Antiepileptogenic effect of curcumin on kainate-induced model of temporal lobe epilepsy

Abstract

Context: Temporal lobe epilepsy (TLE) is an intractable neurological disorder. Curcumin is the bioactive component of turmeric with anti-epileptic and neuroprotective potential.

Objective: The beneficial effect of curcumin on the intrahippocampal kainate-induced model of TLE was investigated.

Materials and methods: Rats were divided into sham, curcumin-pretreated sham, kainate and curcumin-pretreated kainate groups. The rat model of TLE was induced by unilateral intrahippocampal injection of 4?μg of kainate. Rats received curcumin p.o. at a dose of 100?mg/kg/d starting 1 week before the surgery. Seizure activity (SE) and oxidative stress-related markers were measured. Furthermore, the Timm index for evaluation of mossy fiber sprouting (MFS) and number of Nissl-stained neurons were quantified.

Results: All rats in the kainate group had SE, while 28.5% of rats showed seizures in the curcumin-pretreated kainate group. Malondialdehyde and nitrite and nitrate levels significantly increased in the kainate group (p?<?0.01 and p?<?0.05, respectively), and curcumin significantly lowered these parameters (p?<?0.05). Superoxide dismutase activity significantly decreased in the kainate group (p?<?0.05) and curcumin did not improve it. Rats in the kainate group showed a significant reduction of neurons in Cornu Ammonis 1 (CA1) (p?<?0.05), CA3 (p?<?0.005) and hilar (p?<?0.01) regions, and curcumin significantly prevented these changes (p?<?0.05–0.005). The Timm index significantly increased in the kainate group (p?<?0.005), and curcumin significantly lowered this index (p?<?0.01).

Discussion and conclusion: Curcumin pretreatment can attenuate seizures, lower some oxidative stress markers, and prevent hippocampal neuronal loss and MFS in the kainate-induced model of TLE.     

Protective effect of compound Danshen (Salvia miltiorrhiza) dripping pills alone and in combination with carbamazepine on kainic acid-induced temporal lobe epilepsy and cognitive impairment in rats

Context: Temporal lobe epilepsy (TLE) is resistant to antiepileptic drugs (AEDs) and is associated with cognitive impairment. The modern Chinese medicine, compound Danshen dripping pills (CDDP), is clinically effective in treating epilepsy and improving cognitive impairment.

Objective: This study evaluated the protective effects of CDDP alone and in combination with carbamazepine (CBZ) on kainic acid-induced TLE and cognitive impairment in rats.

Materials and methods: Sprague–Dawley rats were randomly divided into five groups: control (sham operated), model, CDDP, CBZ and combined. A TLE model was then created via bilateral intrahippocampal injection of 0.35?μg kainic acid (KA). Rats received CDDP (85?mg/kg), CBZ (100?mg/kg) or combined (85?mg/kg CDDP +100?mg/kg CBZ) via intragastric administration for 90?d, respectively. Seizure intensity, apoptosis and glial cell line-derived neurotrophic factor (GDNF) were measured. Furthermore, the improvement in cognitive impairment and hippocampal neuronal damage was evaluated.

Results: CDDP combined with CBZ significantly decreased seizure severity and frequency (p?p?p?p?p?Conclusion: These findings support the use of CDDP as an adjuvant drug for the treatment of TLE and cognitive deficit. Its mechanism might be related to an anti-apoptosis effect and up-regulation of GDNF.     

Antidepressant-like effects of magnesium lithospermate B in a rat model of chronic unpredictable stress

Abstract

Context: Magnesium lithospermate B (MLB), an active polyphenol acid of Danshen [Radix Salviae miltiorrhizae (Labiatae)], shows neuroprotective and anti-inflammatory effects in vivo and in vitro.

Objective: We hypothesized that MLB might exert antidepressant-like effects by targeting the neuroinflammatory signals.

Materials and methods: Sprague-Dawley rats were subjected to the chronic unpredictable stress (CUS) protocol. Rats in the control group received no CUS during the whole experiment. In the model group, rats were exposed to CUS for 7 weeks. From the beginning of the 5th week, model group rats were randomly grouped and subjected to different treatments. In the experiment, control and model group rats were intraperitoneally (i.p.) injected with saline. MLB was dissolved in saline to give a final concentration, and the rats were injected (i.p.) with 15, 30, or 60?mg/kg MLB once a day for 3 weeks.

