Anti-convulsant action and amelioration of oxidative stress by Glycyrrhiza glabra root extract in pentylenetetrazole- induced seizure in albino rats

Objectives:The aim of the present study was to evaluate the anti-convulsant potential of aqueous and ethanol e xtract of Glycyrrhiza glabra (AEGG and EEGG) and its action on markers of oxidant stress in albino rats.Results:The onset of seizure was delayed (P < 0.01) by all the three doses of EEGG, but the duration of convulsion was reduced (P < 0.01) only in higher dose level (200 and 400 mg/ kg), whereas AEGG up to 400 mg/kg did not alter any of the parameters significantly. Biochemical analysis of rat brain tissue revealed that MDA was increased (P < 0.01), whereas SOD and CAT were decreased (P < 0.01) in PTZ-induced seizure rat, whereas pre-treatment with EEGG (400 mg/kg) decreased (P < 0.01) the MDA and increased (P < 0.01) both SOD and CAT, indicating attenuation of lipid peroxidation due to increase in antioxidant enzymes.Conclusion:The results demonstrated that EEGG poses anti-convulsant potential and ameliorates ROS induced neuronal damage in PTZ-induced seizure.KEY WORDS: Catalase, Glycyrrhiza glabra, malondialdehyde, pentylenetetrazole, seizures, superoxide dismutase     

Effects of Combination of Thiazolidinediones with Melatonin in Dexamethasone-induced Insulin Resistance in Mice

In type 2 Diabetes, oxidative stress plays an important role in development and aggregation of insulin resistance. In the present study, long term administration of the dexamethasone led to the development of insulin resistance in mice. The effect of thiazolidinediones pioglitazone and rosiglitazone, with melatonin on dexamethasone-induced insulin resistance was evaluated in mice. Insulin resistant mice were treated with combination of pioglitazone (10 mg/kg/day, p.o.) or rosiglitazone (5 mg/kg/day, p.o.) with melatonin 10 mg/kg/day p.o. from day 7 to day 22. In the biochemical parameters, the serum glucose, triglyceride levels were significantly lowered (P<0.05) in the combination groups as compared to dexamethasone treated group as well as with individual groups of pioglitazone, rosiglitazone, and melatonin. There was also, significant increased (P<0.05) in the body weight gain in combination treated groups as compared to dexamethasone as well as individual groups. The combination groups proved to be effective in normalizing the levels of superoxide dismutase, catalase, glutathione reductase and lipid peroxidation in liver homogenates may be due to antioxidant effects of melatonin and decreased hyperglycemia induced insulin resistance by thiazolidinediones. The glucose uptake in the isolated hemidiaphragm of mice was significantly increased in combination treated groups (PM and RM) than dexamethasone alone treated mice as well as individual (pioglitazone, rosiglitazone, melatonin) treated groups probably via increased in expression of GLUT-4 by melatonin and thiazolidinediones as well as increased in insulin sensitivity by thiazolidinediones. Hence, it can be concluded that combination of pioglitazone and rosiglitazone, thiazolidinediones, with melatonin may reduces the insulin resistance via decreased in oxidative stress and control on hyperglycemia.     

Corticosteroid insensitive alveolar macrophages from asthma patients; synergistic interaction with a p38 mitogen-activated protein kinase (MAPK) inhibitor

Aims

Some asthma patients remain symptomatic despite using high doses of inhaled corticosteroids (ICS). We used alveolar macrophages to identify individual patients with insensitivity to corticosteroids and to evaluate the anti-inflammatory effects of a p38 mitogen-activated protein kinase (MAPK) inhibitor combined with a corticosteroid on these cells.

Methods

Alveolar macrophages from 27 asthma patients (classified according to the Global Initiative for Asthma (GINA) treatment stage. Six GINA1, 10 GINA2 and 11 GINA3/4) were stimulated with lipoploysaccharide (LPS) (1 μg ml⁻¹). The effects of dexamethasone (dex 1–1000 nm), the p38 MAPK inhibitor 1-(5-tert-butyl-2-p-tolyl-2Hpyrazol-3-yl)-3(4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl)urea (BIRB-796 1–1000 nm) and both drugs combined at all concentrations on supernatant TNFα, IL-6 and CXCL-8 concentrations were analyzed by ELISA. Dose-sparing and efficacy enhancing effects of combination treatment were determined.

