bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergism of simvastatin with losartan prevents angiotensin II-induced cardiomyocyte apoptosis in vitro
Authors: Xu Jian , Lü Xiong-wen , Huang Yan , Zhu Peng-li , Li Jun 
Published: October 2010

Abstract

Objectives
Increasing evidence suggests that cardiomyocyte apoptosis has an important role in the transition from compensatory cardiac remodelling to heart failure. The synergistic effect of statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) and angiotensin II (Ang II) type 1 receptor antagonists reduces the incidence of cardiovascular events. However, the anti-apoptotic potential of the synergism between losartan and simvastatin in heart failure remains unexplored. Here, we demonstrate that Ang II-induced apoptosis is prevented by losartan and simvastatin in neonatal cardiomyocytes.

Methods
The in-vitro cardiomyocyte apoptosis model was established by co-culturing neonate rat cardiomyocytes with Ang II. Cell viability was analysed by the MTT assay. Cell apoptosis was evaluated using fluorescence microscopy and flow cytometry. Apoptosis-related proteins Bax and Bcl-2 expressions were measured by flow cytometry detection.

Key findings
Incubation with 10−7 m Ang II for 48 h increased cardiomyocyte apoptosis and decreased cell viability. Losartan (10−5 m) and simvastatin (10−5 m), either alone or in combination, significantly decreased Ang II-induced cardiomyocyte apoptosis and increased cell viability. The q values calculated by the probability sum test were 1.31 for cardiomyocyte apoptosis and 1.21 for cell viability. Ang II induced a significant increase in Bax protein expression, whereas Bcl-2 protein expression was decreased. Losartan alone or in combination with simvastatin blocked the increased Bax expression and increased Bcl-2 expression. However, simvastatin had no such effect.

Conclusions
Our data provide the first evidence that synergism of simvastatin with losartan prevents angiotensin II-induced cardiomyocyte apoptosis in vitro. Synergism between simvastatin and losartan may provide a new therapeutic approach to the prevention of cardiac remodelling.
Eugenosedin-A prevents hyperglycaemia, hyperlipidaemia and lipid peroxidation in C57BL/6J mice fed a high-fat diet
Authors: Shen Kuo-Ping , Lin Hui-Li , Hsieh Su-Ling , Kwan Aij-Lie , Chen Ing-Jun , Wu Bin-Nan 
Published: October 2010

Abstract

Objectives
Eugenosedin-A is a serotonin (5-hydroxytryptamine; 5-HT) 5-HT1b/2a and α1/α2/β1-adrenoceptor blocker with anti-oxidative, anti-inflammatory and free-radical scavenging activities. Previous reports demonstrated that 5-HT2a blockers could diminish hyperlipidaemia. This study therefore aimed to investigate the possible uses and mechanisms of eugenosedin-A and other agents in treating hyperlipidaemia.

Methods
C57BL/6J mice were randomly divided into seven groups, fed a regular diet or a high-fat diet alone or supplemented with one of five agents: eugenosedin-A, ketanserin, prazosin, propranolol or atorvastatin (5 mg/kg p.o.) for 8 weeks.

Key findings
Compared with the regular diet, the mice fed the high-fat diet had significantly higher body weight and glucose, insulin and lipid levels. Brain malondialdehyde concentration was increased and liver glutathione peroxidase activity decreased. Addition of eugenosedin-A to the high-fat diet resulted in less weight gain and reduced hyperglycaemia, hyperinsulinaemia and hyperlipidaemia. Lipid and glucose homeostasis were related to decreased hepatic lipogenesis mRNAs and proteins (sterol regulatory element binding protein 1a, fatty acid synthase, sterol-CoA desaturase) and restored adipose peroxisome proliferator-activated receptor γ expression. Eugenosedin-A also enhanced low-density lipoprotein receptor mRNA expression.

Conclusions
Eugenosedin-A may improve plasma lipid metabolism by increasing low-density lipoprotein receptor and peroxisome proliferator-activated receptor γ expression and diminishing sterol regulatory element binding protein 1a, fatty acid synthase and sterol-CoA desaturase. Reduction of plasma glucose and lipid levels may, in turn, reduce insulin concentration, which would explain the marked improvement in obesity-related hyperglycaemia and hyperlipidaemia. Furthermore, eugenosedin-A affected malondialdehyde concentration and glutathione peroxidase activity, suggesting it may have anti-peroxidation effects in mice fed a high-fat diet.
Reichardt's dye and its reactions with the alkylating agents 4-chloro-1-butanol, ethyl methanesulfonate, 1-bromobutane and Fast Red B - a potentially useful reagent for the detection of genotoxic impurities in pharmaceuticals
Authors: Corrigan Damion K , Whitcombe Michael J , McCrossen Sean , Piletsky Sergey 
Published: October 2010

