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Adverse events of biologic therapy in psoriasis
Marques, Emanuel Carvalheiro ; Paluch, Zoltán (advisor) ; Kančeva, Radmila (referee) ; Farghali, Hassan (referee)
1 Adverse events of biologic therapy in psoriasis Abstract This doctoral thesis focuses on psoriasis vulgaris and its therapy, especially biologic agents and their safety profiles. The objectives of this research were to identify prognostic factors of severe psoriasis, compare the safety profiles of different therapy types (topical compounds, non-biologic systemic agents and biologic agents) and those of biologic agents themselves (adalimumab, etarnecept, infliximab, secukinumab, ustekinumab). A total of 289 psoriatic patients were followed up for 30 months; these were divided into 3 groups according to therapy type. Comorbidities, epidemiological parameters, and rates of adverse events were compared between the three groups and, also, between each of the 5 biologic agents, and the data were statistically analysed. It was concluded that psoriasis severity is directly related to an increased risk of cardiovascular disease, depression, hyperuricemia, and nonspecific noninfectious liver disease. Male gender, increased height, early age at disease onset, viral upper respiratory infections and periods of hormonal changes seem to be prognostic of higher levels of psoriasis severity. When comparing therapy types, biologic agents were the most effective therapies; however, they were associated with higher rates of...
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Expression of cytokines, particularly chemokines, after application of acyclic nucleoside phosphonates
Potměšil, Petr ; Zídek, Zdeněk (advisor) ; Otová, Berta (referee) ; Farghali, Hassan (referee)
Acyclic nucleoside phosphonates (ANPs) are novel class of virostatics, that inhibit replication of both DNA viruses and retroviruses. ANP approved for the treatment of viral diseases are: tenofovir (Viread®) for the therapy of AIDS, adefovir (Hepsera®) for the treatment of hepatitis B and cidofovir (Vistide®), that is used in HIV-1 positive patients suffering from retinitis caused by cytomegalovirus [23, 24]. Some ANPs, such as tenofovir, are endowed by immunomodulatory properties that can non specifically influence replication of viruses. Tenofovir has been shown previously to increase gene expression of nitric oxide, cytokines TNF- , IL-10 and chemokines RANTES, MIP-1 [6, 22, 30]. In present experiments we investigated possible immunobiological properties of newly synthesized derivatives of ANPs in vitro using mouse macrophages and lymphocytes (or human leukocytes, respectively). N6-substituted derivatives of adenine or 2,6-diaminopurine, that possess phosphonomethoxyethyl or phosphonomethoxypropyl moiety at the position N9 of the heterocyclic base were included in the study. Some of these compounds were found to activate production of nitric oxide, cytokines TNF- , IL-10 and chemokines RANTES, MIP- 1 [21]. Various hydroxylated derivatives of ANPs were also screened for their immunobiological potential....
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Some aspects of molecular mechanisms of xenobiotics' hepatotoxicity and hepatoprotection : Modulatory roles of natural polyphenols
Lekic, Nataša ; Farghali, Hassan (advisor) ; Kršiak, Miloslav (referee) ; Brůha, Radan (referee)
Background & Aims: Oxidative stress and apoptosis are proposed mechanisms of cellular injury in studies of xenobiotic hepatotoxicity. The aim of this work is to find early signal markers of drug-induced injury of the liver by focusing on select antioxidant/oxidant and apoptotic genes. As well, to address the relationship between conventional liver dysfunction markers and the measured mRNA and protein expressions in the D-galactosamine/lipopolysaccharide and tert-butylhydroperoxide hepatotoxicity models. Furthermore, potential hepatoprotective capabilities of antioxidant polyphenols quercetin and curcumin were evaluated in relation to its modulation of the oxidative stress and apoptotic parameters in the given xenobiotic hepatotoxicity models. Methods: Biochemical markers testing the hepatic function included aminotransferases (ALT, AST) and bilirubin. Measurements of TBARS and conjugated dienes were used to assess lipoperoxidation. Plasma levels of catalase and reduced glutathione were used as indicators of the oxidative status of the cell. Real time PCR was used to analyse the mRNA expressions of the inducible nitric oxide synthase (NOS-2), heme oxygenase-1 (HO-1), superoxide dismutase (SOD-1), glutathione peroxidase (Gpx-1), caspase 3 (Casp3), BH3 interacting domain death agonist (Bid) and Bcl-2...
