Phytochemical analysis and gastroprotective effect of Stellaria media (L.) Vill. methanolic extract on piroxicam-induced gastric ulcer in Wistar rats.

Stellaria media L. has traditionally been used to treat inflammatory and gastrointestinal ailments. This study aimed to phytochemically characterize the S. media extract and explore its anti-ulcer efficacy against piroxicam-induced stomach lesions in Wistar rats. Phytochemical analysis was performed and antioxidant capacity of extract was determined using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. In vivo, piroxicam (30mg/kg) was administered to induce gastric ulceration. Gastro protective effect of S. media extract was observed at 150, 300 and 450mg/kg, respectively. While omeprazole (20mg/kg) was used as a conventional anti-ulcer drug. After oral treatment for 14 days, stomach acidic secretions, ulcerogenic indices, hematological markers and oxidative stress parameters were assessed along with histological examination. The existence of polyphenol contents in S. media extract was confirmed in correlation to a marked DPPH inhibition (IC50 27.94µg/mL). S. media extract resulted in a dose-dependent elevation in gastric pH while a decrease in acid volume, acidity and ulceration. Also, S. media extract administration restored the impaired hematological markers (RBCs, Hb, WBCs and PLTs) and decreased oxidative stress by reducing oxidants (TOS and MDA) while raising antioxidants (TAC and CAT). Furthermore, gastric histological results corroborated the aforementioned findings. Conclusively, S. media could provide a promising protective effect against drug-induced gastric ulceration.

Effectiveness of new selenium-enriched mutated probiotics in reducing inflammatory effects of piroxicam medication in liver and kidney.

Piroxicam is used to treat the pain, swelling, and stiffness associated with osteoarthritis and rheumatoid arthritis, but it has many side effects, such as hypertension, elevation of liver enzymes, and hepatitis. This study used selenium-enriched probiotics to reduce the side effects of piroxicam on the liver and kidney tissues and functions. Forty-eight male albino mice were randomly assigned to control, piroxicam (P), piroxicam plus selenium-enriched Lactobacillus plantarum PSe40/60/1 (P + SP), piroxicam plus selenium-enriched Bifidobacterium longum BSe50/20/1 (P + SB), selenium-enriched L. plantarum PSe40/60/1 (SP), and selenium-enriched B. longum BSe50/20/1 (SB) groups. In this study, the function of the liver and kidney was biochemically determined; the histopathology of the liver and kidney tissues was microscopically examined and the expression of inflammatory and anti-inflammatory genes in liver and kidney tissues was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Liver and kidney functions were significantly reduced in the piroxicam group compared with control. Liver and kidney tissues were damaged in the piroxicam group while they appeared more or less normal in the SB group. The expression of inflammatory genes was significantly up-regulated in the liver and kidney tissues of the piroxicam group compared to the control group. The expression of anti-inflammatory genes was significantly down-regulated in the liver and kidney of the piroxicam group and up-regulated in the liver and kidney of the SB group compared to the control group. Therefore, these mutated strains of probiotics were useful in reducing the side effects of the piroxicam drug on the liver and kidney.

Box-Behnken design optimization and in vitro cell based evaluation of piroxicam loaded core-shell type hybrid nanocarriers for prostate cancer.

In the present research, piroxicam entrapped core-shell lipid-polymer hybrid nanocarriers were developed and also evaluated in terms of nanoparticle features and cell-based in vitro efficacy on prostate cancer cells. Box-Behnken optimization approach was implemented to evaluate the impact of the input variables, namely phospholipid/PLGA ratio, total lipids/lecithin molar ratio, and piroxicam concentration, on two output variables: particle size and entrapment efficiency. Surface charge, size distribution, morphological structure of particles, drug release profiles, presence of outer lipid shell, thermal profile and possible interactions and storage stability of core-shell nanocarriers of piroxicam were studied as particle features. Cell viability, apoptosis and cell cycle arrest studies were utilized for in vitro cell-based evaluation of the core-shell nanosystems. The hybrid nanocarrier formulation with a particle size of 119.2 nm and an entrapment efficiency of 91.7% at the center point of the design was selected as the optimized formulation according to the desired function (d) method applied within the scope of the Box-Behnken design approach and RSM strategy. The cell viability and apoptosis experiments were performed on the optimized nanocarrier. In conclusion, this study demonstrates that the optimized core-shell nanoformulation of piroxicam is a more promising strategy in the treatment of prostate cancer compared to the pure molecule.

