bluuebunny/crossref_metadata_2025 huggingface dataset:
Morphine or its withdrawal affects plasma malondialdehyde, vitamin E levels and absence or presence of abstinence signs in rats
Authors: Pinelli Arnaldo , Cighetti Giuliana , Trivulzio Silvio , Accinni Roberto
Published: October 2010

Objectives

Various experimental observations show that morphine treatment generates reactive oxygen species, and that its discontinuation leads to signs of withdrawal. We therefore investigated plasma malondialdehyde and vitamin E levels under both conditions to verify the occurrence of any alterations in oxidative metabolism, and whether these are associated with behavioural changes.

Methods

We investigated the effects of morphine or morphine plus naloxone on plasma malondialdehyde, vitamin E levels and withdrawal signs such as jumping, wet dog shakes and faecal excretion in rats. Furthermore, isopropylnoradrenaline was injected in rabbits to verify its effects on plasma malondialdehyde levels.

Key findings

Morphine treatment increased free malondialdehyde and decreased vitamin E levels. The elevation in malondialdehyde levels were exacerbated by the abrupt removal of morphine by naloxone, which also led to the appearance of withdrawal signs. The increased malondialdehyde values can be attributed to the interactions of reactive oxygen species with unsaturated fatty acids, and the lowered levels of vitamin E to its interactions with reactive oxygen species.

Conclusions

A connection seems to exist between altered peroxide status and withdrawal signs in abstinent animals.
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

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

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

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

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

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

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

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 > 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

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.

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

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

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.

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

Objectives

The 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.

Methods

Paclitaxel and TAX-2′-Et were incubated with rat hepatocyte suspensions in the presence or absence of inhibitors.

Key findings

Paclitaxel 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.

Conclusions

The 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

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.
Inhibition of inducible nitric oxide synthesis by Cimicifuga racemosa (Actaea racemosa, black cohosh) extracts in LPS-stimulated RAW 264.7 macrophages
Authors: Schmid Diethart , Gruber Miriam , Woehs Florian , Prinz Sonja , Etzlstorfer Barbara , Prucker Christina , Fuzzati Nicola , Kopp Brigitte , Moeslinger Thomas
Published: October 2010

Objectives

Cimicifuga racemosa (Actaea racemosa, black cohosh) is used as an anti-inflammatory, antipyretic and analgesic remedy in traditional medicines. The present study focuses on the effects of C. racemosa root extracts on inducible nitric oxide synthase (iNOS) in lipopolysaccharide-stimulated murine macrophages (RAW 264.7).

Methods

C. racemosa rhizome and phosphate-buffered saline extracts were analysed for phenolcarboxylic acids and triterpene glycosides using an HPLC photodiode array/evaporative light-scattering detector system. iNOS was characterised by measurement of iNOS protein (immunoblotting), iNOS mRNA (semiquantitative competitive RT-PCR), nitric oxide production (nitrite levels) and nuclear translocation of nuclear factor-kB (p65 subunit) protein.

Key findings

Incubation of lipopolysaccharide-stimulated macrophages with aqueous C. racemosa extracts (0–6 mg/ml) inhibited nitrite accumulation in a concentration-dependent manner. C. racemosa extracts also reduced iNOS protein expression and iNOS mRNA levels in a dose-dependent manner. C. racemosa extracts did not significantly inhibit iNOS activity and did not affect nuclear translocation of nuclear factor-kB (p65 subunit) protein. Incubation with the extract was associated with a concentration-dependent reduction of interferon beta and interferon regulatory factor 1 mRNA. Among the triterpene glycosides, 23-epi-26-deoxyactein was identified as an active principle in C. racemosa extracts.

Conclusions

Extracts from the roots of C. racemosa inhibit nitric oxide production by reducing iNOS expression without affecting activity of the enzyme. This might contribute to the anti-inflammatory activities of C. racemosa.
The application of Gaussian processes in the prediction of percutaneous absorption
Authors: Moss Gary P , Sun Yi , Prapopoulou Maria , Davey Neil , Adams Rod , Pugh W John , Brown Marc B
Published: October 2010

Objectives

The aim was to assess mathematically the nature of a skin permeability dataset and to determine the utility of Gaussian processes in developing a predictive model for skin permeability, comparing it with existing methods for deriving predictive models.

