http://www.biomedcentral.com/bmcpharmacol/ The latest research articles published by BMC Pharmacology 2011-12-14T00:00:00Z Background: The transdermal application of substances represents an elegant approach to overcome side effects related to injections or oral treatment. Due to benefits like a constant plasma level, no pain during application and a simple therapeutic regime, the optimization of formulations for transdermal drug delivery has gained interest in the last decades. Ibuprofen is a non-steroidal anti-inflammatory compound which is nowadays often used transdermally. The objective of this work was to conduct a study on the effect of different 5% ibuprofen containing formulations (Ibutop® cream, Ibutop® gel, and ibuprofen solution in phosphate buffered saline) on the in vitro-percutaneous permeation of ibuprofen through skin to emphasise the importance of the formulation on percutaneous permeation and skin reservoir. Methods: The permeation experiments were conducted in Franz-type diffusion cells according to OECD guideline 428 with 2 mg/cm2 ibuprofen formulation on each skin sample. Ibuprofen was analysed in the receptor fluid and extracted skin samples by UV-VIS high-performance liquid-chromatography at 238 nm. The plot of the cumulative amount of ibuprofen permeated versus time was employed to calculate the apparent permeability coefficient, the maximum flux and the lagtime, all of which were statistically analysed by One-way ANOVA. Results: Although ibuprofen permeation out of the gel increases rapidly within the first four hours, the cream produced the highest ibuprofen delivery through the skin within 28 hours, followed by the solution and the gel. A significant shorter lagtime was found after gel treatment compared with the cream and the solution. After 28 hours 59% of the applied ibuprofen was found in the receptor fluid of the cream treated samples, 26% in the solution treated samples and 21% in the samples treated with the gel. Fourfold higher ibuprofen reservoirs were found in the solution and gel treated skin samples compared to the cream treated skin samples. Conclusion: The present study demonstrates the importance of the formulation on transdermal drug delivery of ibuprofen and emphasises the differences of drug storage within the skin due to the formulation. Thus, it is a mistaken assumption that formulations comprising the same drug amount are equivalent regarding skin permeability. http://www.biomedcentral.com/1471-2210/11/12 Jessica Stahl Mareike Wohlert Manfred Kietzmann BMC Pharmacology 2011, null:12 2011-12-14T00:00:00Z doi:10.1186/1471-2210-11-12 /content/figures/1471-2210-11-12-toc.gif BMC Pharmacology 1471-2210 ${item.volume} 12 2011-12-14T00:00:00Z XML Background: When stimulated by small molecular agonists, the A3 adenosine receptor (AR) mediates cardioprotective effects without inducing detrimental hemodynamic side effects. We have examined pharmacologically the protective properties of a multivalent dendrimeric conjugate of a nucleoside as a selective multivalent agonist for the mouse A3AR. Results: A PAMAM dendrimer fully substituted by click chemistry on its peripheral groups with 64 moieties of a nucleoside agonist was shown to be potent and selective in binding to the mouse A3AR and effective in cardioprotection in an isolated mouse heart model of ischemia/reperfusion (I/R) injury. This conjugate MRS5246 and a structurally related model compound MRS5233 displayed binding Ki values of 0.04 and 3.94 nM, respectively, and were potent in in vitro functional assays to inhibit cAMP production. A methanocarba (bicyclo[3.1.0]hexane) ring system in place of ribose maintained a North conformation that is preferred at the A3AR. These analogues also contained a triazole linker along with 5'-N-methyl-carboxamido and 2-alkynyl substitution, previously shown to be associated with species-independent A3AR selectivity. Both MRS5233 and MRS5246 (1 and 10 nM) were effective at increasing functional recovery of isolated mouse hearts after 20 min ischemia followed by 45 min reperfusion. A statistically significant greater improvement in the left ventricular developed pressure (LVDP) by MRS5246 compared to MRS5233 occurred when the hearts were observed throughout reperfusion. Unliganded PAMAM dendrimer alone did not have any effect on functional recovery of isolated perfused mouse hearts. 