Effect of warfarin anticoagulation on thrombin generation in patients with idiopathic pulmonary arterial hypertension.

BACKGROUND: Oral anticoagulant therapy is recommended for patients with pulmonary arterial hypertension (PAH). The rationale for the use of anticoagulant treatment is based on thrombophylic predisposition in PAH and improvement of survival in patients treated with anticoagulation. However, the target INR value has not been evaluated. The aim of this study was to analyze thrombin generation in patients with PAH treated with warfarin anticoagulation. METHODS: The study was performed in 58 patients with idiopathic PAH treated with warfarin at stable doses. Thrombin generation assay was performed in all subjects and three parameters were derived from the thrombin generation curves: lag time, maximal concentration of formed thrombin (peak thrombin) and area under the curve (AUC). Thrombin generation parameters were correlated with INR and compared between the patient groups with different intensity of anticoagulant therapy. RESULTS: Significant correlation between the lag time and INR was observed (r = 0.495, p < 0.001). Significant negative correlation between the maximal concentration of formed thrombin and INR and between the area under the curve of thrombin generation and INR was observed (r = -0.709, p < 0.001 and r = -0.784, p < 0.001, respectively). Thrombin generation was significantly reduced in patients with INR between 1.5 and 2.5. CONCLUSIONS: Low-intensity warfarin anticoagulation with target INR between 1.5 and 2.5 could be effective and sufficient to suppress thrombin generation in patients with idiopathic PAH (Fig. 3, Tab. 4, Ref. 12). Full Text in free PDF www.bmj.sk.

Pulmonary arterial hypertension--contemporary management strategy.

Pulmonary arterial hypertension (PAH) is a severe chronic disorder of pulmonary arteries with progressive precapillary pulmonary hypertension, characterized by poor life quality and very poor prognosis. Unless treated, it causes death within 2-3 years from diagnosis. PAH affects mainly younger women. The treatment of PAH should not only be symptomatic, but also directed towards the improvement in patient's survival and quality of life. Many novel drugs putting together so called specific PAH therapy (endothelin receptor antagonists, prostanoids, phosphodiesterase--5 inhibitors) were tested in randomized trials. PAH management requires a highly individualized approach, state of the art knowledge and adequate experience. Patients therefore should be referred to specialized PAH centers providing both complete diagnosis and therapy. In our region a close co-operation between Czech and Slovak PAH centers has also proved to be profitable. Data sources. Literature retrieval was accessed through MEDLINE using the terms pulmonary hypertension, PAH, diagnosis, treatment. Reference citations from publications identified were reviewed (Ref. 47). Full Text (Free, PDF) www.bmj.sk.

[Contemporary methods in the treatment of chronic pulmonary hypertension]. / Aktuální moznosti lécby chronické plicní hypertenze.

Pulmonary hypertension is involved in the development of various diseases and therefore it can be caused by several mechanisms from a simple pressure elevation in the pulmonary artery to the serious impairments of pulmonary vessels. The recently increased interest in the problems of pulmonary hypertension results namely from the new therapeutic means for the treatment of pulmonary arterial hypertension and chronic thrombembolic pulmonary hypertension. The algorism of pharmacotherapy results from the test of acute pulmonary vasodilation. Only the patients with positive test are indicated to the treatment with high doses of calcium channel blockers. Patients with negative test receive beside the chronic anticoagulation therapy also a specific pharmacotherapy (prostanoids, antagonists of endotheline receptors, phosphodiesterase 5 inhibitors) with not only vasodilatory but also with antiproliferative and antiaggregatory effects. When all possibilities of pharmacotherapy are exhausted, balloon atrial septostomy or lung transplantation should be considered. It has been shown recently that similar pharmacotheraeutic approaches as they are used in patients with pulmonary arterial hypertension are effective in some cases of other forms of chronic pulmonary hypertension. Method of choice in the treatment of chronic thromboembolic pulmonary hypertension is the pulmonary endarterectomy in patients with surgically curable thrombotic obstruction. In patients who are not suitable for surgical treatment it is necessary to try pharmacotherapy (prostacycline, bosentan, sildenafil) or lung transplantation. Complicated diagnosis and therapy of pulmonary hypertension requires concentrating the treatment into specialized centres with multidisciplinary background and sufficient experience. In the Czech Republic, the care of patients with pulmonary hypertension is concentrated into the Cardio Center of the 2nd Medical Department of the 1st Faculty of Medicine and General Teaching Hospital in Prague and into the Cardio Center of the Institute of Clinical and Experimental Medicine in Prague. Complex care to patients with chronic thromboembolic pulmonary hypertension is given at the Cardio Center of the General Teaching Hospital in Prague, where since September 2004, 99 patients were surgically treated with results comparable to the best similar departments abroad.

