Comparative Investigation on in vitro release of extemporaneously prepared norfloxacin semisolid formulations with marketed silver sulfadiazine 1% cream, USP using model independent approach

Objective In an attempt for better treatment of bacterial infections, various semisolid formulations containing 5% w/w of norfloxacin were prepared and evaluated for in vitro drug release and in vitro skin permeability using dialysis membrane and rat abdominal skin respectively. The in vitro diffusion and permeation profile of the prepared formulation was compared with marketed silver sulfadiazine cream 1%, USP using model independent approach. Methods Various semisolid formulations were prepared with different dermatological bases using standard procedures. In vitro diffusion and permeation studies were carried out using Keshary-Chein (KC) type diffusion cell using dialysis membrane and rat abdominal skin respectively. Results The f1 lower than 15 and f2 higher than 50 indicated similarities in the in vitro diffusion and permeation profiles of the extemporaneously prepared selected semisolid formulations and marketed silver sulfadiazine 1% cream, USP. Conclusion Amongst all the semisolid formulations prepared, carbopol gel base was found to be most suitable dermatological base for norfloxacin, the results obtained for in vitro diffusion, and in vitro skin permeation studies are comparable with that of marketed silver sulphadiazine 1% cream, USP

Dozirani pripravci aceklofenaka za topičku primjenu: In vitro i in vivo karakterizacija

Aceclofenac is a new generation non-steroidal anti-inflammatory drug showing effective anti-inflammatory and analgesic properties. It is available in the form of tablets of 100 mg. Importance of aceclofenac as a NSAID has inspired development of topical dosage forms. This mode of administration may help avoid typical side effects associated with oral administration of NSAIDs, which have led to its withdrawal. Furthermore, aceclofenac topical dosage forms can be used as a supplement to oral therapy for better treatment of conditions such as arthritis. Ointments, creams, and gels containing 1 % m/m aceclofenac have been prepared. They were tested for physical appearance, pH, spreadability, extrudability, drug content uniformity, in vitro diffusion and in vitro permeation. Gels prepared using Carbopol 940 (AF2, AF3) and macrogol bases (AF7) were selected after the analysis of the results. They were evaluated for acute skin irritancy, anti-inflammatory and analgesic effects using the carrageenan-induced thermal hyperalgesia and paw edema method. AF2 was shown to be significantly (p < 0.05) more effective in inhibiting hyperalgesia associated with inflammation, compared to AF3 and AF7. Hence, AF2 may be suggested as an alternative to oral preparations.Aceklofenak je lijek nove generacije nesteroidnih protuupalnih lijekova sa izraženim protuupalnim i analgetskim djelovanjem. Dostupan je u obliku tableta od 100 mg. U ovom radu razvijeni su dozirani pripravci za topičku primjenu u svrhu smanjenja ili uklanjanja nuspojava povezanih s oralnom primjenom nesteroidnih protuupalnih lijekova. Ti pripravci mogu se upotrijebiti kao dodatak peroralnoj terapiji artritisa i srodnih bolesti. Opisana je priprava mazila, krema i gela s 1 % m/m aceklofenaka te njihova fizička svojstva, pH, mazivost, istiskivost, jednolikost sadržaja ljekovite tvari, difuzija i permeabilnost in vitro. Nakon analize rezultata za daljnja ispitivanja odabrani su gelovi pripravljeni na bazi Carbopola 940 (AF2, AF3) i makrogola (AF7). Ispitana je akutna iritacija kože, protuupalno i analgetsko djelovanje koristeći karagenom induciranu termičku hiperalgeziju i edem šape. Pripravak AF2 bio je značajno (p < 0,05) učinkovitiji u inhibiciji hiperalgezije s upalom nego pripravci AF3 i AF7. Stoga se AF2 može predložiti kao alternativa peroralnim pripravcima

Preparation, Characterization and In Vitro Evaluation of Aceclofenac Solid Dispersions

The objective of the present investigation was to study the effect of various water soluble carriers like urea, mannitol, PVP and PVP/VA-64 on in vitro dissolution of aceclofenac from solid dispersions. Aceclofenac binary solid dispersions (SD) with different drug loadings were prepared using the melting or fusion method. In vitro dissolution of pure drug, physical mixtures and solid dispersions were carried out. Solid dispersion of aceclofenac with all four carriers (urea, mannitol, PVP and PVP/VA-64) showed considerable increase in the dissolution rate in comparison with physical mixture and pure drug in 0.1 N HCl, pH1.2 and phosphate buffer, pH, 7.4. Solid dispersions containing PVP showed maximum dissolution rate in comparison to formulation containing urea, mannitol and PVP/VA-64. Amorphous nature of the drug in solid dispersion was confirmed by scanning electron microscopy and a decrease in enthalpy of drug melting in solid dispersion compared to the pure drug. FT-IR spectroscopy and differential scanning calorimetry studies indicated no interaction between aceclofenac and carriers in solid dispersions in solid state. Dissolution enhancement was attributed to decreased crystallinity of the drug and to the wetting, eutectic formation and solubilizing effect of the carrier from the solid dispersions of aceclofenac. In conclusion, dissolution of aceclofenac can be enhanced by the use of various hydrophilic carriers like urea, mannitol, PVP and PVP/VA-64

