bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulatory effect of Inula racemosa Hook. f. (Asteraceae) on experimental atherosclerosis in guinea-pigs
Authors: Mangathayaru Kalachaveedu , Kuruvilla Sarah , Balakrishna Kedike , Venkhatesh Jayakothandaramaswamy
Published: October 2010

Objectives

Inula racemosa Hook. f. is indicated for precordial chest pain in Ayurveda. In this study, the effects of a hexane (IrH) and an alcohol extract (IrA) of Inula racemosa on atherosclerosis induced by a high-fat diet in guinea-pigs were investigated.

Methods

After 30 days on a high-fat diet (guinea-pig pellet diet + 0.2% w/w cholesterol) six animals were killed and evaluated for the onset of early atherosclerotic changes in coronary artery, aorta and major organs. The remaining animals were assigned to 5 groups of six animals each and fed for the following 90 days with a pellet diet + 0.15% w/w cholesterol (positive control) along with 100 mg/kg IrA, 100 mg/kg IrH or 10 mg/kg atorvastatin calcium. The normal control group received only the pellet diet. At the end of experimental period, serum lipid levels, heart and liver antioxidant status, area of lipophilic aortic lesions and histopathology of coronary artery were estimated.

Key findings

IrA decreased total cholesterol, triglycerides, low-density lipoprotein cholesterol and the atherogenic index, and increased high-density lipoprotein cholesterol compared with the positive control. It scavenged thiobarbituric acid reactive substances and increased reduced glutathione in liver, and enhanced superoxide dismutase and glutathione peroxidase in heart. Aortic lesion area and % bodyweight increase was least in the IrA-treated group. Coronary artery changes due to the high-fat diet were reversed by the extracts. The observed effects are presumably mediated by phenolics in IrA and sesquiterpene lactones in IrH.

Conclusions

The results demonstrate the anti-atherogenic effect of I. racemosa, thus validating the cardioprotective and anti-obesity claims in traditional medicine.
Aminolevulinic acid-loaded Witepsol microparticles manufactured using a spray congealing procedure: implications for topical photodynamic therapy
Authors: Al-Kassas Rasil , Donnelly Ryan F , McCarron Paul A
Published: October 2010

Objectives

The aim was to enhance aminolevulinic acid (ALA) stability by incorporation into low-melting microparticles prepared using a spray congealing procedure and to evaluate temperature-triggered release, allowing topical bioavailability following melting at skin temperature.

Methods

ALA-loaded Witepsol microparticles were prepared using a novel spray congealing technique. Entrapment efficiency was compared with conventional emulsion-based methods and modelled drug release profiles determined using a membrane separation technique. Raised receiver medium temperature was used to determine triggered release. Bioavailability and lipid-mediated enhancement of ALA penetration were determined in excised murine skin.

Key findings

ALA-loaded Witepsol microparticles were spherical, with a mean diameter of 20 μm. Loading and stability studies demonstrated effective encapsulation, ranging from 91% to 100%, with no evidence of degradation to pyrazine derivatives. ALA release correlated with dissolution medium temperature, triggered at temperatures close to that of skin. Results suggested that molten Witepsol enhanced cutaneous permeation, whereas incorporation of microparticles in a semi-solid vehicle attenuated ALA penetration. Optimal use was direct application under occlusion.

Conclusions

Spray congealing is superior to the emulsion-based procedures with respect to encapsulation efficiency of ALA in Witepsol matrices, providing temperature-triggered release, enhanced stability and improved penetration of ALA through keratinised skin. These features could improve ALA delivery to superficial lesions as part of photodynamic therapy.
Diabetic neuropathy: therapies on the horizon
Authors: Mahmood Danish , Singh Bhulan Kumar , Akhtar Mohammad
Published: October 2010

Objectives

This is a review of emerging interventions from the recent preclinical and clinical literature that demonstrate the potential for effectiveness in the therapy of diabetic neuropathy (DN). DN is the most common complication of diabetes mellitus and up to 50% of patients with type 1 and type 2 forms have some or other form of neuropathy. The pathology of DN is characterized by progressive nerve fibre loss that gives rise to positive and negative clinical signs and symptoms such as pain, paraesthesiae and loss of sensation.

Key findings

There are very few drugs available to directly treat DN. Those that are clinically indicated provide symptomatic relief but do not repair or reverse underlying nerve damage. However, some agents are in clinical development that may support adult neurons and direct reparative processes after injury stages. Several disease modifying drugs such as aldose reductase inhibitors and protein kinase C inhibitors are in phase III development. Agents on the horizon include neurotrophic factors, growth factors, gene therapy, immunotherapy, poly(ADP-ribose) polymerase inhibitors and non-immunosuppressive immunophilin ligands.

Progress has been made toward understanding the biochemical mechanisms leading to diabetic neuropathy, and as a result, new treatment modalities are being explored. The pathogenesis, types and approaches for treating DN together with the newer therapeutic interventions on the horizon are discussed.
Retrospective population pharmacokinetic/pharmacodynamic analysis of pyridostigmine, a cholinesterase inhibitor, in Chinese males
Authors: Seng Kok-Yong , Loke Weng-Keong , Moochhala Shabbir , Zhao Bin , Lee Jon-Deoon Edmund
Published: October 2010

Objectives

We have characterised the population pharmacokinetics-pharmacodynamics of pyridostigmine given as pyridostigmine bromide.

