From viewpoint of environmental analysis in the whole world became popular in the latest years the question of drugs’ breakthrough to the component of environment. These contami-nants belong to the biological active compounds, with different physical-chemical and biolog-ical properties and evince great tendency to bioaccumulation. They penetrate to the environ-ment because of their increasing of usage and wrong techniques of liquidation. The most often use drugs are preparations against pain – analgetics, and from this category there are non-steroidal anti-inflammatory drugs. The frequent usage of this compounds relate to their easy accessibility. From this large group of compounds was chosen for monitoring: diclofenac, ibuprofen, ketoprofen, salicylic acid, naproxen and acetaminophen; because they include in favorite preparations. The monitoring matrix was the wastewater from two waste water treat-ment plants (WWTP). The sampling was performed in inflow and outflow because the com-paring of concentration of selected contaminants and discovering of efficiency of removing the polutants reliance on treatment technology. For extraction of selected contaminants was used solid phase extraction (SPE) and for determination was used capillary zone electrophore-sis (CZE) with diode array detection (DAD). There was identified and quantified all of se-lected analgetics in inflow and so in outflow of WWTP. That means, this polutants infuse into surface water and then into other components of environment.

Background: Dipyrone (metamizole) is one of the most widely used non-opioid analgesics for the treatment of cancer pain. Aim: Because evidence-based recommendations are not yet available, a systematic review was conducted for the German Guideline Program in Oncology to provide recommendations for the use of dipyrone in cancer pain. Design: First, a systematic review for clinical trials assessing dipyrone in adult patients with cancer pain was conducted. Endpoints were pain intensity, opioid-sparing effects, safety, and quality of life. Data sources: The search was performed in MedLine, Embase (via Ovid), and the Cochrane Library (1948–2013) and additional hand search was conducted. Finally, recommendations were developed and agreed in a formal structured consensus process by 53 representatives of scientific medical societies and 49 experts. Results: Of 177 retrieved studies, 4 could be included (3 randomized controlled trials and 1 cohort study, n = 252 patients): dipyrone significantly decreased pain intensity compared to placebo, even if low doses (1.5–2 g/day) were used. Higher doses (3 × 2 g/day) were more effective than low doses (3 × 1 g/day), but equally effective as 60 mg oral morphine/day. Pain reduction of dipyrone and non-steroidal anti-inflammatory drugs did not differ significantly. Compared to placebo, non-steroidal anti-inflammatory drugs, and morphine, the incidence of adverse effects was not increased. Conclusion: Dipyrone can be recommended for the treatment of cancer pain as an alternative to other non-opioids either alone or in combination with opioids. It can be preferred over non-steroidal anti-inflammatory drugs due to the presumably favorable side effect profile in long-term use, but comparative studies are not available for long-term use.

What is known and objective: Although non-steroidal anti-inflammatory drugs (NSAIDs) have been studied in randomized, controlled trials and meta-analyses in an effort to determine their cardiovascular (CV) risks, no consensus has been reached. These studies continue to raise questions, including whether cyclooxygenase-2 (COX-2) selectivity plays a role in conferring CV risk. We performed a meta-analysis of current literature to determine whether COX-2 selectivity leads to an increased CV risk. Methods: We utilized randomized, controlled trials and prospective cohort studies. We selected eight NSAIDs based on popularity and COX selectivity and conducted a search of the MEDLINE, EMBASE, and Cochrane databases. Primary endpoints included any