Expression von Parathormone-related Peptide in koronaren Endothelzellen und der glatten Gefäßmuskulatur

Das Parathormon related peptide (PTHrP) wird im gesamten Gefäßsystem einschließlich der koronaren Endothelzellen exprimiert. Im Gegensatz zu den benachbarten Glattmuskelzellen, welche bislang hinsichtlich PTHrP eingehend untersucht wurden, hat man die koronaren Endothelzellen nur als Produktionsstätte des Ventrikels angesehen. Aus diesem Grund blieben bisher die PTHrP-Expression und seine biologische Rolle in diesen Zellen ungeklärt. Deshalb habe ich mich dafür interessiert, ob eine Stimulation a-adrenerger bzw. AT-Rezeptoren die Expression in den koronaren Endothelzellen steigert und ob das endogen exprimierte PTHrP einen sogenannten intrakrinen Effekt in diesem Zelltyp ausübt. Besonders interessant ist diese Fragestellung vor dem Hintergrund, daß diese Zellen keine klassischen Zielzellen des Peptidhormones darstellen, da sie nicht den korrespondierenden PTHrP-Rezeptor besitzen, wie das z. B. bei den Glattmuskelzellen der Fall ist. Was anhand der Ergebnisse gezeigt werden konnte ist die Tatsache, daß durch Stimulation der Zellen mit der a-adrenergen Substanz Phenylephrin im Vergleich zur Stimulation mit Angiotensin II, eine deutliche Steigerung in der Expression des PTHrP hervorgerufen werden konnte. Dieser Effekt konnte jedoch nicht im Stadium der Konfluenz reproduziert werden. Im Gegensatz dazu erhielten wir in den Glattmuskelzellen ein genau umgekehrtes Bild, da hier nur Angiotensin II eine signifikante Expressionssteigerung hervorrief. Deshalb wollte ich mehr über die Lokalisation des endogenen PTHrP in den verschiedenen Proliferationsstadien mit Hilfe der Immunfluoreszenz in Erfahrung bringen. Die Ergebnisse zeigten, daß der Anteil an PTHrP, welcher in den Kern transloziert wird, umso größer ist, je mehr sich die Zellen dem Konfluenzstadium nähern. Diese Tatsache war für mich Anlaß zu vermuten, daß das Peptidhormon einen intrakrinen Effekt auf die koronaren Endothelzellen ausübt. Mit Hilfe der Transfektion der Zellen mit Antisense-Oligonukleotiden gegen PTHrP und der daraus sich ergebenden Herabregulierung seiner Expression untersuchte ich seinen möglichen Einfluß auf die Proliferation bzw. Apoptose. Im Bezug auf die Proliferation ergaben sich keine Hinweise auf eine Beeinflussung. Bei der Betrachtung der Endothelzellen in den unterschiedlichen Konfluenzstadien konnte mit Hilfe einer UV-Bestrahlung in Zellen, in denen der Anteil des nukleären PTHrP normalerweise erhöht wäre, eine stärkere Apoptoserate als unter Basalbedingungen hervorgerufen werden. Im Gegensatz dazu wurde durch eine erhöhte Expression des PTHrP - welche durch Phenylephrin vermittelte wurde -der Anteil der apoptotischen Zellen sowohl gegenüber Basalbedingungen als auch unter UV-Induktion deutlich vermindert. Zusammenfassend läßt sich anhand der Ergebnisse der vorliegenden Studie sagen, daß in koronaren Endothelzellen die PTHrP-Expression durch eine a-Adrenozeptor-Stimulation in einer Zellzyklus-abhängigen und Zelltyp-spezifischen Art und Weise reguliert wird. Diese Studie zeigt eine neue biologische Rolle des PTHrP im Gefäßbett auf, da über den nachgewiesenen intrakrinen Effekt das Peptidhormon einen Anteil am Schutzmechanismus der Endothelschicht vor Apoptose besitzt.Parathyroid hormone related peptide (PTHrP) is expressed throughout the vascular system including coronary endothelial cells. The regulation of endothelial PTHrP expression and the role of PTHrP expression in endothelial cells is not clear. The present study investigates the question whether stimulation of a-adrenergic or angiotensin II receptors increases endothelial expression of PTHrP and whether endogenously expressed PTHrP exerts intracrine effects in coronary endothelial cells. It was found that stimulation of alpha1A-adrenoceptors, but not that of angiotensin II, increases cellular expression of PTHrP in growing, but not in growth arrested, coronary endothelial cells. Angiotensin II increases the expression of PTHrP in smooth muscle cells, but not in endothelial cells. PTHrP enters the nucleus of endothelial cells at the stadium of confluence. This suggests an intracrine effect of PTHrP. It was further investigated whether downregulation of endogenous PTHrP expression by transfection with antisense oligonucleotides alters cell proliferation or apoptosis resistance in growing or non-growing endothelial cells. Downregulation of PTHrP did not modify cell proliferation but increased the amount of UV-induced apoptosis. An increased expression of PTHrP in cells pre-treated with an a-adrenoceptor agonist reduced basal rate of apoptosis and improved resistance against UV-induced apoptosis. These results indicate a novel intracrine effect of PTHrP in coronary endothelial cells that improves cell survival. In endothelial cells, the expression of PTHrP is regulated by alpha-adrenoceptor stimulation in a cell-cycle dependent and cell-type specific manner