Methods

Over three days 50 healthy Chinese male subjects each received seven doses of 30 mg pyridostigmine bromide orally (3 times 10 mg every 8 h). Plasma concentrations of pyridostigmine and red blood cell acetylcholinesterase (AChE) activity were determined at various times within the eight hours after the first and the seventh doses. The resulting pharmacokinetic data were fitted to a single compartment open model with first-order absorption and elimination. The pharmacodynamics were modelled using an inhibitory Emax model. The potential influence of demographic and biological covariates on the model parameters was investigated. Nonlinear mixed effects modelling was performed using NONMEM.

Key findings

The apparent clearance and volume of distribution as well as absorption rate constant of plasma pyridostigmine were estimated to be 136 1/h, 130 1 and 0.68 1/h, respectively. The maximum red blood cell AChE activity decrease (Emax) and plasma pyridostigmine concentration producing 50% of this reduction (EC50) were estimated to be 9.32 AChE units per gram haemoglobin and 51.9 ng/ml, respectively. None of the tested covariates were found to be correlated with any of the model parameters. Dosing simulations suggested that 30 mg repeated every six hours might be needed to achieve steady-state trough percentage inhibition above the recommended 10% in healthy Chinese males.

Conclusions

The pharmacokinetics and the effects of pyridostigmine on red blood cell AChE activity were described using a mixed effects model. For Chinese males, the dosing interval may have been shorter than that recommended for the Caucasian population. Additional studies are needed to confirm these findings.
Contribution of a significant first-pass effect of dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylene dioxybiphenyl-2,2′-dicarboxylate in the liver to its poor bioavailability in rats
Authors: Yu Kyung-Ha , Lee Ye-Rie , Ahn Sung-Hoon , Kim Dae-Duk , Shim Chang-Koo , Chung Suk-Jae
Published: October 2010

Objectives

The objective of this study was to investigate the mechanism responsible for the poor oral bioavailability of dimethyl-4′,4′-dimethoxy-5,6,5′,6′-dimethylene dioxy-biphenyl-2,2′-dicarboxylate (DDB), a hepatoprotective agent, in rats.

Methods

DDB was intravenously administered to rats at doses of 0.2-1 mg/kg. To determine the hepatic first-pass effect in rats, DDB (1 mg/kg) was administered via the pyloric vein and the femoral vein. Direct measurement of intestinal permeability was attempted using Caco-2 cell monolayers and rat intestinal epithelium.

Key findings

A moment analysis indicated that the volume of distribution and clearance remained unchanged with the magnitude of the dose, indicating that DDB exhibited linear pharmacokinetics. When the area under the curve for DDB after administration to the pyloric vein was compared with that after femoral vein administration, the ratio (FH) was found to be 0.294, indicating a significant first-pass effect for DDB. The permeability of DDB was high in the rat intestine (1.78 ± 0.229 × 10−5 cm/s) and in Caco-2 cell monolayers (6.8 ± 0.70 × 10−5 cm/s), suggesting that DDB, in soluble form, was readily permeable across the intestinal epithelium.

Conclusions

These observations indicated that despite the fact that DDB was readily permeable to the intestinal epithelium, a significant first-pass metabolism was associated with its pharmacokinetics in rats.
Rapid absorption of sumatriptan powder and effects on glyceryl trinitrate model of headache following intranasal delivery using a novel bi-directional device
Authors: Luthringer Remy , Djupesland Per G , Sheldrake Colin D , Flint Anthony , Boeijinga Peter , Danjou Philippe , Demazières Agnès , Hewson Graeme
Published: October 2010

Objectives

The aim was to investigate the pharmacokinetics of intranasal sumatriptan (administered using a novel bi-directional powder delivery device) and study its effects on quantitative electroencephalography in patients with migraine. The safety profiles of the two formulations were also compared.

Methods

The pharmacokinetics of intranasal sumatriptan (10 mg and 20 mg) administered using a novel breath-actuated bi-directional powder delivery device were compared with subcutaneous sumatriptan (6 mg), along with an investigation of their effects on the electroencephalogram (EEG) following glyceryl trinitrate (GTN) challenge in 12 patients with migraine using a randomized, three-way cross-over design.

Key findings

Following intranasal delivery, median tmax was 20 min with both doses compared with 10 min after the subcutaneous dose. Mean ± SD values for Cmax were 96 ± 25, 11 ± 7 and 16 ± 6 ng/ml for subcutaneous, intranasal 10 mg and intranasal 20 mg formulations, respectively. Values for area under the curve were also lower with the intranasal doses. Intranasal and subcutaneous sumatriptan induced similar EEG changes characterized by reduced theta-power and increased beta-power. The majority of study participants were free of pain according to the headache severity score with all treatments from 15 min through to 8 h post-dose. All treatments were well tolerated and there were no reports of bitter aftertaste after intranasal delivery. Sumatriptan was rapidly absorbed after intranasal administration using the new device. Using the GTN challenge, sumatriptan powder delivered intranasally at a dose of 20 mg by the new device had effects similar to those of subcutaneous sumatriptan on EEG and reported headache pain, despite much lower systemic exposure.

Conclusions

Administration of sumatriptan intranasally at doses of 10 mg and 20 mg by the breath actuated bi-directional powder delivery device results in rapid absorption. Delivery to target sites beyond the nasal valve induced a similar EEG profile to subcutaneous sumatriptan 6 mg and prevented migraine attacks in patients following GTN challenge. Intranasal administration of sumatriptan powder with the breath actuated bi-directional powder delivery device was well tolerated.
Inhibition of IgE-induced mast cell activation by ethyl tertiary-butyl ether, a bioethanol-derived fuel oxygenate
Authors: Yamaki Kouya , Yoshino Shin
Published: October 2010

Objectives

The effect of ethyl tertiary-butyl ether (ETBE), which is widely used as a fuel oxygenate commonly produced from bioethanol, on immunoglobulin (Ig)E-dependent mast cell activation was investigated.