myocardial infarction (MI), any stroke, CV death, and a combination of all three (composite CV outcomes). Twenty-six studies were found that met inclusion and exclusion criteria. Comparisons were made between all included drugs, against placebo, and against non-selective NSAIDs (nsNSAIDs). Drugs were also compared against COX-2 selective inhibitors (COXIBs) with and without inclusion of rofecoxib. Results and discussion: Incidence of MI was increased by rofecoxib in all comparison categories [all NSAIDs (OR: 1·811, 95% CI: 1·379–2·378), placebo (OR: 1·655: 95% CI: 1·029–2·661), nsNSAIDs (OR: 2·155, 95% CI: 1·146–4·053), and COXIBs (OR: 1·800, 95% CI: 1·217–2·662)], but was decreased by celecoxib and naproxen in the COXIB comparison [(OR: 0·583, 95% CI: 0·396–0·857) and (OR: 0·609, 95% CI: 0·375–0·989, respectively]. Incidence of stroke was increased by rofecoxib in comparisons with all NSAIDs and other COXIBs [(OR: 1·488, 95% CI: 1·027–2·155) and (OR: 1·933, 95% CI: 1·052–3·549), respectively]. Incidence of stroke was decreased by celecoxib when compared with all NSAIDs, nsNSAIDs, and COXIBs [(OR: 0·603, 95% CI: 0·410–0·887), (OR: 0·517, 95% CI: 0·287–0·929), and (OR: 0·509, 95% CI: 0·280–0·925), respectively]. No NSAID reached statistical significance in regard to CV death. Incidence of the composite endpoint was increased by rofecoxib when compared against all NSAIDs, placebo, and other COXIBs [(OR: 1·612, 95% CI: 1·313–1·981), (OR: 1·572, 95% CI: 1·123–2·201) and (OR: 1·838, 95% CI: 1·323–2·554), respectively]. Incidence of composite endpoint was decreased by celecoxib in the all NSAIDs and COXIBs comparisons [(OR: 0·805, 95% CI: 0·658–0·986) and (OR: 0·557, 95% CI: 0.404–0.767), respectively]. When rofecoxib was removed from the COXIBs group, no difference was found with any comparison, suggesting rofecoxib skewed the data. What is new and conclusion: This instead of the meta-analysis suggests that COX-2 selectivity may not play a role in the CV risk of NSAIDs. Rofecoxib was the only drug to demonstrate harm and skewed the data of the COX-2 selective group.

Magister Scientiae Dentium - MSc(Dent) / Background and aim: Managing orthodontic pain traditionally involves the prescription of non-steroidal anti-inflammatory drugs combined with other analgesic medication. Sugar-free chewing gum has been advocated in the control of orthodontic pain due to its mechanical and physiological effects on periodontal tissue; however, the literature is scant. The ‘placebo effect’ that conventional sugar-free chewing gum may have in the relief of orthodontic pain has not been documented. The aim of this study was to compare the effectiveness of conventional sugar-free chewing gum in reducing orthodontic pain associated with fixed appliances with a placebo (sugar-free sweets) medicament. Objectives: The objectives of the study were to determine if there were differences in pain reporting between the sugar-free chewing gum and the placebo, to ascertain whether gender influenced pain scores and to observe any differences in pain reporting between different orthodontic techniques.

The theoretical part shortly describes chirality with focus on chiral pharmaceuticals. The processes of their absorption, distribution, metabolism and elimination in human body are discussed. These points are very important to understand possible fate of chiral drugs in the environment as there is only little data concerning their environmental behaviour. The occurrence and enantioselective toxicity of chiral drugs is also discussed here. One of the chapters describes non-steroidal anti-inflammatory drugs, as they are analyzed in the wastewater in the experimental part, and their occurrence in the environment. The experimental part describes optimization of the enantioselective HPLC method using Chiralpak AD as column for ibuprofen and ketoprofen. Reproducible separation of enantiomers wasn’t achieved for naproxen. Optimized methods were then applied for analysis of samples from municipal wastewater treatment plant in Brno-Modřice.