Results

Dexamethasone reduced LPS-induced TNFα, IL-6 and CXCL-8 in all groups, but maximum inhibition was significantly reduced for GINA3/4 compared with GINA2 and GINA1 (P < 0.01). A subgroup of corticosteroid insensitive patients with a reduced effect of dexamethasone on cytokine secretion were identified. BIRB-796 in combination with dexamethasone significantly increased cytokine inhibition compared with either drug alone (P < 0.001) in all groups. This effect was greater in corticosteroid insensitive compared with sensitive patients. There were significant synergistic dose-sparing effects (P < 0.05) for the combination treatment on inhibition of TNFα, IL-6 and CXCL-8 in all groups. There was also significant efficacy enhancing benefits (P < 0.05) on TNFα and IL-6.

Conclusions

p38 MAPK inhibitors synergistically enhance efficacy of corticosteroids in macrophages from asthma patients. This effect is greater in corticosteroid insensitive asthma patients, suggesting that this class of drug should be targeted to this patient phenotype.     

Effect of ethanolic extracts of Justicia neesii Ramam. against experimental models of pain and pyrexia

Objective:The main objective of this study is to evaluate the analgesic and anti-pyretic activities of ethanolic extracts of Justicia neesii Ramam. by different experimental models.Results:In the hot plate model 400 mg/kg p.o. dose of J. neesii has shown its maximal effect at 3 h. The results are significant (P < 0.05) and comparable to the values of standard drug pentazocine (30 mg/kg i.p.). In acetic acid induced writhing model 400 mg/kg p.o. of plant extracts have shown highly significant activity (P < 0.001) and better than standard drug indomethacin (10 mg/kg p.o.). The 400 mg/kg p.o. dose of plant extract has given significant results against both yeast induced pyrexia and TAB vaccine induced pyrexia (P< 0.01 and 0.05 respectively). These values are comparable to that of paracetamol 100 mg/kg p.o. standard dose.Conclusion:This study shows that the ethanol extract of J. neesii has significant analgesic and antipyretic activity.KEY WORDS: Brewer''s yeast, hot plate, pyrexia, TAB vaccine, writhing     

Extract of Pinus densiflora needles suppresses acute inflammation by regulating inflammatory mediators in RAW264.7 macrophages and mice

ContextPinus densiflora Siebold & Zucc. (Pinaceae) needle extracts ameliorate oxidative stress, but research into their anti-inflammatory effects is limited.ObjectiveTo investigate antioxidant and anti-inflammatory effects of a Pinus densiflora needles (PINE) ethanol extract in vitro and in vivo.Materials and methodsWe measured levels of reactive oxygen species (ROS), superoxide dismutase (SOD) and inflammatory mediators in lipopolysaccharide (LPS)-stimulated RAW264.7 cells at various PINE concentrations (25, 50 and 100 μg/mL; but 6.25, 12.5 and 25 μg/mL for interleukin-1β and prostaglandin E₂ (PGE₂)). Thirty ICR mice were randomized to six groups: vehicle, control, PINE pre-treatment (0.1, 0.3 and 1 mg/left ear for 10 min followed by arachidonic acid treatment for 30 min) and dexamethasone. The posttreatment ear thickness and myeloperoxidase (MPO) activity were measured.ResultsPINE 100 μg/mL significantly decreased ROS (IC₅₀, 70.93 μg/mL, p < 0.01), SOD (IC₅₀, 30.99 μg/mL, p < 0.05), malondialdehyde (p < 0.01), nitric oxide (NO) (IC₅₀, 27.44 μg/mL, p < 0.01) and tumour necrosis factor-alpha (p < 0.05) levels. Interleukin-1β (p < 0.05) and PGE₂ (p < 0.01) release decreased significantly with 25 μg/mL PINE. PINE 1 mg/ear inhibited LPS-stimulated expression of cyclooxygenase-2 and inducible NO synthase in RAW264.7 macrophages and significantly inhibited ear oedema (36.73–15.04% compared to the control, p < 0.01) and MPO activity (167.94–105.59%, p < 0.05).Discussion and conclusionsPINE exerts antioxidant and anti-inflammatory effects by inhibiting the production of inflammatory mediators. Identified flavonoids such as taxifolin and quercetin glucoside can be attributed to effect of PINE.     

