Adherence to prophylactic treatment in adult patients with severe hemophilia in Poland.

INTRODUCTION: Patient adherence to a prophylactic regimen is important for optimal benefit of hemophilia treatment. Despite a growing number of adults with hemophilia in Poland receiving secondary prophylaxis, data on adherence to the regimen are limited. OBJECTIVES: The aim of the study was to assess adherence to secondary prophylaxis in Polish adults with severe hemophilia. PATIENTS AND METHODS: Patients were recruited in 18 hemophilia treatment centers in Poland. Adherence to prophylaxis was assessed with the Validated Hemophilia Regimen Treatment Adherence Scale Prophylaxis (VERITAS­Pro) questionnaire. RESULTS: Data on 270 men on the prophylactic regimen (median [interquartile range, IQR] age, 37 [18-75] years; mean [SD], 38.2 [13.3] years) were analyzed. Median (IQR) VERITAS­Pro score for the study population was 36 (24-76) years; mean (SD), 37.7 (9.9) years, indicating general adherence to the prophylactic regimen. The median subscale scores ranged from 4 for Dosing to 8 for Planning (means, 5.6 and 7.7, respectively). The most pronounced difference in the subscale scores between adherent and nonadherent patients was recorded for Dosing (median, 4 vs 10; mean, 5.3 vs 9.3) and Remembering (median, 5 vs 11; mean, 5.7 vs 10.7). The overall adherence rate was 94%. CONCLUSIONS: Our results show a high rate of adherence to hemophilia prophylaxis by Polish adults. Problems with the management of clotting factor stocks and remembering about the injection of the clotting factor were identified as potential barriers to adherence in adults with hemophilia in Poland.

An epileptic seizure and haemorrhage into the ventricular system of the brain as the first manifestations of acquired haemophilia A - Case report.

Acquired haemophilia (AH) is a suddenly occurring severe blood diathesis that affects both males and females and is caused by autoantibodies which inhibit coagulation factor VIII. The report describes an unusual case of acquired haemophilia in which an epileptic seizure and haemorrhage into the ventricular system of the brain were the first manifestations of the disease. In addition, APTT was prolonged to 94.6 seconds and the factor VIII level was as low as 1.5%. The level of anti-FVIII antibody was extremely high - 272BU/ml. The patient did not undergo invasive diagnostic procedure or an operation. Recombinant factor VIIa was used to control the bleeding. In order to eradicate the inhibitor, the patient received prednisone and cyclophosphamide. Complete remission was achieved after 5.5 weeks of treatment.

Polygonogram with isobolographic synergy for three-drug combinations of phenobarbital with second-generation antiepileptic drugs in the tonic-clonic seizure model in mice.

BACKGROUND: Combination therapy consisting of two or more antiepileptic drugs (AEDs) is usually prescribed for patients with refractory epilepsy. The drug-drug interactions, which may occur among currently available AEDs, are the principal criterion taken by physicians when prescribing the AED combination to the patients. Unfortunately, the number of possible three-drug combinations tremendously increases along with the clinical approval of novel AEDs. AIM: To isobolographically characterize three-drug interactions of phenobarbital (PB) with lamotrigine (LTG), oxcarbazepine (OXC), pregabalin (PGB) and topiramate (TPM), the maximal electroshock-induced (MES) seizure model was used in male albino Swiss mice. MATERIALS AND METHOD: The MES-induced seizures in mice were generated by alternating current delivered via auricular electrodes. To classify interactions for 6 various three-drug combinations of AEDs (i.e., PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC), the type I isobolographic analysis was used. Total brain concentrations of PB were measured by fluorescent polarization immunoassay technique. RESULTS: The three-drug mixtures of PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC protected the male albino Swiss mice from MES-induced seizures. All the observed interactions in this seizure model were supra-additive (synergistic) (p < 0.001), except for the combination of PB + LTG + OXC, which was additive. It was unable to show the impact of the studied second-generation AEDs on total brain content of PB in mice. CONCLUSIONS: The synergistic interactions among PB and LTG, OXC, PGB and TPM in the mouse MES model are worthy of being transferred to clinical trials, especially for the patients with drug resistant epilepsy, who would benefit these treatment options.

Anticonvulsant Effectiveness and Neurotoxicity Profile of 4-butyl-5-[(4-chloro-2-methylphenoxy)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPL-16) in Mice.