What is known and objective: Although non-steroidal anti-inflammatory drugs (NSAIDs) have been studied in randomized, controlled trials and meta-analyses in an effort to determine their cardiovascular (CV) risks, no consensus has been reached. These studies continue to raise questions, including whether cyclooxygenase-2 (COX-2) selectivity plays a role in conferring CV risk. We performed a meta-analysis of current literature to determine whether COX-2 selectivity leads to an increased CV risk. Methods: We utilized randomized, controlled trials and prospective cohort studies. We selected eight NSAIDs based on popularity and COX selectivity and conducted a search of the MEDLINE, EMBASE, and Cochrane databases. Primary endpoints included any myocardial infarction (MI), any stroke, CV death, and a combination of all three (composite CV outcomes). Twenty-six studies were found that met inclusion and exclusion criteria. Comparisons were made between all included drugs, against placebo, and against non-selective NSAIDs (nsNSAIDs). Drugs were also compared against COX-2 selective inhibitors (COXIBs) with and without inclusion of rofecoxib. Results and discussion: Incidence of MI was increased by rofecoxib in all comparison categories [all NSAIDs (OR: 1·811, 95% CI: 1·379-2·378), placebo (OR: 1·655: 95% CI: 1·029-2·661), nsNSAIDs (OR: 2·155, 95% CI: 1·146-4·053), and COXIBs (OR: 1·800, 95% CI: 1·217-2·662)], but was decreased by celecoxib and naproxen in the COXIB comparison [(OR: 0·583, 95% CI: 0·396-0·857) and (OR: 0·609, 95% CI: 0·375-0·989, respectively]. Incidence of stroke was increased by rofecoxib in comparisons with all NSAIDs and other COXIBs [(OR: 1·488, 95% CI: 1·027-2·155) and (OR: 1·933, 95% CI: 1·052-3·549), respectively]. Incidence of stroke was decreased by celecoxib when compared with all NSAIDs, nsNSAIDs, and COXIBs [(OR: 0·603, 95% CI: 0·410-0·887), (OR: 0·517, 95% CI: 0·287-0·929), and (OR: 0·509, 95% CI: 0·280-0·925), respectively]. No NSAID reached statistical significance in regard to CV death. Incidence of the composite endpoint was increased by rofecoxib when compared against all NSAIDs, placebo, and other COXIBs [(OR: 1·612, 95% CI: 1·313-1·981), (OR: 1·572, 95% CI: 1·123-2·201) and (OR: 1·838, 95% CI: 1·323-2·554), respectively]. Incidence of composite endpoint was decreased by celecoxib in the all NSAIDs and COXIBs comparisons [(OR: 0·805, 95% CI: 0·658-0·986) and (OR: 0·557, 95% CI: 0.404-0.767), respectively]. When rofecoxib was removed from the COXIBs group, no difference was found with any comparison, suggesting rofecoxib skewed the data. What is new and conclusion: This instead of the meta-analysis suggests that COX-2 selectivity may not play a role in the CV risk of NSAIDs. Rofecoxib was the only drug to demonstrate harm and skewed the data of the COX-2 selective group.

Made available in DSpace on 2016-01-26T12:51:42Z (GMT). No. of bitstreams: 1 rosasoubhia_tese.pdf: 792706 bytes, checksum: bba71696e22270729d09c3130cc047eb (MD5) Previous issue date: 2005-05-25 / Introduction: Tacrolimus (FK 506) is a potent immunosuppressive drug that may cause nephrotoxicity decreasing the renal blood flow (RBF) and glomerular filtration rate (GFR). Conventional non-steroidal anti-inflammatory drugs (NSAIDs) may cause nephrotoxicity, interfering with renal hemodynamics and fluid and eletrolyte homeostasis. Recently, new selective COX-2 inhibitors have been developed producing less side effects (gastric, cardiac and renal) related to COX-1 inhibition. The increasing use of FK 506 and the intensive use of NSAIDs with analgesic or ani-inflammatory purposes, increases the possibility of a drug combination, potentiating the nephrotoxic risk of the two drugs. Objective : Compare the renal function of rats receiving combination therapy with FK and a non-selective COX inhibitor, sodium diclofenac (SD) with those receiving FK and a selective COX-2 inhibitor, rofecoxib (RO). Material and Methods : Male Munich-Wistar rats receiving a low sodium diet (0.06%) for 7 days and gavage treatment for 7 days with FK (2 