Results: MLB administration significantly reduced: (1) the immobility time in the forced swimming test (19?s, p?<?0.05); (2) the immobility time in the tail suspension test (76.3?s, p?<?0.05); (3) the corticosterone (CORT) concentrations in the serum (21.7?nmol/L, p?>?0.05); (4) the pro-inflammatory cytokine levels in the serum – TNF-α (92.1?pg/ml, p?<?0.05), IL-1β (86.9?pg/ml, p?<?0.05), and IL-6 (93.8?pg/ml, p?<?0.05); (5) pro-inflammatory cytokine levels in tissue – TNF-α (3.2?pg/mg protein, p?<?0.05), IL-1β (1.5?pg/mg protein, p?>?0.05), and IL-6 (6.3?pg/mg protein, p?<?0.05); and (6) phospho-NF-κB (1.6, p?<?0.05) and phospho-IκB-α (0.4, p?<?0.05) expression in tissue.

Discussion and conclusion: The results suggested that MLB might exert therapeutic actions on depression-like behavior and the HPA axis hyperactivity in CUS rats, and the mechanisms underlying the antidepressant-like effects of MLB might be mediated by regulation of the expression of NF-κB and IκB-α in rats.     

Antidiabetic potential of salvianolic acid B in multiple low-dose streptozotocin-induced diabetes

Abstract

Context: Salvianolic acids are the most abundant water-soluble compounds extracted from the herb Salvia miltiorrhiza L. (Lamiaceae) with antioxidant and protective effects.

Objective: This study evaluates the antidiabetic effect of salvianolic acid B (Sal B) in multiple low-dose streptozotocin (MLDS)-induced diabetes in rat.

Materials and methods: Rats were divided into control, Sal B40-treated control, diabetic, Sal B20-, and Sal B40-treated diabetic groups. Sal B was daily administered at doses of 20 or 40?mg/kg (i.p.), started on third day post-STZ injection for 3 weeks. Serum glucose and insulin level and some oxidative stress markers in pancreas were measured in addition to the oral glucose tolerance test (OGTT), histological assessment, and apoptosis determination.

Results: After 3 weeks, treatment of diabetic rats with Sal B20 and Sal B40 caused a significant decrease of the serum glucose (p?<?0.05–0.01) and improvement of OGTT. Meanwhile, serum insulin was significantly higher in Sal B20- and Sal B40-treated diabetics (p?<?0.01) and treatment of diabetics with Sal B40 significantly lowered malondialdehyde (MDA) (p?<?0.05), raised glutathione (GSH) (p?<?0.05), and activity of catalase (p?<?0.01) with no significant change of nitrite. Furthermore, the number of pancreatic islets (p?<?0.05) and their area (p?<?0.01) was significantly higher and apoptosis reactivity was significantly lower (p?<?0.05) in the Sal B40-treated diabetic group versus diabetics.

Discussion and conclusion: Three-week treatment of diabetic rats with Sal B exhibited antidiabetic activity which is partly exerted via attenuation of oxidative stress and apoptosis and augmentation of antioxidant system.     

Biological activities of salvianolic acid B from Salvia miltiorrhiza on type 2 diabetes induced by high-fat diet and streptozotocin

Abstract

Context: Salvia miltiorrhiza Bge. (Labiatae) has been widely used for treating diabetes for centuries. Salvianolic acid B (SalB) is the main bioactive component in Salvia miltiorrhiza; however, its antidiabetic activity and possible mechanism are not yet clear.

Objective: To investigate the effects of SalB on glycometabolism, lipid metabolism, insulin resistance, oxidative stress, and glycogen synthesis in type 2 diabetic rat model.

Materials and methods: High-fat diet (HFD) and streptozotocin-induced diabetic rats were randomly divided into model group, SalB subgroups (50, 100, and 200?mg/kg), and rosiglitazone group.

