Lekoviti preparati u terapiji kardiovaskularnih oboljenja - savremeni farmaceutsko-tehnološki aspekt

Contemporary trends in dosage form development for cardiovascular therapeutics are orientated towards the rationalization and individualization of drug administration with the achievement of good compliance. Therefore, the controlled release dosage forms occupy an important place in the therapy of cardiovascular diseases. In this paper, the survey of commercially available modified release preparations in our country is given, as well as the most commonly employed technologies for development of controlled release dosage forms. Another aspect that is often used in order to attain the flexibility of dosing is divisibility of the scored tablets. The main reasons for tablet divisibility as well as the potential problems and disadvantages are discussed with regards to the literature data and experimental results obtained in a separate study.Savremeni farmaceutsko-tehnološki pristup oblikovanju preparata u terapiji kardiovaskularnih oboljenja vezan je, pre svega, za individualizaciju i racionalizaciju terapije uz obezbeđenje dobre prihvatljivosti od strane pacijenta. U tom smislu, veliki značaj se pridaje razvoju formulacija i primeni peroralnih preparata sa kontrolisanim oslobađanjem aktivne komponente. U radu je dat prikaz najčešće zastupljenih tehnoloških rešenja u formulaciji savremenih, komercijalno dostupnih preparata sa kontrolisanim oslobađanjem, kao i pregled preparata ovog tipa registrovanih u našoj zemlji. Dodatni aspekt koji je često zastupljen u terapiji kardiovaskularnih oboljenja je i obezbeđenje fleksibilnosti doziranja koje se postiže deljenjem komercijalnio dostupnih tableta. Razlozi za deljenje tableta, kao i problemi i poteškoće koje pri tome mogu nastati prodiskutovani su u skladu sa navodima iz literature, kao i rezultatima sopstvenih istraživanja

Autoimunskog miokarditisa primenom pentoksifilina

We designed the present study to provide evidence of the immunomodulatory effects of pentoxifylline (PTX) in experimental autoimmune myocarditis (EAM) in rats. PTX is xantine-derived agent known to inhibit the production of TNF-α and his beneficial effects have been reported in patients with dilated cardiomyopathy. In this study we examined the efficacy of PTX in the treatment of experimental autoimmune myocarditis as a paradigm of the autoimmune mechanisms involved in pathogenesis of dilated cardiomiopathy. Male DA rats immunized with porcine cardiac myosin were treated i.m. with PTX (200 mg/kg/day) over 7 days, begenning either on the day of immunization (early treatment group), or on day 14. postimmunization (late treatment group). Disease course and severity were evaluated by macroscopic score of the heart, heart weight/body weight ratio (Hw/Bw), histological and immunohistochemical analysis of cardiac tisssue. We found in our study that PTX exhibited both preventive and therapeutical effects in EAM.U radu je ispitivan uticaj pentoksifilina (PTX) na razvoj i tok eksperimentalnog autoimunog miokarditisa pacova. Pentoksifilin je derivat ksantina sa inhibitornim efektom na produkciju TNF-α, a klinički je potvrđen i njegov pozitivan učinak u terapiji pacijenata sa dilatacionom kardiomiopatijom. U ispitivanju je testiran imunomodulatorni efekat PTX u tretmanu eksperimentalnog autoimunog miokarditisa koji predstavlja eksperimentalni model za proučavanje autoimunskih mehanizama uključenih u razvoj dilatacione kardiomiopatije. Pacovi DA soja imunizovani srčanim miozinom tretirani su pentoksifilinom u dozi od 200 mg/kg t.m., počev od 0.-6. dana (rani tretman), ili od 14.-20. dana (kasni tretman) u odnosu na termin imunizacije miozinom. Razvoj i intenzitet miokarditisa praćeni su analizom makroskopskih karakteristika srca, indeksa masa srca/telesna masa (Hwt/Bwt), histoloških i imunohistohemijskih analiza miokarda. Dobijeni rezultati su pokazali da PTX ispoljava profilaktičan i terapijski učinak u eksperimentalnom autoimunom miokarditisu

Recent views on cytohistological characteristics and pathogenic mechanisms of atherosclerotic lesions types I, II and III

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Gender modulates development of the metabolic syndrome phenotype in fructose-fed rats