Methods

The rat mast cell line RBL2H3 sensitised with monoclonal anti-ovalbumin IgE was challenged with ovalbumin in the presence or absence of ETBE, tert-butanol (TBA), which is the main metabolite of ETBE in humans, and ethanol. Degranulation of RBL2H3 was examined by the release of β-hexosaminidase. To understand the mechanisms responsible for regulating mast cell function, the effects of ETBE, TBA and ethanol on the levels of intracellular calcium, phosphorylation of Akt (as a marker of phosphatidylinositol 3-kinase) and global tyrosine phosphorylation were also measured as indicators of mast cell activation.

Key findings

In the presence of ETBE, TBA or ethanol, IgE-induced release of β-hexosaminidase was decreased. These compounds also attenuated the IgE-mediated increase in the levels of intracellular Ca2+, phosphorylation of Akt and global tyrosine phosphorylation in RBL2H3 cells.

Conclusions

ETBE, TBA and ethanol inhibited mast cell degranulation by inhibiting the increase in intracellular calcium ion concentration and activation of phosphatidylinositol 3-kinase and protein tyrosine kinase activation, suggesting that exposure to ETBE might affect immune responses, particularly in allergic diseases.
Effect of yokukansan, a traditional Japanese medicine, on social and aggressive behaviour of para-chloroamphetamine-injected rats
Authors: Kanno Hitomi , Sekiguchi Kyoji , Yamaguchi Takuji , Terawaki Kiyoshi , Yuzurihara Mitsutoshi , Kase Yoshio , Ikarashi Yasushi
Published: October 2010

Objectives

Yokukansan, a traditional Japanese medicine, has been approved by the Ministry of Health, Labour, and Welfare of Japan as a remedy for neurosis, insomnia or night crying and irritability in children. It has recently been reported to improve behavioural and psychological symptoms of dementia, such as hallucinations, agitation, and aggressiveness in patients with some forms of senile dementia. Little is known about the mechanism underlying the effectiveness of yokukansan. Our aim was to clarify the involvement of yokukansan in serotonergic function in para-chloroamphetamine (PCA)-induced aggressive behaviour in rats.

Methods

The effect of yokukansan on social interactions, including social and aggressive behaviour, was examined in PCA-injected rats. Concentration and release level of serotonin (5-HT) in the hypothalamus were measured.

Key findings

PCA reduced not only the 5-HT concentration but also the high K+ -induced 5-HT release in the rat hypothalamus. Social interaction tests showed a significant decrease in social behaviour and a significant increase in aggressive behaviour in the PCA-treated rats. The decrease in social behaviour was ameliorated by the 5-HT1A agonist buspirone and further decreased by a 5-HT1A antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-hexanecarboxamide trihydrochloride (WAY-100635), whereas it was further decreased by the 5-HT2A agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), and ameliorated by the 5-HT2A antagonist ketanserin. On the other hand, the increase in aggressive behaviour was ameliorated by buspirone but not affected by WAY-100635, whereas it was enhanced by DOI and ameliorated by ketanserin. A single injection of yokukansan ameliorated the PCA-induced decrease in social behaviour but not aggressive behaviour. Chronic treatment for 14 days with yokukansan ameliorated PCA-induced abnormal behaviour, decreased social behaviour and increased aggressive behaviour, but it did not ameliorate PCA-induced decreases in the cerebral 5-HT concentration and 5-HT release. The ameliorative effects of chronic yokukansan on behaviour were counteracted by co-administration of WAY-100635.

Conclusions

These results suggest that yokukansan might have two different effects: an acute effect on social behaviour and a chronic effect on aggressive behaviour. One of the mechanisms of these effects of yokukansan may be related to the agonistic effect on 5-HT1A receptors.
Effects of iron depletion on antimicrobial activities against planktonic and biofilm Pseudomonas aeruginosa
Authors: Cai Yun , Yu Xu-Hong , Wang Rui , An Mao-Mao , Liang Bei-Bei
Published: October 2010

Objectives

Iron plays an important role in the development of Pseudomonas aeruginosa biofilm. Here we evaluated effects of iron depletion on the antimicrobial activity of ceftazidime, tobramycin and ciprofloxacin against planktonic and biofilm Pseudomonas aeruginosa.

Methods

We tested the sensitivities of wild-type PAO1, type-IV pilus mutant PAO-ΔpilHIJK and the quorum-sensing mutant PAO-JP2 P. aeruginosa planktonic cultures and biofilms to antibiotics under iron-depleted conditions.

Key findings

In planktonic bacteria, the minimum concentration that inhibited visible growth (MIC) of ciprofloxacin was increased slightly in an iron-depleted environment in all three strains, whereas the MIC of tobramycin was similar in iron-depleted and control environments. The MIC of ceftazidime increased in the PAO-JP2 strain when iron was depleted. Tobramycin achieved the best bactericidal effect in biofilms. Viable counts were reduced by one log under iron-depleted conditions in all three strains when tobramycin reached 4 MIC and when ceftazidime and ciprofloxacin reached 8 MIC.

