866 research outputs found
A Role for Proapoptotic BID in the DNA-Damage Response
SummaryThe BCL-2 family of apoptotic proteins encompasses key regulators proximal to irreversible cell damage. The BH3-only members of this family act as sentinels, interconnecting specific death signals to the core apoptotic pathway. Our previous data demonstrated a role for BH3-only BID in maintaining myeloid homeostasis and suppressing leukemogenesis. In the absence of Bid, mice accumulate chromosomal aberrations and develop a fatal myeloproliferative disorder resembling chronic myelomonocytic leukemia. Here, we describe a role for BID in preserving genomic integrity that places BID at an early point in the path to determine the fate of a cell. We show that BID plays an unexpected role in the intra-S phase checkpoint downstream of DNA damage distinct from its proapoptotic function. We further demonstrate that this role is mediated through BID phosphorylation by the DNA-damage kinase ATM. These results establish a link between proapoptotic Bid and the DNA-damage response
Growth- and tumor-promoting effects of deregulated BCL2 in human B-lymphoblastoid cells.
Razvoj i optimizacija sustava za isporuku metoprolol sukcinata sa zadržavanjem u želucu
Metoprolol succinate (MS) gastroretentive (GR) controlled release system was formulated to increase gastric residence time leading to improved drug bioavailability. Box-Behnken model was followed using novel combinations of sodium alginate (SA), sodium carboxymethylcellulose (NaCMC), magnesium alumino metasilicate (MAS) as independent variables. Floating lag time (Flag), t25, t50, t75, diffusion exponent as dependent variables revealed that the amount of SA, NaCMC and MAS have a significant effect (p < 0.05) on t25, t50, t75 and Flag. MSGR tablets were prepared and evaluated for mass, thickness, hardness, friability, drug content and floating property. Tablets were studied for dissolution for 24 h and exhibited controlled release of MS with floating for 16 h. The release profile of the optimized batch MS01 fitted first-order kinetics (R2 = 0.9868, n = 0.543), indicating non-Fickian diffusion or anomalous transport by diffusion and swelling.U radu je opisan razvoj sustava za isporuku metoprolol sukcinata (MS) s kontroliranim oslobađanjem i produljenim vremenom zadržavanja u želucu (GR), u svrhu poboljšanja bioraspoloživosti. Primijenjen je Box-Behnkenov model, a kao zavisne varijable izabrane su nove kombinacije natrijevog alginata (SA), natrijeve soli karboksimetilceluloze (NaCMC) i magnezijevog aluminometasilikata (MAS). Vrijeme plutanja (Flag), t25, t50, t75 i difuzijski eksponent kao zavisne varijable otkrili su da količina SA, NaCMC i MAS ima značajan učinak (p < 0,05) na t25, t50, t75 i Flag. Pripravljenim tabletama određena je masa, debljina, tvrdoća, lomljivost, sadržaj ljekovite tvari i sposobnost plutanja. Oslobađanje MS praćeno je 24 h. Rezultati pokazuju da je oslobađanje kontrolirano, a vrijeme plutanja 16 h. Oslobađanje iz optimiranog pripravka MS01 slijedi kinetiku prvog reda (R2 = 0,9868, n = 0,543), što ukazuje na difuziju koja ne slijedi Fickov zakon već anomalni transport difuzijom i bubrenjem
bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis
Inactivation of p53-dependent apoptosis promotes oncogenic transformation, tumor development, and resistance to many cytotoxic anticancer agents. p53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis. To determine whether bax is required for p53-dependent apoptosis, the effects of bax deficiency were examined in primary fibroblasts expressing the E1A oncogene, a setting where apoptosis is dependent on endogenous p53. We demonstrate that bax can function as an effector of p53 in chemotherapy-induced apoptosis and contributes to a p53 pathway to suppress oncogenic transformation. Furthermore, we show that additional p53 effectors participate in these processes. These p53-controlled factors act synergistically with Bax to promote a full apoptotic response, and their action is suppressed by the Bcl-2 and E1B 19K oncoproteins. These studies demonstrate that Bax is a determinant of p53-dependent chemosensitivity and illustrate how p53 can promote apoptosis by coordinating the activities of multiple effectors