We analyzed the effects of a fructose-rich diet (FRD) to test the assumption that the expression of metabolic syndrome phenotype is different in male and female rats. Two-way ANOVA revealed a significant effect of FRD on feeding behavior and carbohydrate/lipid metabolism. The increased caloric intake in FRD rats of both sexes was followed by a cluster of gender-specific changes typical for the metabolic syndrome. Female rats were characterized by decreased glycemia, increased triglycerides, enlarged visceral adipose tissue and increased absolute mass of liver, without changes in systolic blood pressure and insulin sensitivity. In contrast, male rats developed less disturbances in physical and biochemical characteristics, but blood pressure and insulin sensitivity were impaired by FRD. The results emphasize the detrimental effects of fructose consumption on cardiovascular risk and insulin action in males, whereas females are affected by other metabolic disturbances. These results support the idea of gender-dependent differences in the expression of the metabolic syndrome phenotype.Projekat ministarstva br. 4100

In vitro antitumor actions of extracts from endemic plant Helichrysum zivojinii

Background: The aim of this research was to determine the intensity and mechanisms of the cytotoxic actions of five extracts isolated from the endemic plant species Helichrysum zivojinii Cernjavski & Soska (family Asteraceae) against specific cancer cell lines. In order to evaluate the sensitivity of normal immunocompetent cells implicated in the antitumor immune response, the cytotoxicity of extracts was also tested against healthy peripheral blood mononuclear cells (PBMC). Methods: The aerial parts of the plants were air-dried, powdered, and successively extracted with solvents of increasing polarity to obtain hexane, dichloromethane, ethyl-acetate, n-butanol and methanol extracts. The cytotoxic activities of the extracts against human cervix adenocarcinoma HeLa, human melanoma Fem-x, human myelogenous leukemia K562, human breast adenocarcinoma MDA-MB-361 cells and PBMC were evaluated by the MTT test. The mode of HeLa cell death was investigated by morphological analysis. Changes in the cell cycle of HeLa cells treated with the extracts were analyzed by flow cytometry. The apoptotic mechanisms induced by the tested extracts were determined using specific caspase inhibitors. Results: The investigated Helichrysum zivojinii extracts exerted selective dose-dependent cytotoxic actions against selected cancer cell lines and healthy immunocompetent PBMC stimulated to proliferate, while the cytotoxic actions exerted on unstimulated PBMC were less pronounced. The tested extracts exhibited considerably stronger cytotoxic activities towards HeLa, Fem-x and K562 cells in comparison to resting and stimulated PBMC. It is worth noting that the cytotoxicity of the extracts was weaker against unstimulated PBMC in comparison to stimulated PBMC. Furthermore, each of the five extracts induced apoptosis in HeLa cells, through the activation of both intrinsic and extrinsic signaling pathways. Conclusion: Extracts obtained from the endemic plant Helichrysum zivojinii may represent an important source of novel potential antitumor agents due to their pronounced and selective cytotoxic actions towards malignant cells

Diferencijacija humanih dendritičnih ćelija od monocita in vitro korišćenjem faktora stimulacije granulocitno-makrofagnih kolonija i niske koncentracije interleukina-4

