Tatiana Foltanova

MEG3: a novel long noncoding potentially tumour-suppressing RNA in meningiomas

Meningiomas represent one of the most common types of primary intracranial tumours. However, the specific molecular mechanisms underlying their pathogenesis remain uncertain. Loss of chromosomes 22q, 1p, and 14q have been implicated in most meningiomas. Inactivation of the NF2 gene at 22q12 has been identified as an early event in their pathogenesis, whereas abnormalities of chromosome 14 have been reported in higher-grade as well as recurrent tumours. It has long been supposed that chromosome 14q32 contains a tumour suppressor gene. However, the identity of the potential 14q32 tumour suppressor remained elusive until the Maternally Expressed Gene 3 (MEG3) was recently suggested as an ideal candidate. MEG3 is an imprinted gene located at 14q32 that encodes a non-coding RNA (ncRNA). In meningiomas, loss of MEG3 expression, its genomic DNA deletion and degree of promoter methylation have been found to be associated with aggressive tumour growth. These findings indicate that MEG3 may have a significant role as a novel long noncoding RNA tumour suppressor in meningiomas.

Use of biomarkers in the context of orphan medicines designation in the European Union.

The use of biomarkers within the procedures of the Committee of Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA) is discussed herein. The applications for Orphan Medicinal Product designation in the EU are evaluated at two stages. At the time of orphan designation application, the file undergoes an assessment to establish whether the proposed condition is a distinct and serious condition affecting not more than 5 in 10,000 people in the EU, and whether the product is plausible as a therapy for that condition. In cases where therapies already exist, the significant benefit of the candidate product over existing therapies is also evaluated. The orphan criteria are reassessed at the time of marketing authorisation, so that marketing exclusivity for the product in the orphan medical condition can be granted. Within this context, biomarkers have been used in submissions in order to define an orphan condition and to justify that the criteria for orphan designation are met. The current work discusses specific examples from the experience of the COMP, where biomarkers have played a decisive role. Importantly, it identifies the proposal of sub-sets of non-rare conditions based on biomarkers as a challenging issue in the evaluation of applications. In particular two specific requirements for the candidate orphan medicines in relation to the biomarker-based subsets are highlighted: the “plausible link to the condition” and the “exclusion of effects outside the subset”.

The Effects of Pycnogenol® as Add-on Drug to Metformin Therapy in Diabetic Rats

The progression of diabetes mellitus leads in time to the development of serious cardiovascular complications. Pycnogenol® (PYC) belongs to strong antioxidants that may interfere with different pathways playing an important role in diseases associated with oxidative stress. Metformin (MET), commonly used antidiabetic drug, has cardio‐protective effects via activation of AMP kinase (AMPK). In our study, we examined the effects of PYC as add‐on drug to metformin therapy in streptozotocin (STZ)‐induced diabetic rats. Our results revealed that both used agents, PYC and MET, showed improvement of blood glucose levels, vascular reactivity, left ventricular hypertrophy, expression of AMPK, glucose transporter 4 (GLUT4) and calcium/calmodulin‐dependent protein kinase II (CaMKII) in left ventricle of the hearts. However, the combination of these interventions has failed to possess higher efficacy. Copyright

Caustic Ingestion in the Elderly: Influence of Age on Clinical Outcome

Caustic poisonings are still associated with many fatalities. Studies focusing on the elderly are rare. The purpose of the present study was to compare the clinical outcomes of caustic ingestion injury in elderly and non-elderly adults with regard to gender, intent of exposure, substance ingested, severity of mucosal injury, complications, and mortality. Caustic substance exposures reported to the National Toxicological Information Centre in Slovakia during 1998–2015 were reviewed retrospectively. The patients were divided into two groups: the non-elderly (<60 years) and elderly adults (≥60 years). The mortality rate in the elderly was significantly higher (elderly 23.0% vs. non-elderly 11.3%; p = 0.041). The risk of fatal outcome in the elderly was increased by acid ingestion (OR = 7.822; p = 0.002), particularly hydrochloric acid (OR = 5.714, p = 0.006). The incidence of respiratory complications was almost two times higher in the elderly was 31.1% vs. 17.4% for the non-elderly (p = 0.037). Respiratory complications significantly correlated with an increased mortality rate (p = 0.001) in the elderly whereas there was no association between GI complications and mortality in the elderly (p = 0.480). Elderly patients with respiratory complications had the poorest clinical outcomes. The highest risk of complications and fatalities was observed in patients after hydrochloric acid ingestion.

