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Urbanek K.,Ustav farmakologie
Interni Medicina pro Praxi | Year: 2017

Infliximab is the first monoclonal antibody directed to TNFα. Used in the treatment of rheumatoid arthritis or other arthritis, inflammatory bowel diseases and psoriasis. Infliximab is administered by slow intravenous infusion, typically at doses of 3-5 mg / kg at intervals of 1-8 weeks. It is slowly eliminated from the body with a half-life of 7-12 days. For its high effectiveness and safety is a targeted first-line treatment of these diseases. Its side effects include especially infusion reactions and the risk of opportunistic infections, other adverse reactions are generally mild or infrequent.

Adamcova M.,Ustav fyziologie | Sterba M.,Ustav farmakologie
Kardiologicka Revue | Year: 2017

This review article analyses the contribution of experimental research to the understanding of anti-cancer drug cardiotoxicity mechanisms and the options for cardioprotection. We focused on drugs inducing direct toxicity against cardiomyocytes resulting in left ventricular dysfunction. Typical features of Type I and Type II toxicity (represented by anthracyclines and trastuzumab/sunitinib, respectively) are discussed. The paper also describes in vivo models for experimental study of anthracycline cardiotoxicity. © 2017, Ambit Media a.s. All rights reserved.

Urbanek K.,Ustav farmakologie
Kardiologicka Revue | Year: 2017

Rivaroxaban is an oral selective, direct factor Xa inhibitor. It has well predictable pharmacodynamics and pharmacokinetics. Depending on the size of the dose, it inhibits thrombin formation after 24 hours. It does not block the existing thrombin activity and thus enables continued activation of endogenous anticoagulant factors. After oral administration it is well absorbed, its bioavailability varies between 80 and 100%. It is bound to plasma proteins in 92 to 95%, its average distribution volume is 50 litres. The main metabolising systems are cytochromes P450 3A4 and 2J2. It is excreted mainly via the kidneys; about one third of the administered amount being excreted unchanged, primarily by tubular secretion. The remaining two thirds are excreted as inactive metabolites in urine and bile. The median terminal half-life in younger individuals is 5–9 hours, and 11–13 hours in older individuals. Rivaroxaban pharmacokinetics is minimally affected by age or sex of the patient, and does not require dose adjustments in patients with extremely low or high or with mild-to-moderate renal or hepatic insufficiency. © 2017, Ambit Media a.s. All rights reserved.

Ehrmann J.,II. interni klinika gastro enterologicka a hepatologicka | Urbanek K.,Ustav farmakologie
Kardiologicka Revue | Year: 2014

Irritable bowel syndrome (IBS) and functional dyspepsia are the most common functional gut disorders. The main topic of the article is a summary review of the etiology and pathogenesis of this disease as well as its diagnostic procedures and treatment. Irritable bowel syndrome is characterized by abdomen pain with altered stool frequency or consistency. It is recommended that it be defined and classified according to the Rome III classification. The symptoms are induced by physiological aberrations (like dysmotility and visceral hypersensitivity) or by the mechanisms of the initial inflammation and neuroimmune interaction. This is also the focus of contemporary research. The etiology and pathogenesis, however, remain unclear and the therapy of the day remains at the level of decreasing the main symptoms: abdominal pain, constipation, diarrhea and psychological factors. Sulpiride, an antagonist of the D1 and D3 receptors, at a dose of 50 or 100 mg 3 times daily should be a first-choice treatment of IBS due to its anxiolytic and analgesic effects. The adverse effects of drugs for the treatment of IBS on the cardiovascular system are discussed in the last part of the article.

The medicinal product Relvar Ellipta is a new dry powder inhaler containing a new fixed combination of the inhaled corticosteroid fluticasone furoate (FF) and the selective ultra-long-Acting, 2-Adrenergic agonist vilanterol. The article summarizes the most interesting data from the preclinical development and phase I clinical evaluation of both molecules. Among the modern inhaled corticosteroids, FF has the highest affinity towards the glucocorticoid receptor. In preclinical testing in vitro and in vivo, the glucocorticoid activity of FF was stronger and it had longer duration than that of fluticasone propionate. The inhaled particles of FF dissolve very slowly bringing two major advantages. First, the pulmonary residence time is two-fold longer than that of fluticasone propionate making a once-daily inhalation possible and, second, the slower rate of absorption results in very low concentrations of FF in the blood. The safety profile of FF is further supported with the high velocity of hepatic elimination, biotransformation to inactive metabolites, negligible oral bioavailability and extensive binding to plasma proteins. Preclinical and clinical evaluation of vilanterol was able to document its improved pharmacodynamic characteristics in comparison to salmeterol. Namely, the intrinsic activity of vilanterol is higher and its effect has a more rapid onset and a longer duration. Both the extraordinary 2-selectivity and appropriate pharmacokinetic characteristics (fast hepatic elimination, conversion to inactive metabolites, short half-life, minimal oral bioavailability) are responsible for a favorable safety profile of vilanterol. The duration of action over 24 h following inhalation is ascribed to the high-Afinity binding of vilanterol to specific binding sites on the 2-receptor which enables its retention nearby and a repeated interaction with the receptors active site.