NPH Insulin Versus Insulin Glargine Versus NPH Insulin Plus Insulin Glargine for the Treatment of Dexamethasone-Induced Hyperglycemia in Patients With COVID-19: A Retrospective Cohort Study

Background:Dexamethasone use in patients hospitalized with COVID-19 significantly reduces mortality; however, it commonly results in hyperglycemia. Optimal treatment of dexamethasone-induced hyperglycemia is not well established.Objective:The study purpose was to assess the difference in blood glucose (BG) control between insulin glargine, neutral protamine hagedorn (NPH) insulin, and insulin glargine plus NPH insulin for dexamethasone-induced hyperglycemia in patients with type 2 diabetes (T2DM) and COVID-19 infection.Methods:This retrospective study was conducted in adult inpatients with T2DM and COVID-19 infection who received 6 mg of dexamethasone once daily and insulin during the 5-day study period. The primary outcome was the difference in mean point-of-care (POC) BG levels between study insulins. Secondary outcomes included the incidence of hyperglycemia and hypoglycemia, length of stay, and the percent difference between the mean daily inpatient and home basal insulin doses (for patients who were receiving basal insulin prior to admission in the insulin glargine and insulin glargine and NPH insulin groups only).Results:Ninety-six patients were included in the analysis (67 insulin glargine, 10 NPH insulin, and 19 insulin glargine plus NPH insulin). The difference in mean POC BG level was not different among groups (254 ± 60 mg/dL vs 234 ± 39 mg/dL vs 250 ± 51 mg/dL, respectively; P = 0.548). There were no significant differences in the secondary outcomes.Conclusions:No difference in the mean POC BG level was observed. Dexamethasone-induced hyperglycemia was poorly controlled in patients with T2DM and COVID-19 infection.     

Anti-hypoxic effect of ginsenoside Rbl on neonatal rat cardiomyocytes is mediated through the specific activation of glucose transporter-4 ex vivo

Aim:

The aim of this study was to investigate whether Gs-Rbl relieves the CoCl₂-induced apoptosis of hypoxic neonatal rat cardiomyocytes and in which the role of glucose transporter-4 (GLUT-4).

Methods:

Gs-Rbl (0, 10, 50, 100, 200, 400, and 500 μmol/L), adenine 9-β-D-arabinofuranoside (ara A, 500 μmol/L; AMPK inhibitor) and wortmannin (0.5 μmol/L; PI3K inhibitor) only in combination with 200 μmol/L Gs-Rbl were administered in hypoxic cardiomyocytes, which were induced by 500 μmol/L CoCl₂ for 12 h. Then, the apoptotic rate (AR), 2-[³H]-deoxy-D-glucose (2-[³H]-DG) uptake, and the expression of GLUT-4 (including in plasma membrane, PM), phospho-AMPKα (Thr172), AMPKα and Akt in cells were assayed.

Results:

Compared with simple hypoxia (0 μmol/L Gs-Rbl), Gs-Rb1 greater than 10 μmol/L significantly decreased the apoptotic rate (P<0.01) and significantly increased 2-[³H]-DG uptake (P<0.01), GLUT-4 content in cells and PM (P<0.01), AMPK activity (P<0.01) and Akt (P<0.01) levels in a dose-dependent manner. AMPK activity was completely suppressed by ara-A, just as Akt was suppressed by wortmannin. The AR, glucose uptake and GLUT-4 levels in cells and PM were partly down-regulated by ara-A or wortmannin.