Methods

Principal component analysis was carried out in order to determine the nature of the dataset. MatLab software was used to assess the performance of Gaussian process, single linear networks (SLN) and quantitative structure-permeability relationships (QSPRs) using a range of statistical measures.

Key findings

Principal component analysis showed that the dataset is inherently nonlinear. The Gaussian process model yielded a predictive model that provides a significantly more accurate estimate of skin absorption than previous models, particularly QSPRs (which were consistently worse than Gaussian process or SLN models), and does so across a wider range of molecular properties. Gaussian process models appear particularly capable of providing excellent predictions where previous studies have shown QSPRs to fail, such as where penetrants have high log P and high molecular weight.

Conclusions

A non-linear approach was more appropriate than QSPRs or SLNs for the analysis of the dataset employed herein, as the prediction and confidence values in the prediction given by the Gaussian process are better than with other methods examined. Gaussian process provides a novel way of analysing skin absorption data that is substantially more accurate, statistically robust and reflective of our empirical understanding of skin absorption than the QSPR methods so far applied to skin absorption.
Mannose 6-phosphate-modified bovine serum albumin nanoparticles for controlled and targeted delivery of sodium ferulate for treatment of hepatic fibrosis
Authors: Li Feng-Qian , Su Hua , Chen Xu , Qin Xian-Ju , Liu Ji-Yong , Zhu Quan-Gang , Hu Jin-Hong
Published: October 2010

Objectives

The aim was to prepare neoglycoprotein-based nanoparticles for targeted drug delivery to hepatic stellate cells, and to evaluate their characteristics in vitro and in vivo.

Methods

The neoglycoprotein of bovine serum albumin modified with mannose 6-phosphate was synthesised from mannose, and used as wall material to nanoencapsulate the model natural antifibrotic substance sodium ferulate using a desolvation method. The morphology, drug loading capacity, release in vitro and biodistribution in vivo of the nanoparticles were studied. Selectivity of the nanoparticles for hepatic stellate cells was evaluated by immunohistochemical analysis of fibrotic rat liver sections.

Key findings

The spherical nanoparticles were negatively charged with zeta potential ranging from −2.73 to −35.85 mV, and sizes between 100 and 200 nm with a narrow size distribution. Drug entrapment efficiency of about 90% (w/w) and loading capacity of 20% (w/w) could be achieved. In vitro, the nanoparticles showed an initial rapid continuous release followed by a slower sustained release. After intravenous injection into mice, the nanoparticles showed a slower elimination rate and a much higher drug concentration in liver compared with the sodium ferrate solution, and less distribution to the kidneys and other tissues. Immunohistochemistry indicated that the neoglycoprotein-based nano-particles were taken up specifically by hepatic stellate cells.

Conclusions

The nanoparticles may be an efficient drug carrier targeting hepatic stellate cells.
Reduction of Staphylococcus aureus and Pseudomonas aeruginosa colonisation on PVC through covalent surface attachment of fluorinated thiols
Authors: McCoy Colin P , Cowley John F , Gorman Sean P , Andrews Gavin P , Jones David S
Published: October 2010

Objectives

This study reports the development, characterisation and microbiological testing of surface-modified polyvinylchloride (PVC) films for the purpose of reducing bacterial adherence.

Methods

Irreversible covalent surface modification was achieved via nucleophilic substitution of fluorinated thiol-terminated compounds onto the polymer backbone. Four fluorinated modifiers, 2,3,5,6-tetrafluorothiophenol (TFTP), 4-(trifluoromethyl)thiophenol (TFMTP), 3,5-bis(trifluoromethyl)benzenethiol (BTFMBT) and 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluoro-decane-1-thiol (HDFDT), were investigated. Modification was confirmed using attenuated total reflectance infrared spectroscopy; Raman mapping demonstrated that modification was homogenous on the macroscopic scale. The influence of fluorination on surface hydrophobicity was studied by contact angle analysis. The effect on microbial adherence was examined using Pseudomonas aeruginosa and Staphylococcus aureus.