mg/kg/day), SD (10 mg/kg/day), RO (3 mg/kg/day), FK+SD, FK+RO and vehicle (control) were used. Glomerular filtration rate (GFR, inulin clearance, ml/min/100g); renal blood flow (RBF, Doppler ultrasound, ml/min); mean blood pressure (MBP, intracarotid probe, mmHg); renal vascular resistence ( RVR, mmHg/ml/min); hematocrit (Htc); urinary volume ( UV, &#956;l/min); solute clearance; renal histology; animal weight (g) and FK serum concentration (SCFK, ng/ml) were assessed. Results are presented as a mean±standart deviation and compared by ANOVA followed by Student-Neuman-Keuls test. Results : The GRF of the SD group was 0.98±0.03, RO 1.06±0.04 and FK 0.99±0.06 similar to control values (1.10±0.05). GRF values decreased in the FK+RO (0.86±0.06;p<0.05 vs RO and Control) and FK+SD (0.63±0.06;p<0.001 vs control, FK and SD groups and p<0.01 vs FK+RO) groups. RBF, MBP, RVR and Htc values were similar in all groups. Diuresis was lower in the groups with drug combination, but there was a statistically significant difference only between FK+SD and RO groups (8.38±0.46 vs 12.99±1.22;p<0.05). There were no significant histological chan ges in the treatment groups. The FK+SD group showed statistically significant weigth changes (-18±5) when compared to the Control and RO groups (6±2 and 5±2, respectively; p<0.001) and to the SD an FK+RO groups (0.2±4 and 1±2, respectively; p<0.01). SCFK was significantly decreased (p<0.05) for FK+SD and FK+RO (1.7±0.3 and 1.8±0.4) groups when compared to the FK group (3.2±0.4. Conclusions: The combination of FK and a non-selective COX inhibitor significantly decreased GFR regardless of a RBF decrease or RVR increase, and is probably a result of Kf decrease. The trend to antidiuresis was similar for the combination of FK with both classes of NSAIDs. FK combined to a non-selective COX inhibitor caused a mild systemic toxicity when compared with the COX-2 selective inhibitor. Serum FK concentrations were significantly lower in NSAIDs treated animals. / Introdução: O tacrolimus (FK 506) é uma potente droga imunossupressora, pode causar nefrotoxicidade aguda com diminuição do fluxo sanguíneo renal (FSR) e ritmo de filtração glomerular (RFG). Os antiinflamatórios não-hormonais (AINHs) convencionais podem causar nefrotoxicidade, interferindo na hemodinâmica renal e na homeostase de fluidos e eletrólitos. Recentemente surgiram novas drogas do grupo coxib que são inibidores seletivos da COX-2, e portanto teriam menos efeitos colaterais relacionados à inibição da COX-1 (gástricos, cardíacos e renais). O crescente uso do FK 506 e o intenso uso de AINHs com finalidade analgésica e ou antiinflamatória aumenta a possibilidade de utilização em conjunto, potencializando o risco de nefrotoxicidade das duas drogas. Objetivo: Comparar a função renal de ratos sob os efeitos do uso simultâneo do FK e de um inibidor não-seletivo da COX, o diclofenaco sódico (DS) e do FK e de um inibidor seletivo da COX-2, o rofecoxib (RO). Materiais e Método: Utilizaram-se ratos Munich-Wistar machos em dieta hipossódica (0,06%) por 7 dias e tratamento por gavagem por 7 dias com FK (2 mg/kg/dia), DS (l0mg/kg/dia), RO (3mg/kg/dia), FK+DS, FK+RO e veículo (Contr). Aferidos ritmo de filtração glomerular (RFG, depuração de inulina, ml/min/l00g); o fluxo sanguíneo renal (FSR, ultrasom Doppler, ml/min); a pressão arterial média (PAM, probe intracarotídeo, mmHg); a resistência vascular renal (RVR, mmHg/ml/min); hematócríto (Ht); o volume urinário (VU, pl/min); a depuração de solutos; a histologia renal; o peso dos animais (g) e a concentração sanguínea de FK CSFK, ng/ml). Os resultados são apresentados com médiaserro padrão da média e comparados por ANOVA seguido do teste Student-Neuman-Keuls. Resultados: O RFG do grupo DS foi 0,980,03, do RO foi 1,060,04 e do FK 0,990,06 similares ao controle (1,100,05). Houve queda do RFG nos grupos FK+RO (0,860,06;p<0,Os vs RO e Contr) e FK+DS (0,630,06;p<0,001 vs Contr,DS, RO e FK; p<0,01 vs FK+RO) Nota de Resumo O FSR, a PAM, a RVR e o Ht foram semelhantes em todos os grupos. A diurese foi menor nos