Investigation of in vivo anti-inflammatory and anti-angiogenic attributes of coumarin-rich ethanolic extract of Melilotus indicus.

Inflammation and angiogenesis are two major contributors to tumourigenesis. Melilotus indicus is traditionally used as an anti-inflammatory agent. The current study was designed to investigate the anti-inflammatory and anti-angiogenic properties of ethanolic extract of M. indicus (Miet) whole plant and its marker compound (coumarin) using a series of in vivo methods. Extraction by maceration was adopted to prepare ethanolic extract. Phytochemical compounds present in Miet were investigated using both qualitative and quantitative methods. In vivo safety profile of Miet was investigated in behavioural studies. Four acute oedema models such as carrageenan, serotonin, histamine-induced paw oedema and xylene-induced ear oedema, and chronic formaldehyde-induced paw oedema model were employed to explore the anti-inflammatory potential of Miet. Chorioallantoic chick membrane assay (CAM) was performed to explore anti-angiogenic potential of Miet. Histopathological evaluations were conducted to access improvement in skin texture of paws. TNF-α ELISA kit was used to study effects of treatment on serum levels of TNF-α. Extraction by maceration resulted in formation of greenish coloured semisolid extract with a high coumarin content. In vivo toxicological studies revealed LD50 of Miet was greater than 8000 mg/kg. Data of acute inflammatory models depicted significant (p < 0.05) inhibition of oedema in Miet, coumarin and standard (piroxicam/indomethacin) treated groups. 750 mg/kg of Miet induced comparable (p > 0.05) anti-inflammatory effects to that of standard-treated groups. Coumarin showed better anti-inflammatory effects in carrageenan-induced paw oedema model as compared with histamine- and serotonin-induced oedema models. Data of chronic inflammatory models also depicted dose-dependent anti-inflammatory attributes of Miet which were comparable with standard treated groups. Significant (p > 0.05) downregulation of TNF-α in serum samples of animals treated with Miet and piroxicam was observed as compared with control group. Furthermore, Miet significantly halted blood vessels formation in CAM assay. Overall, data of the current study highlight that M. indicus has anti-inflammatory and anti-angiogenic potentials, and, thus, can potentially be used as an adjuvant therapy in solid tumours management.

Coenzyme Q10 supplementation mitigates piroxicam-induced oxidative injury and apoptotic pathways in the stomach, liver, and kidney.

Piroxicam (PM) is an oxicam-NSAID commonly recommended for various pain and associated inflammatory disorders. However, it is reported to have a gastric and hepato-renal toxic effect. Therefore, the current research was planned to investigate the possible mechanisms behind the mitigating action of the coenzyme (CoQ10), a natural, free radical scavenger, against PM tissue injury. Rats were assigned to five equal groups; Control, CoQ10 (10 mg/kg, orally), PM (7 mg/kg, i.p.), CoQ + PM L, and CoQ + PM H group. After 28 days, PM provoked severe gastric ulceration and marked liver and kidney damage indicated by an elevated gastric ulcer index and considerable alteration in liver and kidney biochemical tests. The toxic effects might be attributed to mitochondrial dysfunction and excess generation of reactive oxygen species (ROS), as indicated by enhanced malondialdehyde (MDA) levels along with decreased reduced-glutathione (GSH) levels and catalase (CAT) activity. Apoptotic cell death also was demonstrated by increased regulation of activated caspase-3 in the stomach, liver, and kidney tissues. Interestingly, external supplementation of CoQ10 attenuated the PM-inflicted deleterious oxidative harm and apoptosis. This ameliorative action was ascribed to the free radical scavenging activity of CoQ10.