Conclusion:

Gs-Rb1 may protect neonatal rat cardiomyocytes from apoptosis induced by CoCl₂. The anti-apoptotic effect of Gs-Rb1 may occur by improving glucose uptake, in which GLUT-4 translocation and expression played a key role. Both the AMPK and the PI3K/Akt pathways may take part in the anti-hypoxic efficacy of Gs-Rb1.     

The influence of combined treatment with propranolol and acetylsalicyclic acid on platelet aggregation in coronary heart disease

1 Antiaggregating agents are frequently prescribed alone or together with β-adrenergic receptor blocking agents in patients after myocardial infarction. The present study was designed to examine the effects of combined treatment with propranolol and acetylsalicylic acid (ASA) on platelet aggregability.

2 Spontaneous platelet aggregation and aggregation induced by fibrinogen and adrenaline were studied in a group of patients with coronary heart disease before treatment, after treatment with propranolol (0.75-1.0 mg/kg daily), and after combined treatment with propranolol in same dose and ASA (20-25 mg/kg daily). Twenty-one patients with stable angina pectoris and/or after myocardial infarction and twelve healthy men were included in the study.

3 There were no significant differences in both spontaneous and induced platelet aggregation between patient and control group before treatment. Propranolol influenced fibrinogen-induced aggregation: it lowered maximal amplitude of aggregation (P < 0.05), but it did not change the reaction time. ASA in combination with propranolol affected both spontaneous and induced aggregation: it diminished the number of pathological spontaneous aggregations (P < 0.025), it inhibited the second wave of adrenaline-induced aggregation (P < 0.01), prolonged the reaction time of fibrinogen-induced aggregation (P < 0.01) and lowered the maximal amplitude of aggregation (P < 0.05).

4 The study showed that propranolol besides its well-known hemodynamic effects had an additional antiaggregating property. The action of combined treatment with propranolol and ASA on platelet aggregation is probably additive.

     

Exploring the role of curcumin containing ethanolic extract obtained from Curcuma longa (rhizomes) against retardation of wound healing process by aspirin

Aim:The aim of the study was to assess the curcumin containing ethanolic extract (EtOH) obtained from Curcuma longa (Cl) against retardation of wound healing by aspirin.Results:Curcumin containing 5% and 10% ethanolic extract ointment have shown significant (P < 0.01) wound healing activity against an aspirin (administered 150 mg/kg body weight orally for 9 days) retarded wound healing process. Topical application of ointment showed significant (P < 0.01) difference as compared to the control group. Histopathological studies also showed healing of the epidermis, increased collagen, fibroblasts and blood vessels.Conclusion:Ethanolic extract of Cl ointment (EtOHCl) containing 10% curcumin displayed remarkable healing process against wound retardation by aspirin.KEY WORDS: Aspirin, Curcuma longa, excision wound, incision wound, wound contraction     

Impact of antidepressants use on risk of myocardial infarction: A systematic review and meta-analysis

Aims:The aim of the study was to perform a systematic review and meta-analysis to determine the association between antidepressants use and risk of myocardial infarction (MI), and whether this association differs between tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs).Methods:A PubMed/MEDLINE search was conducted for studies published up to December 2013. Included studies were evaluated for publication bias and heterogeneity. Depending on the presence of heterogeneity, a random or fixed effects model was used to identify the pooled relative risk (RR) with 95% confidence intervals (CIs). Cumulative meta-analysis, subgroup and sensitivity analyses were also performed. All analyses were performed using comprehensive meta-analysis software.Results:Fourteen (five cohort and nine case–control) studies were included. There was heterogeneity among the studies (P_{heterogeneity} = 0.02; I² = 68%) but no publication bias (Begg''s P = 0.30 and Egger''s P = 0.45). Antidepressants use significantly increases the risk of myocardial infarction (MI) (RR = 2.03; 95% CI = 1.30–3.18; P < 0.01). On subgroup analysis by study design, cohort studies show significant positive association (RR = 2.16; 95% CI = 1.42–3.29; P < 0.01), but not case–control studies (RR = 2.47; 95% CI = 0.69–8.90; P = 0.17). Sensitivity analysis and cumulative meta-analysis confirmed the stability of results. TCAs users are having 36% increased risk of MI after excluding one outlier (RR = 1.36; 95% CI = 1.10–1.67; P < 0.01), but SSRIs showing no association (RR = 0.84; 95% CI = 0.57–1.22; P = 0.35).Conclusions:We found evidence that the use of antidepressants was associated with elevated risk of MI. Further research is needed to identify the underlying biological mechanisms.KEY WORDS: Myocardial infarction, selective serotonin reuptake inhibitors, tricyclic antidepressants     