Key findings

The resultant changes in contact angle relative to control PVC ranged from −4° to +14°. In all cases, adherence of P. aeruginosa and S. aureus was significantly reduced relative to control PVC, with adherence levels ranging from 62% and 51% for TFTP-modified PVC to 32% and 7% for TFMTP-modified PVC.

Conclusions

These results demonstrate an important method in reducing the incidence of bacterial infection in PVC medical devices without compromising mechanical properties.
Freeze-dried liposomes as potential carriers for ocular administration of cytochrome c against selenite cataract formation
Authors: Zhang Jing , Guan Peipei , Wang Tianyi , Chang Di , Jiang Tongying , Wang Siling
Published: October 2010

Objectives

In this study, the preparation, stability and anti-cataract effect of cationic freeze-dried liposomes containing cytochrome c, along with nicotinamide and adenosine, are described.

Methods

Cytochrome c-loaded cationic liposomes (CC-L) were prepared by the thin-layer evaporation technique and lyophilized to obtain freeze-dried cytochrome c liposomes (CC-F). The influence of the preparation components on the liposomal encapsulation efficiency and the stability were studied. The anti-cataract effect of the CC-F was demonstrated through attenuating lens opacity development with slit lamp examination in rats with selenite-induced cataract.

Key findings

Our study indicates that: (1) the liposomal encapsulation efficiency increased with increasing phosphatidylcholine content and reduced in the presence of stearylamine. Moreover, optimal encapsulation efficiency was obtained at an appropriate ratio of phosphatidylcholine to cholesterol; (2) CC-F was stable for at least 12 months at 4°C; (3) satisfactory improvements in lens opacity were shown in the cytochrome c-treated groups, especially for the CC-F-treated group with the decreased percentage of lens opacity at about 28% at the final examination.

Conclusions

CC-F were shown to be stable superior ophthalmic carriers and were able to markedly retard the onset of cataract development.
Novel pepper extract for enhanced P-glycoprotein inhibition
Authors: Aher Suyog , Biradar Shailesh , Gopu C L , Paradkar Anant
Published: October 2010

Objectives

Piperine is one of the most promising bioenhancers to date. Methods used for its extraction suffer from drawbacks such as use of organic solvents, poor extraction efficiency, tedious and expensive methodology. These methods are not encouraged with a view to reducing global warming. The objective was therefore to develop an alternative solvent-free extraction method.

Methods

An aqueous extract of long pepper fruits was prepared using hydrophilic lipid Gelucire 44/14 as the extracting aid and this was compared with an alcoholic extract. Extracts were characterized using high-performance thin layer chromatography and differential scanning calorimetry. P-glycoprotein (P-gp) inhibitory activity of the aqueous and alcoholic extracts and pure piperine was compared using an in-vitro everted rat intestinal model using ornidazole as the model drug. The study was performed using two oral pretreatment dose levels (10 and 20 mg/kg) and durations (1 and 3 days). Exsorption of ornidazole from serosal to mucosal surface was monitored.

Key findings

P-gp inhibitory activity of the aqueous extract was comparable with that of pure piperine (P > 0.05) and was significantly higher than the alcoholic extract (P < 0.05). Pure piperine and the aqueous extract exhibited significant P-gp inhibitory activity compared with control, which was irrespective of oral pretreatment dose and duration levels. No significant effect of oral pretreatment duration of the aqueous extract was observed. The observed enhancement in P-gp inhibitory activity of the aqueous extract may have been attributed to the P-gp inhibitory potential of Gelucire 44/14 and its efficient extraction and solubility enhancement ability.