Results: Compared with the model group, SalB (100 and 200?mg/kg) significantly decreased blood glucose (by 23.8 and 21.7%; p?<?0.05 and p?<?0.01) and insulin (by 31.3 and 26.6%; p?<?0.05), and increased insulin sensitivity index (by 10.9 and 9.3%; p?<?0.05). They also significantly decreased total cholesterol (by 24.9 and 27.9%; p?<?0.01), low-density lipoprotein cholesterol (by 56.2 and 64.6%; p?<?0.01), non-esterified fatty acids (by 32.1 and 37.9%; p?<?0.01), hepatic glycogen (by 41.3 and 60.5%; p?<?0.01), and muscle glycogen (by 33.2 and 38.6%; p?<?0.05), and increased high-density lipoprotein cholesterol (by 50.0 and 61.4%; p?<?0.05 and p?<?0.01), which were originally altered by HFD and streptozotocin. In addition, SalB (200?mg/kg) markedly decreased triglyceride and malondialdehyde (by 31.5 and 29.0%; p?<?0.05 and p?<?0.01), and increased superoxide dismutase (by 56.6%; p?<?0.01), which were originally altered by HFD and streptozotocin.

Discussion and conclusion: The results indicate that SalB can inhibit symptoms of diabetes mellitus in rats and these effects may partially be correlated with its insulin sensitivity, glycogen synthesis and antioxidant activities.     

Metformin pretreatment enhanced learning and memory in cerebral forebrain ischaemia: the role of the AMPK/BDNF/P70SK signalling pathway

Context Metformin induced AMP-activated protein kinase (AMPK) and protected neurons in cerebral ischaemia.

Objective This study examined pretreatment with metformin and activation of AMPK in molecular and behavioral levels associated with memory.

Materials and methods Rats were pretreated with metformin (200?mg/kg) for 2 weeks and 4-vessels occlusion global cerebral ischaemia was induced. Three days after ischaemia, memory improvement was done by passive avoidance task and neurological scores were evaluated. The amount of Brain-Derived Neurotropic Factor (BDNF) and phosphorylated and total P70S6 kinase (P70S6K) were measured.

Results Pretreatment with metformin (met) in the met?+?ischaemia/reperfusion (I/R) group reduced latency time for enter to dark chamber compared with the sham group (p?<?0.001) and increased latency time compared with the I/R group (p?<?0.001). Injection of Compound C (CC) (as an AMPK inhibitor) concomitant with metformin reduced latency time in I/R rats compared with the I/R?+?met group (p?<?0.05). Neurological scores were reduced in met treated rats compared with the sham group. Pretreatment with metformin in I/R animals reduced levels of pro-BDNF compared with the I/R group (p?<?0.001) but increased that compared with the sham group (p?<?0.001). The level of pro-BDNF decreased in the met?+?CC?+?I/R group compared with the met?+?I/R group (p?<?0.01). Pretreatment with metformin in I/R animals significantly increased P70S6K compared with the I/R group (p?<?0.001).

Conclusion Short-term memory in ischaemic rats treated with metformin increased step-through latency; sensory-motor evaluation was applied and a group of ischaemia rats that were pretreated with metformin showed high levels of BDNF, P70S6K that seemed to be due to increasing AMPK.     

Influence of prenatal waterpipe tobacco smoke exposure on renal biomarkers in adult offspring rats

Background: Waterpipe tobacco smoke (WTS) is a popular form of tobacco consumption. Prenatal exposure to cigarette smoke altered kidney function and oxidative stress balance in offspring. However, the effect of prenatal WTS exposure on kidney function parameters, blood pressure and oxidative stress in adult offspring rats were unknown.

Methods: Pregnant Wister rats were exposed to either WTS for 2?hours per day utilizing a whole body exposure system or fresh air from day 0 of gestation to day 21. Systolic blood pressure, histological analysis of kidney, kidney function biomarkers [angiotensin converting enzyme (ACE), angiotensin I, angiotensin II, urea nitrogen, creatinine and albumin], and oxidative stress biomarkers (glutathione peroxidase (GPx), catalase and thiobarbituric acid reactive substances (TBARS)) were measured in male- and female- offspring rats on week 20.