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Possibilities to potentiate effect of non-opioid analgesics
Janovský, Martin ; Kršiak, Miloslav (advisor) ; Farghali, Hassan (referee) ; Kozák, Jiří (referee)
The aim of the present Thesis was to investigate the possibility of the improvement of analgesic efficacy of novel non-opioid analgesics selectively or preferentially inhibiting COX-2, coxibs and meloxicam, by combinations with other substancies. These analgesics have favourable profile of gastrointestinal tolerability. For this purpose, a few different approaches were used. Based on the published data, two members of the cyclooxygenase-2 inhibitors group were selected, etoricoxib and celecoxib, and their interactions with the weak opioid codeine were assayed. Analgesic efficacy of the individual drugs and their combinations was evaluated using the preclinical model of acute visceral pain (the writhing test), in mice, and the statistical method of isobolographic analysis was used to investigate the manner of interactions. Subsequently, the interactions of paracetamol and ibuprofen with codeine were also assayed using the same methods. The interaction between celecoxib and codeine was found to be additive, while that between etoricoxib and codeine was sub-additive. On the other hand, the interactions of paracetamol and ibuprofen with codeine were synergistic. In the second part of the Thesis, the potential improvement of the pharmacological properties of meloxicam was evaluated after its complexation with...
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The effect of analgesics and their combination with neurotropic drugs on pain and brain mediators
Soukupová, Marie ; Kršiak, Miloslav (advisor) ; Farghali, Hassan (referee) ; Rokyta, Richard (referee)
The first aim was to investigate changes in analgesic efficacy of several analgesics in combination with selected drugs affecting nervous system after systemic administration. The second aim was to ascertain changes of levels of pain mediators in vivo in supraspinal brain structures (in periaqueductal gray matter, central amygdala, striatum) in pain and under the drug influence. The analgesic efficacy of combinations of analgesics with neurotropic drugs was investigated in the writhing test in mice. Interactions between analgesics and neurotropic drugs were evaluated by the isobolographic analysis, which enables to distinguish the supra-additive (synergistic) interactions from solely additive and sub-additive ones. A possible negative effect of neurotropic drugs on motor functions was determined in the rota-rod test in mice. Changes of levels of pain mediators in the brain during pain and under the drug influence in rats were measured by microdialysis in vivo coupled with a high performance liquid chromatography. A model of inflammatory pain induced by intraplantar injection of carrageenan and a model of neuropathic pain produced by a spared sciatic nerve injury model were used in rats. We evaluated pain in plantar and von Frey filament test. Our microdialysis experiments revealed that inflammatory pain...
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Pharmacological modifications of potential signal systems regulating metabolism of adipocytes and hepatocytes and their influence on obesity
Hodis, Jiří ; Farghali, Hassan (advisor) ; Kršiak, Miloslav (referee) ; Otová, Berta (referee)
v anglickém jazyce: Thesis abstract: Background and aims: Both obesity and metabolic syndrome form severe health problems in the whole world. Nevertheless the armament of pharmacotherapy for both diseases remains unsatisfactory. We aimed our work to main organs in risk of the mentioned diseases -liver and visceral fat using hepatocytes and visceral adipocytes as model. We detected 3 main metabolic and signalization activities- glycogenolysis, Nitric oxide (NO) production and transcription of inducible NO synthase (iNOS) in hepatocytes, lipolysis, NO production and iNOS transcription rate in adipocytes. We directed our interest to combination of peroxisome proliferation activator receptor γ (PPARγ) agonist, antagonist and β3 adrenergic agonist in the culture of epididymal rat adipocytes in the first part of our work. While in the second part we investigated the influence of β and α adrenergic mimetics, adrenergic blockers in the culture of rat high glycogen content hepatocytes. Methods: NO production was detected under the active agents treatments by detection of NO oxidative products NO2 and NO3 in media. Glycogenolysis was measured as free glucose rise released by hepatocytes into the media. NOS transcription level was extrapolated after comparative polymerase chain reaction with reverse...