Development of Biodegradable Injectable In situ Forming Implants for Sustained Release of Lornoxicam.

OBJECTIVE: The focus of this study was to develop in situ injectable implants of Lornoxicam which could provide sustained drug release. METHODS: Biodegradable in situ injectable implants were prepared by polymer precipitation method using polylactide-co-glycolide (PLGA). An optimized formulation was obtained on the basis of drug entrapment efficiency, gelling behavior and in vitro drug release. The compatibility of the formulation ingredients were tested by Fourier transform infrared (FT-IR) spectroscopy, and differential scanning colorimetry (DSC). SEM study was performed to characterize in vivo behavior of in situ implant. Pharmacokinetic study and in vivo gelling study of the optimized formulation were performed on Sprague-Dawley rats. Stability testing of optimized formulation was also performed. RESULTS: The drug entrapment efficiency increased and burst release decreased with an increase in the polymer concentration. Sustained drug release was obtained up to five days. SEM photomicrographs indicated uniform gel formation. Chemical interaction between the components of the formulation was not observed by FT-IR and DSC study. Pharmacokinetic studies of the optimized formulation revealed that the maximum plasma concentration (Cmax), time to achieve Cmax (Tmax) and area under plasma concentration curve (AUC) were significantly higher than the marketed intramuscular injection of lornoxicam. Stability study of optimized batch showed no change in physical and chemical characteristics. CONCLUSION: Lornoxicam can be successfully formulated as in situ injectable implant that provides long-term management of inflammatory disorders with improved patient compliance.

Pectin, beta-cyclodextrin, chitosan and albumin based gastroprotective systems for piroxicam maleate: Synthesis, characterization and biological evaluation.

In order to optimize drug action, new drug formulations have been developed based upon the prodrug approach. This study was inspired by the increasing interest in the field of macromolecular prodrugs and Piroxicam maleate was used as a model drug. A total of five prodrugs were synthesized using beta cyclodextrin, chitosan, pectin, egg albumin, bovine serum albumin. The synthesized conjugates were characterized on the basis of UV, IR and NMR techniques. In-vitro hydrolysis studies were carried out at pH 1.2, pH 7.4, pH 9.0 and in 80% human plasma followed by in-vivo evaluation of analgesic, anti-inflammatory and anti-ulcerogenic potential. The extent of hydrolysis was found to be proportional to increase in pH. Beta cyclodextrin conjugate was found to possess significant analgesic activity whereas chitosan conjugate was found to be the best anti-inflammatory. Pectin conjugate provided maximum protection against ulcers.

Lecithin and PLGA-based self-assembled nanocomposite, Lecithmer: preparation, characterization, and pharmacokinetic/pharmacodynamic evaluation.

The present study investigates the drug delivery potential of polymer lipid hybrid nanocomposites (Lecithmer®) composed of poly(D,L-lactide-co-glycolide (PLGA) and soya lecithin. Core-shell structure of Lecithmer was evident from cryo-TEM images. Daunorubicin (DNR) and lornoxicam (LNX)-incorporated Lecithmer nanocomposites were evaluated for anticancer and anti-inflammatory activity. DNR- and LNX-loaded Lecithmer had mean particle size of ∼335 and ∼282.7 nm, respectively. Lecithmer formulated with different cationic lipids resulted in lower particle size (∼120 nm) and positive zeta potential. Entrapment efficiency of DNR and LNX was 93.16 and 88.59 %, respectively. In vitro release of DNR from Lecithmer was slower compared to PLGA nanoparticles. DNR release from Lecithmer was significantly higher at pH 5.5 (80.96 %) as compared to pH 7.4 (55.95 %), providing advantage for selective tumor therapy. Similarly, sustained release of LNX (30 % in 10 h) was observed at pH 7.4. DNR in Lecithmer showed superior cytotoxicity on human erythroleukemic K562 cells. Pharmacokinetic study in Wistar rats with i.v. administered DNR-loaded Lecithmer showed higher volume of distribution, lower elimination rate constant, and longer half-life (81.68 L, 0.3535 h(-1), 1.96 h) as compared to DNR solution (57.46 L, 0.4237 h(-1), 1.635 h). Pharmacodynamic evaluation of orally administered LNX-loaded Lecithmer showed superior anti-inflammatory activity with maximum inhibition of 81.2 % vis-à-vis 53.57 % in case of LNX suspension. In light of these results, Lecithmer can be envisaged as a promising nanosystem for parenteral as well as oral drug delivery.