Conclusions

This study suggests that once the biofilm is formed, iron depletion may only slightly promote the bactericidal effect of antibiotics on PAO1, PAO-ΔpilHIJK and PAO-JP2. Although these changes were relatively small, iron as one of the environmental factors should not be ignored when evaluating bactericidal effect of antibiotics. The combination of an iron chelator and antibiotics may have therapeutic value under certain bacterial growth conditions.
In-vitro interaction of l-dopa with bacterial adhesins of Helicobacter pylori: an explanation for clinicial differences in bioavailability?
Authors: Niehues Michael , Hensel Andreas
Published: October 2010

Objectives

Recent investigations on the pharmacokinetics of levodopa (l-dopa) indicated that the presence of Helicobacter pylori in patients with Parkinson's disease, orally treated with l-dopa, influences the absorption of this compound, which consequently leads to decreased plasma levels. Therefore this work aims to study a potential in-vitro interaction of l-dopa with H. pylori and its surface adhesins.

Methods

Solutions containing l-dopa of different concentrations were incubated with H. pylori at different bacterial densities and time intervals. Free l-dopa was quantified from the incubation supernatants by HPLC. A flow cytometric assay with fluorescence labelled H. pylori was used to investigate the influence of l-dopa on the bacterial adhesion of H. pylori: FITC-labelled bacteria were pre-incubated with l-dopa, followed by incubation with gastric epithelial cells (AGS cells) and FACS quantification of adhering bacteria.

Key findings

Evaluation of time- and concentration-dependent incubation experiments indicated a significant decrease in l-dopa concentrations when coming into contact with H. pylori. The reduction in l-dopa concentrations was determined as 47 to 12%, referred to the initial starting concentration, with time-dependency and dependency of the H. pylori density. FITC-labelled H. pylori, pre-incubated with differing l-dopa concentrations, were shown to have a significantly reduced bacterial adhesion to AGS cells, with a maximum reduction of 22 ± 9%. These results demonstrate a direct interaction of l-dopa with the outer membrane proteins of H. pylori responsible for the adhesion to gastric epithelial cells. By this interaction the unbound l-dopa concentration in bacterial suspension was strongly reduced.

Conclusions

This study suggests a potential in-vitro interaction of l-dopa with H. pylori adhesins, confirming the clinical changes found in pharmacokinetics of l-dopa therapy by H. pylori-positive patients with Parkinson's disease.
Effect of intestinal ischaemia/reperfusion on P-glycoprotein-mediated ileal excretion of rhodamine 123 in the rat
Authors: Tomita Mikio , Takizawa Yusuke , Kishimoto Hisanao , Hayashi Masahiro
Published: October 2010

Objectives

We have shown that ischaemia/reperfusion in the small intestine at an early phase, such as 1 h after reperfusion, induced not only functional changes in the membrane, such as P-glycoprotein (P-gp) dysfunction, but also decreased expression of P-gp protein and mdr1a mRNA. In the present study we examined whether intestinal ischaemia/reperfusion modifies the P-gp-mediated ileal excretion transport system in rats beyond 1 h after reperfusion.

Methods

To evaluate the contribution of P-gp-mediated transport to the ileal excretion of rhodamine 123, we used Western blotting to measure the expression of P-gp protein levels isolated from the ileum at different reperfusion times after 60 min of ischaemia. We also measured the expression of inducible nitric oxide synthase (iNOS) mRNA using real-time RT-PCR.

Key findings

Ileal excretion of rhodamine 123 decreased at 3 h after reperfusion and had recovered at 24 h. Changes in villi structure at 3 h and its recovery at 24 h were also observed. Verapamil, a competitive inhibitor of P-gp, significantly inhibited ileal clearance of rhodamine 123 to the lumen at 24 h after reperfusion, suggesting that P-gp was working at this time. These results suggest that intestinal ischaemia/reperfusion-induced decrease in P-gp-mediated ileal excretion of rhodamine 123 was probably due to impaired P-gp-mediated transport. Levels of P-gp protein and iNOS mRNA in the ileum decreased 3 h after ischaemia/reperfusion and returned to control levels after 24 h.

Conclusions

These findings suggest that intestinal ischaemia/reperfusion markedly decreases P-gp-mediated ileal excretion of rhodamine 123, probably by decreasing the expression of P-gp protein, which is likely to be due to increased lipid peroxidation via iNOS.
Therapeutic index of methotrexate depends on circadian cycling of tumour necrosis factor-α in collagen-induced arthritic rats and mice
Authors: To Hideto , Irie Sadaharu , Tomonari Mari , Watanabe Yuko , Kitahara Takashi , Sasaki Hitoshi
Published: October 2010

Objectives

Rheumatoid arthritis is an autoimmune disorder of unknown aetiology. Morning stiffness, a characteristic feature of rheumatoid arthritis, shows a 24-h rhythm. Noticing this rhythm, we hypothesized the presence of a similar rhythm for a rheumatoid arthritis indicator, in addition to dosing-time dependency of the anti-rheumatic effect of methotrexate in arthritis induced by collagen in rats and mice, which reflect the symptomatology of rheumatoid arthritis patients.

Methods

To measure tumour necrosis factor (TNF)-α concentration, blood was taken at different times (2, 6, 10, 14, 18 or 22 h after the light was turned on (HALO)) in collagen-induced arthritic mice. Methotrexate was administered at two different dosing times based on these findings to estimate arthritis.

Key findings

The arthritis score was significantly lower in the 22 HALO-treated group than in the control and 10 HALO-treated groups in collagen-induced arthritic rats and mice. Plasma TNF-α concentrations showed obvious 24-h rhythms, with higher levels at light phase and lower levels at dark phase after rheumatoid arthritis crisis. Arthritis was relieved after administration of methotrexate during the dark phase in synchronization with the 24-h rhythm.