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Protein and amino acid metabolism in protein catabolic states - effect of leucine metabolites
Kovařík, Miroslav ; Holeček, Milan (advisor) ; Farghali, Hassan (referee) ; Hlúbik, Pavol (referee)
Protein catabolism and muscle wasting are basic features characterizing the complex metabolic syndrome, called cachexia, which is a severe complication of many diseases, in whose pathogenesis are often participant the systemic inflammatory response and endotoxemia. Branched-chain amino acids (leucine, isoleucine and valine) are not only an important substrate for protein synthesis, but they are also involved in the regulation of protein metabolism, insulin synthesis and secretion, and serve as the source of amino group in the alanine and glutamine formation in the muscle. Not only leucine but also some of its metabolites, - ketoisocaproic acid (KIC) and -hydroxy--methylbutyrate (HMB), have protein anabolic activity and thus some of leucine effects could be induced by these metabolites. In the last years there is paid attention to the HMB, which is used as a supplement for athletes and tested for its potential use in cachexia treatment. The aim of our experiments was to study: 1) endotoxin-induced effect on metabolism of proteins and amino acids in different types of skeletal muscle and the dose dependence of these changes; 2) effects of selected leucine metabolites (KIC and HMB) on the metabolism of proteins and amino acids - in different types of skeletal muscle; under in vivo and in vitro...
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Antiproliferative effects of heme catabolic pathway's products
Koníčková, Renata ; Vítek, Libor (advisor) ; Haluzík, Martin (referee) ; Farghali, Hassan (referee)
Presented work is focused on heme metabolism with the main interest in bile pigments. Recent data indicate that bilirubin is not only a waste product of the heme catabolic pathway, but also emphasize its important biological impacts, including possible antiproliferative effects. Until today metabolism of bilirubin has not been completely elucidated, which has prevented detailed evaluation of its potential anticancer action. The aim of this study was to clarify some aspects of heme catabolism with respect for antiproliferative properties of its products. Based on the fact that bilirubin potently affects carcinogenesis of the intestine, we initially investigated not properly known bilirubin metabolism by intestinal bacteria. We studied bilirubin neurotoxic effects in hyperbilirubinemic Gunn rats - its distribution in the brain tissue and its degradation during pathological conditions, such as severe newborn jaundice or Crigler-Najjar syndrome. Possible approaches to improve the treatment of severe unconjugated hyperbilirubinemias, combination of the phototherapy and human albumin administration were also investigated. The main reason of these studies was the fact that mechanisms of neurotoxic effects of bilirubin are predominantly identical with those, by which bilirubin inhibits cancer cells growth....
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The biological role of the metabolic products of haem and bilirubin.
Jašprová, Jana ; Vítek, Libor (advisor) ; Farghali, Hassan (referee) ; Mičuda, Stanislav (referee)
Present work has been focused on the importance of the products of the heme catabolic pathway, in particular under conditions of unconjugated hyperbilirubinemias (neonatal jaundice and Crigler-Najjar syndrome (CNS)). The second part of the project was focused on the improvement of some pharmacological approaches used in the treatment of these diseases, as well as on studies of bilirubin products that are formed during the treatment by phototherapy (PT). Neonatal jaundice is one of the most common complications in neonates. Currently, there is no efficient pharmacotherapy and the treatment with blue light is used as a gold standard for severe neonatal jaundice. However, the absolute safety of PT has still not been confirmed. In this context, it is important to note that some neonatologists start the PT before serum bilirubin levels reach the recommended values and that patients with CNS type I (CNSI) are forced to be on life-long PT (unless undergoing liver transplantation). The focus of the present project was to study biological effects of bilirubin photoisomers (PI) in an in vitro model of the human neuroblastoma SH-SY5Y cells that are used for studies of the neuronal metabolism. In further studies performed on animal model of hyperbilirubinemic rats and mice, we investigated a suitable gene...
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