Histopathological Evaluation of Heart Toxicity of a Novel Selective PPAR-γ Agonists CKD-501 in db/db Mice

High risk of cardiovascular diseases caused by existing PPAR-γ agonists such as rosiglitazone and pioglitazone has been recently reported. CKD-501 is a novel selective PPAR-γ agonist as a potential target to reduce cardiovascular risk in non-insulin dependent diabetes mellitus (NIDDM). In this study, We investigated potential cardiotoxicity of CKD-501 and compared its toxicity with that of rosiglitazone or pioglitazone using db/db mice. After 12-week repeated administration of CKD-501 at doses of 3, 10 and 30 mg/kg/day or rosiglitazone at doses of 10 and 30 mg/kg/day or pioglitazone at doses of 200 and 540 mg/kg/day, animals were sacrificed for investigation of potential toxicities. Diameters of left ventricles and areas of cardiomyocytes were measured. And lipid accumulation and apoptosis in heart muscle were examined by oil red O staining and TUNEL staining, respectively. Diameters of left ventricles were significantly increased in high dose treatment group of pioglitazone compared to control (p<0.05), while other groups showed a tendency for an increase. All test articles induced significantly the increase of area of cardiomyocytes in heart compared to control (p<0.01), in regular order as pioglitazone > CKD-501 ≥ rosiglitazone. However, lipid accumulation and apoptotic changes in heart were not observed in all dosing groups. Taken together, the myocardial cell hypertrophy of CKD-501 are relatively lower than that of pioglitazone and similar to rosiglitazone. And it is suggested that the myocardial cell hypertrophy of CKD-501 are less adverse in clinical use for the management of the NIDDM.     

Short-term differences in drug prices after implementation of the national essential medicines system: A case study in rural Jiangxi Province,China

Objectives:

China''s 2009 national essential medicine system (NEMS) was designed to reduce prices through a zero-markup policy and a centralized bidding system. To analyze NEMS''s short-term impact on drug prices, we estimated the retail and wholesale prices before and after the reform at health institutions in rural Jiangxi Province.

Materials and Methods:

We undertook two cross-sectional surveys of prices of 39 medicines in November 2008 and May 2010, calculated inflation adjusted prices, and used the Wilcoxon signed-rank and rank-sum tests to examine price changes at different health institutions.

Results:

Retail prices at pilot (P < 0.01) and nonpilot (P < 0.01) township health centers decreased significantly, whereas the declines at retail pharmacies (P = 0.57) and village clinics (P = 0.29) were insignificant. The decline at pilot township health centers was the largest, compared with other kinds of health institutions (P < 0.01). Retail prices of essential and non-essential medicines declined significantly at pilot facilities (P < 0.05); price drops for non-essential medicines occurred only at pilot facilities (P < 0.05). No significant decline of wholesale prices were found at pilot (P = 0.86) and nonpilot units (P = 0.18), retail pharmacies (P = 0.18), and village clinics (P = 0.20). The wholesale prices changes at pilot units before and after the reform were higher than at nonpilot public units (P < 0.05), retail pharmacies (P < 0.05), and village clinics (P < 0.05).