Conclusions

Our findings suggest that choosing an optimal dosing time associated with the 24-h cycling of TNF-α could lead to effective treatment of rheumatoid arthritis by methotrexate.
Comparative study between the effect of the peroxisome proliferator activated receptor-α ligands fenofibrate and n-3 polyunsaturated fatty acids on activation of 5′-AMP-activated protein kinase-α1 in high-fat fed rats
Authors: Motawi Tarek M Kamal , Hashem Reem M , Rashed Laila A , El-Razek Sabry M Abd
Published: October 2010

Objectives

Obesity is a risk factor for type 2 diabetes mellitus. It results from an energy imbalance in which energy intake exceeds energy expenditure. The cellular fuel gauge 5′-AMP-activated protein kinase (AMPK) is a heterotrimeric protein consisting of one catalytic subunit (α) and two non-catalytic subunits (β and γ), and approximately equal levels of α1 and α2 complexes are present in the liver. AMPK regulates metabolic pathways in response to metabolic stress and in particular ATP depletion to switch on energy-producing catabolic pathways such as β-oxidation of fatty acids and switch off energy-depleting processes such as synthesis of fatty acid and cholesterol. A high-fat diet alters AMPK-α1 gene expression in the liver and skeletal muscle of rats and results in body weight gain and hyperglycaemia. The aim of this study was to investigate and compare the potential effects of peroxisome proliferator-activated receptor (PPAR)-α agonists fenofibrate and n-3 polyunsaturated fatty acids (PUFAs) in modulation of AMPK-α1 activity in liver and skeletal muscle of high-fat diet fed rats.

Methods

Reverse transcription–polymerase chain reaction was used for determination of AMPK-α1 in liver and soleus muscle and both PPAR-α and CPT-1 in hepatic tissues. Serum, total cholesterol, triacylglycerol, fatty acid and fasting blood glucose were determined colorimetrically.

Key findings

Both PPAR-α agonists, fenofibrate and n-3 PUFA, increased the mRNA expression of AMPK-α1 activity in liver and skeletal muscle of obese diabetic rats. Fenofibrate was superior in its activation of hepatic mRNA expression of AMPK-α 1 to exert more lipolytic effect and body weight reduction, as estimated through the decrease of triacylglycerol output and serum levels of fatty acid on the one hand and the increase in CPT-1 mRNA expression, the key enzyme in β-oxidation of fatty acid, on the other hand. n-3 PUFA activated AMPK-α1 mRNA expression in skeletal muscle much more than fenofibrate to reveal more hypoglycaemic effect.

Conclusions

The PPAR-α agonists fenofibrate and n-3 PUFA could efficiently activate AMPK-α1 mRNA expression in liver and skeletal muscle to exert body weight reduction and hypoglycaemic effect, respectively.
Enhanced anticancer activity of glutamate prodrugs of all-trans retinoic acid
Authors: Cui Chunying , Zhang Yunwei , Wang Lili , Liu Hu , Cui Guohui
Published: October 2010

Objectives

All-trans retinoic acid (ATRA), an active metabolite of vitamin A, is widely used in the treatment of acute promyelocytic leukaemia and myelodysplastic syndrome. However, its high lipophilicity is thought to be responsible for the slow dissolution and low bioavailability following oral administration. In order to obtain compounds with better solubility characteristics to improve the transportation and bioavailability of ATRA, derivatives of ATRA containing glutamic acid or its sodium salt were synthesised.

Methods

The ATRA derivatives synthesised – all-trans retinoyl glutamate (RAE) and all-trans retinoyl sodium glutamate (RAENa2) – were characterised in terms of melting point, optical rotation, mass spectrometry, NMR and partition coefficient. A liposomal preparation formed from RAE was characterised by particle size and zeta potential. The anti-tumour activity of RAE and RAENa2 was compared with that of ATRA in mice bearing S180 tumours and their effects on the cell cycle were determined in human pro-myelocytic leukaemia HL-60 cells.

Key findings

RAE and RAENa2 were more active than ATRA against tumour growth. Flow cytometry indicated that RAE and RAENa2 induced HL-60 cell cycle arrest, similar to ATRA. DNA fragmentation studies suggested that apoptosis may be one of the mechanisms responsible for the anti-tumour activities.

Conclusions

The two derivatives of ATRA, RAE and RAENa2, exhibited improved aqueous solubility and were more effective in mice bearing S180 tumours.
Hepatoprotective effects of salidroside on fulminant hepatic failure induced by d-galactosamine and lipopolysaccharide in mice
Authors: Wu Yan-Ling , Lian Li-Hua , Jiang Ying-Zi , Nan Ji-Xing
Published: October 2010

Objectives

The aim was to investigate the protective effect of salidroside isolated from Rhodiola sachalinensis A. Bor. (Crassulaceae) on d-galactosamine/lipopolysaccharide-induced fulminant hepatic failure.

Methods

Hepatotoxicity was induced by an intraperitoneal injection of d-galactosamine (700 mg/kg) and lipopolysaccharide (10 μg/kg); salidroside (20, 50 and 100 mg/kg) was administered intraperitoneally 1 h before induction of hepatoxicity. Liver injury was assessed biochemically and histologically.

Key findings

Salidroside attenuated the induced acute increase in serum aspartate aminotransferase and alanine aminotransferase activities, and levels of tumour necrosis factor-alpha levels and serum nitric oxide. It restored depleted hepatic glutathione, superoxide dismutase, catalase and glutathione peroxidase activities, decreased malondialdehyde levels and considerably reduced histopathological changes. Histopathological, immunohistochemical and Western blot analyses also demonstrated that salidroside could reduce the appearance of necrotic regions and expression of caspase-3 and hypoxia-inducible factor-1α in liver tissue.

