Michał Tomaszewski

Statin-induced myopathies.

Statins are considered to be safe, well tolerated and the most efficient drugs for the treatment of hypercholesterolemia, one of the main risk factor for atherosclerosis, and therefore they are frequently prescribed medications. The most severe adverse effect of statins is myotoxicity, in the form of myopathy, myalgia, myositis or rhabdomyolysis. Clinical trials commonly define statin toxicity as myalgia or muscle weakness with creatine kinase (CK) levels greater than 10 times the normal upper limit. Rhabdomyolysis is the most severe adverse effect of statins, which may result in acute renal failure, disseminated intravascular coagulation and death. The exact pathophysiology of statin-induced myopathy is not fully known. Multiple pathophysiological mechanisms may contribute to statin myotoxicity. This review focuses on a number of them. The prevention of statin-related myopathy involves using the lowest statin dose required to achieve therapeutic goals and avoiding polytherapy with drugs known to increase systemic exposure and myopathy risk. Currently, the only effective treatment of statin-induced myopathy is the discontinuation of statin use in patients affected by muscle aches, pains and elevated CK levels.

The multidrug transporter P-glycoprotein in pharmacoresistance to antiepileptic drugs

This review provides an overview of the knowledge on P-glycoprotein (P-gp) and its role as a membrane transporter in drug resistance in epilepsy and drug interactions. Overexpression of P-gp, encoded by the ABCB1 gene, is involved in resistance to antiepileptic drugs (AEDs), limits gastrointestinal absorption and brain access of AEDs. Although several association studies on ABCB1 gene with drug disposition and disease susceptibility are completed to date, the data remain unclear and incongruous. Although the literature describes other multidrug resistance transporters, P-gp is the main extensively studied drug efflux transporter in epilepsy.

The interactions of atorvastatin and fluvastatin with carbamazepine, phenytoin and valproate in the mouse maximal electroshock seizure model.

The aim of this study was to determine the influence of acute (single) and chronic (once daily for 7 consecutive days) treatments with atorvastatin and fluvastatin on the anticonvulsant potential of three antiepileptic drugs: carbamazepine, phenytoin and valproate in the mouse maximal electroshock-induced seizure model. Additionally, the effects of acute and chronic administration of both statins on the adverse effect potential of three antiepileptic drugs were assessed in the chimney test (motor performance) and passive avoidance task (long-term memory). To evaluate the pharmacokinetic characteristics of interaction between antiepileptic drugs and statins, the total brain concentrations of antiepileptic drugs were estimated with the fluorescence polarization immunoassay technique. Results indicate that atorvastatin at doses up to 80mg/kg in chronic experiment attenuated the anticonvulsant potential of carbamazepine by increasing its ED(50) value against maximal electroconvulsions. Acute fluvastatin (80mg/kg) enhanced the anticonvulsant potential of carbamazepine and valproate by decreasing their ED(50) values. Acute fluvastatin (80mg/kg) also markedly increased the total brain carbamazepine concentration by 61% in a pharmacokinetic reaction. Atorvastatin (acute and chronic) and fluvastatin (chronic) in combinations with valproate impaired long-term memory in mice. Both statins in combinations with all three antiepileptic drugs had no impact on their adverse effects in the chimney test. Based on this preclinical study, one can conclude that chronic administration of atorvastatin reduces the anticonvulsant action of carbamazepine and acute fluvastatin can enhance the anticonvulsant potency of the carbamazepine and valproate. The former interaction was pharmacokinetic in nature.

QT Interval Prolongation and QRS Voltage Reduction in Patients with Liver Cirrhosis

BACKGROUNDnLiver cirrhosis is associated with functional abnormalities of the cardiovascular system with co-existing electrocardiographic (ECG) abnormalities.nnnOBJECTIVESnThe aim was to analyze ECG changes in patients with cirrhosis, to evaluate whether alcoholic etiology of cirrhosis and ascites has an impact on ECG changes.nnnMATERIAL AND METHODSnThe study involved 81 patients with previously untreated alcoholic cirrhosis (64 patients with ascites, classes B and C according to the Child-Pugh classification; and 17 without ascites, categorized as class A); 41 patients with previously untreated cirrhosis due to chronic hepatitis C (HCV--30 patients with ascites, classes B and C; and 11 without ascites, class A); 42 with alcoholic steatohepatitis and 46 with alcoholic steatosis. The control group consisted of 32 healthy volunteers. Twelve-lead ECG recordings were performed and selected parameters were measured.nnnRESULTSnSignificantly longer QT and QTc intervals and lower QRS voltage were found in patients with alcoholic and HCV cirrhosis compared to the controls. Significantly lower QRS voltage was found in subjects with ascites than in those without ascites. Removal of ascites significantly increased QRS voltage.nnnCONCLUSIONSnIn cirrhosis, irrespective of etiology, ECG changes involved prolonged QT and QTc intervals and reduced QRS voltage. Prolonged QT and QTc intervals were not related to the severity of cirrhosis or to the presence of ascites. However, low QRS voltage was associated with the presence of ascites. Removal of ascites reverses low QRS voltage.