Polimerne mješavine obložene Eudragitom: Potencijalni sustav za kontroliranu peroralnu isporuku teofilina
Sustained release (SR) dosage forms enable prolonged and continuous deposition of the drug in the gastrointestinal (GI) tract and improve the bioavailability of medications characterized by a narrow absorption window. In this study, a new strategy is proposed for the development of SR dosage forms for theophylline (TPH). Design of the delivery system was based on a sustained release formulation, with a modified coating technique and swelling features aimed to extend the release time of the drug. Different polymers, such as Carbopol 71G (CP), sodium carboxymethylcellulose (SCMC), ethylcellulose (EC) and their combinations were tried. Prepared matrix tablets were coated with a 5 % (m/m) dispersion of Eudragit (EUD) in order to get the desired sustained release profile over a period of 24 h. Various formulations were evaluated for drug concentration and in vitro drug release. It was found that the in vitro drug release rate decreased with increasing the amount of polymer. Coating with EUD resulted in a significant lag phase in the first two hours of dissolution in the acidic pH of simulated gastric fluid (SGF) due to decreased water uptake, and hence decreased driving force for drug release. Release became faster in the alkaline pH of simulated intestinal fluid (SIF) owing to increased solubility of both the coating and matrixing agents. The optimized formulation was subjected to in vivo studies in rabbits and the pharmacokinetic parameters of developed formulations were compared with the commercial (Asmanyl®) formulation. Asmanyl® tablets showed faster absorption (tmax 4.0 h) compared to the TPH formulation, showing a tmax value of 8.0 h. The cmax and AUC values of TPH formulation were significantly (p < 0.05) higher than those for Asmanyl®, revealing relative bioavailability of about 136.93 %. Our study demonstrated the potential usefulness of eudraginated polymers for the oral delivery of the sparingly soluble drug theophylline.Pripravci za produljeno oslobađanje (SR) omogućavaju produljeno i kontinuirano oslobađanje lijeka u gastrointestinalnom (GI) traktu i poboljšavaju bioraspoloživost lijekova s uskim apsorpcijskim prozorom. U radu se predlaže nova strategija za razvoj formulacija s produljenim oslobađanjem teofilina (TPH), koja se temelji na sustavu za produljeno oslobađanje, kojem je u svrhu produljenja vremena oslobađanja modificiran način oblaganja i bubrenja. Korišteni su različiti polimeri, kao što su Carbopol 71G (CP), natrijeva karboksimetilceluloza (SCMC), etilceluloza (EC) i njihove kombinacije. Pripravljene matriks tablete obložene su 5-postotnom (m/m) disperzijom Eudragita (EUD) kako bi se postiglo produljeno oslobađanje tijekom 24 h. U pripravljenim formulacijama određena je koncentracija lijeka i in vitro oslobađanje. Rezultati pokazuju da se povećanjem udjela polimera smanjuje brzina oslobađanja in vitro. Oblaganje s EUD značajno je produljilo lag fazu tijekom prva 2 sata otapanja u kiselom pH simuliranog želučanog soka (SGF). Naime, oblaganje usporava ulazak vode i tako smanjuje pogonsku silu za oslobađanje lijeka. Zbog povećane topljivosti obložnog sloja i matriksa u lužnatom mediju, oslobađanje u simuliranoj intestinalnoj tekućini (SIF) je brže. Optimizirana formulacija ispitana je in vivo na zečevima. Farmakokinetički parametri novih formulacija uspoređivani su s komercijalnim pripravkom Asmanyl®. Asmanyl® tablete pokazuju bržu apsorpciju (tmax 4,0 h) u odnosu na TPH formulaciju (tmax 8,0 h). cmax i AUC vrijednosti TPH formulacije bile su značajno (p < 0,05) više od onih za Asmanyl®, što ukazuje na relativnu bioraspoloživost od oko 136,93 %. Stoga smatramo da su polimeri obloženi eudragitom potencijalno korisni za oralnu upotrebu teško topljivog lijeka teofilina
Free Boundary Problems in Controlled Release Pharmaceuticals. I: Diffusion in Glassy Polymers
Priprava, in vitro i in vivo evaluacija bioadhezivnih mikrosfera s algino-pektinom: ispitivanje utjecaja polimera pomoću multiple poredbene analize