Conclusions

Salidroside protected liver tissue from the oxidative stress elicited by d-galactosamine and lipopolysaccharide. The hepatoprotective mechanism of salidroside appear to be related to antioxidant activity and inhibition of hypoxia-inducible factor-1α.
Penetration of oseltamivir and its active metabolite into the brain after lipopolysaccharide-induced inflammation in mice
Authors: Oshima Shigeru , Nemoto Eiichi , Kuramochi Mika , Saitoh Yukiya , Kobayashi Daisuke
Published: October 2010

Objectives

Oseltamivir phosphate is used for the treatment of influenza virus infections. Recently, oral intake has been associated with abnormal behaviour. The present study examined the brain penetration of oseltamivir phosphate and oseltamivir carboxylate, its active metabolite, during inflammation.

Methods

Male C57BL/6 mice were given three i.p. injections of lipopolysaccharide (LPS) or saline. We studied the concentration of Evans blue (a marker of blood–brain barrier function) and oseltamivir phosphate and its active metabolite in the brain and plasma.

Key findings

The brain-to-plasma ratio of Evans blue compared with saline-treated control mice increased significantly with LPS dose. LPS-induced inflammation increased the permeation of drugs through the blood-brain barrier. The concentration of oseltamivir phosphate in both brain and plasma was 2-fold higher in mice treated with LPS than in control mice. Although the plasma concentration of the active carboxylate was not significantly altered by inflammation, the brain concentration was increased 2.7-fold in mice treated with LPS compared with control mice.

Conclusions

Administration of oseltamivir phosphate in the presence of inflammation increased the brain concentration of both parent drug and active metabolite, which may explain the central nervous system side-effects observed with this agent.
Antimalarial compounds isolated from plants used in traditional medicine
Authors: Bero Joanne , Frédérich Michel , Quetin-Leclercq Joëlle
Published: October 2010

Objectives

This review covers the compounds with antiplasmodial activity isolated from plants published from 2005 to the end of 2008, organized according to their phytochemical classes. Details are given for substances with IC50 values ≤ 11 μM.

Key findings

Malaria is a major parasitic disease in many tropical and subtropical regions and is responsible for more than 1 million deaths each year in Africa. The rapid spread of resistance encourages the search for new active compounds. Nature and particularly plants used in traditional medicine are a potential source of new antimalarial drugs as they contain molecules with a great variety of structures and pharmacological activities.

A large number of antimalarial compounds with a wide variety of structures have been isolated from plants and can play a role in the development of new antimalarial drugs. Ethnopharmacological approaches appear to be a promising way to find plant metabolites that could be used as templates for designing new derivatives with improved properties.
Non-phenolic radical-trapping antioxidants
Authors: Foti Mario C , Amorati Riccardo
Published: October 2010

Objectives

The aim of this review article is to introduce the reader to the mechanisms, rates and thermodynamic aspects of the processes involving the most biologically relevant non-phenolic radical-trapping antioxidants.

Key findings

Antioxidant defences in living organisms rely on a complex interplay between small molecules and enzymes, which cooperate in regulating the concentrations of potentially harmful oxidizing species within physiological limits. The noxious effects of an uncontrolled production of oxygen- and nitrogen-centered radicals are amplified by chain reactions (autoxidations), sustained mainly by peroxyl radicals (ROO•), that oxidize and alter essential biomolecules such as lipids, lipoproteins, proteins and nucleic acids.

Non-phenolic antioxidants represent an important and abundant class of radical scavengers in living organisms. These compounds react with peroxyl radicals through various mechanisms: (i) formal H-atom donation from weak X-H bonds (X = O, N, S), as in the case of ascorbic acid (vitamin C), uric acid, bilirubin and thiols; (ii) addition reactions to polyunsaturated systems with formation of C-radicals poorly reactive towards O2, for example β-carotene and all carotenoids in general; (iii) co-oxidation processes characterized by fast cross-termination reactions, for example γ-terpinene; and (iv) catalytic quenching of superoxide (O2•−) with a superoxide dismutase-like mechanism, for example di-alkyl nitroxides and FeCl3. Kinetic data necessary to evaluate and rationalize the effects of these processes are reported. The mechanisms underlying the pro-oxidant effects of ascorbate and other reducing agents are also discussed.
Montmorillonite adsorbs uric acid and increases the excretion of uric acid from the intestinal tract in mice
Authors: Ma Zhao , Long Li-hui , Liu Jing , Cao Yong-xiao
Published: October 2010

Objectives

The aim was to evaluate the adsorbing effect of montmorillonite on uric acid, promoting diffusion of uric acid from blood to intestine, preventing absorption of uric acid in intestine and reducing uric acid level in serum.

Methods

The adsorbing effect of montmorillonite on uric acid was observed in vitro. The intestine and blood vessel of rats were circularly perfused with intestinal perfusate and vascular perfusate, respectively. A model of hyperuricaemia in mice was prepared by intraperitoneal injection of hypoxanthine and potassium oteracil. The concentration of uric acid was determined by the method of urate oxidase and peroxide enzyme.

Key findings

The results showed that different concentrations of montmorillonite could adsorb uric acid in a concentration-dependent manner. The adsorbing effect was fast. The adsorptive rate was high in acid solution and was low in alkaline solution. When blood vessels were circularly perfused by vascular perfusate containing uric acid, the concentration of uric acid in vascular perfusate was decreased and the concentration of uric acid in intestinal perfusate was increased, suggesting that uric acid in blood vessels diffused into the intestine. When the intestine was perfused with intestinal perfusate containing uric acid, the uric acid concentration in vascular perfusate was increased, but the uric acid concentration of intestinal perfusate was decreased, suggesting that uric acid was absorbed in the intestine. The uric acid concentrations of intestinal perfusate and vascular perfusate in montmorillonite 0.5 and 1.0 g/kg groups were lower than the control group. Concentrations of uric acid in serum and urine in the montmorillonite 1 and 2 g/kg groups were lower compared with mice in the hyperuricaemic group.