Percutaneous recanalisation of chronically occluded coronary arteries with the CrossBoss/Stingray system: first experience (report of three cases).

BACKGROUND AND AIMnPercutaneous coronary interventions (PCI) within chronically occluded coronary arteries remain challenging procedures with a lower success rate compared to classic PCI. However, over the last years we have witnessed many technological advances in the treatment of chronic total occlusion (CTO) including new wires, retrograde approach, subintimal tracking and re-entry technique, all underlying which the current success rate of up to 95% in dedicated centres. Subintimal space wire penetration is no longer a problem that would require terminating the procedure. It is now a desired part of hybrid CTO approach involving both antegrade and retrograde crossing and re-entry. The new device which facilitates controlled dissection and true lumen re-entry is the Boston Scientific Coronary CTO Crossing System consisting of a CrossBoss micro-catheter and Stingray balloon and dedicated wire.nnnMETHODSnOn October 29th and 30th, 2014, percutaneous coronary recanalisation using the CrossBoss/Stingray system was performed in 3 men aged 63-75, with symptoms of stable CCS class II/III angina, without prior myocardial infarction in the area of CTO artery supply and with preserved myocardial contractility. Each patient underwent at least one previous unsuccesful antegrade/retrograde CTO recanalisation procedure. The J-CTO score was 3-4.nnnRESULTSnThe procedure was successful in all 3 patients: 2 right coronary arteries and 1 left anterior descending artery were opened. In all 3 cases, both the CrossBoss catheter and the Stingray re-entry system were used. Two to three drug eluting stents were implanted in each patient, with the total length of 62-106 mm and final TIMI 3 flow. The mean procedure time was 141 min (130-150 min), mean fluoroscopy time was 53 min (48-56 min), absorbed dose was 4772 mGy (4098-5633 mGy), dose area product was 565,208 cGy × cm² (535,109-590,266 cGy × cm²), and the mean contrast volume was 343 mL (320-350 mL). No procedure-related complications were note except for an asymptomatic increase in high-sensitivity troponin T level up to 157 ng/mL (reference range 0-14 ng/mL) in 1 patient.nnnCONCLUSIONSnThe Boston Scientific Coronary CTO Crossing System is a useful device for percutaneous recanalisation of chronically occluded coronary arteries. It helps to achieve procedural success in more complex cases within relatively short crossing times and with a limited amount of the contrast agent and X-ray dose.

The effects of cimetidine chronic treatment on conventional antiepileptic drugs in mice

PURPOSEnThe aim of this study was to evaluate the effects of 1-day, 7-day and 14-day administrations of cimetidine on the anticonvulsant activity of conventional antiepileptic drugs (AEDs; valproate, carbamazepine, phenytoin and phenobarbital) against maximal electroshock (MES)-induced convulsions in mice.nnnMETHODSnElectroconvulsions were evoked in Albino Swiss mice by a current delivered via ear-clip electrodes. In addition, the effects of cimetidine, AEDs alone and their combinations were studied on performance and long-term memory tests. Pharmacokinetic changes in plasma and brain concentrations of AEDs after cimetidine administration were evaluated with immunofluorescence.nnnRESULTSnCimetidine (up to 100mg/kg) after 1-day administration did not affect the electroconvulsive threshold in animals. Moreover, in the 14-day treatment, cimetidine administered at a dose of 40mg/kg did not significantly change the electroconvulsive threshold in the MES-test, cimetidine administered 14-day (at 20mg/kg) significantly increased the anticonvulsant activity of carbamazepine, staying without effects after a 1-day and 7-day studies. In contrast, both the 7-day and 14-day administrations of cimetidine resulted in significant reductions of protective efficacy of the phenobarbital. Only valproate and phenytoin were not affected by cimetidine (20mg/kg) in all experimental period. Cimetidine administered 1-day, did not alter total brain concentrations and free plasma levels of all AEDs tested, whilst the 14-day study elevated carbamazepine plasma and brain concentration and reduced phenobarbital brain concentration. Cimetidine co-applied with AEDs did not impair performance of mice evaluated in the chimney test however, it worsened long-term memory in animals.nnnCONCLUSIONSnBased on this preclinical study, a special caution is advised when treating epileptic patients with combinations of phenobarbital or carbamazepine with cimetidine.

Strange echocardiographic finding after transvenous lead extraction in a patient with lead-associated infective endocarditis

We present a lead silicone tube discovery in the right atrium after transvenous lead extraction that was identified by echocardiography.