Bultas J.,Ustav Farmakologie
Casopis Lekaru Ceskych | Year: 2015

Mountaineering brings many health risks, one of which is mountain sickness. Its mildest form - acute mountain sickness - is mainly characterized by subjective symptoms (headache, loss of appetite, insomnia, weakness, nausea and rarely also vomiting). Advanced and life-threatening forms are characterized by tissue edema - cerebral or pulmonary high altitude edema. The common denominator of these acute forms is the low oxygen tension leading to hypoxemia and tissue ischemia. Sum of maladaptive or adaptive processes can modify the clinical picture. Underlying mechanisms of the chronic forms of pulmonary disease are the adaptation processes - pulmonary hypertension and polycythemia leading to heart failure. The only causal therapeutic intervention is to restore adequate oxygen tension, descend to lower altitudes or oxygen therapy. Pharmacotherapy has only a supportive effect. The prophylaxis includes stimulation of the respiratory center by carbonic anhydrase inhibitors (acetazolamide) antiedematous treatment with glucocorticoids (dexamethasone), increase lymphatic drainage of the lungs and brain by β2-agonists (salmeterol) or mitigation of pulmonary hypertension by calcium channel blockers or phosphodiesterase-5 inhibitors (sildenafil or tadalafil).

An advent of each new group of drugs associated with big expectations is inevitably followed by a period of critical evaluation. From the perspective of a gastroenterologist, a higher incidence of bleeding in the gastrointestinal tract associated with the use of some of the novel oral anticoagulants in comparison with warfarin is somewhat disappointing. Increased incidence of gastrointestinal haemorrhagic events was observed in both direct thrombin inhibitor - dabigatran, as well as some direct factor Xa inhibitors - xabans, specifically in rivaroxaban and edoxaban. In phase III clinical studies, the meta-analyses and analyses of registers has observed a relative increase in all bleeding events as well as major bleeding into the gastrointestinal tract of about a quarter to a half, but in absolute values the increase in the incidence is on average low, only 0.3%. However, for the individual drugs the absolute increase may be greater, e.g. in the case of rivaroxaban 1%. Given the fact that there are significant differences amongst individuals, rivaroxaban and dabigatran (at a dose of 2 × 150 mg) have a higher risk and the therapy with apixaban is not associated with a higher incidence of gastrointestinal bleeding, it is advisable for people at high risk of gastrointestinal bleeding to choose apixaban as the optimal anticoagulation therapy. The incidence of bleeding in the gastrointestinal tract is growing for a number of reasons, which increase the exposure to different drugs. These factors include in particular drug and food interactions, decreased renal functions, lower weight and some pharmacogenetic factors. Independently of the level of anticoagulants, the risk of gastrointestinal bleeding increases also the use of non-steroidal (even steroidal) anti-inflammatory drugs, infection with Helicobacter pylori or e.g. diverticulosis.

Direct oral anticoagulants (DOACs) are agents that have recently been introduced into clinical practice to replace warfarin. In addition to improved efficacy and safety, one of the anticipated benefits was the absence of the need for regular monitoring of coagulation parameters with the necessity of adjusting the doses on the basis of the obtained results. However, increasing need for quantitative determination of these substances in plasma in specific cases has been found. The gold standard for the essay of DOACs’ plasma concentrations is the LC-MS method. In daily practice, the use of indirect methods such as dTT for inhibitors of thrombin and chromogenic determination of anti-Xa for factor Xa inhibitors is more usual. So far, it has not been recommended for any DOAC that therapeutic drug monitoring should be performed repeatedly for dosage adjustment. Plasma concentrations measurements are used in cases such as suspected noncompliance, bleeding complications during treatment, the need for acute thrombolysis or surgical procedures. © 2015, Ambit Media a.s. All rights reserved.

Methotrexate (MTX) is a conventional immunosuppressive drug of first choice in oral therapy of moderate-to-severe plaque psoriasis. Its use is comfortable and cost effective. The therapy improves the skin status according to the PASI score (psoriasis area and severity index) by 50% or more in up to 75% of patients. However, a high inter-individual variability in pharmacokinetics is one of the major factors responsible for either insufficient efficacy of the therapy or its premature discontinuation due to adverse effects of MTX. The review article critically evaluates the possible benefits of therapeutic drug monitoring (TDM) of MTX as a tool for personalized pharmacotherapy of psoriasis. Prospective clinical studies unraveled a relationship between the pharmacokinetics and the therapeutic effect of MTX. Recommendations on how to perform TDM were worked out and verified, which helped to improve the outcomes of the initial treatment phase (remission induction). Besides the individualization of MTX dosing, supplementation with folic acid was individually tailored only to patients with a proven folate deficit. © 2015, Ambit Media a.s. All rights reserved.

Karetova D.,II. interni klinika kardiologie a angiologie | Bultas J.,Ustav farmakologie
Kardiologicka Revue | Year: 2012

Warfarin has a long history as a golden standard in oral anticoagulation medication. In recent years, however, new anticoagulants have appeared, aspiring to take over the helm. Development has focused mainly on direct inhibitors of thrombin and direct inhibitors of Factor Xa. The greatest progress in the registration process has been achieved by dabigatran (Pradaxa®), followed by rivaroxaban (Xarelto®) and apixaban (Eliquis®). They are peroral agents with pointed effect, i.e. they block individual factors of the coagulation cascade - Factor Xa (xabans) and Factor II (gatrans), without any monitoring being necessary, but without any possibility to administer a specific antidote. They are already commonly used in the prevention of thromboembolic disease (TED) in orthopaedics and are starting to be administered as part of the prevention of systemic embolization in patients with atrial fibrillation. Registration for the purpose of treatment of acute venous thrombosis, pulmonary embolism and secondary prophylaxis of these events is approaching. Other molecules are currently at the stage of clinical trials (for instance, edoxaban, betrixaban, otomixaban).

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