10 nM MRS5246 did not improve functional recovery after I/R in hearts from A3AR gene "knock-out" (A3KO) mice compared to control, indicating the effects of MRS5246 were A3AR-specific. Conclusions: Covalent conjugation to a versatile drug carrier enhanced the functional potency and selectivity at the mouse A3AR and maintained the cardioprotective properties. Thus, this large molecular weight conjugate is not prevented from extravasation through the coronary microvasculature. http://www.biomedcentral.com/1471-2210/11/11 Tina Wan Dilip Tosh Lili Du Elizabeth Gizewski Kenneth Jacobson John Auchampach BMC Pharmacology 2011, null:11 2011-10-31T00:00:00Z doi:10.1186/1471-2210-11-11 PAMAM conjugate activates adenosine receptor A Polyamidoamine (PAMAM) dendrimer conjugated to 64 moieties of a nucleoside agonist binds to the mouse A3 adenosine receptor with enhanced potency and selectivity, and mediates cardioprotective effects in an isolated heart model of ischemia/reperfusion injury. /content/figures/1471-2210-11-11-toc.gif BMC Pharmacology 1471-2210 ${item.volume} 11 2011-10-31T00:00:00Z XML Background: Under conditions of cardiovascular dysfunction, protease-activated receptor 2 (PAR2) agonists maintain vasodilatation activity, which has been attributed to increased cyclooxygenase-2, nitric oxide synthase and calcium-activated potassium channel (SK3.1) activities. Protease-activated receptor 2 agonist mediated vasodilatation is unknown under conditions of dysfunction caused by angiotensin II. The main purpose of our study was to determine whether PAR2-induced vasodilatation of resistance arteries was attenuated by prolonged angiotensin II treatment in mice. We compared the vasodilatation of resistance-type arteries (mesenteric) from angiotensin II-treated PAR2 wild-type mice (WT) induced by PAR2 agonist 2-furoyl-LIGRLO-amide (2fly) to the responses obtained in controls (saline treatment). We also investigated arterial vasodilatation in angiotensin II-treated PAR2 deficient (PAR2-/-) mice. Results: 2fly-induced relaxations of untreated arteries from angiotensin II-treated WT were not different than saline-treated WT. Treatment of arteries with nitric oxide synthase inhibitor and SK3.1 inhibitor (L-NAME + TRAM-34) blocked 2fly in angiotensin II-treated WT. Protein and mRNA expression of cyclooxygenase-1 and -2 were increased, and cyclooxygenase activity increased the sensitivity of arteries to 2fly in only angiotensin II-treated WT. These protective vasodilatation mechanisms were selective for 2fly compared with acetylcholine- and nitroprusside-induced relaxations which were attenuated by angiotensin II; PAR2-/- were protected against this attenuation of nitroprusside. Conclusions: PAR2-mediated vasodilatation of resistance type arteries is protected against the negative effects of angiotensin II-induced vascular dysfunction in mice. In conditions of endothelial dysfunction, angiotensin II induction of cyclooxygenases increases sensitivity to PAR2 agonist and the preserved vasodilatation mechanism involves activation of SK3.1. http://www.biomedcentral.com/1471-2210/11/10 Elizabeth Chia Satomi Kagota Enoka Wijekoon John McGuire BMC Pharmacology 2011, null:10 2011-09-28T00:00:00Z doi:10.1186/1471-2210-11-10 PAR2 protects against vascular dysfunction Vasodilatation mediated by protease-activated receptor 2 (PAR2) is retained in a mouse model of Angiotensin-II induced hypertension and mesenteric arterial vascular dysfunction, through a mechanism dependent on the calcium-activated potassium channel SK3.1. /content/figures/1471-2210-11-10-toc.gif BMC Pharmacology 1471-2210 ${item.volume} 10 2011-09-28T00:00:00Z XML Background: Trypanosoma brucei (T. brucei) is an infectious agent for which drug development has been largely neglected. We here use a recently developed computer program called AutoGrow to add interacting molecular fragments to S5, a known inhibitor of the validated T. brucei drug target RNA editing ligase 1, in order to improve its predicted binding affinity. Results: The proposed binding modes of the resulting compounds mimic that of ATP, the native substrate, and provide insights into novel protein-ligand interactions that may be exploited in future drug-discovery projects. Conclusions: We are hopeful that these new predicted inhibitors will aid medicinal chemists in developing novel therapeutics to fight human African trypanosomiasis. http://www.biomedcentral.com/1471-2210/11/9 Jacob Durrant J. Andrew McCammon BMC Pharmacology 2011, null:9 2011-08-30T00:00:00Z doi:10.1186/1471-2210-11-9 /content/figures/1471-2210-11-9-toc.gif BMC Pharmacology 1471-2210 ${item.volume} 9 2011-08-30T00:00:00Z XML Background: Since its recent discovery, interleukin-23 has been shown to be involved in the pathogenesis of autoimmune diseases favoring the development of a T cell subset referred to as T helper 17. Glucocorticoids are widely employed in inflammatory and autoimmune diseases as they inhibit pro-inflammatory signaling and prevent production of inflammation mediators. Very limited information is available about the efficacy of synthetic glucocorticoids in containing the expression of interleukin-23 under cell activation. Results: We demonstrate here that the glucocorticoid analogue dexamethasone administered to human monocyte-derived macrophages is indeed able to restrain the expression of interleukin-23 once it has been triggered by a pro-inflammatory stimulus. This effect of dexamethasone is here demonstrated being secondary to suppression of p38 MAPK activity, and involving a protein phosphatase - likely MAPK phosphatase-1 (MKP-1). Conclusions: Results reported in this paper show that a 10 nanomolar dose of dexamethasone not only prevents inflammatory activation but is also efficacious in confining active inflammation. This effect is here demonstrated not to occur through "canonical" inhibition of the NF-κB transcription factor but through a distinct cascade of down-modulation, that underlines the importance of the transactivating activity of glucocorticoid receptor in the context of its anti-inflammatory action. http://www.biomedcentral.com/1471-2210/11/8 Linda Palma Carla Sfara Antonella Antonelli Mauro Magnani BMC Pharmacology 2011, null:8 2011-07-26T00:00:00Z doi:10.1186/1471-2210-11-8 Synthetic glucocorticoids limit inflammation The glucocorticoid analogue dexamethasone reduces the expression of interleukin-23p19 in human monocyte-derived macrophages via a distinct cascade of down-modulation, secondary to the suppression of p38 MAPK activity and likely involving MAPK phosphatase-1 (MKP-1). /content/figures/1471-2210-11-8-toc.gif BMC Pharmacology 1471-2210 ${item.volume} 8 2011-07-26T00:00:00Z XML Background: Breast cancers due to germline mutations or altered expression of the BRCA1 gene associate with an aggressive clinical course and frequently exhibit a "triple-negative" phenotype, i.e. lack of expression of the estrogen and progesterone hormone receptors and lack of overexpression of the HER2/NEU oncogene, thereby rendering them relatively insensitive to hormonal manipulation and targeted HER2 therapy, respectively. BRCA1 plays a role in multiple DNA repair pathways, and thus, when mutated, results in sensitivity to certain DNA damaging drugs. Results: Here, we used a Brca1 murine mammary epithelial cell (MMEC) model to examine the effect of loss of Brca1 on cellular sensitivity to various chemotherapy drugs. To explore novel therapeutic strategies, we included DNA damaging and non-DNA damaging drugs whose mechanisms are dependent and independent of DNA repair, respectively, and drugs that are used in standard and non-standard lines of therapy for breast cancer. To understand the cellular mechanism, we also determined the role that DNA repair plays in sensitivity to these drugs. We found that cisplatin and gemcitabine had the greatest specific therapeutic benefit to Brca1-deficient MMECs, and that when used in combination produced a synergistic effect. This sensitivity may be attributed in part to defective NER, which is one of the DNA repair pathways normally responsible for repairing DNA adducts produced by cisplatin and is shown in this study to be defective in Brca1-deficient MMECs. Brca1-deficient MMECs were not differentially sensitive to the standard breast cancer chemotherapy drugs doxorubicin, docetaxel or 5-FU. Conclusions: Both cisplatin and gemcitabine should be explored in clinical trials for first line regimens for BRCA1-associated and triple-negative breast cancer. http://www.biomedcentral.com/1471-2210/11/7 Elizabeth Alli Vandana Sharma Anne-Renee Hartman Patrick Lin Lisa McPherson James Ford BMC Pharmacology 2011, null:7 2011-07-19T00:00:00Z doi:10.1186/1471-2210-11-7 /content/figures/1471-2210-11-7-toc.gif BMC Pharmacology 1471-2210 ${item.volume} 7 2011-07-19T00:00:00Z XML Background: The contributions of brain cannabinoid (CB) receptors, typically CB1 (CB type 1) receptors, to the behavioral effects of nicotine (NC) have been reported to involve brain transient receptor potential vanilloid 1 (TRPV1) receptors, and the activation of candidate endogenous TRPV1 