Diuretic effects and urinary electrolyte excretion induced by Aspidosperma subincanum Mart. and the involvement of prostaglandins in such effects.

ETHNOPHARMACOLOGICAL RELEVANCE: Aspidosperma subincanum Mart. is a medicinal herb known for its diuretic properties and used for the treatment of cardiovascular-related illnesses. Although our earlier study has shown that the ethanol extract of Aspidosperma subincanum (EEAS) induces hypotension and vasodilation, no scientific data have been recorded to evaluate the diuretic effects of this Brazilian medicinal plant. The aim of this study was to evaluate the diuretic activity of EEAS, and possible mechanism of action, using Wistar rats. MATERIAL AND METHODS: EEAS (60 and 120mg/kg), furosemide (20mg/kg) or saline (control) were orally administered to rats individually held in metabolic cages for urine collection 1, 2, 4, 6, 8, 12 and 24h after treatment. In order to evaluate the involvement of prostaglandins in the diuretic action of EEAS, the animals received piroxicam (5mg/kgi.p.), a nonselective inhibitor of cyclooxygenase, before treatment with EEAS at 120mg/kg. The control groups received only saline (NaCl, 0.9%), or saline and piroxicam. Urinary volume, electrolyte excretion and pH were measured. RESULTS: Oral administration of EEAS 60 and 120mg/kg significantly increased diuresis and electrolyte excretion of Na(+) and K(+) on a continuous basis throughout the study period. Both EEAS 60 and 120mg/kg caused a relative increase of around 77% and 142%, respectively, in cumulative diuresis compared with the control group. From 4th hour until the end of the experiment, the group treated with EEAS 120mg/kg provided a greater excretion of Na(+) than the furosemide group. The diuretic effects of EEAS were neutralized by piroxicam between 4 and 8h after treatment. CONCLUSION: The results suggest that EEAS could present compound(s) responsible for diuretic activities, and the mechanism could involve the prostaglandin system.

Alleviation of glutamate mediated neuronal insult by piroxicam in rodent model of focal cerebral ischemia: a possible mechanism of GABA agonism.

Neurotransmitter imbalance is an inevitable outcome in cerebral ischemia that leads to neuronal death. In the present study, we evaluated the effects of piroxicam, a nonsteroidal anti-inflammatory drug (NSAID), on extracellular brain glutamate and γ-aminobutyric acid (GABA) release, survival time, and neuronal cell death. Transient focal cerebral ischemia in male Charles Foster rat led to neuronal infarction and compromised intrinsic antioxidant status. Thirty-minute preadministration of piroxicam (10 mg/kg b.w.) showed a significant (P < 0.01) reduction in cerebral infarct volume and potentiation of the intrinsic antioxidant status. High-performance liquid chromatography of brain cortex and striatum revealed changes in extracellular concentrations of neurotransmitters which were found to be 0.519 ± 0.44 pmole/mg (GABA); 1.18 ± 0.28 pmole/mg (glutamate), and 0.63 ± 0.21 pmole/mg (serotonin), respectively. Hydroxyl radical (·OH) adduct of salicylate in the frontal cortex and striatum in control, untreated, and treated groups was found to be 0.261 ± 0.06, 0.68 ± 0.52, and 0.401 ± 0.68 pmole/mg, respectively. After stroke, the extracellular level of glutamate in rat brain increases continuously as compared to that of control group. However, piroxicam administration in stroke rat significantly reduced (P < 0.05) elevated extracellular cerebral glutamate. This indicates that piroxicam attenuates extracellular glutamate release and also reduces neuronal cell death due to reduction in oxidative stress in cerebral ischemia. Our results also indicate a consequent increase of extracellular GABA in brain regions administered with piroxicam, which hints that piroxicam alleviates glutamate excitotoxicity possibly by GABA agonism.

