Onset of fever and pain syndrome in children is one of the most frequent reasons parents take their children to a paediatrician. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve such symptoms. The mechanism of action of NSAIDs is to inhibit the activity of the enzyme called cyclooxygenase (COX). Paracetamol, one of the drugs that inhibit COX, exerts its pharmacodynamic effect in the central nervous system, thereby providing antipyretic and analgesic effects, but it is ineffective in stopping inflammation. Such common conditions in children as fever and pain syndrome of mild to medium intensity are among the indications for use of Efferalgan containing paracetamol as an active ingredient. Solution and rectal suppositories are the most commonly used dosage forms of Efferalgan in children, as these dosage forms can be used, when the child reaches 1 and 3 months of age, respectively. The correct dose of paracetamol for a child depends on their weight. It should be remembered that the relief of a fever or pain syndrome is a symptomatic treatment. Therefore, if they appear, you should visit a doctor to identify carefully the possible cause and select the appropriate therapy.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common drugs in clinical practice and account for 5–10% of all drugs prescribed each year. However, the use of this group of drugs is associated with the risk of a wide range of side effects, most of which are cardiovascular complications. In addition, NSAIDs interact with other drugs, for example, their effect on antihypertensive therapy has recently been recognized as particularly important. Improvement of not only efficacy, but also safety is another important principle of rational pharmacotherapy. Adverse drug reactions (ADR) can very often result from underlying genetic factors of the human body. In this regard, a personalized approach suggesting the prescription of drugs according to the individual characteristics of patients is especially important. In such cases, pharmacogenetic testing is the most promising method that identifies the genetic factors of patients and allows to predict patients’ responses to specific drugs. This applies especially to a large range of drugs metabolised via the cytochrome P450 system in the liver. Results from numerous studies show that the effect of P450 family gene polymorphism determines the individual sensitivity to antihypertensive drugs, as it is these isozymes that are involved in the metabolism of drugs used to treat arterial hypertension (AH). In particular, the cytochrome (CYP) 450 isoenzyme is one of the basic enzymes involved in the biotransformation of losartan, an angiotensin receptor antagonist. Therefore, the CYP2C9 gene polymorphism largely determines the pharmacological response to NSAIDs and affects the effectiveness of antihypertensive therapy due to the change in the drug metabolism, as well as the structure and function of the receptors, on which they have an effect.

Pharmacotherapy in patients with comorbidity is a current issue for clinical practice. Combination of hypertension and musculoskeletal diseases can be found in 40% of outpatients, which requires simultaneous administration of different drugs. The main mechanisms of drug interactions are associated with pharmacokinetics or pharmacodynamics alterations. It has been proven that changes in drugs pharmacokinetics can be due to cytochromes P450 activity. The main symptom of musculoskeletal diseases is chronic pain, which requires long-term therapy with non-steroidal anti-inflammatory drugs (NSAIDs). The 2C19 isoenzyme takes part in metabolism of some NSAIDs. Losartan, the inhibitor of renin-angiotensinaldosterone system (RAAS), is also metabolized by the 2C9 isoenzyme and is quite often prescribed to outpatients to treat hypertension. Hence, an influence of genetic factors on efficacy and safety of antihypertensive drugs and NSAIDs combinations requires further studies.

Objective: to study the pharmacokinetic parameters and safety of Dorsumio® (mirtazapine + tizanidine, extended-release tablets, 15 mg + 6 mg, JSC Valenta Pharm, Russia) taken once by healthy volunteers in comparison with Calixta®, a monocomponent drug (INN: Mirtazapine, filmcoated tablets, 30 mg, Belupo, Drugs and Cosmetics d.d., Republic of Croatia) and Sirdalud® MR (INN: Tizanidine, modified-release capsules, 6 mg, Novartis Pharma AG, Switzerland) with an evaluation of their drug interactions when taken concomitantly or separately.Material and methods. A two-stage, randomized, comparative cross-over study of the pharmacokinetics and safety of the complex drug Dorsumio® was conducted. In the first stage, volunteers alternated between taking one or two tablets of the study drug in two administration periods; in the second stage, subjects alternated between taking the reference monodrugs Calixta® and Sirdalud® MR alone and in a joint combination in three administration periods. A total of 38 volunteers were randomized into the study, of which 14 subjects participated in the first and 24 in the second stage of the study. Quantitative levels of mirtazapine and tizanidine were determined by high-performance liquid chromatography with tandem mass spectrometry. Based on the data obtained, the main pharmacokinetic parameters reflecting the bioavailability of each drug were calculated, and the mutual influence of their combination on pharmacokinetics was also studied. During the study, vital signs and laboratory parameters of the subjects were monitored, and the occurrence of adverse events (AEs) and serious AEs was recorded.Results. A two-fold increase in the dose of the combination drug Dorsumio® resulted in a comparable increase in the pharmacokinetics of the individual drugs. There was no significant reciprocal effect of mirtazapine and tizanidine on their pharmacokinetic parameters. In one of the subjects participating in the second stage of the study, two mild side effects were registered after the joint use of Calixta® and Sirdalud® MR that did not require medical intervention and resolved on their own without health consequences.Conclusion. There were no differences in the safety profile of the combined use of mirtazapine and tizanidine in the form of a free or fixed combination. It was shown that the investigated drug combination had no mutual influence on the pharmacokinetics of the individual components.