ligands is expected to be therapeutically effective. In the present study, the effects of TRPV1 ligands with or without affinity for CB1 receptors were examined on NC-induced depression-like behavioral alterations in a mouse model in order to elucidate the "antidepressant-like" contributions of TRPV1 receptors against the NC-induced "depression" observed in various types of tobacco abuse. Results: Repeated subcutaneous NC treatments (NC group: 0.3 mg/kg, 4 days), like repeated immobilization stress (IM) (IM group: 10 min, 4 days), caused depression-like behavioral alterations in both the forced swimming (reduced swimming behaviors) and the tail suspension (increased immobility times) tests, at the 2 h time point after the last treatment. In both NC and IM groups, the TRPV1 agonists capsaicin (CP) and olvanil (OL) administered intraperitoneally provided significant antidepressant-like attenuation against these behavioral alterations, whereas the TRPV1 antagonist capsazepine (CZ) did not attenuate any depression-like behaviors. Furthermore, the endogenous TRPV1-agonistic CB1 agonists anandamide (AEA) and N-arachidonyldopamine (NADA) did not have any antidepressant-like effects. Nevertheless, a synthetic "hybrid" agonist of CB1 and TRPV1 receptors, arvanil (AR), caused significant antidepressant-like effects. The antidepressant-like effects of CP and OL were antagonized by the TRPV1 antagonist CZ. However, the antidepressant-like effects of AR were not antagonized by either CZ or the CB1 antagonist AM 251 (AM). Conclusions: The antidepressant-like effects of TRPV1 agonists shown in the present study suggest a characteristic involvement of TRPV1 receptors in NC-induced depression-like behaviors, similar to those caused by IM. The strong antidepressant-like effects of the potent TRPV1 plus CB1 agonist AR, which has been reported to cause part of its TRPV1-mimetic and cannabimimetic effects presumably via non-TRPV1 or non-CB1 mechanisms support a contribution from other sites of action which may play a therapeutically important role in the treatment of NC abuse. http://www.biomedcentral.com/1471-2210/11/6 Tamaki Hayase BMC Pharmacology 2011, null:6 2011-07-18T00:00:00Z doi:10.1186/1471-2210-11-6 /content/figures/1471-2210-11-6-toc.gif BMC Pharmacology 1471-2210 ${item.volume} 6 2011-07-18T00:00:00Z XML Background: The emergence of drug resistant tuberculosis poses a serious concern globally and researchers are in rigorous search for new drugs to fight against these dreadful bacteria. Recently, the bacterial GlmU protein, involved in peptidoglycan, lipopolysaccharide and techoic acid synthesis, has been identified as an important drug target. A unique C-terminal disordered tail, essential for survival and the absence of gene in host makes GlmU a suitable target for inhibitor design. Results: This study describes the models developed for predicting inhibitory activity (IC 50 ) of chemical compounds against GlmU protein using QSAR and docking techniques. These models were trained on 84 diverse compounds (GlmU inhibitors) taken from PubChem BioAssay (AID 1376). These inhibitors were docked in the active site of the C-terminal domain of GlmU protein (2OI6) using the AutoDock. A QSAR model was developed using docking energies as descriptors and achieved maximum correlation of 0.35/0.12 (r/r2) between actual and predicted pIC 50 . Secondly, QSAR models were developed using molecular descriptors calculated using various software packages and achieved maximum correlation of 0.77/0.60 (r/r2). Finally, hybrid models were developed using various types of descriptors and achieved high correlation of 0.83/0.70 (r/r2) between predicted and actual pIC 50 . It was observed that some molecular descriptors used in this study had high correlation with pIC 50 . We screened chemical libraries using models developed in this study and predicted 40 potential GlmU inhibitors. These inhibitors could be used to develop drugs against Mycobacterium tuberculosis. Conclusion: These results demonstrate that docking energies can be used as descriptors for developing QSAR models. The current work suggests that docking energies based descriptors could be used along with commonly used molecular descriptors for predicting inhibitory activity (IC 50 ) of molecules against GlmU. Based on this study an open source platform, http://crdd.osdd.net/raghava/gdoq, has been developed for predicting inhibitors GlmU. http://www.biomedcentral.com/1471-2210/11/5 Deepak Singla Meenakshi Anurag