bluuebunny/crossref_metadata_2025 huggingface dataset:
The importance of brain PGE2 inhibition versus paw PGE2 inhibition as a mechanism for the separation of analgesic and antipyretic effects of lornoxicam in rats with paw inflammation
Authors: Futaki Nobuko , Harada Masahiro , Sugimoto Masanori , Hashimoto Yuki , Honma Yusuke , Arai Iwao , Nakaike Shiro , Hoshi Keiko
Published: October 2010

Objectives

Lornoxicam is a non-selective cyclooxygenase inhibitor that exhibits strong analgesic and anti-inflammatory effects but a weak antipyretic effect in rat models. Our aim was to investigate the mechanism of separation of potencies or analgesic and antipyretic effecls of lornoxicam in relatioin to its effect on prostaglandin E2 (PGE2) production in the inflammatory paw and the brain.

Methods

A model of acute or chronic paw inflammation was induced by Freund's complete adjuvant injection into the rat paw. Lornoxicam (0.01–1 mg/kg), celecoxib (0.3–30 mg/kg) or loxoprofen (0.3–30 mg/kg) was administered orally to the rats and the analgesic and antipyretic effects were compared. The paw hyperalgesia was assessed using the Randall–Selitto test or the flexion test. Dorsal subcutaneous body temperature was measured as indicator of pyresis. After the measurement of activities, the rats were sacrificed and the PGE2 content in the paw exudate, cerebrospinal fluid or brain hypothalamus was measured by enzme-immunoassay.

Key findings

In a chronic model of arthritis, lornoxicam, celecoxib and loxoprofen reduced hyperalgesia with an effective dose that provides 50% inhibition (ED50) of 0.083, 3.9 and 4.3 mg/kg respectively, whereas the effective dose of these drugs in pyresis was 0.58, 0.31 and 0.71 mg/kg respectively. These drugs significantly reduced the PGE2 level in paw exudate and the cerebrospinal fluid. In acute oedematous rats, lornoxicam 0.16 mg/kg, celecoxib 4 mg/kg and loxoprofen 2.4 mg/kg significantly reduced hyperalgesia to a similar extent. On the other hand, lornnoxicam did not affect the elevated body temperature, whereas celecoxib and loxoprofen siginificantly reduced the pyrexia to almost the normal level. These drugs significantly reduced the PGE2 level in inflamed paw exudate lo almost the normal level. On the other hand, lornoxicam did not change PGE2 level in the brain hypothalamus, whereas celecoxib and loxoprofen strongly decreased it.

Conclusions

Lornoxicam exhibits strong analgesic but weak antipyretic effects in rats with paw inflammation. Such a separation of effects is related to its efficacy in the reduction of PGE2 levels in the paw and brain hypothalamus.
Influence of dosing schedules on toxicity and antitumour effects of combined cisplatin and docetaxel treatment in mice
Authors: Kodama Ayumi , To Hideto , Kinoshita Tomohiro , Ieiri Ichiro , Higuchi Shun
Published: October 2010

Objectives

The combination of cisplatin and docetaxel shows a better cure rate against non-small-cell lung cancer than other drug combinations in clinical studies; however, severe myelosuppression and nephrotoxicity are dose-limiting factors. The purpose of this study was to establish a suitable dosing schedule to reduce adverse effects and improve the antitumour effects.

Methods

Cisplatin and docetaxel were administered i.p. to male ICR mice simultaneously, or sequentially with either cisplatin or docetaxel first followed by the second drug 12 h later (docetaxel–cisplatin and cisplatin–docetaxel groups). Antitumour effects of these schedules were also tested in C57BL/6N mice bearing Lewis lung carcinomas.

Key findings

The simultaneous docetaxel/cisplatin group showed the lowest survival rate and the highest blood urea nitrogen (BUN) concentration. Cisplatin concentrations in the plasma and kidney were higher in the simultaneous dosing group than the sequential dosing groups. Antitumour effect was the greatest in the docetaxel–cisplatin group.

Conclusions

The docetaxel–cisplatin regimen inhibited tumour growth the best and reduced mortality and nephrotoxicity.
Mechanisms involved in the antinociceptive and anti-inflammatory effects of bis selenide in mice
Authors: Jesse Cristiano R , Savegnago Lucielli , Nogueira Cristina W
Published: October 2010

Objectives

The present study examined the mechanisms involved in the antinociceptive effects of bis selenide [(Z)-2,3-bis(4-chlorophenylselanyl)prop-2-en-1-ol].

Methods

The effects of oral bis selenide were tested against licking behaviour and oedema in mice induced by formalin, serotonin, histamine, glutamate, phorbol 12-myristate 13-acetate (PMA), 8-bromoadenosine 3′,5′-cyclic monophosphate (8-BrcAMP) and pros-taglandin E2. The effects of a variety of receptor antagonists on the antinociceptive activity were tested to determine the likely mechanism of action of bis selenide.

Key findings

Bis selenide caused antinociception on the first and second phases of the formalin test, with mean ID50 values of 34.21 (29.66–39.45) and 15.86 (12.17–20.67) mg/kg and maximal inhibition of 65 ± 3% and 90 ± 1%, respectively. At 50 mg/kg bis selenide significantly inhibited (31 ± 2%) paw oedema induced by intraplantar injection of formalin. At 25 mg/kg given 5 min after the formalin injection, bis selenide caused a significant inhibition (42 ± 5%) in the second phase of the formalin test, whereas the prophylactic treatment caused more intense inhibition (64 ± 3%). Oral administration of bis selenide reduced licking and paw oedema induced by serotonin, histamine, glutamate, PGE2, PMA and 8-BrcAMP. The antinociceptive effect of bis selenide (25 mg/kg, p.o.) on the formalin test was reversed by i.p. administration of p-chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis), ketanserin (a selective 5-HT2a receptor antagonist), ondansetron (a 5-HT3 receptor antagonist) and ranitidine (a histamine H2-receptor antagonist).