Development of a novel HPTLC fingerprint method for simultaneous estimation of berberine and rutin in medicinal plants and their pharmaceutical preparations followed by its application in antioxidant assay

The present study was designed to develop and validate a high-performance thin-layer chromatography (HPTLC) system for the simultaneous quantitative determination of berberine and rutin in Tinospora cordifolia extract and their pharmaceutical preparations. Chromatographic development was done using a blend of n-hexane, ethyl acetate, glacial acetic acid and methanol (10:1.1:1.1:2.5, v/v) as the mobile phase. Detection was completed densitometrically at 254 nm. The RF estimation of berberine and rutin was observed to be 0.67 ± 0.02 and 0.47 ± 0.02, respectively. The developed HPTLC method was validated according to ICH guidelines; the method was specific, linear and accurate and can be used to determine berberine and rutin in marketed herbal preparations. The Tinospora cordifolia plant extract was further evaluated for antioxidant activity using HPTLC, and berberine was found to be more active than rutin during DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging activity. The method was found simple, rapid, accurate, specific and robust for the analysis of berberine and rutin in crude drug using the same method

The extracellular surface of the GLP-1 receptor is a molecular trigger for biased agonism

Ligand-directed signal bias offers opportunities for sculpting molecular events, with the promise of better, safer therapeutics. Critical to the exploitation of signal bias is an understanding of the molecular events coupling ligand binding to intracellular signaling. Activation of class B G protein-coupled receptors is driven by interaction of the peptide N terminus with the receptor core. To understand how this drives signaling, we have used advanced analytical methods that enable separation of effects on pathway-specific signaling from those that modify agonist affinity and mapped the functional consequence of receptor modification onto three-dimensional models of a receptor-ligand complex. This yields molecular insights into the initiation of receptor activation and the mechanistic basis for biased agonism. Our data reveal that peptide agonists can engage different elements of the receptor extracellular face to achieve effector coupling and biased signaling providing a foundation for rational design of biased agonists

Pharmacological properties of bergapten: mechanistic and therapeutic aspects

Bergapten (BP) or 5-methoxypsoralen (5-MOP) is a furocoumarin compound mainly found in bergamot essential oil but also in other citrus essential oils and grapefruit juice. This compound presents antibacterial, anti-inflammatory, hypolipemic, and anticancer effects and is successfully used as a photosensitizing agent. The present review focuses on the research evidence related to the therapeutic properties of bergapten collected in recent years. Many preclinical and in vitro studies have been evidenced the therapeutic action of BP; however, few clinical trials have been carried out to evaluate its efficacy. These clinical trials with BP are mainly focused on patients suffering from skin disorders such as psoriasis or vitiligo. In these trials, the administration of BP (oral or topical) combined with UV irradiation induces relevant lesion clearance rates. In addition beneficial effects of bergamot extract were also observed in patients with altered serum lipid profiles and in people with nonalcoholic fatty liver. On the contrary, there are no clinical trials that investigate the possible effects on cancer. Although the bioavailability of BP is lower than that of its 8-methoxypsoralen (8-MOP) isomer, it has fewer side effects allowing higher concentrations to be administered. In conclusion, although the use of BP has therapeutic applications on skin disorders as a sensitizing agent and as components of bergamot extract as hypolipemic therapy, more trials are necessary to define the doses and treatment guidelines and its usefulness against other pathologies such as cancer or bacterial infections.info:eu-repo/semantics/publishedVersio

Albumin Nano-Encapsulation of Piceatannol Enhances Its Anticancer Potential in Colon Cancer Via Downregulation of Nuclear p65 and HIF-1 alpha

Piceatannol (PIC) is known to have anticancer activity, which has been attributed to its ability to block the proliferation of cancer cells via suppression of the NF-kB signaling pathway. However, its effect on hypoxia-inducible factor (HIF) is not well known in cancer. In this study, PIC was loaded into bovine serum albumin (BSA) by desolvation method as PIC-BSA nanoparticles (NPs). These PIC-BSA nanoparticles were assessed for in vitro cytotoxicity, migration, invasion, and colony formation studies and levels of p65 and HIF-1α. Our results indicate that PIC-BSA NPs were more effective in downregulating the expression of nuclear p65 and HIF-1α in colon cancer cells as compared to free PIC. We also observed a significant reduction in inflammation induced by chemical colitis in mice by PIC-BSA NPs. Furthermore, a significant reduction in tumor size and number of colon tumors was also observed in the murine model of colitis-associated colorectal cancer, when treated with PIC-BSA NPs as compared to free PIC. The overall results indicate that PIC, when formulated as PIC-BSA NPs, enhances its therpautice potential. Our work could prompt further research in using natural anticancer agents as nanoparticels with possiable human clinical trails. This could lead to the development of a new line of safe and effective therapeutics for cancer patients