low-dosage intravenous nitrate therapy on the anticoagulant effect of heparin]. / Einfluss einer niedrigdosierten intravenösen Nitrattherapie auf die antikoagulatorische Wirkung von Heparin.

BACKGROUND AND AIM: Controversial studies concerning the fact that simultaneous i.v. administration of heparin and glyceroltrinitrate (GTN) might reduce the anticoagulatory effect of heparin have been published. In a controlled and comparative study we therefore investigated the influence of the nitrates GTN or isosorbide dinitrate (ISDN) in comparison to placebo on the anticoagulatory effect of a constant heparin infusion in patients with CAD. PATIENTS AND METHODS: 22 stable and mobile inpatients (two female, 20 male; aged 47 to 80; documented CAD in 20 patients, one patient with atrial fibrillation, one patient with suspected CAD), kept on a therapeutic heparin infusion for several days (prolongation of the partial thromboplastin time [PTT] by 1.5 to two-fold), were included. Study course: Day 1: Discontinuation of nitrate medication, optimization of heparin therapy and fixation of the heparin dose (mean dose 33,800 E/24 h in the GTN group and 32,700 E/24 h in the ISDN group). Day 2: Intravenous simultaneous administration of 0.9% NaCl solution as placebo (3 ml/h) with heparin over 24 hours. Day 3: Substitution of NaCl solution by randomised single-blind intravenous administration of GTN (n = 10; 0.1%, solved in NaCl; dose 2.8 +/- 0.5 mg/h) or ISDN (n = 12; 0.1%, solved in NaCl, dose: 4.8 +/- 0.8 mg/h) for 24 hours. Day 4: Discontinuation of nitrates. RESULT: As compared to placebo, the intravenous simultaneous administration of GTN or ISDN and heparin over 24 hours had no influence on the anticoagulatory effect of heparin when the areas under the curve of PTT values on days 2 and 3 were compared (PTT measurements at 8, 10 a.m., 1, 3, 6, 11 p.m.; Mann-Whitney test). After GTN or ISDN had been discontinued, no change in PTT values was seen during the following five hours. CONCLUSION: There is no indication of a pharmacodynamic relevant interaction between heparin and low-dose intravenous nitrate therapy in patients with CAD.

[Ultrasonographic findings in varicose phlebitis of the great saphenous vein. Evidence of thrombus growth and detachment with asymptomatic lung embolism]. / Sonographische Befunde bei Varikophlebitis der Vena saphena magna. Dokumentation von Thrombuswachstum und -ablösung mit asymptomatischer Lungenembolie.

In five women (mean age 58 [31-74] years) with clinically diagnosed varicose phlebitis of the long saphenous vein appositional thrombus growth was demonstrated by serial ultrasonography (B-mode compression and colour-coded duplex sonography). In one patient the appositional thrombus was found to be free-floating as far as the common femoral vein, but this was not seen by phlebography. During therapeutic heparinization there was ultrasonographic evidence of softening and partial liquefaction of thrombus material in a cranial direction. There were no clinical signs of pulmonary embolism, but pulmonary perfusion scintigraphy demonstrated perfusion deficit characteristic of emboli. Four of the five patients had a surgical crossectomy and partial saphenous vein resection. The congruence between ultrasonographic and macro- as well as micropathological findings demonstrates the great value of B-mode and duplex ultrasound examination in the area of the epifascial veins. Ultrasonography should be performed in every case of varicose phlebitis of the large veins to exclude the presence of apposition thrombi.

Lack of effect of cefixime on the metabolism of vitamin K1.

It seems that cephalosporins bearing a N-methyl-thio-tetrazole or a methyl-thiadiazole moiety in their molecule can cause hypoprothombinemia in patients via inhibition of the metabolism of vitamin K1 if they are in addition in a vitamin K1-deficient state. The authors therefore studied the effects of two different oral doses (200 and 400 mg) of the cephalosporin cefixime on the metabolism of vitamin K1 in healthy volunteers, because the accumulation of vitamin K1-2,3-epoxide in plasma is a sensitive marker of coumarin-like activity of drugs. The results indicate that the development of hypoprothrombinemia due to an impairment of the metabolism of vitamin K1 by cefixime seems unlikely because only trace amounts of vitamin K1-2,3-epoxide could be determined in the plasma of the subjects investigated.

Mechanism of cephalosporin-induced hypoprothrombinemia: relation to cephalosporin side chain, vitamin K metabolism, and vitamin K status.