Conclusions

Glutamatergic, prostaglandin E2, serotonergic (5-HT2a and 5-HT3) and histamine H2 receptors are involved in the antinociceptive effects of bis selenide in mice. The interaction of bis selenide with protein kinase C and A signalling pathways was also demonstrated.
Recent cancer drug development with xanthone structures
Authors: Na Younghwa
Published: October 2010

Objectives

Xanthones are simple three-membered ring compounds that are mainly found as secondary metabolites in higher plants and microorganisms. Xanthones have very diverse biological profiles, including antihypertensive, antioxidative, antithrombotic and anticancer activity, depending on their diverse structures, which are modified by substituents on the ring system. Although several reviews have already been published on xanthone compounds, few of them have focused on the anticancer activity of xanthone derivatives. In this review we briefly summarize natural and synthetic xanthone compounds which have potential as anticancer drugs.

Key findings

The interesting structural scaffold and pharmacological importance of xanthone derivatives have led many scientists to isolate or synthesize these compounds as novel drug candidates. In the past, extensive research has been conducted to obtain xanthone derivatives from natural resources as well as through synthetic chemistry. Xanthones interact with various pharmacological targets based on the different substituents on the core ring. The anticancer activities of xanthones are also dramatically altered by the ring substituents and their positions.

The biological activities of synthetic xanthone derivatives depend on the various substituents and their position. Study of the biological mechanism of action of xanthone analogues, however, has not been conducted extensively compared to the diversity of xanthone compounds. Elucidation of the exact biological target of xanthone compounds will provide better opportunities for these compounds to be developed as potent anticancer drugs. At the same time, modification of natural xanthone derivatives aimed at specific targets is capable of expanding the biological spectrum of xanthone compounds.
l-Carnosine: multifunctional dipeptide buffer for sustained-duration topical ophthalmic formulations
Authors: Singh Swita R , Carreiro Samantha T , Chu Jessie , Prasanna Ganesh , Niesman Michael R , Collette Walter W , Younis Husam S , Sartnurak Soisurin , Gukasyan Hovhannes J
Published: October 2010

Objectives

The use of L-carnosine as an excipient in topical ophthalmic formulations containing gellan gum, a carbohydrate polymer with in-situ gelling properties upon mixing with mammalian tear fluid, was developed as a novel platform to extend precorneal duration. Specific utilisation of L-carnosine as a buffer in gellan gum carrying vehicles was characterised.

Methods

Buffer capacity was evaluated using 7.5, 13.3, and 44.2 mM L-carnosine in a pH range of 5.5–7.5. Accelerated chemical stability was determined by HPLC at L-carnosine concentrations of 5–100 mM. Combinations of 7.5 mM L-carnosine with 0.06–0.6% (w/v) gellan gum were characterised rheologically. L-Carnosine-buffered solutions of gellan gum were tested for acute topical ocular tolerance in vivo in pigmented rabbits. A unique formulation combining timolol (which lowers intraocular pressure) in L-carnosine-buffered gellan gum was compared with Timoptic-XE in normotensive dogs.

Key findings

L-Carnosine exhibited optimal pharmaceutical characteristics for use as a buffer in chronically administered topical ocular formulations. Enhancement trends were observed in solution-to-gel transition of L-carnosine-buffered vehicles containing gellan gum vs comparators. Topical tolerability of L-carnosine-buffered gellan gum formulations and lowering of intraocular pressure were equivalent with timolol and Timoptic-XE.

Conclusions

Functional synergy between excipients in gellan gum formulations buffered with L-carnosine has potential for topical ocular dosage forms with sustained precorneal residence.
Evaluation of population pharmacokinetic models for amikacin dosage individualization in critically ill patients
Authors: de Gatta María del Mar Fernández , Moreno Silvia Romano , Calvo María Victoria , Ardanuy Ramón , Domínguez-Gil Alfonso , Lanao José M
Published: October 2010

Objectives

The aim of this study was to evaluate the reliability for dosage individualization and Bayesian adaptive control of several literature-retrieved amikacin population pharmacokinetic models in patients who were critically ill.

Methods

Four population pharmacokinetic models, three of them customized for critically-ill patients, were applied using pharmacokinetic software to fifty-one adult patients on conventional amikacin therapy admitted to the intensive care unit. An estimation of patient-specific pharmacokinetic parameters for each model was obtained by retrospective analysis of the amikacin serum concentrations measured (n = 162) and different clinical covariates. The model performance for a priori estimation of the area under the serum concentration-time curve (AUC) and maximum serum drug concentration (Cmax) targets was obtained.

Key findings

Our results provided valuable confirmation of the clinical importance of the choice of population pharmacokinetic models when selecting amikacin dosages for patients who are critically ill. Significant differences in model performance were especially evident when only information concerning clinical covariates was used for dosage individualization and over the two most critical determinants of clinical efficacy of amikacin i.e. the AUC and Cmax values.

Conclusions

Only a single amikacin serum level seemed necessary to diminish the influence of population model on dosage individualization.
Hypercholesterolaemia induces early renal lesions characterized by upregulation of MMP-9 and iNOS and ETAR: alleviated by a dual endothelin receptor antagonist CPU0213 and simvastatin
Authors: Luo Lu , Dai De-Zai , Zheng Yu-Fen , Dai Yin
Published: October 2010

Objectives

We aimed to investigate hypercholesterolaemia-induced early renal lesions which result in abnormal expression of endothelin A receptor (ETAR), induced nitric oxide synthase (iNOS) and matrix metalloproteinase 9 (MMP-9). We hypothesized that this is due to an upregulated endothelin (ET) pathway consequent to hypercholesterolaemia and that CPU0213, a dual ET antagonist, could mitigate these changes.