Suboptimal use of gastroprotective medication in elderly antiplatelet users.

BACKGROUND Use of acetylsalicylic acid (ASA) or thienopyridines in monotherapy or combination of both drugs is associated with increased risk of gastrointestinal (GI) bleeding. The administration of drugs inhibiting gastric acid production represents an effective way to avoid GI disorders associated with antiplatelet therapy. OBJECTIVES The aim of our study was to evaluate the use of gastroprotective medication in elderly antiplatelet users in relation to risk factors for GI bleeding. METHODS Patients (n = 428) aged ≥ 65 years who were prescribed low dose ASA or clopidogrel in monotherapy or combination at hospital discharge were enrolled in the study. RESULTS Only 39.7 % of patients with 2 or more risk factors for GI bleeding were prescribed gastroprotective medication at hospital discharge. The probability of elderly antiplatelet drug user for prescription of gastroprotective medication was improved with following risk factors: age ≥ 85 years (OR = 2.99); history of peptic ulcer disease/ GI bleeding (OR = 15.79); other GI disorders (OR = 15.48); concomitant therapy with drugs increasing the risk of GI bleeding - systemic corticosteroids (OR = 29.03) and NSAIDs (OR = 4.79). CONCLUSION Results of our study indicate the necessity to increase the awareness of GI bleeding risk in long-term antiplatelet users among prescribing physicians.