Conclusion:

While the NEMS zero-markup policy significantly reduced retail prices at pilot health institutions, the centralized bidding system was insufficient to lower wholesale prices. A drug price management system should be constructed to control medicine prices and a long-term price information system is needed to monitor price changes.KEY WORDS: China, drug prices, healthcare reform, national essential medicine system, rural healthcare     

The anti-depressant effects of a novel PDE4 inhibitor derived from resveratrol

ContextResveratrol has shown anti-stress and anti-depressant-like abilities involved in inhibiting phosphodiesterase-4 (PDE4) enzyme. However, its application is limited due to its low efficacy, bioavailability and selectivity.ObjectiveThis study synthesized a new resveratrol derivative RES003 and evaluated its PDE4 inhibitory and anti-depressant-like activities in vitro and in vivo, respectively.Materials and methodsPDEs inhibitory activities were evaluated by radioactive tracer method. Anti-depressant-like activities of novel resveratrol analogue (RES003) at doses of 2.5, 5.0 and 10 mg/kg was investigated by sugar water consumption and forced swimming tests using male ICR mice under chronic unpredictable stress procedure for 10 days. A total of 84 mice were randomly distributed into seven groups (n = 12). Drugs and vehicle were administered (intra-gastric or intra-peritoneal) once a day from the first to the last day. The molecular mechanisms were identified by western blot.ResultsRES003 showed more potent PDE4 inhibitory activity (half maximal inhibitory concentration (IC₅₀), 0.87 μM) and better selectivity than resveratrol (IC₅₀, 18.8 μM). RES003 could significantly increase the consumption of sugar water (p < 0.01) and immobility time (p < 0.01) compared to vehicle-treated stressed groups at doses of 5 and 10 mg/kg. Furthermore, RES003 could significantly increase the levels of cyclic adenosine monophosphate response element binding protein phosphorylation (10 mg/kg, p < 0.05) and brain-derived neurotrophic factor (BDNF) expression (5 and 10 mg/kg, p < 0.05 and 0.01) in mouse brain.Discussion and conclusionsRES003 could ameliorate chronic stress induced depression-like behaviours through inhibition of PDE4 and activation of cAMP-triggered phosphorylation of cAMP response element binding protein/BDNF signalling pathway. Consequently, RES003 is a promising lead compound for the treatment of depression.     

Improved Pharmacokinetics of Aceclofenac Immediate Release Tablets Incorporating its Inclusion Complex with Hydroxypropyl-β-Cyclodextrin

The present investigation reports the various pharmacokinetic parameters of immediate release aceclofenac tablets incorporating its inclusion complex with hydroxypropyl-β-cyclodextrin. The tablets were prepared using aceclofenac: hydroxypropyl-β-cyclodextrin in a 1:1 molar ratio by the direct compression method (TKN). The results were compared with those of the marketed brand (MKT) and pure drug (TAC). The P-values indicated that mean plasma concentrations were significantly different among all three formulations administered (P<0.05, P<0.01). TKN showed significantly higher plasma levels when compared to the pure drug (P<0.01). The C_max and AUC_(0-∞) of TKN were significantly higher (P<0.05) compared to the pure drug and marketed formulation. Furthermore, the first-order overall elimination rate constant (K_el) of TKN was also significantly higher (P<0.05) compared to the pure drug and its marketed formulation. These results suggested that tablets prepared by incorporating the AC-HPβCD inclusion complex (TKN) would provide a more rapid onset of pharmacological effects in comparison to the marketed formulation and pure drug.     

Effect of thiamine pyrophosphate on ischemia-reperfusion induced oxidative damage in rat kidney

Objectives:

The biochemical effects of thiamine pyrophosphate on ischemia-reperfusion (IR) induced oxidative damage and DNA mutation in rat kidney tissue were investigated, and compared to thiamine.

Materials and Methods:

Rats were divided into four groups: Renal ischemia-reperfusion (RIR); thiamine pyrophosphate + RIR (TPRIR); thiamine + RIR (TRIR); and sham group (SG).