[Long-term experience with trerpostinil infusion treatment in patients with pulmonary arterial hypertension in the Czech Republic]. / Dlouhodobé zkusenosti s infuzní lécbou treprostinilem u nemocných s plicní arteriální hypertenzí v Ceské republice.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a serious primary illness of the pulmonary arterioles, characterised by progressive precapillary pulmonary hypertension. The conventional therapy for this condition is so-called specific pharmacotherapy, which addresses the key mechanisms in the pathophysiology of the illness, making use of drugs from the prostanoid group, endothelin receptor antagonists and phosphodiesterase inhibitors. Treprostinil is a stable analogue of prostacyclin, which can be administered subcutaneously, intravenously or by inhalation. PATIENT SAMPLE AND METHOD: In the centre for pulmonary hypertension in the Second Internal Clinic of Cardiology and Angiology of 1st Faculty of Medicine, Charles University, and the General Teaching Hospital in Prague, 22 patients with PAH (idiopathic PAH, familial PAH, PAH associated with congenital heart disease and PAH associated with systemic connective tissue disease) were treated with trerpostinil, 18 patients with a continuous subcutaneous infusion and 4 patients with a continuous intravenous infusion. The indicators followed were the distance reached in a 6-minute walking test, functional capacity assessed by NYHA classification and mortality. RESULTS: The patients for whom treprostinil treatment was indicated had an average pressure in the right atrium of 11.9 +/- 4.2 mm Hg, average pressure in the pulmonary artery of 56.8 +/- 10.7 mm Hg, a cardiac index of 1.78 +/- 0.25 l/min/m2 and a total pulmonary resistance of 16.26 +/- 4.48 WU. 15 patients were functionally NYHA III and 7 patients were NYHA IV. The average distance achieved in a 6-minute walk test before the start of treatment was 326 +/- 83 m. When treated with gradually increasing doses of treprostinil the distance achieved in the 6-minute walk test improved. After 6 months, the group that received subcutaneous treatment had extended their distance to 359 m, after 12 months it was 393 m, after 24 months 447 m and after 36 months 494 m. After 6 months, the group that received intravenous treatment had extended their distance to 473 m, which increased to 451 m after 12 months and 489 m after 24 months. Functional capacity also improved. In total 5 patients were unable to tolerate the subcutaneous infusion, of whom 3 were placed on intravenous treprostinil and 2 on oral bosentan. 7 of the patients died in the period examined (31.8%). CONCLUSION: Treprostinil improves symptoms and hemodynamics for PAH patients and reduces mortality.

[The quality of vision in premature infants--first results]. / Kvalita videní u nedonosených detí--první výsledky.

In last years, thanks to the development in neonatology, the numbers of saved premature children with high co-morbidity are rapidly growing. Contrary to great advances in contemporary neonatology, the saved premature children are not spared different health's problems in the future life, including the vision. The main cause remains the retinopathy of prematurity and neurological diseases. In the study the authors present first results of their examinations of visual functions in premature children at the school age comparing with the group of healthy, mature children of the same age.

[Dexrazoxane in patients with B-lymphomas or acute leukemias in the 2nd complete remission enables further therapy with cardiotoxic anthracyclines over recommended cumulative doses]. / Dexrazoxan u nemocných s B-lymfomy nebo akutními leukémiemi ve 2. kompletní remisi umoznuje dalsí lécbu kardiotoxickými antracykliny nad doporucené kumulativní dávky.