Abstract

Objectives
Alkylating agents are potentially genotoxic impurities that may be present in drug products. These impurities occur in pharmaceuticals as by-products from the synthetic steps involved in drug production, as impurities in starting materials or from in-situ reactions that take place in the final drug product. Currently, analysis for genotoxic impurities is typically carried out using either HPLC/MS or GC/MS. These techniques require specialist expertise, have long analysis times and often use sample clean-up procedures. Reichardt's dye is well known for its solvatochromic properties. In this paper the dye's ability to undergo alkylation is reported.

Methods
The reaction between Reichardt's dye and alkylating agents such as 4-chloro-1-butanol and ethyl methanesulfonate was monitored spectrophotometrically at 618 nm in acetonitrile and 624 nm in N,N-dimethylformamide.

Key findings
Changes in absorption were observed using low levels of alkylating agent (5–10 parts per million). Alkylation of the dye with 4-chloro-1-butanol and ethyl methanesulfonate was confirmed. Reichardt's dye, and its changing UV absorption, was examined in the presence of paracetamol (10 and 100 mg/ml). Whilst the alkylation-induced changes in UV absorption were not as pronounced as with standard solutions, detection of alkylation was still possible.

Conclusions
Using standard solutions and in the presence of a drug matrix, Reichardt's dye shows promise as a reagent for detection of low levels of industrially important alkylating agents.
Evaluation of solid lipid microparticles produced by spray congealing for topical application of econazole nitrate
Authors: Passerini Nadia , Gavini Elisabetta , Albertini Beatrice , Rassu Giovanna , Di Sabatino Marcello , Sanna Vanna , Giunchedi Paolo , Rodriguez Lorenzo 
Published: October 2010

Abstract

Objectives
The aims of this study were to evaluate the suitability of the spray congealing technique to produce solid lipid microparticles (SLMs) for topical administration and to study the skin permeation of a drug from SLMs compared with solid lipid nanoparticles (SLNs).

Methods
Econazole nitrate was used as model drug and Precirol ATO 5 as the lipidic carrier. SLMs and SLNs were both prepared at 5: 1, 10: 1 and 12.5: 1 lipid: drug weight ratios and characterised in terms of particle size, morphology, encapsulation efficiency and chemical analysis of the particle surface. SLMs and SLNs were also incorporated into HPMC K 100M hydrogels for ex-vivo drug permeation tests using porcine epidermis.

Key findings
SLMs had particle sizes of 18–45 μm, while SLNs showed a mean diameter of 130–270 nm. The encapsulation efficiency was 80–100%. Permeation profiles of econazole nitrate were influenced by both particle size (significant difference until 9 h) and the amount of lipid.

Conclusions
The results confirm the usefulness of SLNs as carriers for topical administration and suggest the potential of SLMs for the delivery of drugs to the skin.
Stress-induced cardiac insufficiency relating to abnormal leptin and FKBP12.6 is ameliorated by CPU0213, an endothelin receptor antagonist, which is not affected by the CYP3A suppressing effect of erythromycin
Authors: Cheng Yu-Si , Dai De-Zai , Dai Yin 
Published: October 2010

Abstract

Objectives
Cardiac injury induced by isoprenaline produces stress. This stress can be mediated by the activated endothelin and leptin pathway; thus, the endothelin receptor antagonist CPU0213 may reverse these changes. CPU0213 is metabolized mainly by cytochrome P450 (CYP)3A, thus, erythromycin, an inhibitor of CYP3A, could affect its effects by raising its plasma levels.

Methods
Forty rats were divided into five groups. Group 1 rats were normal. Group 2 rats were administered isoprenaline (1 mg/kg, s.c.) for 10 days. Groups 3, 4 and 5 were administered isoprenaline, but group 3 was given erythromycin (100 mg/kg, p.o.) alone on days six to ten, group 4 was given CPU0213 20 mg/kg (s.c.) on days six to ten, whilst group 5 received erythromycin plus CPU0213 on days six to ten. Measurements were conducted to observe changes in the haemodynamics, cardiac weight index, serum lactate dehydrogenase and creatine kinase levels, and expression of endothelin receptor A (ETa), leptin and its OBRb receptor.