Conclusions

In the field of phytopharmaceuticals efficient and eco-friendly extraction processes are still a goal to be achieved. Extraction with Gelucire 44/14 could be a potential method of extraction for phytopharmaceuticals. Compared with conventional methods of extraction it is more efficient, easier to prepare, eco-friendly and scalable.
Permeability of a novel β-lactamase inhibitor LK-157 and its ester prodrugs across rat jejunum in vitro
Authors: Igličar Petra , Legen Igor , Vilfan Gregor , Selič Lovro , Preželj Andrej
Published: October 2010

Objectives

LK-157 is a novel 10-ethylidene tricyclic carbapenem that resembles the structure of the broad-spectrum antibiotic sanfetrinem and acts as a potent inactivator of β-lactamases of classes A, C and D. LK-157 is a highly soluble but poorly permeable drug. Since most of the β-lactams are poorly absorbed, ester prodrugs LK-159, LK-157E1 and LK-157E2 were designed to enhance membrane permeability. This study investigated the permeability of LK-157 and the three ester prodrugs across rat intestine in vitro. The morpholinoethyl ester of sanfetrinem was also investigated.

Method

Permeability across rat jejunum was determined using EasyMount side-by-side diffusion chambers.

Key findings

The solubility and permeability of morpholinoethyl ester LK-157E2 were superior to those of LK-159 and LK-157E1. The morpholinoethyl ester of sanfetrinem LK-176E1 had the highest observed permeability coefficient and consequently the highest predicted absorption in humans.

Conclusions

These results suggest that the morpholinoethyl esters of LK-157 and sanfetrinem could be further investigated to assess bioavailability in vivo.
Synthesis of a quaternary bis derivative of imipramine as a novel compound with potential anti-enuretic effect
Authors: Jamali Bardia , Roodsari Mahmoodreza Sadeghipoor , Soleymani Zohre , Faizi Mehrdad , Shafaghi Bijan , Kobarfard Farzad
Published: October 2010

Objectives

Imipramine has been used for over four decades (early reports in 1960s) for the treatment of nocturnal enuresis, although the reason for its effect is not clear. Imipramine is a tertiary amine, which may act both in the periphery and/or pass through the blood-brain barrier (BBB) in unionized form and exhibit a central effect. Since imipramine has anti-cholinergic properties, some believe it may exert its anti-enuretic effect by affecting peripheral cholinergic receptors, i.e. its anti-enuretic effect may be due to peripheral anti-cholinergic properties, whereas others think it can pass through the BBB and interact with central nervous system (CNS) receptors. If the anti-enuretic effect of imipramine is due to its peripheral anti-cholinergic effects, its entrance into the CNS is unnecessary. Therefore, the synthesis of a form of imipramine that can exhibit peripheral anti-cholinergic effects but does not have CNS adverse effects would have a safer drug profile in this case. On the other hand, if the anti-enuretic effect of imipramine is primarily due to its action on the CNS, a form of imipramine that cannot pass through the BBB has no effect on nocturnal enuresis treatment and thus may help to clarify the mechanism of action of imipramine in nocturnal enuresis treatment.

Methods

This article describes the synthesis and evaluation of the anti-cholinergic effect of a new bis derivative of imipramine, which contains two imipramine units in its structure.

Key findings

The compound exhibited anti-cholinergic activity comparable with that of imipramine on isolated guinea pig ileum.

Conclusions

Being a quaternary ammonium, this compound is not expected to be able to cross the BBB and thus would cause fewer CNS side effects.
Importance of pharmaceutical composition and evidence from clinical trials and pharmacological studies in determining effectiveness of chondroitin sulphate and other glycosaminoglycans: a critique
Authors: Rainsford K D
Published: October 2010

Objectives

Chondroitin sulphate (CS) has attracted much interest over the past two decades or so as a biological agent for use in the relief of pain and joint symptoms in osteoarthritis. Earlier clinical investigations produced variable, if encouraging results. This variability was partly due to limitations on the study designs and the lack of availability of standardized CS. Recently, high quality and fully standardized CS (Condrosulf) has become available and its effects have been studied in large-scale osteoarthritis trials, which are discussed here.