Conclusions

The results suggested that montmorillonite adsorbed uric acid and promoted diffusion of uric acid from blood vessels to intestine, prevented absorption of uric acid in intestine and decreased uric acid level in serum.
Efficacy of different doses of aspirin in decreasing blood levels of inflammatory markers in patients with cardiovascular metabolic syndrome
Authors: Gao Xiu-ren , Adhikari Chandar M , Peng Long-yun , Guo Xiao-gang , Zhai Yuan-sheng , He Xu-yu , Zhang Li-Yuan , Lin Jun , Zuo Zhi-yi
Published: October 2010

Objectives

Inflammation and platelet aggregation and activation are key processes in the initiation of a cardiovascular event. Patients with metabolic syndrome have a high risk of cardiovascular events. This study determined whether small and medium doses of aspirin have anti-inflammation and antiplatelet aggregation effects in patients with metabolic syndrome.

Methods

One hundred and twenty-one consecutive patients with metabolic syndrome were randomized into three groups, receiving 100 mg/day of aspirin, 300 mg/day of aspirin or a placebo, respectively, for 2 weeks. The blood levels of thromboxane B2 (TXB2), a stable product of the platelet aggregation mediator TXA2, 6-keto-prostaglandin F1-α (6-keto-PGF1-α), a stable product of the endogenous cyclooxygenase metabolite prostaglandin I2, and inflammatory mediators including high-sensitivity C-reactive protein (hs-CRP), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were determined by ELISA and radioimmunoassay.

Key findings

The blood levels of hs-CRP, TNF-α, IL-6 and TXB2 were significantly decreased after 2 weeks of treatment with 300 mg/day of aspirin. Patients who received 100 mg/day of aspirin had decreased blood levels of hs-CRP and TXB2. The blood level of IL-6 in the 300 mg/day aspirin group was significantly lower than that in the other two groups after 2 weeks of therapy. Aspirin at either dose did not affect the blood level of 6-keto-PGF1-α.

Conclusions

Aspirin at all doses suppresses the blood levels of inflammatory markers and the platelet aggregation mediator TXA2 in Chinese patients with metabolic syndrome. Since the suppression induced by 300 mg/day of aspirin was greater than that induced by 100 mg/day of aspirin, these data suggest that 300 mg/day of aspirin may be beneficial in decreasing the risk of cardiovascular events in Chinese patients with metabolic syndrome.
Catecholamine-induced myocardial fibrosis and oxidative stress is attenuated by Terminalia arjuna (Roxb.)
Authors: Kumar Santosh , Enjamoori Rajesh , Jaiswal Amardeep , Ray Ruma , Seth Sandeep , Maulik Subir Kumar
Published: October 2010

Objectives

Myocardial fibrosis and oxidative stress accompany a number of cardiac disorders such as hypertrophic cardiomyopathy, hypertensive heart disease and cardiac failure. Stem bark of Terminalia arjuna has been advocated for cardiac ailments. The present study evaluated the effects of T. arjuna bark extract on myocardial fibrosis and oxidative stress induced by chronic beta-adrenoceptor stimulation.

Methods

Aqueous extract of T. arjuna bark was evaluated at 63, 125 and 250 mg/kg given orally for antifibrotic and antioxidant effects in rats given the selective β-adrenoceptor agonist isoprenaline (5 mg/kg s.c.) for 28 days. Captopril (50 mg/kg per day, given orally), an inhibitor of angiotensin-converting enzyme used as a standard cardioprotective drug, was used as a positive control.

Key findings

Isoprenaline caused fibrosis, increased oxidative stress and cardiac hypertrophy (increased heart weight: body weight ratio and cardiomyocyte diameter). The T. arjuna bark extract and captopril significantly prevented the isoprenaline-induced increase in oxidative stress and decline in endogenous antioxidant level. Both also prevented fibrosis but not the increase in heart weight: body weight ratio.

Conclusions

T. arjuna protects against myocardial changes induced by chronic beta-adrenoceptor stimulation.
Review: physical chemistry of solid dispersions
Authors: Janssens Sandrien , Van den Mooter Guy
Published: October 2010

Objectives

With poorly soluble drug candidates emerging in the drug discovery pipeline, the importance of the solid dispersion formulation approach is increasing. This strategy includes complete removal of drug crystallinity, and molecular dispersion of the poorly soluble compound in a hydrophilic polymeric carrier. The potential of this technique to increase oral absorption and hence bioavailability is enormous. Nevertheless, some issues have to be considered regarding thermodynamic instability, as well in supersaturated solutions that are formed upon dissolution as in the solid state.

Key findings

After a brief discussion on the historical background of solid dispersions and their current role in formulation, an overview will be given on the physical chemistry and stability of glass solutions as they form supersaturated solutions, and during their shelf life.

Conclusions

Thorough understanding of these aspects will elicit conscious evaluation of carrier properties and eventually facilitate rational excipient selection. Thus, full exploitation of the solid dispersion strategy may provide an appropriate answer to drug attrition due to low aqueous solubility in later stages of development.
Electrostatics of pharmaceutical inhalation aerosols
Authors: Kwok Philip Chi Lip , Chan Hak-Kim
Published: October 2010

Objectives

This review focuses on the key findings and developments in the rapidly expanding research area of pharmaceutical aerosol electrostatics.