Ionotropic gelation was used to entrap aceclofenac into algino-pectinate bioadhesive microspheres as a potential drug carrier for the oral delivery of this anti-inflammatory drug. Microspheres were investigated in vitro for possible sustained drug release and their use in vivo as a gastroprotective system for aceclofenac. Polymer concentration and polymer/drug ratio were analyzed for their influence on microsphere properties. The microspheres exhibited good bioadhesive property and showed high drug entrapment efficiency. Drug release profiles exhibited faster release of aceclofenac from alginate microspheres whereas algino-pectinate microspheres showed prolonged release. Dunett\u27s multiple comparison analyis suggested a significant difference in percent inhibition of paw edema when the optimized formulation was compared to pure drug. It was concluded that the algino-pectinate bioadhesive formulations exhibit promising properties of a sustained release form for aceclofenac and that they provide distinct tissue protection in the stomach.U radu je opisana priprava algino-pektinskih bioadhezivnih mikrosfera protuupalnog lijeka aceklofenaka metodom ionotropnog geliranja. In vitro je ispitivana mogućnost postupnog oslobađanja ljekovite tvari iz mikrosfera te mogućnost upotrebe mikrosfera kao gastroprotektivnog sustava za isporuku aceklofenaka in vivo. Ispitivan je utjecaj koncentracije polimera i omjera polimera i lijeka na svojstva mikrosfera. Mikrosfere su bile bioahezivne i sadržavale su veliki udio lijeka. Oslobađanje aceklofenaka iz alginatnih mikrosfera bilo je brže, a iz mikrosfera s algino-pektinom usporeno. Dunnetova multipla analiza ukazuje na značajnu razliku u postotku inhibicije edema šape kada se usporede optimizirana formulacija i čista ljekovita tvar. Može se zaključiti da su bioadhezivne mikrosfere s algino-pektinom povoljne za usporeno oslobađanje aceklofenaka te da pružaju umjerenu zaštitu sluznice želuca
Učinak formulacijskih parametara na oslobađanje lijeka i svojstva dvoslojnih tableta koje plutaju u želucu
Floating dosage forms of acetylsalicylic acid, used for its antithrombotic effect, were developed to prolong gastric residence time and increase bioavailability. In the two-layer tablet formulation, hydroxypropyl methylcellulose (HPMC) of high viscosity and an effervescent mixture of citric acid and sodium bicarbonate formed the floating layer. The release layer contained the drug, direct tableting agent and different types of matrix-forming polymers such as HPMC of low viscosity, sodium carboxymethylcellulose and chitosan. Tablets were prepared using a direct compression technique. The effect of formulation variables on physicochemical and floating properties and the drug release from tablets were investigated. Floating ability was dependent on the amount of effervescent agent and gel-forming polymer of the floating layer. Drug release was prolonged to 8 hours by changing the type and viscosity of the matrix-forming polymer in the drug-loading layer and all formulations showed a diffusion release mechanism.U radu su opisane plutajuće tablete acetilsalicilne kiseline za antikoagulacijsku upotrebu s produljenim zadržavanjem u želucu i većom bioraspoloživošću. Plutajući dio tih dvoslojnih tableta sadržavao je hidroksipropil metilcelulozu (HPMC) visoke viskoznosti i efervescentnu smjesu limunske kiseline i natrijevog hidrogenkarbonata. Drugi sloj sadržavao je ljekovitu tvar, sredstvo za izravno tabletiranje i različite vrste matriksnog polimera poput HPMC niske viskoznosti, natrij-karboksimetilceluloze i kitozana. Tablete su pripravljene metodom izravne kompresije. Ispitivan je utjecaj formulacijskih varijabli na fizikokemijska i plutajuća svojstva, te oslobađanje ljekovite tvari. Plutajuća svojstva ovise o količini efervescentnih tvari i gelirajućeg polimera u plutajućem sloju. Promjenom vrste i viskoznosti polimera u matriksnom sloju s lijekom produljeno je oslobađanje ljekovite tvari na 8 sati. Iz svih formulacija ljekovita tvar oslobađala se difuzijom
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