Results:

The results of biochemical experiments have shown that malondialdehyde (MDA) levels in rat kidney tissue after TRIR and TPRIR treatment were 7.2 ± 0.5 (P > 0.05) and 3.3 ± 0.3 (P < 0.0001) μmol/g protein, respectively. The MDA levels in the SG rat kidney tissue and in RIR group were 3.6 ± 0.2 (P < 0.0001) and 7.6 ± 0.6 μmol/g protein, respectively. Total glutathione (tGSH) levels in TRIR, TPRIR, SG, and RIR animal groups were 2.2 ± 0.3 (P > 0.05), 5.8 ± 0.4 (P < 0.0001), 6.2 ± 0.2 (P < 0.0001), and 1.7 ± 0.2 nmol/g protein, respectively. In the TRIR, TPRIR, SG, and RIR animal groups; 8-hydroxyguanine (8-OHGua)/Gua levels, which indicate mutagenic DNA, were 1.75 ± 0.12 (P > 0.05), 0.93 ± 0.1 (P < 0.0001), 0.85 ± 0.08 (P < 0.0001), and 1.93 ± 0.24 pmol/L, respectively.

Conclusions:

It has been shown that thiamine pyrophosphate prevents increase in mutagenic DNA in IR induced oxidative damage, whereas thiamine does not have this effect.KEY WORDS: DNA mutation, ischemia-reperfusion, oxidative damage, rat, thiamine pyrophosphate     

Evaluation of anti-osteoarthritic activity of Vigna mungo in papain induced osteoarthritis model

Aim:This study was carried out to evaluate the effect of Vigna mungo hydroalcoholic extract (VMHA) by papain induced osteoarthritis (OA) in the rat model.Results:VMHA improved inflammatory condition with all the doses, but significant (P < 0.05) attenuation of inflammation was present only with 400 mg/kg dose. The grip strength, locomotion activity and hanging time were also significantly (P < 0.05) improved at dose level of 100 mg/kg however other two doses (200 mg/kg and 400 mg/kg) were not found to be effective. VMHA did not show any mortality or any toxic clinical signs after oral administration of 2 g/kg dose.Conclusion:VMHA improved arthritic condition by significantly reducing pain and inflammation.KEY WORDS: Grip strength, inflammation, osteoarthritis, papain     

Aspirin relieves the calcification of aortic smooth muscle cells by enhancing the heat shock response

ContextVascular calcification is a major complication of chronic renal failure, which has been identified as an active process partly driven by osteogenic transition of vascular smooth muscle cells (VSMCs). Aspirin could prevent cardiomyocyte damage by inducing heat shock response.ObjectiveThis study investigates the effect of aspirin on alleviating VSMC calcification.Materials and methodsAn in vitro VSMC calcification model was established by 10-day calcification induction in osteogenic medium. VSMCs were grouped as following: control group (normal medium), calcified group (osteogenic medium) and treated group (osteogenic medium with 1 or 4 mmol/L aspirin). VSMC calcification was evaluated by calcified nodules formation, intracellular calcium concentration and osteoblastic marker (OPN and Runx2) expression.ResultsAfter 10-day culture, the intracellular calcium concentration in calcified group was significantly higher than that in control group (1.16 ± 0.04 vs. 0.14 ± 0.01 μg/mg, p < 0.01), but significantly reduced in 1 mmol/L aspirin treated group (0.74 ± 0.05 μg/mg, p < 0.01), and 4 mmol/L aspirin treated group (0.93 ± 0.03 μg/mg, p < 0.01). The elevated expression of OPN and Runx2 induced by osteogenic medium was significantly relieved after 1 or 4 mmol/L aspirin treatment. The expression of HSF1, HSP70 and HSP90 was decreased in calcification-induced VSMCs, but significantly increased after treatment of aspirin. Furthermore, inhibition of HSP70 (or HSP90) by small-molecule inhibitor or small interfering RNA could partially abolish the anti-calcification effect of aspirin, proved by the changes of intracellular calcium concentration and osteoblastic marker expression.Discussion and conclusionsAspirin could relieve the calcification of VSMCs partially through HSP70- or HSP90-mediated heat shock response. These findings expanded the understanding of aspirin pharmacology, and imply that local induction expression of HSPs might be a potential therapeutic strategy for the prevention and therapy of vascular calcification.     