Results: Prenatal exposure to WTS significantly decreased kidneys’ weight and glomeruli area (p?<?0.05) in offspring rats. Prenatal WTS exposure increased blood pressure in offspring rats (p?<?0.05). Further, prenatal WTS exposure increased the level of urine albumin (p?<?0.05) in offspring rats. Prenatal WTS exposure increased the level of ACE and angiotensin I (p?<?0.05) in female offspring rats. Prenatal WTS exposure increased the level of TBARS (p?<?0.05) in female offspring rats and there was a trend of decreased activity of GPx in male and female offspring rats, but was not significant (p?>?0.05).

Conclusions: Maternal WTS exposure during pregnancy resulted in detrimental effects on the renal system as indicated by altered kidney parameters and function, increased systolic blood pressure and oxidative stress in adult offspring rats.     

Ameliorative effects of physcion 8-O-β-glucopyranoside isolated from Polygonum cuspidatum on learning and memory in dementia rats induced by Aβ1–40

Abstract

Context: Polygonum cuspidatum Sieb. Et Zucc. (Polygonaceae) has been traditionally used in folk medicine to treat various diseases.

Objective: This study investigates the ameliorative effects of physcion 8-O-β-glucopyranoside (PSG) isolated from P. cuspidatum on learning and memory in dementia rats induced by Aβ_1–40.

Materials and methods: Dementia rats were prepared by intracerebroventricular injection of Aβ_1–40. PSG (5, 10, 20, and 40?mg/kg/d, for 5?d) was administered orally. Ameliorative activity of PSG in dementia rats was evaluated by the Morris water maze (MWM) test, and its mechanisms were explored by evaluating AchE activity, levels of DA, NE, and 5-HT in hippocampus, and drebrin protein expressions in hippocampus.

Results: Our results indicated that PSG (5, 10, 20, and 40?mg/kg/d) significantly inhibited the prolonged latency in dementia rats (p?<?0.05), and inhibitory rates were 16.5, 22.7, 33.0, and 44.8% after 5?d of learning, indicating that PSG improves learning and memory of dementia rats. Furthermore, PSG significantly decreased AchE activity (10, 20, and 40?mg/kg/d; p?<?0.05), increased 5-HT (20 and 40?mg/kg/d, p?<?0.05), NE (10, 20, and 40?mg/kg/d; p?<?0.05), and DA levels (5, 10, 20, and 40?mg/kg; p?<?0.05) in the hippocampus. Additionally, PSG obviously decreased the Aβ contents in hippocampus (10, 20, and 40?mg/kg/d; p?<?0.05), and up-regulated drebrin protein expressions (5, 10, 20, and 40?mg/kg/d; p?<?0.05).

Conclusions: PSG can significantly enhance learning and memory in Aβ_1–40-induced dementia rats, and the mechanisms may be related to increase levels of Ach, 5-HT, NE, and DA, decrease Aβ contents, and up-regulation of drebrin proteins in hippocampus.     

Dual targeting of TNF-α and free radical toxic stress as a promising strategy to manage experimental polycystic ovary

Context: It is now clear that oxidative stress (OS) and chronic low-grade inflammation are two main pathways involved in polycystic ovary syndrome (PCOS) pathogenesis. Therefore, simultaneous targeting of these pathways by means of carvedilol and Semelil (ANGIPARS?), as established medicines with dual anti-cytokine and anti-oxidant potential may be a therapeutic alternative approach to the current treatments.

Objective: The objective of this study is to study the protective effects of carvedilol and ANGIPARS? on inflammatory and oxidative response in hyperandrogenism-induced polycystic ovary (PCO).

Materials and methods: The murine model of PCO was induced by letrozole (1?mg/kg/d; orally) and effective doses of carvedilol (10?mg/kg/d; orally) and ANGIPARS? (2.1?mg/kg/d; orally) were administrated for 21?d in PCO and non-PCO healthy rats. Ovarian folliculogenesis, sex hormones concentrations, OS, inflammatory, and metabolic biomarkers were assessed in serum and ovaries.