UNLABELLED: Daunorubicin (DNR) and doxorubicin (DOX) have significant antitumor activity in acute myeloid leukemias (AML) and non-Hodgkin's lymphomas (NHL) but their use is limited by their life-threatening cumulative dose related cardiotoxicity. It is generally recommended not to administer DOX or DNR to patients in doses greater than 500 mg/sqm or 700 mg/sqm, respectively. the aim of the study was to follow up cardiotoxicity and efficacy of DNR or DOX above these limits in the 2nd complete remission (CR) patients pretreated with anthracyclines when they were given 30 minutes after cardioprotective agent dexrazoxane (DRZ) in the ratio 1:10 of DZR. RESULTS: Two patients (54 and 53 years old) with mantle cell or diffuse large cell B-NHL, stage IV, who had relapsed after 6-8 cycles of classical CHOP therapy, reached their 2nd CR after 2-3 cycles of IDEA therapy (ifosfamide 1000 mg/sqm/day x 4, dexamethasone 30 mg/sqm/day x 4, etoposide 75 mg/sqm/day x 4, DOX 30 mg/sqm/day on days 1 and 3). Then they received further 3 cycles IDEA with DRZ 300 mg/sqm before every dose of DOX. After cumulative doses of DOX 600 mg/sqm and 700 mg/sqm these patients survived 12 months in their 2nd CR without significant signs of cardiotoxicity, even after their successful autologous peripheral stem cells transplantation. Their left ventricular ejection fraction (LVEF) remained above 60%. Six patients with AML in their 2nd CR were treated with consolidation cycles consisting of 10 high doses of cytosine arabinoside (2000 mg/sqm/12 hr) plus 2 doses of DNR 45 mg/sqm on the day 4 and 5. Two patients received cumulative doses corresponding to 1300 mg/sqm and 1000 mg/sqm of DNR, the other received DNR doses 550-850 mg/sqm. No signs of significant cardiotoxicity were observed in all 6 patients and their LVEF remained over 50%. One of two patients, transplanted with HLA-identical sibling bone marrow in her 2nd complete remission (CR), is still 8 years in her 2nd CR. Dexrazoxane enables to administer anthracyclines in doses over the recommended cumulative ones in pretreated patients with B-NHL or AML in their 2nd CR with the follow-up of their LVEF.

[Shock-wave lithotripsy in choledocholithiasis in a female patient with a cardiac pacemaker]. / Litotrypse rázovou vlnou pro choledocholitiázu u nemocné s kardiostimulátorem.

BACKGROUND: Extracorporeal shock wave lithotripsy is relatively contraindicated in patients with an implanted cardiac pacemaker. Shock waves can damage the pacemaker by mechanical pressure and also by electromagnetic induction. Since the distance between the applicator and the pacemaker is small during biliary lithotripsy, the risk of damaging the pacemaker is greater. In the following case, the patient presented with a stone in the common bile duct, and had an implanted pacemaker. Lithotripsy with non-synchronized shock waves was the method of choice since conventional surgery was high risk in this specific case. CASE REPORT: In an 84-year-old woman with a stone in the proximal part of the common bile duct, endoscopic attempts of extraction failed. Therefore, shock wave lithotripsy was indicated. This patient had serious heart disease with an interference of spontaneous heart action with the pacemaker at a ratio of 1:1. We decided to treat with shock wave lithotripsy. The application of shock waves was without side effects on the patient and the pacemaker. CONCLUSION: This case is interesting as it highlights the possibility of using the Czech made MEDILIT lithotriptor in the treatment of choledocholitiasis in patients with a pacemaker. Even so, it is necessary to monitor the patient's ECG to ensure the possibility of immediate external stimulation.

Efficacy of dexrazoxane as a cardioprotective agent in patients receiving mitoxantrone- and daunorubicin-based chemotherapy.

Dexrazoxane (DEX) selectively blocks the development of irreversible diffuse myocardial toxicity induced by anthracyclines and related antitumor agents, such as mitoxantrone (MTX). Therefore, daunorubicin (DNR) should not be administered to patients with cumulative DNR doses higher than 550 to 700 mg/m2, which we used for remission induction and consolidation therapy in patients with acute myeloid leukemia (AML). To administer further doses of anthracyclines without risks in seven relapsed AML patients and in one patient with impaired heart functions receiving consolidation therapy, we used DEX as a cardioprotective agent. Patients received DEX 30 minutes before DNR 45 mg/m2 or MTX 10 mg/m2 in doses eight to 13 times higher (DNR) or 30 to 60 times higher (MTX) in the treatment cycle with 10 high doses (2,000 mg/m2/12 hr) of cytosine arabinoside plus two doses of DNR or MTX on the fourth and fifth day. When this cycle was used as reinduction therapy, complete remission was achieved in all five cases. A cycle of MTX and etoposide was given three times with DEX as consolidation. Myelotoxicity of the treatment cycles with DEX was similar to the cycles without it. Two patients received cumulative anthracyclines doses corresponding to more than 1,300 and 1,000 mg/m2 of DNR, respectively; the remaining five relapsed patients received 550 to 850 mg/m2 of DNR, all without signs of cardiac toxicity. Delayed administration of DEX after cumulative doses of DNR 500 mg/m2 in AML patients at relapse provides cardioprotection against DNR or MTX in combination with high doses of cytosine arabinoside. This type of chemotherapy seems to be effective for remission induction in relapsed, heavily pretreated AML patients or in patients with impaired heart functions.