grupos com associação de drogas, mas houve diferença estatisticamente significante apenas entre os grupos FK+DS e RO (8,380,46 vs l299l,22;p<0,05). Não ocorreram modificações histológicas significativas nos grupos estudados. O grupo FK+DS apresentou variação de peso (-185) estatisticamente significante em relação aos grupos Contr 62 e RO 52 (p<0,001) e DS 0,24 e FK+RO -12 (p<0,01). A CSFK diminuiu significativamente (p<0,05) para os grupos FK+DS e FK+RO (1,70,3 e 1,80,4) em relação ao grupo FK (3,20,4). Conclusões: A associação do FK com um inibidor não-seletivo da COX causou diminuição mais acentuada do RFG independentemente da diminuição do FSR ou aumento da RVR, sendo provavelmente decorrente da diminuição do Kf. A tendência à antidiurese foi similar para a associação do FK com as duas classes de AINHs. O FK associado com um inibidor não-seletivo da COX causou discreta toxicidade sistêmica quando comparado com inibidor seletivo da COX-2. Nos animais tratados com AINHs, as concentrações sanguíneas do FK foram significativamente menores.

L'obtention des données a été subventionnée par CIORA (Canadian Initiative for Outcomes in Rheumatology Care). CIORA a aussi financé l'analyse des données effectuées par Justine Zehr. L'Initiative Canadienne Pour Des Resultats En Soins Rhumatologiques (ICORA) a financé l'obtention des données et une partie de l'analyse statistique présentée dans ce mémoire. / La plupart des femmes ayant été atteintes d’arthrite juvénile idiopathique (AJI) continuent de souffrir d’arthrite à l’âge adulte. Certains des médicaments utilisés dans le traitement de l’arthrite tels que les corticostéroïdes et les antiinflammatoires non stéroïdiens (AINS) ne sont pas recommandés durant la grossesse. Le but de ce mémoire est d’estimer l’impact de la prise de ces médicaments sur les événements néfastes à l’accouchement chez ces femmes et leur bébé. Des données administratives sur les prescriptions de médicaments et les hospitalisations d’une cohorte de 1756 femmes ayant souffert d’AJI sont utilisées. Elles ont permis de reconstruire l’historique de consommation de médicaments contre l’arthrite chez les femmes durant la grossesse et l’année précédente. Pour ce faire, deux sous-cohortes de femmes ayant souffert d’AJI ont été formées : une pour la période grossesse et une autre pour la grossesse et l’année précédant celle-ci. Les événements d’intérêt étaient : malformations congénitales, complications néonatales, complications maternelles et petit poids pour l’âge gestationnel. Les proportions de cas présentant l’un de ces événements variaient entre 11,52% et 37,08%. Les médicaments ont été modélisés en terme d’utilisation ou de durée totale de consommation durant la période d’étude. Pour chaque événement, des modèles logistiques ont été estimés pour mesurer l’association entre la prise de médicaments et l’événement, en ajustant pour des variables de confusion potentielles : hypertension avant la grossesse, âge à l’accouchement et obtention du diplôme de secondaire. La consommation de corticostéroïdes semble augmenter statistiquement significativement le risque de présenter des malformations congénitales mais n’avoir aucun impact sur les autres événements. Aucun lien statistiquement significatif n’a été observé entre la consommation de AINS et les événements d’intérêt. / Most women diagnosed with juvenile idiopathic arthritis (JIA) continue to suffer from arthritis in adulthood. Some of the drugs used to treat arthritis such as corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) are not recommended during pregnancy. The objective of this thesis is to estimate the impact of these drugs on adverse birth outcomes in women previously diagnosed with JIA and their baby. Administrative data on drug prescriptions and hospitalizations in a cohort of 1756 women with a history of JIA were used to determine individual histories of drug use for the treatment of arthritis during pregnancy and during the year leading to the pregnancy. Two sub-cohorts of women who suffered from JIA were created : one corresponding to