Key findings
In isoprenaline-treated rats, cardiac hypertrophy and dysfunction were found. This was associated with upregulated myocardial leptin protein and OBRb receptor mRNA. Immunohistochemical assay of ETa was upregulated, accompanied with downregulation of FKBP12.6 (calstabin 2) in isoprenaline-treated rats. These effects were significantly reversed by CPU0213. HPLC assay presented an increased plasma level of CPU0213 by erythromycin, but no change in its effects.

Conclusions
CPU0213 improved isoprenaline-induced cardiomyopathy by modulating ETa, leptin and FKBP12.6. However, erythromycin increased plasma levels but did not change its effects.
Effect of sodium houttuyfonate on myocardial hypertrophy in mice and rats
Authors: Gao Jian Ping , Chen Chang Xun , Wang Ying , Lü Jian , Gu Wei Liang 
Published: October 2010

Abstract

Objectives
The aim of the study was to determine the effect of sodium houttuyfonate on myocardial hypertrophy and its mechanism of action in mice and rats.

Methods
A mouse model of myocardial hypertrophy was established by subcutaneous injection with isoproterenol. Mice were randomly divided into five groups: normal control; isoproterenol control; isoproterenol plus metoprolol; isoproterenol plus low- and high-dose sodium houttuyfonate. A rat model of myocardial hypertrophy was established by intraperitoneal injection with l-thyroxine. Rats were randomly divided into five groups: normal control; l-thyroxine control; l-thyroxine plus captopril; l-thyroxine plus low- and high-dose sodium houttuyfonate. At the end of the experiments, the left ventricular weight index and heart weight index were determined in mice and rats, the size of cardiomyocytes was measured in rats and the concentrations of cAMP in plasma and angiotensin II in ventricular tissue of mice were detected by radioimmunoassay. The endothelin-1 concentration was measured by radioimmunoassay and the hydroxyproline content was measured by a digestive method in ventricular tissue of rats.

Key findings
After 7–9 days of treatment, sodium houttuyfonate significantly reduced the left ventricular weight index and heart weight index in mice and rats with myocardial hypertrophy, decreased the size of cardiomyocytes in rats, and reduced the content of cAMP and angiotensin II in mice with myocardial hypertrophy. It also decreased the endothelin-1 concentration and the hydroxyproline content in ventricular tissue in rats.

Conclusions
Sodium houttuyfonate can inhibit myocardial hypertrophy in mouse and rat models by restricting the activity of the sympathetic nervous system and decreasing the levels of angiotensin II and endothelin-1 in ventricular tissue.
Antitrypanosomal and cytotoxic activities of pyrrolizidine alkaloid-producing plants of Ethiopia
Authors: Nibret Endalkachew , Sporer Frank , Asres Kaleab , Wink Michael 
Published: October 2010

Abstract

Objectives
The objective was to determine the in-vitro effect of extracts from 19 Ethiopian plant species and four pure pyrrolizidine alkaloids on bloodstream forms of Trypanosoma brucei brucei and human leukaemia HL-60 cells.

Methods
Crude plant extracts were prepared using methanol and dichloromethane. The alkaloidal extracts from Solanecio angulatus flowers were prepared with and without zinc reduction using the acid-base extraction method. Cell proliferation inhibitory activity of the extracts and compounds was assessed using Alamarblue.

Key findings
The most active extract was the dichloromethane extract of Solanecio angulatus flowers, with an IC50 value of 12.17 μg/ml. The best selectivity index (SI &gt; 41.08) was obtained for the same extract determined with HL-60 cells. The reduced alkaloidal extract prepared from S. angulatus flowers and after acid-base extraction showed more antitrypanosomal activity than unreduced alkaloidal extract with an IC50 value of 14.35 μg/ml and with a selectivity index of 12.23.
The second most active extract was the dichloromethane extract of Crotalaria phillipsiae twigs with an IC50 value of 12.67 μg/ml and a selectivity index of 34.35. Most of the other extracts tested showed moderate antitrypanosomal activities to variable extents. Among the four pure pyrrolizidine alkaloids tested, senecionine showed moderate antitrypanosomal activity with an IC50 value of 41.78 μg/ml.

Conclusions
Solanecio angulatus (flowers) and Crotalaria phillipsiae (twigs) could serve as sources of novel trypanocidal compounds for the treatment of trypanosomiasis.
Neuropharmacological and pharmacokinetic properties of berberine: a review of recent research
Authors: Ye Minzhong , Fu Sheng , Pi Rongbiao , He Feng 
Published: October 2010

Abstract

Objectives
This review summarizes recent research on the neuropharmacological and pharmacokinetic properties of berberine, an isoquinoline alkaloid extracted from Coptidis rhizoma.