Results: PCO rats exhibited ovarian cystogenesis which was preserved by the application of carvedilol and ANGIPARS?. In comparison with controls, decreased level of the total antioxidant power (TAP) and higher levels of reactive oxygen species (ROS) and lipid peroxidation (LPO) in serum and ovaries (2.41?±?0.67 versus 0.72?±?0.11; and 0.17?±?0.04 versus 0.05?±?0.01; 5.48?±?1.30 versus 10.56?±?0.77; and 7.06?±?1.94 versus 17.98?±?0.98; p?<?0.05, respectively) were detected in PCO rats. Moreover, the PCO rats exhibited hyperandrogenism due to a 3.7-fold increase in serum testosterone concentration (35.04?±?3.17 versus 131.09?±?13.24; p?<?0.05) along with a 2.98-fold decrease in serum progesterone (6.19?±?0.40 versus 18.50?±?1.03; p?<?0.05) and 5.2-fold decrease in serum estradiol (9.30?±?0.61 versus 48.3?±?2.10; p?<?0.05) when compared with those of the control group. However, similar to the control group, normal levels of OS markers and sex hormones were detected in ANGIPARS? and carvedilol co-treated PCO rats. Besides, when compared with controls, increased levels of TNF-α (770.75?±?42.06 versus 477.14?±?28.77; p?<?0.05) and insulin (1.27?±?0.10 versus 0.36?±?0.05; p?<?0.05) in PCO rats were significantly inhibited by carvedilol and ANGIPARS? co-treatment.

Discussion and conclusion: We evidenced the beneficial effects of carvedilol and ANGIPARS? in PCO, which underpin the new alternative approach in using these kinds of medicines in female reproductive disorders.     

Cognitive effects of vanillic acid against streptozotocin-induced neurodegeneration in mice

Abstract

Context: Vanillic acid (VA), a flavoring agent used in food and drug products, obtained naturally from the plant Angelica sinensis (Oliv.) Diels (Apiaceae), used in the traditional Chinese medicine. It is reported to possess strong antioxidant, anti-inflammatory, and neuroprotective effects. However, the pharmacological effects on oxidative stress-induced neurodegeneration are not well investigated.

Objective: This study investigates the neuroprotective effect of VA on streptozotocin (STZ)-induced neurodegeneration in mice through behavioral and biochemical parameters.

Materials and methods: The behavioral effects were determined using the Y-maze and open-field habituation memory. In biochemical parameters, acetylcholinesterase (AChE), corticosterone, tumor necrosis factor (TNF)-α, and antioxidants (superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase) were measured. Five groups of animals used were of control, negative control, and three separate groups treated with 25, 50, and 100?mg/kg of VA, respectively, for 28?d. Intracerebroventricular (ICV) injections of STZ were performed for all groups except control on 14th and 16th of 28?d of VA treatment.

Results: VA improved spatial learning and memory retention by preventing oxidative stress compared with control animals. VA at 50 and 100?mg/kg dose significantly (p?<?0.001) improved the habituation memory, decreased the AChE, corticosterone, TNF-α, and increased the antioxidants (p?<?0.001). VA (100?mg/kg) exhibited dose-dependent effect in all parameters with p?<?0.001 except antioxidants in which VA showed the significance of p?<?0.01.

Discussion and conclusion: VA exhibited reduction in AChE, TNF-α, and corticosterone with improved antioxidants to contribute neuroprotection and could be an effective therapeutic agent for treating neurodegenerative disorders.     

The effect of lipoic acid on acrylamide-induced neuropathy in rats with reference to biochemical,hematological, and behavioral alterations

Abstract

Context: Acrylamide (ACR) is a well-known neurotoxicant and carcinogenic agent which poses a greater risk for human and animal health.

Objective: The present study evaluates the beneficial effects of α-lipoic acid (LA) on ACR-induced neuropathy.

Materials and methods: A total of 40 male rats were divided into four groups: a placebo group; LA-treated group, administered orally 1% (w/w) LA mixed with diet; ACR-treated group, given 0.05% (w/v) ACR dissolved in drinking water; and LA?+?ACR-treated group, given LA 1% 7?d before and along with ACR 0.05% for 21?d. After 28?d, blood samples were collected, the rats were decapitated, and the tissues were excised for the measurement of brain biomarkers, antioxidant status, and hematological analysis. Also, the gait score of rats was evaluated.