Methods

Rats were randomly divided into four groups: (1), control; (2), high-fat diet for 60 days (HFD); HFD rats medicated in the last 15 days with either (3) CPU0213 (30 mg/kg daily, s.c.) or (4) simvastatin (4 mg/kg daily, p.o.).

Key findings

Body weight, serum triglycerides, total cholesterol and low-density-lipoprotein cholesterol were significantly increased, whereas high-density lipoprotein cholesterol decreased in the HFD group, relative to normal. Meanwhile, these changes were associated with upregulation of mRNA and protein of ETAR, iNOS and MMP-9 in the kidney. The lipid-lowering effect of simvastatin was predominant, lessening abnormal expression of these molecules in the kidney dramatically. Interestingly, CPU0213 significantly normalized expression of mRNA and protein of ETAR, iNOS and MMP-9, comparable with simvastatin, leaving no changes in hyperlipidaemia.

Conclusions

CPU0213 relieves renal lesions by blunting hypercholesterolaemia caused by the upregulated ET system, iNOS and MMP-9 in the kidney. This indicates that CPU0213 is promising in treating patients with end stage renal disease.
Study on the antidiabetic mechanism of a shark liver peptide, S-8300, in alloxan-induced diabetes
Authors: Huang Fengjie , Wu Wutong
Published: October 2010

Objectives

The aim was to evaluate the antidiabetic mechanism of S-8300 in alloxandiabetic mice.

Methods

Diabetes was induced by a single intravenous injection of alloxan (60 mg/kg). The effects of S-8300 on diabetic mice were investigated by observing the change in fasting plasma glucose, detecting Fas mRNA by reverse transcriptase-polymerase chain reaction, Fas protein expression in the pancreas by immunohistochemistry and Western blot, and the DNA fragmentation pattern forming a ladder by electrophoresis.

Key findings

A significant decrease in fasting plasma glucose was observed, and Fas mRNA and Fas protein expression in the pancreas were attenuated in diabetic mice treated with S-8300. Treatment with S-8300 also attenuated DNA ladder formation.

Conclusions

The results suggest that S-8300 inhibits Fas protein-mediated apoptosis of pancreas cells.
Hepatoprotective effect of chrysin on prooxidant-antioxidant status during ethanol-induced toxicity in female albino rats
Authors: Sathiavelu Jayanthi , Senapathy Giftson Jebakkan , Devaraj Rajkumar , Namasivayam Nalini
Published: October 2010

Objectives

To evaluate the effect of chrysin, a natural, biologically active compound extracted from many plants, honey and propolis, on the tissue and circulatory antioxidant status, and lipid peroxidation in ethanol-induced hepatotoxicity in rats.

Methods

Rats were divided into four groups. Groups 1 and 2 received isocaloric glucose. Groups 3 and 4 received 20% ethanol, equivalent to 5 g/kg bodyweight every day. Groups 2 and 4 received chrysin (20 mg/kg bodyweight) dissolved in 0.5% dimethylsulfoxide.

Key findings

The results showed significantly elevated levels of tissue and circulatory thiobarbituric acid reactive substances, conjugated dienes and lipid hydroperoxides, and significantly lowered enzymic and non-enzymic antioxidant activity of superoxide dismutase, catalase and glutathione-related enzymes such as glutathione peroxidase, glutathione reductase, glutathione-S-transferase, reduced glutathione, vitamin C and vitamin E in ethanol-treated rats compared with the control. Chrysin administration to rats with ethanol-induced liver injury significantly decreased the levels of thiobarbituric acid reactive substances, lipid hydroperoxides and conjugated dienes, and significantly elevated the activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase and the levels of reduced glutathione, vitamin C and vitamin E in the tissues and circulation compared with those of the unsupplemented ethanol-treated rats. The histological changes observed in the liver and kidney correlated with the biochemical findings.

Conclusions

Chrysin offers protection against free radical-mediated oxidative stress in rats with ethanol-induced liver injury.
Glutathione depletion upregulates P-glycoprotein expression at the blood-brain barrier in rats
Authors: Wu Jing , Hong Hao , Ji Hui , Wang Ying Yu , Wang Ying , Li Yong Qi , Li Wei Guang , Long Yan , Xia Yuan Zheng
Published: October 2010

Objectives

Glutathione (GSH) depletion has been implicated in the pathogenesis of neurological diseases. During GSH depletion, cells of the blood-brain barrier are subjected to chronic oxidative stress. Using an in-vivo system, we have investigated whether glutathione depletion changed expression of P-glycoprotein at the blood-brain barrier in rats.

Methods

Diethyl maleate was intraperitoneally injected to induce GSH depletion in rats. P-glycoprotein expression at the blood-brain barrier was examined by Western blotting and RT-PCR, and its function was assessed by measuring the brain-to-plasma concentration ratios (Kp values) of rhodamine 123 (Rh123). Evans Blue dye was used as a blood-brain barrier indicator for examining the extravasation from the blood to the brain.

Key findings

Four hours after treatment of rats with diethyl maleate, the brain GSH content significantly reduced. The mdr1a mRNA expression at the blood-brain barrier was upregulated, whereas no significant change in mdr1b mRNA expression was found. The P-glycoprotein level was significantly increased compared with control rats. At the same time, the Kp values of Rh123 suggested that function of P-glycoprotein was significantly enhanced at the blood-brain barrier in rats with GSH depletion induced by diethyl maleate. No significant difference of the Evans Blue dye concentration in the brain cortex was found between GSH depletion rats and control rats. Treatment of rats with N-acetylcysteine decreased P-glycoprotein upregulation induced by diethyl maleate.