the pregnancy and the other to the pregnancy and the year leading to the pregnancy. The events of interest were : congenital anomalies, neonatal adverse outcomes, maternal adverse outcomes and small for gestational age babies. Proportions of the events ranged between 11,52% and 37,08%. Drugs were modelled in terms of use or duration of use during each of the study periods. Logistic regression models were fitted to measure the association between drugs and each of the events, adjusting for the following potential confounding variables : hypertension before pregnancy, maternal age and graduating from high school. The consumption of corticosteroids was associated with a statistically significant increased risk of congenital anomalies but had no impact on the other adverse events. No statistically significant associations were observed between consumption of NSAIDs and the adverse events of interest.

L'objectiu principal d'aquestaTesi Doctoral és el desenvolupament de diferents estratègies per disminuir els límits de detecció de l’electroforesicapil•lar per a la determinació de compostos farmacèutics i els productes de cura personal. Aquestes estratègies es basen en les tècniques de preconcentració electroforètiques i cromatogràfiques, i l'ús de l’espectrometria de masses com a sistema de detecció. Com a tècniques de preconcentració electroforètiques s'han estudiat les tècniques de samplestacking i sweeping, i com a tècnica de preconcentració cromatogràficas’ha avaluat l'acoblament en línia entre l'extracció en fase sòlida i l'electroforesicapil•lar (In-line SPE-CE). Entre elsPPCPs, aquesta tesi doctoral es centra específicament en els antiinflamatoris no esteroïdals(AINE), els parabens i els filtres ultraviolats. Un altre dels objectius d'aquestaTesi Doctoral és estudiarl’aplicabilitat de les metodologies desenvolupades per a l'anàlisi de mostres ambientals per determinar PPCP. / The main objective of this Doctoral Thesis is the development of different strategies to decrease the detection limits of capillary electrophoresis for the determination of pharmaceutical and personal care products. These strategies are based on electrophoretic and chromatographic preconcentration techniques, and the use of mass spectrometry as a detection system. The electrophoretic preconcentration techniques studied included sample stacking techniques and sweeping while the chromatographic preconcentration technique evaluated was in-line coupling between solid phase extraction and capillary electrophoresis. With respect to PPCPs, this Doctoral Thesis focuses specifically on non-steroidal anti-inflammatory drugs (NSAIDs), parabens and UV-filters. Another objective of this Doctoral Thesis is to study the suitability of the developed methodologies for the determination of PPCPs in environmental samples.

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Eliška Holinská Supervisor: Prof. MUDr. Radomír Hrdina, CSc. Title of diploma thesis: Pharmacoteraphy of headache in adults Headache is one of the most common health problem that encounters almost everyone during the life. Depending on the cause, headaches can be divided on the primary headaches, which are the subject of the diploma thesis, and secondary headaches, which are caused by other diseases. The primary headaches are migraine, tension-type headache, cluster headache and primary chronic daily headache. Headache is not a life-threating condition but it can significantly reduce the quality of life, particularly the chronic forms of headache. The determination of the right diagnosis is essential for the choice of appropriate therapy. For primary headache are typical negative test results, there are no structural lesions or signs of organic brain damage. Diagnostics is comlicated and it is primarily based on a carefully processed medical history. In the therapy of primary headache are used both pharmacological and non-pharmacological methods, optimaly in combination. Pharmacological treatment consists of preventive and acute therapy. The preventive treatment is given to reduce the...