PI3K/AKT signaling is essential for communication between tissue-infiltrating mast cells, macrophages, and epithelial cells in colitis-induced cancer.

PURPOSE: To understand signaling pathways that shape inflamed tissue and predispose to cancer is critical for effective prevention and therapy for chronic inflammatory diseases. We have explored phosphoinositide 3-kinase (PI3K) activity in human inflammatory bowel diseases and mouse colitis models. EXPERIMENTAL DESIGN: We conducted immunostaining of phosphorylated AKT (pAKT) and unbiased high-throughput image acquisition and quantitative analysis of samples of noninflamed normal colon, colitis, dysplasia, and colorectal cancer. Mechanistic insights were gained from ex vivo studies of cell interactions, the piroxicam/IL-10(-/-) mouse model of progressive colitis, and use of the PI3K inhibitor LY294002. RESULTS: Progressive increase in densities of pAKT-positive tumor-associated macrophages (TAM) and increase in densities of mast cells in the colonic submucosa were noted with colitis and progression to dysplasia and cancer. Mast cells recruited macrophages in ex vivo migration assays, and both mast cells and TAMs promoted invasion of cancer cells. Pretreatment of mast cells with LY294002 blocked recruitment of TAMs. LY294002 inhibited mast cell and TAM-mediated tumor invasion, and in mice, blocked stromal PI3K, colitis, and cancer. CONCLUSION: The PI3K/AKT pathway is active in cells infiltrating inflamed human colon tissue. This pathway sustains the recruitment of inflammatory cells through a positive feedback loop. The PI3K/AKT pathway is essential for tumor invasion and the malignant features of the piroxicam/IL-10(-/-) mouse model. LY294002 targets the PI3K pathway and hinders progressive colitis. These findings indicate that colitis and progression to cancer are dependent on stromal PI3K and sensitive to treatment with LY294002.

Inhibition of mitochondrial complex I by various non-steroidal anti-inflammatory drugs and its protection by quercetin via a coenzyme Q-like action.

Mitochondrial dysfunction plays a major role in the development of oxidative stress and cytotoxicity induced by non-steroidal anti-inflammatory drugs (NSAIDs). A major objective of the present study was to investigate whether in vitro the NSAIDs, aspirin, indomethacin, diclofenac, piroxicam and ibuprofen, which feature different chemical structures, are able to inhibit mitochondrial complex I. All NSAIDs were effective inhibitors when added both, directly to mitochondria isolated from rat duodenum epithelium (50 µM) or to Caco-2 cells (250 µM). In the former system, complex I inhibition was concentration-dependent and susceptible to competition and reversion by the addition of coenzyme Q (32.5-520 µM). Based on reports suggesting a potential gastro-protective activity of quercetin, the ability of this flavonoid to protect isolated mitochondria against NSAIDs-induced complex I inhibition was evaluated. Low micromolar concentrations of quercetin (1-20 µM) protected against such inhibition, in a concentration dependent manner. In the case of aspirin, quercetin (5 µM) increased the IC50 by 10-fold. In addition, the present study shows that quercetin (5-10 µM) can behave as a "coenzyme Q-mimetic" molecule, allowing a normal electron flow along the whole electron transporting chain (complexes I, II, III and IV). The exposed findings reveal that complex I inhibition is a common deleterious effect of NSAIDs at the mitochondrial level, and that such effect is, for all tested agents, susceptible to be prevented by quercetin. Data provided here supports the contention that the protective action of quercetin resides on its, here for first time-shown, ability to behave as a coenzyme Q-like molecule.

Topical anti-inflammatory and analgesic activity of kirenol isolated from Siegesbeckia orientalis.