Conclusions

The oxidative stress induced by GSH depletion played a positive role in the regulation of function and expression of P-glycoprotein at the blood-brain barrier in rats.
Cannabinoid receptor ligands as potential anticancer agents — high hopes for new therapies?
Authors: Oesch Susanne , Gertsch Jürg
Published: October 2010

Objectives

The endocannabinoid system is an endogenous lipid signalling network comprising arachidonic-acid-derived ligands, cannabinoid (CB) receptors, transporters and endocannabinoid degrading enzymes. The CB1 receptor is predominantly expressed in neurons but is also co-expressed with the CB2 receptor in peripheral tissues. In recent years, CB receptor ligands, including Δ9-tetrahydrocannabinol, have been proposed as potential anticancer agents.

Key findings

This review critically discusses the pharmacology of CB receptor activation as a novel therapeutic anticancer strategy in terms of ligand selectivity, tissue specificity and potency. Intriguingly, antitumour effects mediated by cannabinoids are not confined to inhibition of cancer cell proliferation; cannabinoids also reduce angiogenesis, cell migration and metastasis, inhibit carcinogenesis and attenuate inflammatory processes. In the last decade several new selective CB1 and CB2 receptor agents have been described, but most studies in the area of cancer research have used non-selective CB ligands. Moreover, many of these ligands exert prominent CB receptor-independent pharmacological effects, such as activation of the G-protein-coupled receptor GPR55, peroxisome proliferator-activated receptor gamma and the transient receptor potential vanilloid channels.

The role of the endocannabinoid system in tumourigenesis is still poorly understood and the molecular mechanisms of cannabinoid anticancer action need to be elucidated. The development of CB2-selective anticancer agents could be advantageous in light of the unwanted central effects exerted by CB1 receptor ligands. Probably the most interesting question is whether cannabinoids could be useful in chemoprevention or in combination with established chemotherapeutic agents.
Enhanced skin delivery of quercetin by microemulsion
Authors: Kitagawa Shuji , Tanaka Yuko , Tanaka Manami , Endo Kanako , Yoshii Akiko
Published: October 2010

Objectives

For topical application of quercetin it is necessary to improve the low efficiency of its intradermal delivery as well as its low solubility in aqueous and organic vesicles. The aim of this study was to determine the usefulness of a microemulsion for that purpose.

Methods

A microemulsion consisting of isopropyl myristate, 150 mm NaCl solution, Tween 80 and ethanol was prepared. The skin delivery of quercetin by microemulsion using excised guinea-pig and Yucatan micropig skin in Franz diffusion cells was examined. Lipid peroxidation in skin was also tested using iron(II) and citrate.

Key findings

Using a w/o microemulsion as a vehicle, intradermal delivery of quercetin was significantly increased, as was its solubility. Quercetin penetrated deep into the skin, but no transfer was observed into the receptor compartment. It was confirmed that quercetin retained in the skin dose-dependently inhibited lipid peroxidation.

Conclusions

The findings indicate the potential use of microemulsions for the skin delivery of quercetin, where it exerts antioxidative effects.
Preparation and in-vitro bioactivity of a novel superantigen conjugate targeting bladder carcinoma
Authors: Zhen Gong , Cong-hui Han , Lin Hao , Jian-jun Yang , Wen-hao Tang , Gao-jun Teng
Published: October 2010

Objectives

Superantigens have shown potent effects against bladder tumours by inducing Vβ-specific T-lymphocyte proliferation and massive cytokine release but therapeutic benefit is compromised by cytotoxicity towards non-malignant cells and hypotoxicity to major histocompability complex (MHC) II-negative tumour cells. We are therefore interested in a conjugate preparation of a monoclonal antibody (MAb)—superantigens conjugate for which these drawbacks would be resolved.

Methods

The Fab fragment of the anti-bladder carcinoma MAb BDI-1 was conjugated to one member of the staphylococcal enterotoxin A (SEA) superantigen using the chemical conjugating reagent, N-succinimidyl 3-(2-pyridyldithio) propionate.

Results

After HPLC purification through a Superdex-200 gel column, another peak with a molecular mass of 250 KDa was observed before Fab and SEA were eluted. Indirect immunocytochemical analysis and immunofluorescence tests showed that the cell membranes of most human bladder cancer cells were positively stained only by the conjugate, confirming the ability of the conjugate to target human bladder carcinoma. Peripheral blood mononuclear cell proliferation and cytokine release were similar with the conjugate and SEA. Cytotoxicity targeting in MHC II-negative bladder cancer cell lines, evaluated by flow cytometry, showed significant differences between the conjugate and SEA, whereas there was no difference in the Lovo colon cancer cell line.

Conclusions

These findings indicate the conjugate of SEA protein and BDI-1 Fab fragment was prepared successfully and targeted bladder carcinoma in vitro.
Metabolic interactions with piperazine-based ‘party pill’ drugs
Authors: Antia Ushtana , Tingle Malcolm D , Russell Bruce R
Published: October 2010

Objectives

‘Party pills’ have found use worldwide as a substitute for amphetamine-derived designer drugs. Whilst some information exists about the metabolism of these drugs, there is little information about their ability to inhibit the metabolism of co-administered drugs. This study aimed to determine whether predictions can be made about global interactions between ‘party pills’ constituents and other drugs metabolised by the same cytochrome P450 (CYP) isoenzymes.

Methods

The inhibitory effects of seven benzyl and phenyl piperazines were measured in microsomal incubation assays of probe substrates for five major CYP isoenzymes. In addition, the metabolism of benzylpiperazine and trifluoromethylphenylpiperazine, the two most commonly used constituents of ‘party pills’, was investigated using human liver microsomes assays and known inhibitors of CYP isoenzymes.