Protective (antiseizure) effects of 4-butyl-5-[(4-chloro-2-methylphenoxy)-methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPL-16) and acute neurotoxic effects were determined in the tonic-clonic seizure model and rotarod test in mice. The interaction profile of four classic antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) with TPL-16 was also determined in the tonic-clonic seizure model in mice. The protective effects of TPL-16 from tonic-clonic seizures (as ED50 values) and acute neurotoxic effects of TPL-16 (as TD50 values) were determined in 4 pretreatment times (15, 30, 60 and 120 min after its i.p. administration), in adult male albino Swiss mice. The interaction profile of TPL-16 with carbamazepine, phenobarbital, phenytoin and valproate in the tonic-clonic seizure model was determined with isobolographic analysis. Total concentrations of carbamazepine, phenobarbital, phenytoin and valproate were measured in the mouse brain homogenates. The candidate for novel antiepileptic drug (TPL-16) administered separately 15 min before experiments, has a beneficial profile with protective index (as ratio of TD50 and ED50 values) amounting to 5.58. The combination of TPL-16 with valproate produced synergistic interaction in the tonic-clonic seizure model in mice. The combinations of TPL-16 with carbamazepine, phenobarbital and phenytoin produced additive interaction in terms of protection from tonic-clonic seizures in mice. None of the total brain concentrations of classic AEDs were changed significantly after TPL-16 administration in mice. Synergistic interaction for TPL-16 with valproate and the additive interaction for TPL-16 with carbamazepine, phenobarbital and phenytoin in the tonic-clonic seizures in mice allows for recommending TPL-16 as the promising drug for further experimental and clinical testing.

Induction therapy alters plasma fibrin clot properties in multiple myeloma patients: association with thromboembolic complications.

Induction therapy in patients with multiple myeloma increases the risk of thromboembolism. We have recently shown that multiple myeloma patients tend to form denser fibrin clots displaying poor lysability. We investigated the effect of induction therapy on fibrin clot properties in multiple myeloma patients. Ex-vivo plasma fibrin clot permeability, turbidity, susceptibility to lysis, thrombin generation, factor VIII and fibrinolytic proteins were compared in 48 multiple myeloma patients prior to and following 3 months of induction therapy, mainly with cyclophosphamide-thalidomide-dexamethasone regimen. Patients on thromboprophylaxis with aspirin or heparins were eligible. A 3-month induction therapy resulted in improved clot properties, that is higher clot permeability, compaction, shorter lag phase and higher final turbidity, along with shorter clot lysis time and higher rate of D-dimer release from fibrin clots than the baseline values. The therapy also resulted in lower thrombin generation, antiplasmin and thrombin-activatable fibrinolysis inhibitor (TAFI), but elevated factor VIII. Progressive disease was associated with lower posttreatment clot permeability and lysability. Despite thromboprophylaxis, two patients developed ischemic stroke and 10 had venous thromboembolism. They were characterized by pretreatment lower clot permeability, prolonged clot lysis time, longer lag phase, higher peak thrombin generation, TAFI and plasminogen activator inhibitor -1. Formation of denser plasma fibrin clots with reduced lysability and increased thrombin generation at baseline could predispose to thrombotic complications during induction treatment in multiple myeloma patients. We observed improved fibrin clot properties and thrombin generation in multiple myeloma patients except those with progressive disease.

Altered plasma fibrin clot properties and fibrinolysis in patients with multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is associated with increased risk of venous and arterial thromboembolism. Formation of denser and poorly lysable fibrin clots is observed in patients with arterial and venous thromboembolism. We investigated fibrin clot properties and their determinants in MM patients. MATERIALS AND METHODS: Ex vivo plasma fibrin clot permeability, turbidity and susceptibility to lysis were evaluated in 106 MM patients at the time of diagnosis vs. 100 age- and sex-matched controls. MM patients had lower clot permeability (Ks ), compaction, indicating denser fibrin clots, impaired fibrin polymerization with longer lag phase and lower final turbidity (D-Dmax ), combined with hypofibrinolysis reflected by longer lysis time and slower rate of D-dimer release from fibrin clots (D-Drate ) compared with controls (all P < 0·001). RESULTS: Patients with IgG MM had lower Ks compared with IgA MM [5·9 (5·1-6·4) vs. 6·3 (5·9-7·2) 10(-9)  cm(2) ; P = 0·007] and longer lysis time compared with light-chain-disease patients [11·4 (10·9-12·3) vs. 10·7 (9·8-11·9) min; P = 0·022]. Of the fibrin variables, only Ks was significantly lower in patients with International Staging System (ISS) grade III than in those with ISS grade I and II [5·9 (4·9-6·6) vs. 6·2 (5·7-6·8) 10(-9)  cm(2) ; P = 0·015]. Multivariate analysis adjusted for age and fibrinogen showed that in MM patients elevated peak thrombin levels determine Ks and D-Dmax , while thrombin-activatable fibrinolysis inhibitor (TAFI) activity predicts Ks , t50% , D-Drate and lag phase. CONCLUSIONS: Our study demonstrates prothrombotic fibrin clot phenotype in patients with MM, with a significant impact of increased thrombin formation and TAFI activity.