ETHNOPHARMACOLOGICAL RELEVANCE: Siegesbeckia orientalis has been traditionally used as a topical anti-inflammatory and analgesic agent. AIMS OF THE STUDY: Current study was designed to explore the topical anti-inflammatory and analgesic effects of a constituent isolated from Siegesbeckia orientalis (Compositae), in order to validate its folk use. MATERIALS AND METHODS: Kirenol was isolated from ethanolic extract of Siegesbeckia orientalis. Several topical formulations containing kirenol were investigated for anti-inflammatory and analgesic activities in rat. The effects were studied using carrageenan-induced rat acute inflammation model, complete Freund's adjuvant (CFA)-induced chronic inflammation and formalin test in rats. Piroxicam gel and methyl salicylate ointment were studied as positive control for anti-inflammatory and analgesic activity, respectively. RESULTS: The anti-inflammatory effect of kirenol 0.4-0.5% (w/w) was similar to the effect of piroxicam gel 4h after carrageenan injection. The analgesic activity of topical preparation with more than 0.4% (w/w) was observed in the late phase. These effects may be due, at least in part, to the pro-inflammatory cytokine production of IL-1ß and TNF-α. The administration of kirenol cream at the dose of 0.3, 0.4 and 0.5% (w/w) significantly inhibited the development of joint swelling induced by CFA, which was auxiliary supported by histopathological studies. CONCLUSION: Kirenol has demonstrated its significant potential to be further investigated for its discovery as a new lead compound for management of topical pain and inflammation, although further pharmacological research is necessary to fully understand its mechanism of action. It also supports the potential beneficial effect of topically administered Siegesbeckia orientalis in inflammatory diseases.

Analgesic effects and anti-inflammatory properties of the crude methanolic extract of Schwenckia americana Linn (Solanaceae).

AIM OF THE STUDY: To evaluate analgesic effect and anti-inflammatory properties of Schwenckia americana (Solanaceae), a medicinal plant used for treating rheumatic pains and swelling in North-western Nigeria. MATERIALS AND METHODS: Three doses (25mg/kg, 50mg/kg and 100mg/kg) of the crude methanolic extract of Schwenkia americana were evaluated for analgesic and anti-inflammatory activities using acetic acid induced writhing test, formalin induced nociception, and formalin induced hind paw oedema in rats. RESULTS: All doses (25, 50, 100mg/kg) of the extract tested were effective. The extract at the tested doses produced a percentage inhibition of the acetic acid induced abdominal constriction of (53.3, 58.0 and 86.7%), respectively. A percentage inhibition of the formalin induced nociception of 44.00, 56.04, and 56.04% (early phase) and 33.00, 36.63 and 59.71% (late phase) was also produced. The inhibition of oedema formation increased with increasing dosage from 25 to 100mg/kg. The crude extract produced a statistically significant analgesic and anti-inflammatory activity comparable to the effect of standard drug (10mg/kg Piroxicam). CONCLUSION: This study demonstrated the potential analgesic and anti-inflammatory properties of crude methanolic extract of Schwenkia americana thus justifying its traditional usage.

[Synthesis, physicochemical and pharmacological properties of pentacyclic alkaloid-analogues]. / Pentaciklusos alkaloid-analógok szintézise, fizikokémiai és farmakológiai vizsgálata.