Key findings

All piperazine analogues tested showed significant inhibitory activity against most, if not all, isoenzymes tested. The metabolism of benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) involved CYP2D6, CYP1A2 and CYP3A4. Furthermore, BZP and TFMPP inhibited each other's metabolism.

Conclusions

Fluorophenylpiperazine, methoxyphenylpiperazine, chlorophenylpiperazine, methylbenzylpiperazine and methylenedioxybenzylpiperazine had significant inhibitory effects on CYP2D6, CYP1A2, CYP3A4, CYP2C19 and CYP2C9 isoenzymes but each piperazine had a different inhibitory profile. The metabolic interaction between BZP and TFMPP may have clinical implications, as these agents are often combined in ‘party pills’.
Whole-body physiologically based pharmacokinetic population modelling of oral drug administration: inter-individual variability of cimetidine absorption
Authors: Willmann Stefan , Edginton Andrea N , Kleine-Besten Marcus , Jantratid Ekarat , Thelen Kirstin , Dressman Jennifer B
Published: October 2010

Objectives

Inter-individual variability of gastrointestinal physiology and transit properties can greatly influence the pharmacokinetics of an orally administered drug in vivo. To predict the expected range of pharmacokinetic plasma concentrations after oral drug administration, a physiologically based pharmacokinetic population model for gastrointestinal transit and absorption was developed and evaluated.

Methods

Mean values and variability measures of model parameters affecting the rate and extent of cimetidine absorption, such as gastric emptying, intestinal transit times and effective surface area of the small intestine, were obtained from the literature. Various scenarios incorporating different extents of inter-individual physiological variability were simulated and the simulation results were compared with experimental human study data obtained after oral cimetidine administration of four different tablets with varying release kinetics.

Key findings

The inter-individual variability in effective surface area was the largest contributor to absorption variability. Based on in-vitro dissolution profiles, the mean plasma cimetidine concentration–time profiles as well as the inter-individual variability could be well described for three cimetidine formulations. In the case of the formulation with the slowest dissolution kinetic, model predictions on the basis of the in-vitro dissolution profile underestimated the plasma exposure.

Conclusions

The model facilitates predictions of the inter-individual pharmacokinetic variability after oral drug administration for immediate and extended-release formulations of cimetidine, given reasonable in-vitro dissolution kinetics.
Interaction of morphine but not fentanyl with cerebral α2-adrenoceptors in α2-adrenoceptor knockout mice
Authors: Höcker Jan , Böhm Ruwen , Meybohm Patrick , Gruenewald Matthias , Renner Jochen , Ohnesorge Henning , Scholz Jens , Bein Berthold
Published: October 2010

Objectives

α2-Adrenergic and μ-opioid receptors belong to the rhodopsin family of G-protein coupled receptors and mediate antinociceptive effects via similar signal transduction pathways. Previous studies have revealed direct functional interactions between both receptor systems including synergistic and additive effects. To evaluate underlying mechanisms, we have studied whether morphine and fentanyl interacted with α2-adrenoceptor-subtypes in mice lacking one individual α2-adrenoceptor-subtype (α2-adrenoceptor knockout).

Methods

Opioid interaction with α2-adrenoceptors was investigated by quantitative receptor autoradiography in brain slices of α2A-, α2B- or α2C-adrenoceptor deficient mice. Displacement of the radiolabelled α2-adrenoceptor agonist [125I]paraiodoclonidine from α2-adrenoceptors in different brain regions by increasing concentrations of morphine, fentanyl and naloxone was analysed. The binding affinity of both opioids to α2-adrenoceptor subtypes in different brain regions was quantified.

Key findings

Morphine but not fentanyl or naloxone provoked dose-dependent displacement of [125I]paraiodoclonidine from all α2-adrenoceptor subtypes in the brain regions analysed. Binding affinity was highest in cortex, medulla oblongata and pons of α2A-adrenoceptor knockout mice.

Conclusions

Our results indicated that morphine interacted with α2-adrenoceptors showing higher affinity for the α2B and α2C than for the α2A subtype. In contrast, fentanyl and naloxone did not show any relevant affinity to α2-adrenoceptors. This effect may have an impact on the pharmacological actions of morphine.
Hexa-, hepta- and nonaprenylhydroquinones isolated from marine sponges Sarcotragus muscarum and Ircinia fasciculata inhibit NF-k B signalling in H4IIE cells
Authors: Wätjen Wim , Putz Annika , Chovolou Yvonni , Kampkötter Andreas , Totzke Frank , Kubbutat Michael H G , Proksch Peter , Konuklugil Belma
Published: October 2010

Objectives

Marine organisms have proven to be a rich source of potent pharmacologically active compounds. Three polyprenyl-1,4-hydroquinone derivates (hexaprenyl-1,4-hydroquinone, heptaprenyl-1,4-hydroquinone and nonaprenyl-1,4-hydroquinone) were isolated from the Zoobenthos-inhabiting sponges Sarcotragus muscarum and Ircinia fasciculata from the Eastern Mediterranean Sea (phylum: Porifera; class: Demospongiae).

Methods

Hexa-, hepta- and nonaprenylhydroquinone were identified by 1H-NMR, H,H-COSY, heteronuclear multiple bond correlation, FAB-MS and UV spectroscopy. The effects of the compounds on cell viability was determined using the MTT assay; anti-oxidative potential was measured using the Trolox equivalent antioxidative capacity assay. Inhibition of nuclear factor-k B activity was detected by secreted alkaline phosphatase assay. Activity against an array of protein kinases was determined in 96-well FlashPlates.