Key findings

There is now evidence for symptom - and structure-modifying (radio-logically-observed) effects. These studies show that CS (a) has slow onset of response and that relief of pain may not be like that of the direct analgesic actions of non-steroidal anti-inflammatory drugs (NSAIDs), (b) there are indications of reduced need for intake of analgesics (e.g. NSAIDs) in patients taking CS, and (c) quality of life and cost-benefits may be associated with use of CS. Safety evaluations show that the incidence of adverse reactions is low. Pharmacokinetic studies indicate that although oral absorption is relatively fast CS has moderate oral bioavailability (15–24%) and that depolymerised and degraded CS that is evident after absorption, together with CS itself, may take some time to accumulate in target joints. The pharmacodynamic actions of CS indicate that it has anti-inflammatory effects that include multiple actions involving reduction of catabolic reactions and enhanced anabolic (proteoglycan) synthetic reactions in cartilage and may block osteoclast activation in bone. Further studies are required to (a) establish the effects of depolymerised and degraded CS on degradation of cartilage and bone in vitro, and (b) MRI and other investigations of the effects in osteoarthritis of long-term CS treatment.

The findings from this review show there may be potential value of CS in reducing the dependence on intake of NSAIDs and analgesics in patients with osteoarthritis, while at the same time having favourable safety.
Quality of different chondroitin sulfate preparations in relation to their therapeutic activity
Authors: Volpi Nicola
Published: October 2010

Objectives

Chondroitin sulfate is currently recommended by the European League Against Rheumatism (EULAR) as a SYSADOA (symptomatic slow acting drug for osteoarthritis) in Europe in the treatment of knee and hand osteoarthritis based on research evidence and meta-analysis of numerous clinical studies. Furthermore, recent clinical trials demonstrated its possible structure-modifying effects. Chondroitin sulfate, alone or in combination with glucosamine or other ingredients, is also utilized as a nutraceutical in dietary supplements in Europe and the USA. However, it is derived from animal sources by extraction and purification processes. As a consequence, source material, manufacturing processes, the presence of contaminants and many other factors contribute to the overall biological and pharmacological actions of these agents. We aim to review the quality control of chondroitin sulfate in pharmaceutical-grade preparations and nutraceuticals.

Key findings

Pharmaceutical-grade formulations of chondroitin sulfate are of high and standardized quality, purity and properties, due to the stricter regulations to which this drug is subjected by local national health institutes as regards production and characteristics. On the contrary, as several published studies available in literature indicate, the chondroitin sulfate quality of several nutraceuticals is poor. Additionally, there are no definite regulations governing the origin of the ingredients in these nutraceuticals and the origin of the ingredients in natural products is the most important factor ensuring quality, and thus safety and efficacy, in particular for chondroitin sulfate, due to its extraction from different sources.

Conclusions

Due to the poor chondroitin sulfate quality of some nutraceuticals, we conclude that stricter regulations regarding their quality control should be introduced to guarantee the manufacture of high quality products for nutraceutical utilization and to protect customers from low-quality, ineffective and potentially dangerous products. There is a need for specific and accurate analytical procedures, which should be enforced to confirm purity and label claims both for raw materials and finished chondroitin sulfate products, and also to govern the origin of ingredients. Until these stricter regulations are in place, then it is strongly recommended that pharmaceutical-grade chondroitin sulfate is used rather than food supplements.
Arsthinol nanosuspensions: pharmacokinetics and anti-leukaemic activity on NB4 promyelocytic leukaemia cells
Authors: Ajana Imane , Astier Alain , Gibaud Stéphane
Published: October 2010

Objectives

The organoarsenical arsthinol was used in the 1950s in the treatment of amoebiasis and yaws and was considered as ‘highly tolerated’. The aim of this work was to study its anti-leukaemic activity and to develop nanosuspensions of the drug, thereby limiting brain concentrations and the risk of encephalopathy.