Results: ACR-exposed rats exhibited abnormal gait deficits with significant (p?<?0.05) decline in acetylcholine esterase (AChE) and creatine kinase in serum and brain tissues, respectively. However, the lactate dehydrogenase activity was increased in serum by 123%, although it decreased in brain tissues by ?74%. ACR significantly (p?<?0.05) increased the malondialdehyde level by 273% with subsequent depletion of glutathione S-transferase (GST), glutathione peroxidase (GPx), and glutathione reductase (GR) activities and reduced the glutathione (GSH) level in brain tissue. Interestingly, LA significantly (p?<?0.05) improved brain enzymatic biomarkers, attenuated lipid peroxidation (LPO), and increased antioxidant activities compared with the ACR-treated group.

Discussion and conclusion: These results suggested that LA may have a role in the management of ACR-induced oxidative stress in brain tissues through its antioxidant activity, attenuation of LPO, and improvement of brain biomarkers.     

The ginsenoside metabolite compound K exerts its anti-inflammatory activity by downregulating memory B cell in adjuvant-induced arthritis

Context: Compound K (CK, 20-O-d-glucopyranosyl-20(S)-protopanaxadiol), a novel ginsenoside metabolite, is structurally a member of the dammarane-type triterpene saponins. Several studies have identified the anti-inflammatory activity of CK. Our previous study demonstrated that CK exerted its anti-inflammatory effect via inhibition of abnormal activation and differentiation of T cells. However, its mechanism of action on B cells remains unclear.

Objective: The objective of this study is to investigate the effect and underlying mechanisms of CK’s effects on memory B cells in the setting of adjuvant-arthritis (AA).

Materials and methods: Complete Freund’s adjuvant was used to induce AA in rats. Rats were administered, either CK (10, 40, and 160?mg/kg), once daily for 15?d, or methotrexate (MTX; 0.5?mg/kg) once every 3?d, for a total of six times. To evaluate the anti-inflammatory effect of CK, a global assessment and a swollen joint count of AA rats were performed every 3?d. Spleen index and histopathology were examined. Subsets of B cells including CD45R⁺IgM⁺ (total B cells) and CD45R⁺CD27⁺ (memory B cells) and expression of CD40 and CD40L were assayed by flow cytometry.

Results: Compared with the AA rats, global assessment scores and swollen joint counts were significantly lower in the treated groups received CK (40 and 160?mg/kg; p?<?0.05 and p?<?0.01, respectively). CK (40 and 160?mg/kg) decreased the spleen index (p?<?0.01), and alleviated hyperplasia of lymph nodes (p?<?0.05 and p?<?0.01, respectively) and marginal zone (p?<?0.05) in the spleen. In addition, CK (40 and 160?mg/kg) suppressed memory B cell subsets (p?<?0.05), and suppressed CD40L expression on T cells and CD40 expression on B cells (p?<?0.05 and p?<?0.01, respectively).

Discussion and conclusion: This study demonstrated that CK downregulated memory B cells in AA rats, and this down-regulation may be T-cell dependent.     

Antidiabetic mechanism of Coptis chinensis polysaccharide through its antioxidant property involving the JNK pathway

Abstract

Context: Antidiabetic activity of Coptis chinensis Franch (Ranunculaceae) polysaccharide (CCPW) has been reported. However, its molecular mechanism remains unclear.

Objective: An attempt was made to further verify the antidiabetic activity of CCPW on type 2 diabetes mellitus (T2DM) and elucidate the mechanism of antidiabetic activity.

Materials and methods: Male Wistar rats were fed with high-fat diet (HFD) and injected with streptozotocin (STZ) to generate a T2DM model. Effects of CCPW on fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), glutathione (GSH), glutathione peroxidases (GSH-Px), superoxide dismutases (SOD), catalase (CAT), malondialdehyde (MDA), c-jun n-terminal kinase (JNK), phosphorylated insulin receptor substrate 1 (phospho-IRS1), phosphorylated phosphatidylinositol 3 kinase (phospho-PI3Kp85) and glucose transporter 4 (Glut4) were investigated.