Key findings

All compounds had prominent antioxidative activity, comparable to that of the synthetic vitamin E derivate Trolox. Hexaprenylhydroquinone showed the greatest cytotoxicity in H4IIE hepatoma cells (EC50 2.5 μM). All three compounds inhibited NF-k B signalling in this cell line, with heptaprenylhydroquinone being the most active. Screening of 23 kinases involved in signal transduction pathways (cell proliferation, survival, angiogenesis and metastasis) showed that hexaprenylhydroquinone and heptaprenylhydroquinone inhibited the activity of the epidermal growth factor receptor (IC50 1.6 and 1.4 μg/ml, respectively), and heptaprenylhydroquinone also inhibited the activity of other kinases (Src tyrosine kinase, vascular endothelial growth factor receptor 3 and insulin-like growth factor 1 receptor).

Conclusions

The prenylated hydroquinones isolated from the marine sponges S. muscarum and I. fasciculata showed cytotoxic and antioxidative activities and inhibited NF-k B signalling in H4IIE hepatoma cells and protein kinases. These findings may result in the generation of new lead substances in cancer therapy.
Protection afforded by a herbal medicine, Sho-seiryu-to (TJ-19), against oleic acid-induced acute lung injury in guinea-pigs
Authors: Yang Chang-qing , Ishitsuka Yoichi , Moriuchi Hiroshi , Golbidi Saeid , Jin Zhen-ji , Irikura Mitsuru , Irie Tetsumi
Published: October 2010

Objectives

The effect of a herbal medicine, Sho-seiryu-to (TJ-19), on oleic acid-induced lung injury, an animal model of acute respiratory distress syndrome or acute lung injury (ARDS/ALI), was examined.

Methods

Acute lung injury was induced by an intravenous injection of 15 μl/kg oleic acid to guinea-pigs. TJ-19 was administered by a single oral dose (3 g/kg) or by multiple oral doses (0.75 g/kg).

Key findings

The decrease in partial oxygen pressure of arterial blood (Pao2) and the increase in airway vascular permeability induced by the oleic acid injection were attenuated by a single dose of TJ-19. When TJ-19 was administered orally twice a day for two weeks and then oleic acid was injected, a potent prophylactic effect of the drug was observed. TJ-19 also prevented airway vascular hyperpermeability, lung cell injury, oxidative stress and thromboxane A2 generation, associated with the oleic acid injection.

Conclusions

TJ-19 significantly attenuated the oleic acid-induced lung injury probably through the antioxidative effect and inhibitory effect of thromboxane A2 generation, although the precise inhibitory mechanisms were not fully elucidated due to the diversity in constituents of the herbal medicine. We suggest that TJ-19 is a promising drug candidate and a medicinal resource for preventing ARDS/ALI.
Protection of DNA and membranes from gamma-radiation induced damages by Centella asiatica
Authors: Joy Jisha , Nair Cherupally Krishnan Krishnan
Published: October 2010

Objectives

The objective of the present study was to examine the ability of Centella asiatica extract to offer protection to DNA and membranes against the deleterious effects of ionizing radiation exposure.

Methods

Protection of DNA under in-vitro conditions of irradiation was estimated using plasmid relaxation assay. For in-vivo studies the extract was administered orally to mice exposed to whole-body γ-radiation. The ability of the extract to offer protection against whole-body γ-radiation exposure was analysed by performing an alkaline comet assay on mouse bone marrow cells. The extent of lipid peroxidation was estimated using the TBARS (thio-barbituric acid reacting substances) method, in order to monitor membrane damage. Radiation-induced mortality of the animals following a lethal dose of γ-radiation was also examined.

Key findings

Centella asiatica extract significantly reduced radiation-induced damage to DNA. The extent of radiation-induced mortality and lipid peroxidation was also found to be considerably reduced in animals administered with the extract.

Conclusions

Centella asiatica rendered radioprotection to DNA and membranes against radiation exposure, both in vitro and in vivo. We have earlier reported that administration of the extract can prevent a radiation-induced decline in antioxidant enzyme levels. This suggests that radioprotection by Centella asiatica extract could be mediated by mechanisms that act in a synergistic manner, especially involving antioxidant activity.
Characterization of the effect of penehyclidine hydrochloride on muscarinic receptor subtypes mediating the contraction of guinea-pig isolated gastrointestinal smooth muscle
Authors: Xiao Hong-tao , Liao Zhi , Meng Xian-min , Yan Xiao-yan , Chen Shu-jie , Mo Zheng-ji
Published: October 2010

Objectives

The aim was to characterize the effect of penehyclidine hydrochloride, which mediates the relaxation of guinea-pig isolated gastrointestinal smooth muscle, on muscarinic receptor subtypes.

Methods

Radioimmune assay was used to determine cAMP levels in isolated guinea-pig gastrointestinal smooth muscle to compare the selective effects of penehyclidine hydrochloride on muscarinic receptor subtypes.

Key findings

The results indicated that the relaxing effect of penehyclidine hydro-chloride on isolated gastrointestinal smooth muscle contraction induced by acetylcholine was stronger than that of atropine (based on PA2 values). In the radioimmune assay, penehyclidine hydrochloride increased the cAMP content in isolated guinea-pig stomach smooth muscle and decreased the cAMP content in isolated guinea-pig intestinal smooth muscle, but the difference was not statistically significant at a dose of 10 μmol/1.

Conclusions

The results suggest that penehyclidine hydrochloride has little or no effect on M2 receptor subtypes in guinea-pig gastrointestinal smooth muscle.
Immunomodulatory activity of Zingiber officinale Roscoe, Salvia officinalis L. and Syzygium aromaticum L. essential oils: evidence for humor- and cell-mediated responses
Authors: Carrasco Fábio Ricardo , Schmidt Gustavo , Romero Adriano Lopez , Sartoretto Juliano Luiz , Caparroz-Assef Silvana Martins , Bersani-Amado Ciomar Aparecida , Cuman Roberto Kenji Nakamura
Published: October 2010

Objectives

The immunomodulatory effect of ginger, Zingiber officinale (Zingiberaceae), sage, Salvia officinalis (Lamiaceae) and clove, Syzygium aromaticum (Myrtaceae), essential oils were evaluated by studying humor- and cell-mediated immune responses.