The problem of low peak concentration of gentamicin in clinical practice

The problem of low peak concentration of gentamicin in clinical practice Aminoglycoside antibiotics have particular importance in the treatment of Gram-negative infections. Toxicity of gentamicin is well-known, but patients often receive insufficient dosage in clinical practice. The purpose of this study was to refer to the problem of insufficient dosages that were confirmed by low peak concentration and to determine relationship between low peak levels and pharmacokinetic parameters, renal function and body weight. We studied 68 patients who were treated with gentamicin for one year (August 2010 - August 2011). Therapeutic drug monitoring (TDM) was applied for all the patients. Gentamicin peak and trough concentrations were measured by the FPIA (Fluorescence Polarization Immunoassay) method with an analyser, AxSYM of ABBOTT company. We divided the patients into 3 groups according to peak and trough levels. Together 13 (19%) patients had high trough concentrations and optimal peak concentrations. Only 6 (9%) patients had optimal trough and peak levels in the first measurement of plasma concentrations. The third group included 49 patients (72%). These patients had optimal trough levels and low peak levels in the first measurement. 34 patients of the third group (28 males, 6 females) had optimal peak levels after adjustment of dosage in the second measurement. 15 patients, only males did not reach optimal peak levels even after adjustment of dosage in the second measurement. The patients with low peak levels of gentamicin are more frequent than patients with toxic adverse effects in clinical practice. Especially, these are the patients with higher value of body weight and following increased pharmacokinetic parameters: creatinine clearance, total volume of distribution, total clearance and elimination rate constant. The clinical pharmacists have to adjust dosage regimens, especially according to Therapeutic drug monitoring (TDM) and clinical experience. The results of the study have confirmed that the clinical pharmacists must adjust dose regimen not only for patients who require reduced doses but more often for patients who require higher doses than are commonly used in clinical practice. These patients are at risk of underdosing of aminoglycoside antibiotics. Problém nízkych vrcholových koncentrácii gentamicínu v klinickej praxi Aminoglykozidové antibiotiká sú veľmi dôležitými antibiotikami v liečbe gram negatívnych infekcií. Účinok aminoglykozidových antibiotík je závislý na ich koncentrácii. Toxicita gentamicínu je dobre známa, v klinickej praxi sa však stretávame s pacientmi, ktorí dostávajú nedostatočné dávky. Cieľom tejto práce bolo poukázať na pretrvávajúci problém poddávkovania gentamicínom, ktorý potvrdzujú nízke vrcholové koncentrácie a nájsť súvislosť medzi farmakokinetickými parametrami, obličkovými funkciami, telesnou hmotnosťou a nízkymi vrcholovými koncentráciami. V práci sme analyzovali údaje o 68 pacientoch, ktorí sa liečili gentamicínom počas jedného roka (august 2010 - august 2011). Terapeutické monitorovanie hladín sa uskutočnilo u všetkých pacientov. Reziduálne a vrcholové hladiny gentamicínu sa merali analytickou metódou FPIA (flurescenčnou polarizačnou imunoanalýzou) na analyzátore AxSYM firmy ABBOTT. Pacientov sme rozdelili do 3 skupín. Celkovo 13 (19 %) malo vysoké reziduálne hladiny a optimálne vrcholové koncentrácie gentamicínu. Iba 6 (9 %) pacientov malo pri prvom meraní sérových koncentrácií optimálne obe hladiny. Tretia skupina zahŕňala 49 pacientov (72 %). Títo pacienti mali optimálne reziduálne hladiny, ale nízke vrcholové hladiny pri prvom meraní. Až 34 pacientov (28 mužov, 6 žien) z tretej skupiny malo optimálne vrcholové koncentrácie po úprave dávkových režimov pri druhom meraní. U 15 pacientov (len muži) sa nedosiahli optimálne vrcholové koncentrácie pri druhom meraní ani po úprave dávky. V klinickej praxi sa častejšie vyskytujú pacienti s nízkymi vrcholovými hladinami gentamicínu ako pacienti s nežiaducimi účinkami. Sú to pacienti s vyššími hodnotami telesnej hmotnosti, farmakokinetických parametrov a dobrými renálnymi funkciami. Určiť optimálne dávkové režimy pre týchto pacientov nie je ľahké. Chýbajú odporúčania vhodných dávok, aby sa mohla čo najskôr zvoliť optimálna dávka. Riešenie tohto problému sa ešte nenašlo. Klinickí farmaceuti upravujú dávkové režimy pre týchto pacientov podľa TDM (terapeutické monitorovanie hladín liekov) a klinických skúseností. Z výsledkov našej štúdie vyplýva, že klinickí farmaceuti musia upravovať dávky nielen pacientom, ktorí potrebujú redukované dávky ale častejšie pacientom, ktorí potrebujú vyššie dávky ako sa bežne používajú v klinickej praxi. Týmto pacientom hrozí riziko poddávkovania gentamicínu.