Key findings
Berberine has multiple neuropharmacological properties, such as neuroprection, anti-neuronal apoptosis, improvement of cerebral microcirculation and anti-Alzheimer's disease, and so on. The pharmacokinetic characteristics of berberine are that it is not easily absorbed and it is not stable in the gastrointestinal tract of animals or humans.

Summary
Further studies need to be carried out to develop berberine as a drug for nervous system diseases, such as brain ischaemia and Alzheimer's disease, that has favorable pharmacokinetic properties.
The role of polar phytocomplexes on anticonvulsant effects of leaf extracts of Lippia alba (Mill.) N.E. Brown chemotypes
Authors: Neto Antônio C , Netto Joaquim C , Pereira Paulo S , Pereira Ana M S , Taleb-Contini Sílvia H , França Suzelei C , Marques Márcia O M , Beleboni René O 
Published: October 2010

Abstract

Objectives
The purpose of the present work was to characterize the pharmacological profile of different L. alba chemotypes and to correlate the obtained data to the presence of chemical constituents detected by phytochemical analysis.

Methods
Essential oils from each L. alba chemotype (LP1—LP7) were characterized by gas chromatography–mass spectrometry (GC-MS) and extracted non-volatile compounds were analysed by HPLC and GC-MS. The anticonvulsant actions of the extracted compounds were studied in pentylenetetrazole-induced clonic seizures in mice and their effect on motor coordination was studied using the rota-rod test in rats. The synaptosomes and synaptic membranes of the rats were examined for the influence of LP3 chemotype extract on GABA uptake and binding experiments.

Key findings
Behavioural parameters encompassed by the pentylenetetrazole test indicated that 80% ethanolic extracts of LP1, LP3 and LP6 L. alba chemotypes were more effective as anticonvulsant agents. Neurochemical assays using synaptosomes and synaptic membranes showed that L. alba LP3 chemotype 80% ethanolic extract inhibited GABA uptake and GABA binding in a dose-dependent manner. HPLC analysis showed that LP1, LP3 and LP6 80% ethanolic extracts presented a similar profile of constituents, differing from those seen in LP2, LP4, LP5 and LP7 80% ethanolic extracts, which exhibited no anticonvulsant effect. GC-MS analysis indicated the occurrence of phenylpropanoids in methanolic fractions obtained from LP1, LP3 and LP6 80% ethanolic extracts and also the accumulation of inositol and flavonoids in hydroalcoholic fractions.

Conclusions
Our results suggest that the anticonvulsant properties shown by L. alba might be correlated to the presence of a complex of non-volatile substances (phenylpropanoids, flavonoids and/or inositols), and also to the volatile terpenoids (β-myrcene, citral, limonene and carvone), which have been previously validated as anticonvulsants.
Analysis of solid-state transformations of pharmaceutical compounds using vibrational spectroscopy
Authors: Heinz Andrea , Strachan Clare J , Gordon Keith C , Rades Thomas 
Published: October 2010

Abstract

Objectives
Solid-state transformations may occur during any stage of pharmaceutical processing and upon storage of a solid dosage form. Early detection and quantification of these transformations during the manufacture of solid dosage forms is important since the physical form of an active pharmaceutical ingredient can significantly influence its processing behaviour, including powder flow and compressibility, and biopharmaceutical properties such as solubility, dissolution rate and bioavailability.

Key findings
Vibrational spectroscopic techniques such as infrared, near-infrared, Raman and, most recently, terahertz pulsed spectroscopy have become popular for solidstate analysis since they are fast and non-destructive and allow solid-state changes to be probed at the molecular level. In particular, Raman and near-infrared spectroscopy, which require no sample preparation, are now commonly used coupled to fibreoptic probes and are able to characterise solid-state conversions in-line. Traditionally, uni- or bivariate approaches have been used to analyse spectroscopic data sets; however, recently the simultaneous detection of several solid-state forms has been increasingly performed using multivariate approaches where even overlapping spectral bands can be analysed.