Methods

Essential oils were administered to mice (once a day, orally, for a week) previously immunized with sheep red blood cells (SRBCs).

Key findings

Clove essential oil increased the total white blood cell (WBC) count and enhanced the delayed-type hypersensitivity (DTH) response in mice. Moreover, it restored cellular and humoral immune responses in cyclophosphamide-immunosuppressed mice in a dose-dependent manner. Ginger essential oil recovered the humoral immune response in immunosuppressed mice. Contrary to the ginger essential oil response, sage essential oil did not show any immunomodulatory activity.

Conclusions

Our findings establish that the immunostimulatory activity found in mice treated with clove essential oil is due to improvement in humor- and cell-mediated immune response mechanisms.
Dendrimers as therapeutic agents: a systematic review
Authors: Gajbhiye Virendra , Palanirajan Vijayaraj K , Tekade Rakesh K , Jain Narendra K
Published: October 2010

Objectives

Dendrimers by virtue of their therapeutic value have recently generated enormous interest among biomedical scientists. This review describes the therapeutic prospects of the dendrimer system.

Key findings

Their bioactivity suggests them to be promising therapeutic agents, especially in wound healing, bone mineralisation, cartilage formation and tissue repair, and in topical treatments to prevent HIV transmission. Findings also demonstrate their potential as anti-prion, anti-Alzheimer's, anticoagulant, antidote, anti-inflammatory and anticancer agents. One of the dendrimer-based formulations with activity against herpes simplex virus (VivaGel from Starpharma) has successfully completed phase I clinical trials and is expected to be available on the market soon.

All reports cited in this review demonstrate the use of dendrimers as medical therapeutics in different ailments. The review focuses on the current state of therapeutic potential of the dendrimer system.
Trypsin as a novel potential absorption enhancer for improving the transdermal delivery of macromolecules
Authors: Li Ying-zhe , Quan Ying-shu , Zang Lei , Jin Mei-na , Kamiyama Fumio , Katsumi Hidemasa , Tsutsumi Sadami , Yamamoto Akira
Published: October 2010

Objectives

The aim was to assess the effect of trypsin on the transdermal delivery of macromolecules by applying its specific biochemical properties to the stratum corneum of the skin.

Methods

Fluorescein isothiocyanate (FITC)-labelled dextrans (FDs), with molecular weights of 4 to 250 kDa, and FITC-insulin were used as model macromolecules and a model polypeptide, and the in-vitro transdermal permeation experiments, with or without trypsin (0.1–2.5%), were carried out using rat skin and cultured human epidermis. The mechanism for the enhancement of trypsin was also studied using fluorescence and conventional light microscopy.

Key findings

Trypsin significantly increased the transdermal permeability of all FDs through the rat skin (2.0- to 10.0-fold). It also markedly enhanced the permeation of FD4 through three-dimensional cultured human epidermis (3.1-fold), which was used to evaluate the transport pathways other than the transfollicular route. Furthermore, the permeation flux of FITC-insulin was increased by 10.0-fold with trypsin pretreatment (from 0.02 ± 0.00 to 0.20 ± 0.07 μg/cm2 per h). Mechanistic studies indicated that trypsin affects both the intercellular pathway and the hair follicular route, and may alter stratum corneum protein structures, thereby affecting skin barrier properties.

Conclusions

This study suggests that trypsin could be effective as a biochemical enhancer for the transdermal delivery of macromolecules including peptide and protein drugs.
Evaluation of percutaneous absorption of the repellent diethyltoluamide and the sunscreen ethylhexyl p-methoxycinnamate-loaded solid lipid nanoparticles: an in-vitro study
Authors: Puglia Carmelo , Bonina Francesco , Castelli Francesco , Micieli Dorotea , Sarpietro Maria Grazia
Published: October 2010

Objectives

Diethyltoluamide and ethylhexyl p-methoxycinnamate (OMC) are two active ingredients in insect repellent and sunscreen products, respectively. The concurrent application of these two substances often increases their systemic absorption, compromising the safety and efficiency of the cosmetic product. In this study, diethyltoluamide and OMC were incorporated into solid lipid nanoparticles, a colloidal drug delivery system, to reduce percutaneous absorption and avoid toxic effects and also maintain the efficacy of the two active compounds on the skin surface for a long duration.

Methods

Solid lipid nanoparticles were prepared based on an ultrasonication technique and characterized by differential scanning calorimetry (DSC) analyses. In-vitro studies determined the percutaneous absorption of diethyltoluamide and OMC.

Key findings

DSC data carried out on unloaded and diethyltoluamide- and/or OMC-loaded solid lipid nanoparticles highlighted that diethyltoluamide and OMC modified the temperature and the enthalpy change associated to the calorimetric peak of solid lipid nanoparticles. The concurrent presence of the two compounds in the solid lipid nanoparticles caused a synergic effect, indicating that the lipid matrix of nanoparticles guaranteed a high encapsulation of both diethyltoluamide and OMC. Results from the in-vitro study demonstrated that the particles were able to reduce the skin permeation of the two cosmetic ingredients in comparison with an oil-in-water emulsion.

Conclusions

This study has provided supplementary evidence as to the potential of lipid nanoparticles as carriers for topical administration of cosmetic active compounds.
The role of an alginate suspension on pepsin and bile acids – key aggressors in the gastric refluxate. Does this have implications for the treatment of gastro-oesophageal reflux disease?
Authors: Strugala Vicki , Avis Jeanine , Jolliffe Ian G , Johnstone Lesley M , Dettmar Peter W
Published: October 2010

Objectives

During a reflux event the oesophagus is exposed to a heterogeneous mixture of gastric juice components. The role of non-acid components of the refluxate in causing damage to the oesophagus is now well established but no therapeutic option exists to address this.