Methods

Arsthinol nanosuspensions were produced by high-pressure homogenization. The anti-leukaemic activity was assessed on NB4 acute promyelocytic leukaemia cells (vs solutions of arsthinol, As2O3 and melarsoprol). In addition, a pharmacokinetics study was performed to compare the nanosuspensions and the solution of arsthinol.

Key findings

Arsthinol induced growth inhibition of NB4 cells at lower concentration (IC50 (concentration inhibiting growth by 50%) = 0.78 ± 0.08 μmol/l after 24 h) than As2O3 (IC50 = 1.60 ± 0.23 μmol/l after 24 h) or melarsoprol (IC50 = 1.44 ± 0.08 μmol/l after 24 h). When formulated as nanosuspension, arsthinol remained cytotoxic (IC50 = 1.33 ± 0.30 μmol/l after 24 h). This formulation also reduced the drug's access to the brain (Cmax = 0.03 μmol/g) whereas bone marrow concentrations remained very high (Cmax = 2 μmol/g).

Conclusions

Nanosuspensions of arsthinol could be proposed for further studies in the treatment of acute promyelocytic leukaemia.
Acetoside inhibits α-MSH-induced melanin production in B16 melanoma cells by inactivation of adenyl cyclase
Authors: Song Ho Sun , Sim Sang Soo
Published: October 2010

Objectives

The aim of the study was to determine the mechanism of the whitening effect of acteoside.

Methods

We used tyrosinase activity and melanin production stimulated in B16 melanoma cells by α-melanocyte stimulating hormone (α-MSH) or forskolin to measure the whitening effect of acteoside.

Key findings

Acteoside did not directly inhibit mushroom tyrosinase activity, but dose-dependently inhibited tyrosinase activity and melanin production in B16 melanoma cells stimulated by 1 μmol/l α-MSH. Acteoside also reduced cyclic AMP levels in cells stimulated by 1 μmol/l α-MSH, suggesting direct inhibition of adenyl cyclase. Acteoside also inhibited productionofbothmelanin and cyclic AMP in cells stimulated by 1 μmol/l forskolin, an adenyl cyclase activator. Acteoside showed antioxidant activity in a cell-free DPPH (1-diphenyl-2-picrylhydroazyl) assay and inhibited generation of intracellular reactive oxygen species.

Conclusions

These results suggest that the whitening activity of acteoside results from inhibition of adenyl cyclase and α-MSH signalling.
Intestinal inflammation and seizure susceptibility: understanding the role of tumour necrosis factor-α in a rat model
Authors: Medhi Bikash , Prakash Ajay , Avti Pramod K , Chakrabarti Amitava , Khanduja Krishan L
Published: October 2010

Objectives

The aim of the study was to evaluate the correlation between colitis and susceptibility to seizures.

Methods

Colitis was induced in Wistar rats by a single intracolonic administration of trinitrobenzene sulfonic acid (TNBS; 20 mg in 35% ethanol). The control group were given intracolonic vehicle. One group of rats with colitis were treated with thalidomide (150 mg/kg p.o.) daily for 14 days. The other colitis group received vehicle only. On day 15, seizure susceptibility was tested by administration of pentylenetetrazole (40 mg/kg i.p.). Colonic tissue was collected for estimation of morphological score, and malondialdehyde, superoxide dismutase, catalase and glutathione peroxidase. Tumour necrosis factor (TNF)-α levels were measured in serum and brain samples.

Key findings

The colitis group showed a significant increase in seizure score and reduction in onset time compared with the control group. Thalidomide was protective against seizures, resulting in decreased seizure score and significantly delaying the onset of seizures. Thalidomide also provided significant protection against TNBS-induced colonic damage in terms of morphological and histological score and levels of lipid peroxidation, superoxide dismutase, catalase and glutathione peroxidase in colonic tissue. The level of TNF-α in serum was also reduced significantly whereas brain TNF-α level was reduced but not significantly.

Conclusions

TNBS-induced colitis increased seizure susceptibility to a subconvulsive dose of pentylenetetrazole; the immunomodulator thalidomide was protective.