Results: FBG level of diabetic rats could be significantly inhibited by 51.2, 42.7, and 23.3% through administration of CCPW at doses of 200, 100, and 50?mg/kg b.w., respectively (p?<?0.01). CCPW also could significantly reduce TG by 19.2, 12.1, and 7.4%, and TC by 24.2, 20.9, and 18.7%, respectively (p?<?0.05 or p?<?0.01). CCPW showed an obvious antioxidant effect through increasing GSH-Px, SOD, and CAT activities, and decreasing GSH and MDA contents (p?<?0.05 or p?<?0.01). Furthermore, CCPW could inhibit JNK and phospho-IRS1 expression and promote the expression of phospho-PI3Kp85 and Glut4 compared with those in the DM group (p?<?0.05 or p?<?0.01).

Discussion and conclusion: CCPW can produce antidiabetic activity in rats with T2DM through its antioxidative effect, which is closely related to the JNK/IRS1/PI3K pathway.     

The correlation between metastasis-free survival and overall survival in non-metastatic castration resistant prostate cancer patients from the Medical Data Vision claims database in Japan

Background and purpose: Several recent randomized controlled trials (RCTs) in non-metastatic castration resistant prostate cancer (nmCRPC) have demonstrated a significant improvement in metastasis-free survival (MFS); however, an improvement in overall survival (OS) is not reported yet. Since the surrogacy of MFS to OS has not been formally investigated in nmCRPC in Japan, this study evaluated the correlation between MFS and OS among a nmCRPC population in Japan.

Methods: This is a retrospective longitudinal observational cohort study in patients with nmCRPC using the Japanese Medical Data Vision (MDV) database covering over 20 million patients. A total of 1236 patients with CRPC who had no prior medical history of cancer except prostate cancer and no distant metastasis, and who fulfilled PCWG2 criteria, were identified. Following the identification of nmCRPC, patients’ medical records were investigated for subsequent events of metastasis and death.

Results: The median follow-up time was 24?months. Median MFS was 28?months (95% CI: 24.0 to 33.0?months) and median OS could not be estimated (95% CI: not estimated). There was a statistically significant correlation between MFS and OS (Pearson’s correlation coefficient?=?0.62; 95% CI: 0.58–0.65; p?<?.0001, Spearman’s correlation coefficient?=?0.62; 95% CI: 0.58–0.65; p?<?.0001 and Kendall’s τ statistic?=?0.53; 95% CI: 0.49–0.56; p?<?.0001).

Conclusions: The results of this study indicate a significant correlation between MFS and OS. It may justify the usefulness of MFS as surrogate for OS in nmCRPC.     

Trends in RA patients’ adherence to subcutaneous anti-TNF therapies and costs

ABSTRACT

Objective: To examine adherence to adalimumab (ADA) and etanercept (ETA) and health care costs in rheumatoid arthritis (RA) patients, and to explore the association between adherence, utilization and costs.

Research design and methods: Using administrative claims data from a large managed health care plan, RA patients treated with etanercept or adalimumab during the period from 01/01/2005 through 12/31/2005 were identified. The first dispensing date was defined as the index date. Patient adherence and costs were assessed during the 1 year post-index period.

Main outcome measures: Nonadherence (medication possession ratio <80%) was modeled using logistic regression. Hazard ratios (HR) comparing time to discontinuation were estimated using Cox proportional hazard (PH) models. Propensity score matching with multivariate generalized linear modeling adjustment was done to assess cost difference between ADA and ETA.

Results: Of 3829 eligible RA patients, 1292 (765 existing, 527 naïve) and 2537 (1834 existing, 703 naïve) patients used ADA and ETA, respectively. Compared with ADA users, ETA users had longer average treatment duration (316 vs. 291 days; p?<?0.0001). Unadjusted adherence rates for naïve and existing users were 63% and 70% (ADA), and 65% and 73% (ETA). Logistic regression analysis indicated that compared with ETA users, ADA users were more likely to be nonadherent (OR, naïve 1.24; existing; 1.25). Cox PH models indicated that existing ADA users were more likely to discontinue (HR?=?1.11; p?=?0.06) their medication than existing ETA users. Compared with ADA users, ETA users had significantly lower RA-related pharmacy costs (naïve: $10,892 vs. $12,534, p?<?0.01; existing: $12,192 vs. $13,752, p?<?0.01) and RA-related total costs (naïve: $11,976.42 vs. $13,511.99, p?<?0.05; existing: $14,031 vs. $15,454, p?<?0.05).