Thalidomide, dexamethasone and lovastatin with autologous stem cell transplantation as a salvage immunomodulatory therapy in patients with relapsed and refractory multiple myeloma.

The treatment of patients with multiple myeloma usually includes many drugs including thalidomide, lenalidomide and bortezomib. Lovastatin and other inhibitors of HMG-CoA reductase demonstrated to exhibit antineoplasmatic and proapoptotic properties in numerous in vitro studies involving myeloma cell lines. We treated 91 patients with relapsed or refractory multiple myeloma with thalidomide, dexamethasone and lovastatin (TDL group, 49 patients) or thalidomide and dexamethasone (TD group, 42 patients). A clinical response defined of at least 50% reduction of monoclonal band has been observed in 32% of TD patients and 44% of TDL patients. Prolongation of overall survival and progression-free survival in the TDL group as compared with the TD group has been documented. The TDL regimen was safe and well tolerated. The incidence of side effects was comparable in both groups. Plasma cells have been cultured in vitro with thalidomide and lovastatin to assess the impact of both drugs on the apoptosis rate of plasma cells. In vitro experiments revealed that the combination of thalidomide and lovastatin induced higher apoptosis rate than apoptosis induced by each drug alone. Our results suggest that the addition of lovastatin to the TD regimen may improve the response rate in patients with relapsed or refractory myeloma.

Amiloride enhances the anticonvulsant action of various antiepileptic drugs in the mouse maximal electroshock seizure model.

Accumulating evidence indicates that amiloride (a potassium-sparing diuretic) exerts the anticonvulsant action in various in vivo and in vitro experiments. Therefore, the objective of this study was to assess the influence of amiloride on the protective action of numerous conventional and second-generation antiepileptic drugs [AEDs: carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), topiramate (TPM), and valproate (VPA)] against maximal electroshock (MES)-induced seizures in mice. Results indicate that amiloride [up to 100 mg/kg, intraperitoneally (i.p.), at 30, 60, and 120 min before the test] neither altered the threshold for electroconvulsions, nor protected the animals against MES-induced seizures in mice. Moreover, amiloride (75 and 100 mg/kg, i.p., 120 min prior to the test) significantly enhanced the anticonvulsant effects of all studied AEDs, except for LTG, by reducing their ED(50) values in the MES test. In contrast, amiloride at 50 mg/kg (i.p.) had no significant effect on the antielectroshock action of the tested AEDs in mice. Estimation of total brain AED concentrations revealed that amiloride (75 mg/kg) significantly increased total brain concentrations of CBZ, OXC, and PB, but not those of LTG, TPM, and VPA in mice. In conclusion, one can ascertain that the potentiation of the antiseizure action of TPM and VPA by amiloride in the MES test and lack of any pharmacokinetic interactions between drugs, make the combinations of amiloride with TPM and VPA of pivotal importance for epileptic patients.

Furosemide potentiates the anticonvulsant action of valproate in the mouse maximal electroshock seizure model.

Accumulating evidence indicates that furosemide (FUR, a loop diuretic) exerts the anticonvulsant action in various in vitro and in vivo experiments. Therefore, the aim of this study was to assess the influence of FUR on the protective action of numerous conventional and newer antiepileptic drugs (carbamazepine [CBZ], lamotrigine [LTG], oxcarbazepine [OXC], phenobarbital [PB], topiramate [TPM] and valproate [VPA]) in the mouse maximal electroshock seizure (MES) model. Results indicate that FUR (up to 100mg/kg, i.p., 30 min before the test) neither altered the threshold for electroconvulsions nor protected the animals against MES-induced seizures in mice. FUR (100 mg/kg, i.p.) enhanced the anticonvulsant effects of VPA in the MES test by reducing its ED(50) value from 230.4 to 185.4 mg/kg (P<0.05). In contrast, FUR at 100 mg/kg had no significant effect on the antielectroshock action of the remaining drugs tested (CBZ, LTG, OXC, PB, and TPM) in mice. Estimation of free plasma and total brain VPA concentrations revealed that the observed interaction between FUR and VPA in the MES test was pharmacodynamic in nature because neither free plasma nor total brain VPA concentrations were altered after i.p. administration of FUR. In conclusion, one can ascertain that the selective potentiation of the antielectroshock action of VPA by FUR and lack of any pharmacokinetic interactions between drugs, make this combination of pivotal importance for epileptic patients treated with VPA and received FUR from other than epilepsy reasons.