The mechanism of cephalosporin-induced hypoprothrombinemia has been investigated in hospitalized patients, with respect to cephalosporin structure, vitamin K metabolism, and vitamin K status. Cephalosporins containing side chains of N-methylthiotetrazole (latamoxef, cefmenoxime, cefoperazone, cefotetan, cefamandole) or methyl-thiadiazole (cefazolin) all caused the transient plasma appearance of vitamin K1 2,3-epoxide in response to a 10-mg intravenous dose of vitamin K1, whereas two cephalosporins without a heterocyclic side chain (cefotaxime and cefoxitin) did not. The plasma accumulation of vitamin K1 2,3-epoxide was qualitatively similar to, but quantitatively less than, that produced by the oral anticoagulant phenprocoumon. Patients eating normally had plasma vitamin K1 concentrations (176 to 1184 pg/mL) that were within the normal range (150 to 1550 pg/mL) and their clotting tests remained consistently normal for all antibiotics tested. Patients on total parenteral nutrition had lower plasma vitamin K1 concentrations (50 to 790 pg/mL) but normal clotting before starting antibiotic therapy. Of 19 parenterally fed patients, all seven treated with latamoxef developed hypoprothrombinemia, PIVKA-II and a decrease of protein C within four days whereas 12 patients treated with cefotaxime or cefoxitin showed no clotting changes. Latamoxef-associated hypoprothrombinemia was readily reversible by 1 mg of vitamin K1 given intravenously, but hypoprothrombinemia and sub-normal plasma vitamin K1 could recur within two to three days. The data suggest that NMTT-cephalosporins are inhibitors of hepatic vitamin K epoxide reductase and that a lower nutritional-vitamin K status predisposes to hypoprothrombinemia.

Alteration of hemostasis associated with cefoperazone treatment.

21 Patients with normal and impaired renal function were given cefoperazone in a recommended dose of 4 g/day, irrespective of renal function. Platelet function and plasmatic coagulation were analyzed before and on day 7 of therapy. In patients with normal renal function on their usual diets, there was neither impairment of platelet function nor plasmatic coagulation. High serum antibiotic trough levels, prolongation of bleeding time and decreased vitamin K-dependent coagulation factors, as verified by the prolongation of prothrombin time and the appearance of descarboxyprothrombin, could be observed in those patients with impaired renal function whose insufficiency was far advanced and accompanied by a complex clinical picture. In this situation vitamin K deficiency may be due to poor oral intake, along with interference of hepatic vitamin K metabolism, showing an effect similar to that seen after coumarin therapy. Dosage reduction of the antibiotic in advanced renal failure and repeated control of prothrombin time is advised.

Possible coumarin-like mechanism of action for cephalosporins.

In three patients treated with cephalosporins (one patient with latamoxef, two patients with cefazedone) vitamin K1 was injected to investigate whether this was followed by an increase in vitamin K1 2,3-epoxide plasma concentrations as compared to controls. Such a rise in K1-epoxide concentrations in the plasma can be demonstrated following treatment with coumarins. This reflects an inhibition of the vitamin K1-epoxide reductase in the liver. Coumarins are thought to induce hypoprothrombinaemia by such a mechanism. In all three patients we found a considerable increase in the vitamin K1-epoxide plasma concentrations following injection of 10 mg vitamin K1, whereas in normal subjects only traces of K1-epoxide could be detected (less than 0.030 micrograms/ml). The K1-epoxide concentrations found in our three patients treated with cephalosporins were 0.12, 0.16 and 0.19 micrograms/ml, respectively. This indicates that latamoxef or cefazedone might reduce clotting factor synthesis by a coumarin-like mechanism of action in these patients. Although the effect of cephalosporins in enhancing vitamin K1-epoxide plasma concentrations is less than that of coumarins, it might cause severe hypoprothrombinaemia in the presence of latent vitamin K deficiency.

Evidence for impaired hepatic vitamin K1 metabolism in patients treated with N-methyl-thiotetrazole cephalosporins.

In 8 patients on no oral intake and with parenteral alimentation, administration of cephalosporins with N-methyl-thiotetrazole side chain (moxalactam, cefamandole), was associated with prolongation of prothrombin time, appearance in the circulation of descarboxy-prothrombin (counter immunoelectrophoresis and echis carinatus assay) and diminution of protein C. Acute administration of 10 mg vitamin K1 was followed by the transient appearance of vitamin K1 2,3-epoxide, indicating an impaired hepatocellular regeneration of vitamin K1 from the epoxide. Impaired hepatic vitamin K1 metabolism, tentatively ascribed to the N-methyl-thiotetrazole group, is one (but possibly not the only) cause of bleeding complications and depression of vitamin K1-dependent procoagulants in patients treated with the new class of cephalosporins.