Quinazolinocarboline rutaecarpine and evodiamine (Evodia rutaecarpa) are main alkaloid components of traditional Chinese folk-remedies. Evodiamine exhibited selective antitumor and antimetastatic effects on several cancer cell lines and became lead structure of anticancer agents. During our synthetic research we achieved to gain alkaloid hybrid derivatives by combining the structural elements of quinazolinocarbolines with analogous alkaloids or drug molecules having similar effects by bioisosteric replacements. 8-norrutaecarpine, a hybrid molecule of rutaecarpine and luotonin A containing the indolo-pyrroloquinazolinone ring system has been synthesized. The hybrids of rutaecarpine and piroxicam bearing the indolo-pyridobenzothiazine and the 12-azaindolo-pyridobenzothiazine structures were prepared on two alternative routes. Two new heterocondensed pentacyclic compounds, 5-sulfarutaecarpine and 5-sulfa-8-norrutaecarpine were reached via bioisosteric replacement on the structure of rutaecarpine and 8-norrutaecarpine. Two new tricyclic ring systems, pyrido-benzothiadiazine and pyrrolo-benzothiadiazine were produced as intermediaries of these pentacyclic molecules. Series of substituted derivatives were prepared for pharmacological studies by modification of the structures with various substituents and solubilizing groups. During our work alternative way for synthesis of nauclefine (Nauclea latifolia) was laboured, and we published the synthesis of indolylquinazolinone derivative bouchardatine (Bouchardata neurococca) for the first time. Some of the physicochemical attributes of the synthesized intermediaries were defined, such as the pKa constants of 2,3-poly-methylene-benzothiadiazines. Proton/deuteron exchange kinetic constants of active methylene-groups of five tricyclic compounds were measured by 1H NMR technique. Solvent-dependent ratio of the Z/E isomers of phenyhydrazone-derivatives in polar and apolar solvents were determined. In the case of 18 produced compounds our work was completed by in vitro pharmacological studies performed within co-operation with the Institute of Pharmacology. The viability of HeLa cells was inhibited by five of our compounds to similar extent as the effect of evodiamine. Eight of our compounds induced apoptosis on HeLa cells to similar extent as evodiamine.

[Analysis of the effects of different medicines on hypercoagulability state variations of femoral shaft fracture and after its operation].

OBJECTIVE: To explore the role of Tong Mai Tang & Lornoxicam on the serum concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin (IL-6) , D-dipolymer( D-Di), Platelet count (PLC) in treatment of femoral shaft fracture among period surgery time. METHODS: We selected 120 cases of traumatic femoral shaft fracture patients according to the inclusion criteria and exclusion criteria, which were randomized dividend into four groups (I, II, III, IV respectively) of the same size based on the random number table method of 30 patients each. Therapeutic methods of four groups following as: Group I, Tpanax Notoginseng Pills PO; Group II, Tpanax Notoginseng Pills PO, Lornoxicam For Injection, 8 mg IM; Group III, Tpanax Notoginseng Pills PO, Tong Mai Decoctions 200 mL PO; Group IV, Tpanax Notoginseng Pills PO, Lornoxicam For Injection 8 mg IM, Tong Mai Decoctions 200 mL PO. The above medications were administered to the four groups after admission to hospital the next day. Peripheral blood samples were taken for immune determination of pro-inflammatory cytokines of TNF-alpha, IL-6, D-Di, PLC in blood serum on the 2nd and 6th day before operation and on the 8th and 13th day after operation in the morning. And all patients received liver and kidney function examination 2nd and 13th day after admission. Analysis of variance and least significant difference-test were done with the help of SPSS 17.0 statistic software. RESULTS: The difference among four groups in TNF-alpha and IL-6 were significant (P < 0.05). And there were also significant statistic difference between group II/III/IV and group I group (P < 0.05). But the difference between group II and group III was insignificant (P > 0.05). However, the group contrast result between group IV and group II/III had statistics difference (P < 0.05). The difference in D-Di PLC at 6th day and 8th day were significant (P < 0.05). The group comparisons in group I/II/IV were also significant. There were non-statistics significance in group II compared 6th day/8th day with 2nd day (P > 0.05). The comparison between the 13th day with the first three time sections had statistics significance. And there were statistics significance at the 13th day between group IV and group II (P < 0.05). CONCLUSION: The serum concentrations of TNF-alpha, IL-6, D-Di and PLC level were significantly increased in peroperative period, These results seem to indicate that the Tong Mai Decoctions & Lornoxicam may play an important role in inhibiting the release of TNF-alpha, IL-6, D-Di and PLC into the blood stream and decreasing the incunabula complication at early traumatic stage. The Tong Mai Decoctions & Lornoxicam was the worth promoting screened China and the West union medication combination.

Drug reprofiling using zebrafish identifies novel compounds with potential pro-myelination effects.