Calotropis procera: A potential cognition enhancer in scopolamine and electroconvulsive shock-induced amnesia in rats

Objectives:

Present study evaluates the effect of Calotropis procera (Apocynaceae) dry latex on cognitive function in rats using scopolamine and electroconvulsive shock (ECS) induced amnesia model.

Materials and Methods:

Male Wistar rats were pretreated with 200, 400 and 800 mg/kg of C. procera dry latex in scopolamine-induced amnesia model. Dose showing maximum effect in cognitive performance was selected and further evaluated using scopolamine and ECS-induced amnesia model for its effect on neurochemical enzymes and cognitive performance. Acetylcholinesterase (AChE) activity, β amyloid_1-42, and dopamine level were analyzed, while the cognitive performance was assessed by elevated plus maze, step-through passive avoidance test, and Morris water maze. Simultaneously, C. procera dry latex (25, 50, 100, 250, 500, and 1000 μg/mL) was screened for in vitro AChE inhibition assay.

Results:

Pretreatment with (200, 400 and 800 mg/kg) C. procera dry latex shows dose dependent increase in cognitive performance in scopolamine-induced amnesia. Further, pretreatment with the selected dose (800 mg/kg) showed significant improvement in transfer latency (P < 0.001, P < 0.01), escape latency (P < 0.05), time spent in target quadrant (P < 0.001) also significant decrease in AChE activity (P < 0.05), β amyloid_1-42 level (P < 0.001), and increase in dopamine level (P < 0.01) in rat brain homogenate when compared with scopolamine and ECS disease control groups. IC₅₀ for C. procera dry latex was found to be <1000 μg/mL.

Conclusions:

Pretreatment with C. procera dry latex (800 mg/kg) produced significant cognition enhancement by improving cognitive performance and decreasing the marker neurochemical enzyme activity in scopolamine and ECS-induced amnesia model.KEY WORDS: Acetylcholinesterase, Alzheimer''s disease, Dopamine, β amyloid1-42     

Studies on the clinical pharmacology of prazosin: I: cardiovascular, catecholamine and endocrine changes following a single dose

1 Cardiovascular, catecholamine and neuroendocrine changes were studied following administration of prazosin to ten normal subjects. In response to a fall in standing blood pressure from 87±5 (s.d.) mmHg to 49±20 (P < 0.01) heart rate (measured by continuous ECG monitoring) rose from 81±11 to 118±20 (P < 0.01). Five of the ten subjects sustained their tachycardia on standing and developed at most mild symptoms. In the other five, tachycardia suddenly gave way to bradycardia and they became syncopal.

2 In the supine position, when blood pressure was not significantly different from control, plasma noradrenaline concentration (nmol/l) was 2±0.5 compared with a control value of 1.2±0.3 (P < 0.01). In response to standing hypotension plasma noradrenaline was 4.2±2.7 compared with a standing control value of 1.9±0.4 (P < 0.02).

3 Four hours after taking prazosin five of the subjects stood for 30 min and blood was drawn for plasma renin activity (PRA). Blood pressure at this time was 15 mmHg below control (P < 0.02). PRA (ng ml^-1 h^-1) was 6.4±2.3 compared with time matched placebo control of 1.4±0.8 (P < 0.01).

4 At the same time as the PRA sampling, plasma cortisol was 15.6±2.6 μg/100 ml during hypotension and 8.2±3.9 following placebo (P < 0.01). Growth hormone was 1.4±0.3 ng/ml during hypotension and 1.0±0.2 following placebo (P < 0.01). Prolactin did not rise significantly during hypotension induced by prazosin.

5 Isoprenaline infusion produced the same change in heart rate during the time of maximum prazosin action as when given alone.

6 It is concluded that these observations are not in keeping with earlier reports that prazosin lowers blood pressure without producing a reflex increase in heart rate or renin release. Nor are these findings in keeping with current theories of the mechanism of action of prazosin which variously suggest that noradrenaline concentration should not increase, or that the heart is incapable of responding to an adrenergic stimulus in the presence of prazosin.