Orphan drugs used for treatment in pediatric patients in the slovak republic

Orphan drugs used for treatment in pediatric patients in the slovak republic Due to the enormous success of scientific research in the field of paediatric medicine many once fatal childrens diseases can now be cured. Great progress has also been achieved in the rehabilitation of disabilities. However, there is still a big group of diseases defined as rare, treatment of which has been traditionally neglected by the drug companies mainly due to unprofitability. Since 2000 the treatment of rare diseases has been supported at the European level and in 2007 paediatric legislation was introduced. Both decisions together support treatment of rare diseases in children. In this paper, we shortly characterise the possibilities of rare diseases treatment in children in the Slovak republic and bring the list of orphan medicine products (OMPs) with defined dosing in paediatrics, which were launched in the Slovak market. We also bring a list of OMPs with defined dosing in children, which are not available in the national market. This incentive may help in further formation of the national plan for treating rare diseases as well as improvement in treatment options and availability of rare disease treatment in children in Slovakia. Lieky na zriedkavé choroby, používané na liečbu detských pacientov v slovenskej republike Vďaka vedeckému pokroku v liečbe detských ochorení, mnohé doposiaľ neliečiteľné detské choroby sa stávajú liečiteľnými. Veľký pokrok sa zaznamenal tiež v rehabilitácii porúch. Stále však existuje skupina chorôb, definovaných ako zriedkavé, liečba ktorých bola zo strany farmaceutického priemyslu nedostatočne podporovaná a to najmä kvôli finančnej nerentabilite investovaných prostriedkov. Od roku 2000 liečba zriedkavých chorôb je podporovaná európskou legislatívou a v roku 2007 bola predstavená legislatíva na podporu liečby detských chorôb. Obidve rozhodnutia tak spoločne podporujú liečbu zriedkavých chorôb u detí. V tejto práci prinášame stručnú charakteristiku liečebných možností zriedkavých chorôb u detí v Slovenskej republike, zoznam liekov na zriedkavé choroby s definovaným dávkovaním u detí, ktoré sú dostupné na slovenskom trhu. Tiež uvádzame zoznam liekov na zriedkavé choroby s definovaným dávkovaním u detí, ktoré v Slovenskej republike nie sú priamo dostupné. Touto prácou chceme dalej podporiť rozvoj Národného plánu pre zriedkavé choroby.

Acute Pain Treatment at Department of Traumatology

Abstract The aim of this retrospective study was to characterize the acute pain management in patients admitted to Department of Traumatology and to identify the efficacy of analgesic pharmacotherapy. The study involved 83 patients divided into two groups: 52 patients (63%) in Group 1 underwent operation; the remaining 31 patients (37%) in Group 2 had conservative treatment. The characteristics of the patients (diagnosis, analgesic therapy, age, comorbidities, drugs used during hospitalisation, analgesic efficacy) were obtained from electronic database and medical reports by the hospital. Therapy during the first seven days of hospitalisation and the recommended therapy after discharging home were analysed. Records of drug adverse reactions during the whole hospitalisation were monitored. Metamizol was the most frequently prescribed as a primal analgesic. Adequate analgesia solely by metamizol was reached in 20% of all patients; the remaining 80% required increased doses or combination with another analgesic. Metamizol was combined mainly with tramadol, morphine or pethidine. Our study proved metamizol to be an effective analgesic. No clinical manifestation of agranulocytosis was observed in this study. Cieľom tejto retrospektívnej štúdie bolo charakterizovať zvládanie akútnej bolesti u hospitalizovaných pacientov na oddelení traumatológie a identifikovať úspešnosť analgetickej farmakoterapie. Sledovaný súbor tvorilo 83 pacientov, z toho 52 pacientov (63 %) podstúpilo operáciu a 31 pacientov (37 %) bolo ošetrených konzervatívne. Charakteristiky pacientov (príčina hospitalizácie, analgetická terapia, vek, komorbidity, súčasne užívané liečivá, reakcia na analgetickú liečbu) sme získali z elektronickej databázy a chorobopisov nemocnice. Analyzovali sme terapiu počas prvých 7 dní hospitalizácie a odporúčanú terapiu do domáceho ošetrenia po ukončení hospitalizácie. Záznamy o výskyte nežiaducich reakcií sme sledovali počas celej doby hospitalizácie pacientov. Najčastejšie primárne ordinovaným analgetikom bol metamizol. Dostatočná analgézia podľa základnej ordinácie výlučne (v monoterapii) metamizolom sa dosiahla u 20 % zo všetkých pacientov, 80 % pacientov si vyžadovalo zvýšenie dávky alebo kombináciu s iným analgetikom. Metamizol sa najčastejšie kombinoval s tramadolom, morfínom alebo petidínom. V našej štúdii sa metamizol ukázal ako účinné analgetikum. Zároveň sme nezaznamenali výskyt klinických prejavov agranulocytózy.