Debasis Dash Gajendra. Raghava BMC Pharmacology 2011, null:5 2011-07-06T00:00:00Z doi:10.1186/1471-2210-11-5 Predicting tuberculosis inhibitors A Quantitative Structure Activity Relationship (QSAR) model based on docking energy descriptors predicts potential inhibitors of the Mycobacterium tuberculosis drug target GlmU, that could be used in the development of drugs against tuberculosis. /content/figures/1471-2210-11-5-toc.gif BMC Pharmacology 1471-2210 ${item.volume} 5 2011-07-06T00:00:00Z XML Background: Curcumin is known to possess many anti-tumor properties such as inhibition of tumor growth and induction of apotosis. However, limited bioavailability of curcumin prevents its clinical application. A synthesized curcumin analog, 1,5-diaryl-3-oxo-1,4-pentadiene such as GO-Y030, has the improved anti-tumor potential in vitro as well as in mouse model of colorectal carcinogenesis. Results: These compounds were divided into two groups; one is the higher anti-proliferative group, in which 79.7% of 1,5-diaryl-3-oxo-1,4-pentadienes were clustered. One of the 1,5-diaryl-3-oxo-1,4-pentadiene analogs, GO-Y078 has the most enhanced growth inhibition, and its solubility was improved, compared with curcumin. GO-Y078 inhibits NF-κB transactivation, as well as expression of TP53 and DR5 more effectively than curcumin. In a mouse model, GO-Y078 presented 1.4 fold more survival elongation that was not achieved by curcumin and GO-Y030. Conclusions: The 1,5-diaryl-3-oxo-1,4-pentadiene analogs can yield good lead compounds for cancer chemotherapy, to overcome low bioavailability of curcumin. http://www.biomedcentral.com/1471-2210/11/4 Chieko Kudo Hiroyuki Yamakoshi Atsuko Sato Hiroshi Nanjo Hisatsugu Ohori Chikashi Ishioka Yoshiharu Iwabuchi Hiroyuki Shibata BMC Pharmacology 2011, null:4 2011-05-28T00:00:00Z doi:10.1186/1471-2210-11-4 Chemotherapeutic curcuminoids Synthetic analogs of natural curcumin, found in the popular Indian spice turmeric, overcome the compound's low bioavailability and display enhanced chemotherapeutic potential both in vitro and in a mouse model of colorectal carcinogenesis. /content/figures/1471-2210-11-4-toc.gif BMC Pharmacology 1471-2210 ${item.volume} 4 2011-05-28T00:00:00Z XML Background: The serotonin 5-HT2C receptor (5-HT2CR) is expressed in amygdala, a region involved in anxiety and fear responses and implicated in the pathogenesis of several psychiatric disorders such as acute anxiety and post traumatic stress disorder. In humans and in rodent models, there is evidence of both anxiogenic and anxiolytic actions of 5-HT2C ligands. In this study, we determined the responsiveness of 5-HT2CR in serotonin transporter (SERT) knockout (-/-) mice, a model characterized by increased anxiety-like and stress-responsive behaviors. Results: In the three-chamber social interaction test, the 5-HT2B/2C agonist mCPP decreased sociability and sniffing in SERT wildtype (+/+) mice, both indicative of the well-documented anxiogenic effect of mCPP. This 5-HT2C-mediated response was absent in SERT -/- mice. Likewise, in the open field test, the selective 5-HT2C agonist RO 60-0175 induced an anxiogenic response in SERT +/+ mice, but not in SERT -/- mice. Since 5-HT2CR pre-mRNA is adenosine-to-inosine (A-to-I) edited, we also evaluated the 5-HT2CR RNA editing profiles of SERT +/+ and SERT -/- mice in amygdala. Compared to SERT +/+ mice, SERT-/- mice showed a decrease in less edited, highly functional 5-HT2C isoforms, and an increase in more edited isoforms with reduced signaling efficiency. Conclusions: These results indicate that the 5-HT2CR in the amygdala of SERT -/- mice has increased RNA editing, which could explain, at least in part, the decreased behavioral responses to 5-HT2C agonists in SERT -/- mice. These alterations in 5-HT2CR in amygdala may be relevant to humans with SERT polymorphisms that alter SERT expression, function, and emotional behaviors. http://www.biomedcentral.com/1471-2210/11/3 Pablo Moya Meredith Fox Catherine Jensen Justin Laporte Helen French Jens Wendland Dennis Murphy BMC Pharmacology 2011, null:3 2011-04-07T00:00:00Z doi:10.1186/1471-2210-11-3 Altered RNA editing in SERT knock-outs Knock-out mice for the serotonin transporter (SERT) are impaired in the anxiogenic response induced by serotonin receptor agonists and display an increased editing of the serotonin 5-HT2C receptor RNA compared to wild-type. /content/figures/1471-2210-11-3-toc.gif BMC Pharmacology 1471-2210 ${item.volume} 3 2011-04-07T00:00:00Z XML