Key findings

Data from limited in-vivo and computational studies suggest that charges may potentially affect particle deposition in the airways. Charging occurs naturally in the absence of electric fields through triboelectrification, that is contact or friction for solids and flowing or spraying for liquids. Thus, particles and droplets emitted from pulmonary drug delivery devices (dry powder inhalers, metered dose inhalers with or without spacers, and nebulisers) are inherently charged. Apparatus with various operation principles have been employed in the measurement of pharmaceutical charges. Aerosol charges are dependent on many physicochemical parameters, such as formulation composition, device construction, relative humidity and solid-state properties. In some devices, electrification has been purposefully applied to facilitate powder dispersion and liquid atomisation.

Currently, there are no regulatory requirements on characterising electrostatic properties of inhalation aerosols. As research in this area progresses, the new knowledge gained may become valuable for the development and regulation of inhalation aerosol products.
Investigations on cellular interaction of polyelectrolyte based nano-walled reservoir using MCF-7 cell lines: a novel chemotherapeutic approach
Authors: Gupta Girish K , Gupta Vivek K , Shukla Prashant , Pant Aditya B , Mishra Prabhat R
Published: October 2010

Objectives

A polyelectrolyte (PE) based nano-walled reservoir (NwR) was developed using alternate deposition of natural polyions on a decomposable core (CaCO3). The system was charged with paclitaxel (PTX) using the trigger property of an organic solvent (NwR-PTX). In addition, the surface of the nano-walled reservoir was modified with PE-PEG2000 (NwR-PTX-PEG)) in order to investigate any changes in the interaction of surface-modified polyelectrolyte shells with breast cancer cells, since surface chemistry greatly influences the performance of microcapsules in the biological environment.

Methods

The surface modification was confirmed by differential scanning calorimetry studies, which showed a shifting of the endothermic peak after pegylation. Layer-by-layer (LBL) growth of the system was confirmed by the sequential change in the ζ-potential. The release of paclitaxel from the formulations followed first order kinetics (r2 = 0.9), indicating matrix diffusion. The interaction of NwR-PTX with MCF-7 cell lines was investigated by coating the system with FITC-dextran (NwR-PTX-FITC) and quantitated using flow cytometry.

Key findings

Cellular uptake of positively charged NwR reached 56% after 4 h and 76% after 24 h. This was reduced significantly after pegylation. The negatively charged NwR reached only 49% after 24 h.

Conclusions

This study opens the possibility of specific targeting of tumour cells that can control the release of chemotherapeutic agent either by means of a physiological or chemical trigger. This suggests potential application of this system as a novel approach for the delivery of chemotherapeutic agents.
Effect of hepatic CYP inhibitors on the metabolism of sildenafil and formation of its metabolite,N-desmethylsildenafil, in ratsin vitroandin vivo
Authors: Bae Soo H , Bae Soo K , Lee Myung G
Published: October 2010

Objectives

It has been reported that hepatic cytochrome P450 (CYP)2C9 and CYP3A4 are responsible for the metabolism of sildenafil and formation of its metabolite, N-desmethylsildenafil, in humans. However, in-vivo studies in rats have not been reported.

Methods

Sildenafil (20 mg/kg) was administered intravenously to rats pretreated with sulfaphenazole, cimetidine, quinine hydrochloride or troleandomycin, inhibitors of CYP2C6, CYP2C11, CYP2D subfamily and CYP3A1/2, respectively. In-vitro studies using rat liver microsomes were also performed.

Key findings

The area under the plasma-concentration time curve (AUC) was increased and clearance of sildenafil decreased in rats pretreated with cimetidine or troleandomycin. The AUC ratio for N-desmethylsildenafil (0–4 h): sildenafil (0–∞) was significantly decreased only in rats pretreated with cimetidine. Similar results were obtained in the in-vitro study using rat liver microsomes.

Conclusions

Sildenafil is metabolised via hepatic CYP2C11 and 3A1/2, and N-desmethylsildenafil is mainly formed via hepatic CYP2C11 in rats. Thus, rats could be a good model for pharmacokinetic studies of sildenafil and N-desmethylsildenafil in humans.
Hypolipidaemic activity of orally administered diphenyl diselenide in Triton WR-1339-induced hyperlipidaemia in mice
Authors: Da Rocha Juliana Trevisan , Sperança Adriane , Nogueira Cristina Wayne , Zeni Gilson
Published: October 2010

Objectives

A significant association between the trace element selenium and hyper-cholesterolaemia has been reported. This study was designed to investigate a potential hypolipidaemic effect of diphenyl diselenide ((PhSe)2) in Triton WR-1339-induced hyperlipidaemia in mice.

Methods

Triton was administered intraperitoneally (400 mg/kg) to overnight-fasted mice to develop acute hyperlipidaemia. (PhSe)2 was administered orally (10 mg/kg) 30 min before Triton. At 24 h after Triton injection, blood samples were collected to measure plasma lipid levels. The hepatic thiobarbituric acid reactive substances and ascorbic acid levels as well as catalase and glutathione peroxidase activity were recorded.

Key findings

(PhSe)2 administration significantly lowered total cholesterol, non-high-density lipoprotein-cholesterol and triglycerides, whilst it increased high-density lipoprotein-cholesterol levels in plasma of hyperlipidaemic mice. Neither oxidative stress nor the antioxidant effect of (PhSe)2 was observed in the mouse liver in this experimental protocol.

Conclusions

These findings indicated that (PhSe)2 was able to lower plasma lipid concentrations. Further studies are needed to elucidate the exact mechanism by which (PhSe)2 exerted its hypolipidaemic effect in the management of hyperlipidaemia and atherosclerosis.