Methods

The role of Gaviscon Advance (GA), a raft-forming alginate suspension, in protecting the oesophagus from damage by pepsin and bile acids (aggressors) was investigated using a series of in-vitro models.

Key findings

GA was able to dose-dependently inhibit pepsin activity over and above the neutralisation effect of the formulation. This was evident against both protein and collagen substrates using two distinct colorimetric assays. GA was able to retard the diffusion of pepsin and multiple bile acids using a Franz cell model. Using the raft-forming mode of action GA was able to remove both pepsin and multiple bile acids from a simulated reflux event. There was capacity in the GA raft to accommodate aggressors from multiple reflux events.

Conclusions

GA can specifically remove both pepsin and bile acids from the refluxate, limit their diffusion and affect enzymatic activity of pepsin. There is a role for GA to reduce the damaging potential of the refluxate and thus protect the oesophagus.
Synthesis and in-vitro antitumour activity of new naphthyridine derivatives on human pancreatic cancer cells
Authors: Banti Irene , Nencetti Susanna , Orlandini Elisabetta , Lapucci Annalina , Breschi Maria Cristina , Fogli Stefano
Published: October 2010

Objectives

The aim of the study was to evaluate the antitumour effect in vitro of newly synthesized 7-substituted 2,3-dihydro-1,8-naphthyridines.

Methods

Characterization tools included cell viability assay, caspase 3/7 induction, DNA fragmentation, fibroblast growth factor type 1 receptor kinase inhibition, and in-vitro antiangiogenic analysis.

Key findings

Treatment of MIA PaCa-2 human pancreatic cancer cells with test compounds showed time- and concentration-dependent cytotoxicity with IC50 values in the micromolar range. Compounds with an aminoalkyl or a diaminoalkyl side chain at the 7-position exhibited remarkable cytotoxicity, whereas the presence of a methyl group or a cyclic amine in the same position led to a significant decrease in their biological activity. Cytotoxicity screening demonstrated that the most active was compound 11 (mean 50% inhibition of cell proliferation (IC50) 11 μM). This compound had an in-vitro antitumour efficacy superior to 5-fluorouracil (the lowest cell viability value after treatment (Emax) 0.2% and 19%, respectively) and proved to be less toxic than 5-fluorouracil against non-cancerous human oral epithelial cells. In addition, compound 11 induced apoptosis in MIA PaCa-2 cells and it was able to promote antiangiogenic effects in vitro. Finally, its cytotoxicity was enhanced in pancreatic cancer cells stimulated with fibroblast growth factor, while no substantial effect was observed on human bronchial smooth muscle cells stimulated with the same growth factor.

Conclusions

These findings suggest that 1,8-naphthyridine derivatives are a promising class of compounds in cancer research. In particular, the antitumour activity of compound 11 is worth further investigation.
Acute effect of Copaifera reticulata Ducke copaiba oil in rats tested in the elevated plus-maze: an ethological analysis
Authors: Curio Mateus , Jacone Hellena , Perrut Jaime , Pinto Âengelo C , Filho Valdir F Veiga , Silva Regina C B
Published: October 2010

Objectives

Copaiba oil oleoresin exuded from Copaifera reticulata Ducke (CRD) is commonly used in anti-inflammatory, healing and anti-tumoral folk medicines. The purpose of this study was to investigate the putative anxiolytic effect of acute administration of CRD.

Methods

CRD was administered (100, 400 and 800 mg/kg, p.o.) to male Wistar rats submitted to the elevated plus-maze model of anxiety using an ethopharmacological analysis.

Key findings

In comparison with control rats, CRD increased the percentage of entries in the open arms over the entire dose range tested (vehicle, 33.6 ± 4.5; CRD 100 mg/kg, 44.67 ± 3.68; CRD 400 mg/kg, 47.2 ± 2.3; CRD 800 mg/kg, 50.7 ± 2.2) and the percentage of time spent in the open arms of the elevated plus-maze at the highest dose (800 mg/kg) (vehicle, 26.4 ± 5.7; CRD 800 mg/kg, 52.0 ± 2.7). A standard anxiolytic, diazepam (3 mg/kg, p.o.), was used as a positive control. In a similar way, diazepam increased the percentage of entries and time spent in the open arms when compared with vehicle (% open entries: vehicle, 45.4 ± 1.3; diazepam, 50.7 ± 1.9; % time spent in open arms: vehicle, 28.2 ± 0.9; diazepam, 38.9 ± 1.2). Regarding ethological measures, CRD at the highest dose (800 mg/kg) reduced peeping out (anxiety-related behaviour) (vehicle, 3.1 ± 0.6; CRD, 0.9 ± 0.2) and increased end-arm activity (vehicle, 0.2 ± 0.2; CRD, 2.0 ± 0.4), indicating an enhanced tendency of the rats to explore actively the potentially dangerous areas of the maze. Diazepam decreased peeping out (vehicle, 3.3 ± 0.3; diazepam, 1.0 ± 0.2) and flat-back approach (vehicle, 0.8 ± 0.2; diazepam, 0.2 ± 0.1) and increased end-arm activity (vehicle, 0.3 ± 0.1; diazepam, 2.5 ± 0.3) and head-dipping (vehicle, 8.2 ± 0.4; diazepam, 12.0 ± 0.5).

Conclusions

These data showed, for the first time, that acute treatment with CRD copaiba oil produced a dose-dependent anxiolytic-like effect over the dose range tested, on conventional and ethological parameters, without adversely affecting general activity levels.