Acute exposure to caffeine decreases the anticonvulsant action of ethosuximide, but not that of clonazepam, phenobarbital and valproate against pentetrazole-induced seizures in mice.

This study examines the effect of acute administration of caffeine sodium benzoate (CAF) on the anticonvulsant action of four conventional antiepileptic drugs (AEDs: clonazepam - CZP, ethosuximide - ETS, phenobarbital - PB and valproate - VPA) against pentetrazole (PTZ)-induced clonic seizures in mice. The results indicate that CAF at a dose of 92.4 mg/kg significantly reduced the threshold for PTZ-induced clonic seizures in mice from 69.5 to 51.7 mg/kg (p<0.05), being ineffective at lower doses of 69.3 and 46.2 mg/kg. Moreover, CAF at doses of and 92.4 mg/kg attenuated the protective action of ETS against PTZ-induced seizures, by increasing its median effective dose (ED50) from 127.7 to 182.3 (p<0.05), and 198.3 mg/kg (p<0.01), respectively. In this case, no pharmacokinetic changes in total brain ETS concentrations after systemic ip administration of CAF (at 92.4 mg/kg) were observed, indicating a pharmacodynamic nature of interaction between ETS and CAF in the PTZ-test in mice. In contrast, CAF (at a dose of 92.4 mg/kg reducing the threshold for PTZ-induced seizures) combined with other AEDs (CZP, PB and VPA) did not affect their anticonvulsant action in the PTZ test in mice. Moreover, CAF (92.4 mg/kg) did not alter significantly total brain concentrations of the remaining AEDs (CZP, PB and VPA). The evaluation of potential acute adverse effects produced by AEDs in combination with CAF revealed that neither CAF (up to 92.4 mg/kg) administered alone nor combined with the studied drugs (at doses corresponding to their ED(50) values in the PTZ-test) affected motor performance of animals in the chimney test. In conclusion, the acute exposure to CAF may diminish the antiseizure protection offered by ETS in epileptic patients. Therefore, patients treated with ETS should avoid CAF.

7-Nitroindazole enhances dose-dependently the anticonvulsant activities of conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model.

7-Nitroindazole (7NI, a nitric oxide synthase [NOS] inhibitor) administered intraperitoneally (ip), 30 min before the test, at doses ranging between 50-200 mg/kg, raised the threshold for electroconvulsions in mice. Linear regression analysis revealed that the doses increasing the threshold by 50% (TID50) and 100% (TID100) over the control value for 7NI were 115.2 and 173.4 mg/kg, respectively. Moreover, 7NI dose-dependently potentiated the anticonvulsant effects of four conventional antiepileptic drugs (AEDs: carbamazepine - CBZ, phenobarbital - PB, phenytoin - PHT, and valproate - VPA) in the mouse maximal electroshock-induced seizure (MES) model. 7NI at 50 mg/kg enhanced only the anticonvulsant effect of PB, whereas the drug at 75 and 100 mg/kg potentiated the antiseizure effects of PB, PHT and VPA, but not those of CBZ against MES-induced seizures. Only 7NI at 150 mg/kg enhanced considerably the antielectroshock action of all studied AEDs in the MES test. Pharmacokinetic evaluation of interactions between 7NI and the investigated AEDs revealed that 7NI (150 mg/kg; ip) did not alter total brain concentrations of conventional AEDs in mice. L-arginine (L-Arg - a natural precursor of NO; administered ip, 500 mg/kg, 60 min before electroconvulsions) did not reverse the activity of 7NI (150 mg/kg), but in contrast, it significantly potentiated the anticonvulsant action of conventional AEDs combined with 7NI (150 mg/kg). Pharmacokinetic increase in total brain AED concentrations was observed for the combinations of L-Arg (500 mg/kg) with 7NI (150 mg/kg) and PHT (by 32%; p<0.01) or VPA (by 22%; p<0.05). Neither total brain CBZ nor PB concentrations were altered following the co-administration of L-Arg (500 mg/kg) with 7NI (150 mg/kg). 7NI at doses of 100-200 mg/kg significantly impaired spontaneous ambulatory activity in mice subjected to the Y-maze task. The NOS inhibitor at doses of 50 and 75 mg/kg had no significant effect on locomotor activity of animals, although the number of arm entries within the 5 min of observational time was reduced. Finally, it can be concluded that the enhancement of anticonvulsive efficacy of CBZ, PB, PHT and VPA by 7NI alone or in combination with L-Arg in the MES test, deserves more attention and further neurochemical studies are required to elucidate the exact role of NO in the brain.