Several laboratories have developed culture systems that allow the generation of large numbers of human dendritic cells (DC) from monocytes using granulocyte-macrophage colony stimulating factor (GM-CSF), and interleukin-4 (IL-4). In this work we provided evidence that GM-CSF (100 ng/ml) in combination with a low concentration of IL-4 (5 ng/ml) was efficient in the generation of immature, non-adherent, monocyte-derived DC as the same concentration of GM-CSF, and ten times higher concentration of IL-4 (50 ng/ml). This conclusion was based on the similar phenotype profile of DC such as the expression of CD1a, CD80, CD86, and HLA-DR, down-regulation of CD14, and the absence of CD83, as well as on their similar allostimulatory activity for T cells. A higher number of cells remained adherent in cultures with lower concentrations of IL-4 than in cultures with higher concentrations of the cytokine. However, most of these adherent cells down-regulated CD14 and stimulated the proliferation of alloreactive T cells. In contrast adherent cells cultivated with GM-CSF alone were predominantly macrophages as judged by the expression of CD14 and the inefficiency to stimulate alloreactive T cells. DC generated in the presence of lower concentrations of IL-4 had higher proapoptotic potential for the Jurkat cell line than DC differentiated with higher concentrations of IL-4, suggesting their stronger cytotoxic, anti-tumor effect.U više laboratorija su uspostavljeni sistemi za kultivaciju velikog broja humanih dendritičnih ćelija (DĆ) od monocita korišćenjem faktora stimulacije granulocitno--makrofagnih kolonija (GM-CSF) i interleukina-4 (IL-4). U ovom radu je pokazano da je kombinacija GM-CSF (100 ng/ml) i mala koncentracija IL-4 (5 ng/ml) podjednako efikasna za dobijanje nezrelih, neadherentnih, DĆ monocitnog porekla kao i kombinacija GM-CSF sa deset puta većom koncentracijom IL-4 (50 ng/ml). Ovaj zaključak izveden je na osnovu sličnog fenotipskog profila DĆ (ispoljavanje CD1a, CD80, CD86 i HLA-DR, smanjenje ekspresije CD14 i odsustva CD83), kao i slične alostimulatorne aktivnosti ovih ćelija za limfocite T. U kulturama sa nižim koncentracijama IL-4 prisutan je bio veći broj adherentnih ćelija nego u kulturama sa većim koncentracijama IL-4. Međutim, većina ovih ćelija je smanjivala ekspresiju CD14 i stimulisala proliferaciju aloreaktivnih limfocita T. Nasuprot njima adherentne ćelije, diferentovane samo u prisustvu GM-CSF, koje su ispoljavale CD14 i nisu imale sposobnost stimulacije aloreakativnih limfocita T pokazivale su karakteristike makrofaga. DĆ obrazovane u prisustvu manjih koncentracija IL-4 imale su veći potencijal za indukciju apoptoze Jurkat ćelijske linije, a time i snažniji citotoksični, antitumorski efekat nego DĆ diferentovane u prisustvu većih koncentracija IL-4

Does oestradiol attenuate the damaging effects of a fructose-rich diet on cardiac Akt/endothelial nitric oxide synthase signalling?

Fructose-rich diets (FRD) cause cardiac insulin resistance manifested by impairment of Akt/endothelial NO synthase (eNOS) signalling. In contrast, oestradiol (E2) activates this signalling pathway in the heart. To study the ability of E2 to revert the detrimental effect of fructose on cardiac Akt/eNOS, female rats were subjected to a FRD and ovariectomy followed with or without E2 replacement. We also analysed the effects of the FRD and E2 on cardiac extracellular signal-regulated kinase (Erk 1/2) signalling related to their role in cardiac hypertrophy development. Expression of Akt, eNOS and Erk 1/2, as well as regulatory phosphorylations of these molecules were determined. The protein expression of cardiac Akt and eNOS was not affected by the diet or E2 treatment. However, the FRD was accompanied by a decrease in Akt phosphorylation at Ser(473) and Thr(308), and eNOS at Ser(1177), while the phosphorylation of eNOS at Thr(495) was increased. E2 replacement in ovariectomised fructose-fed rats caused a reversion of the diet effect on Akt and eNOS serine phosphorylation, but mostly had no effect on threonine phosphorylation of the molecules. The FRD and E2 treatment did not influence Erk 1/2 expression and phosphorylation and heart mass as well. The data show that E2 selectively suppress the negative effects of a FRD on Akt/eNOS signalling and probably point to the different effects of E2 on kinase/phosphatase pathways responsible for phosphorylation/dephosphorylation of Akt and eNOS. Furthermore, the results suggest that the heart of females in the reproductive period is partially protected against the damaging effects of increased fructose intake

Gender modulates development of the metabolic syndrome phenotype in fructose-fed rats

We analyzed the effects of a fructose-rich diet (FRD) to test the assumption that the expression of metabolic syndrome phenotype is different in male and female rats. Two-way ANOVA revealed a significant effect of FRD on feeding behavior and carbohydrate/lipid metabolism. The increased caloric intake in FRD rats of both sexes was followed by a cluster of gender-specific changes typical for the metabolic syndrome. Female rats were characterized by decreased glycemia, increased triglycerides, enlarged visceral adipose tissue and increased absolute mass of liver, without changes in systolic blood pressure and insulin sensitivity. In contrast, male rats developed less disturbances in physical and biochemical characteristics, but blood pressure and insulin sensitivity were impaired by FRD. The results emphasize the detrimental effects of fructose consumption on cardiovascular risk and insulin action in males, whereas females are affected by other metabolic disturbances. These results support the idea of gender-dependent differences in the expression of the metabolic syndrome phenotype.Projekat ministarstva br. 4100