Treatment of the autoimmune demyelinating disease multiple sclerosis (MS) requires therapies that both limit and repair damage. While several immunomodulatory treatments exist to limit damage there are currently no treatments that promote the regenerative process of remyelination. A rapid way of screening potential pro-remyelination compounds is therefore required. The use of larval zebrafish in a drug reprofiling screen allows rapid in vivo screening and has been used successfully in the past as an efficient way of identifying new indications for existing drugs. A novel screening platform for potential pro-myelination compounds was developed using zebrafish larvae. Two percent of compounds screened from reprofiling libraries altered oligodendrocyte lineage cell recruitment and/or proliferation, as measured by the numbers of dorsally migrated spinal cord olig2(+) cells. Selective screening identified three compounds that altered levels of myelination, as measured by whole larvae myelin basic protein (mbp) transcript levels; the src family kinase inhibitor PP2, a biogenic amine and a thioxanthene. As well as many previously unrecognised compounds, identified compounds included those with previously known effects on myelin and/or the oligodendrocyte lineage, such as a PPAR agonist, steroid hormones and src family kinase inhibitors. As well as providing methods for further assessment of potentially beneficial compounds, this screen has highlighted 25 targets that are able to alter oligodendrocyte lineage cell recruitment or proliferation and/or mbp transcript levels in vivo and are worthy of further investigation for their potential effects on remyelination.

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.

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 effects of lornoxicam in relation 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 enzyme-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, lornoxicam did not affect the elevated body temperature, whereas celecoxib and loxoprofen significantly 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.

Effect of mangiferin on the development of periodontal disease: involvement of lipoxin A4, anti-chemotaxic action in leukocyte rolling.

UNLABELLED: Mangiferin is a polyphenol compound obtained from mango and has been reported to possess antioxidant and anti-inflammatory properties. AIM: We propose to evaluate the influence of mangiferin in preventing and treating experimental periodontitis induced in Wistar rats. MAIN METHODS: Periodontitis was induced in rats by applying a ligature around the lower right first molar. After ligature, groups of animals were submitted orally to the following treatments: saline 10 mL/kg, piroxicam 20 mg/kg or mangiferin 100 mg/kg. On days 1, 4 or 7 after ligature application the alveolar bone loss (ABL) was determined. We evaluated the effect of mangiferin on ABL by histological techniques (alveolar bone loss and cellularity), enzyme immunoassay (lipoxin A(4)), intravital microscopy (rolling leukocytes and endothelial-leukocyte adhesion), zymographic analyses (metalloproteinases, MMPs 2 and 9), immunohistochemistry (PCNA, COX-2 and CXCR4) and toxicology. KEY FINDINGS: Oral administration of mangiferin significantly reduced ABL. We also observed the reduction of cellularity in mangiferin-treated rats. Treatment with mangiferin inhibited COX-2 expression and the rolling and adhesion of leukocytes, while maintaining normal lipoxin A(4) levels. The mangiferin did not interfere in the activity of MMP-2 or -9. The mangiferin-treated rats presented an earlier peak of cell proliferation and augmented angiogenesis in the injured region. SIGNIFICANCE: Our results have demonstrated promising therapeutic potential of mangiferin both in the prevention and treatment of periodontitis.

Ultrasonic vocalization response elicited in adjuvant-induced arthritic rats as a useful method for evaluating analgesic drugs.

Adjuvant-induced arthritic (AIA) rats develop a severe chronic polyarthritis which shares some features in common with human rheumatoid arthritis. The purpose of the present study was to examine whether AIA rats emit ultrasonic vocalizations (USVs) when they are confronted with a healthy 'stimulus rat' in social interactions. We also examined the effects of three analgesic drugs (piroxicam, rofecoxib and ketoprofen) on USV responses using the same paradigm. In social interactions, AIA rats and intact controls emitted USVs in the 22-28 kHz range. Vocalization activities were significantly higher in AIA rats than those in intact controls. Moreover, the USVs of AIA rats were significantly inhibited by the three analgesic drugs. These results suggest that the USV responses elicited in AIA rats are useful for the evaluation of analgesic drugs.