Summary
This review discusses the applications of different vibrational spectroscopic techniques to detect and monitor solid-state transformations possible for crystalline polymorphs, hydrates and amorphous forms of pharmaceutical compounds. In this context, the theoretical basis of solid-state transformations and vibrational spectroscopy and common experimental approaches are described, including recent methods of data analysis.
Organic anion transporting polypeptide 2-mediated uptake of paclitaxel and 2′-ethylcarbonate-linked paclitaxel in freshly isolated rat hepatocytes
Authors: Tanino Tadatoshi , Nawa Akihiro , Nakao Mao , Noda Manabu , Fujiwara Sawako , Iwaki Masahiro 
Published: October 2010

AbstractObjectivesThe P-glycoprotein (P-gp) efflux pump plays an important role in paclitaxel detoxification. However, hepatic uptake of paclitaxel mediated by a solute-linked carrier transporter family is still poorly understood in animals and humans. Freshly isolated hepatocyte suspensions are a well established in-vitro model for studying drug transport and xenobiotic metabolism. Therefore, the hepatic uptake of paclitaxel and its P-gp-insensitive prodrug, 2′-ethylcarbonate-linked paclitaxel (TAX-2′-Et), has been characterized using freshly isolated and pregnenolone-16-α-carbonitrile (PCN)-treated hepatocytes in rats.MethodsPaclitaxel and TAX-2′-Et were incubated with rat hepatocyte suspensions in the presence or absence of inhibitors.Key findingsPaclitaxel and TAX-2′-Et showed concentration-dependent uptake in rat hepatocytes. The intrinsic transport capacity was two-fold higher for paclitaxel uptake than for TAX-2′-Et uptake. Rifampicin (a potent inhibitor of organic anion transporting polypeptide (Oatp) 2), but not indometacin (a representative inhibitor of organic anion transporter (Oat) 2 and Oatp1) treatment, significantly inhibited the uptake of paclitaxel and TAX-2′-Et. We characterized the rifampicin-sensitive uptake of paclitaxel and TAX-2′-Et using rat hepatocytes treated with PCN, which dramatically enhances hepatic Oatp2 protein levels. PCN-treated hepatocytes displayed a 1.6-fold greater uptake of paclitaxel and TAX-2′-Et than the vehicle-treated hepatocytes. The uptake of the two compounds was significantly reduced by rifampicin but not by indometacin treatment. These findings demonstrated that the rat Oatp2, but not Oatp1 orOat2, was a candidate transporter for the hepatic uptakeofpaclitaxel and TAX-2′-Et.ConclusionsThe findings have provided an important step towards identifying a key transporter in hepatic detoxification of paclitaxel and TAX-2′-Et in small animals.
Relative inhibitory activity of bile acids against 12-O-tetradecanoylphorbol-13-acetate-induced inflammation, and chenodeoxycholic acid inhibition of tumour promotion in mouse skin two-stage carcinogenesis
Authors: Yasukawa Ken , Iida Takashi , Fujimoto Yasuo 
Published: October 2010

Abstract

Objectives
Bile acids are present in Bezoar Bovis and Fel Ursi, traditionally used as antipyretics and antispasmodics. However the anti-inflammatory activity of individual bile acids and related compounds has not yet been investigated. In this paper, we report the structure–activity relationships influencing the anti-inflammatory activity of a variety of structurally different bile acid derivatives and also the inhibitory activity of chenodeoxy-cholic acid against tumour promotion.

Methods
Fifty derivatives of bile acids were examined for their inhibitory activity against the induction of oedema in mouse ear by application of 12-O-tetradecanoylphorbol-13-acetate (TPA). Also, the effect of chenodeoxycholic acid was studied in mouse skin in which tumours had been induced by topical application of 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by TPA.

Key findings
Many bile acid derivatives had an inhibitory effect against TPA-induced ear oedema at a similar grade to that of indometacin. Chenodeoxycholic acid, methyl 3α,7α,15α-trihydroxy-5β-cholan-24-oate and methyl 3α,7α,15β-trihydroxy-5β-cholan-24-oate showed the most potent activity with an ID50 value of 71–110 nmol/ear, a level corresponding to that of hydrocortisone (69 nmol/ear). Furthermore, chenodeoxycholic acid markedly suppressed tumour-promoting activity by TPA following initiation by DMBA in mouse skin.

Conclusions
This is the first report on the anti-inflammatory activity of bile acids on TPA-induced inflammatory ear oedema in mice. Chenodeoxycholic acid, methyl 3α,7α,15α-trihydroxy-5β-cholan-24-oate and methyl 3α,7α,15β-trihydroxy-5β-cholan-24-oate showed the most potent activity, at a level corresponding to that of hydrocortisone. Furthermore, chenodeoxycholic acid markedly inhibited tumour promotion in a two-stage carcinogenesis model in mouse skin.