Protective effects of cardioxane against anthracycline-induced cardiotoxicity in relapsed acute myeloid leukemias.

The clinical use of anthracyclines and related antitumor agents is limited by their cumulative dose-related cardiac toxicity. Cardioxane (ICRF-187) is an agent that has been recommended to block selectively this toxicity which e.g. limits the use of daunorubicin (DNR) in doses higher than 550-700 mg/m2. We decided to use cardioxane in patients with relapsed acute myeloid leukemias (AML) who have previously been treated with DNR doses above 500 mg/m2. Seven patients with relapsed AML received cardioxane 30 min before DNR or mitozantrone (MTZ) in doses 8-13x higher than DNR or 40-60x higher than MTZ. Two patients received anthracyclines cumulative doses corresponding to more than 1300 mg/m2 and 1000 mg/m2 of DNR, respectively, without any signs of cardiac toxicity. The other 5AML patients in relapse received 1-3 chemotherapy cycles with cardioxane. Their total cumulative doses of DNR were 550-750 mg/m2 and their left ventricular ejection fraction remained above 50% as were their pretreatment values. Cardioxane seems to be a useful cardioprotective agent in relapsed AML which enables further treatment with anthracyclines.

[Pulmonary hemorrhage in a neonate]. / Plicní krvácení u novorozence.

The authors describe a case of pulmonary haemorrhage in a neonate associated with adnatal pneumonia and infection with Staphylococcus epidermidis. The authors discuss the problem of this serious complication of the neonatal period as well as the limited diagnostic and therapeutic possibilities.

[Kinetics of gentamycin in premature infants with a low birth weight during the first four days of postnatal life]. / Kinetika gentamycinu u nedonosených detí s nízkou porodní hmotností v prubehu prvních ctyr dnu postnatálního zivota.

The authors investigated in a group of 19 premature neonates with a low birthweight (0.65-2.1 kg) during the first four days of postnatal life the pharmacokinetics of gentamycin after indicated administration of 2 mg/kg of the antibiotic by the i.v. route by a 30-minute infusion in 18-hour intervals. Serum concentrations of gentamycin were assessed by immunoassay 0.5 hours before administration and then 0.5, 5.5, 11.5 and 17.5 hours after the 5th infusion, i.e. in a steady state. The maximum serum concentrations detected 0.5 hours after the completed infusion exceeded 10 mg/l in 21% of the neonates, while the minimal concentrations of the antibiotic before the next administration were above 2 mg/l in 42% of the infants. The calculation of pharmacokinetic parameters according to the one-compartment model revealed considerable interindividual differences of all values. The authors consider particularly important the low clearance value of the antibiotic (30.24 +/- 14.55 ml/kg.hour-1) which may lead to cumulation of gentamycin and its toxic action. Gentamycin administration to premature neonates should be associated with monitoring of serum concentrations of the drug which would make individual adjustment of the dosage possible.

The influence of experimentally induced pathological states on the flow and composition of central lymph in the rat.

The flow of central lymph in the rat was examined and its concentration of total proteins was determined. Experiments were performed both on healthy animals and on animals with experimentally induced pathological states. The following results were obtained: The flow of the lymph is increased in chronic liver damage, acute kidney damage and the malabsorption syndrome. On the other hand, lymph flow is decreased in fasting animals, and it is unaffected by acute liver damage. Total protein concentration was increased in fasting rats and in the group with acute liver damage, and on the contrary, it was decreased in the group with chronic damage, acute kidney damage, and malabsorption syndrome. The lymph flow or total protein concentration are not sex-dependent.