Conclusions: ETA users had longer treatment duration, were more likely to adhere to their medication regimen and had lower RA-related pharmacy and RA-related total costs compared with ADA users. These findings must be considered within the limitations of this database analysis.     

Proulcerogenic effect of water extract of Boswellia sacra oleo gum resin in rats

Context: The water extract of Boswellia sacra Flueck. (Burseraceae) is used in the treatment of gastric and hepatic disorders in the Arab countries.

Objective: The effect of Boswellia sacra water extract on gastric secretion and experimentally induced gastric ulcers in rats was studied.

Materials and methods: Acetic acid-induced chronic gastric ulcers, pylorus ligation, aspirin-induced, ethanol-induced, and restraint plus cold stress-induced gastric ulcer models were employed. The effect on normal rats was also studied. The water extract of B. sacra was administered orally at doses of 2 and 5?ml/kg once daily ranging from single dose to 30?d treatment depending on the model. The extract was subjected to GC-MS analysis to determine the presence of various phytoconstituents.

Results: Boswellia sacra water extract (5?ml/kg, p.o (per os)) aggravated acetic acid-induced chronic ulcers, wherein an increase in ulcer index (p?<?0.01) and ulcer score (p?<?0.05) was observed. In pylorus-ligated rats, the extract increased gastric content volume (p?<?0.01), free acidity (p?<?0.01), total acidity (p?<?0.01), ulcer index (p?<?0.01), and pepsin activity (p?<?0.05). There was no significant effect on the development of ethanol-induced and aspirin-induced ulcers while an increase in the development of stress-induced ulcers was observed (p?<?0.01). The extract did not produce any ulcers when administered to normal rats. The dose of 2?ml/kg was less proulcerogenic compared with 5?ml/kg. The GC-MS analysis revealed the presence of several phytoconstituents that included menthol, 3-cyclohexen-1-ol, and octanoic acid.

Conclusion: Boswellia sacra water extract has proulcerogenic activity due to its gastric hypersecretory effect.     

Ethanol extract of Cotinus coggygria leaves accelerates wound healing process in diabetic rats

Context: Cotinus coggygria Scop. (Anacardiaceae) leaves that were used as wound healing in traditional Balkan and Anatolian folk medicine, could be potentially effective in treating diabetic wounds.

Objective: This study investigates biochemical and histological effects of ethanol extract of C. coggygria (CCE) on excision wound model in diabetic rats.

Materials and methods: This study was conducted on diabetic Wistar albino rats, which were injected by a single dose (50?mg/kg i.p.) streptozotocin. Afterward an excision wound model was created in all animals; diabetic control rats were applied topically simple ointment and diabetic treatment rats were applied topically 5% (w/w) ointment with CC, once a day during the experimental period. Malondialdehyde, glutathione and hydroxyproline levels in wound tissues were investigated at the end of 3rd, 7th, and 14th days. Histopathological examination was also performed.

Results: Hydroxyproline content was significantly increased in the CCE treated group versus control after the 3rd and 7th days (15.33 versus 11.83; 19.67 versus 15.67?mg/g, p?<?0.05; respectively). A statistically significant elevation in glutathione at the end of 3rd, 7th, and 14th days (5.13 versus 1.58, p?<?0.05; 4.72 versus 1.88, p?<?0.05; 3.83 versus 1.88?μmol/g, p?<?0.05, respectively) and a statistically significant decrease in malondialdehyde level at the end of 7th day (4.49 versus 1.48?nmol/g, p?<?0.05) were determined in the treated group versus control group. These results were also supported by histological analyses.

Discussion and conclusion: These findings indicate that CCE accelerated the cutaneous wound healing process in diabetic wounds, in confirmation of its traditional use.     

Metabolic effect of repaglinide or acarbose when added to a double oral antidiabetic treatment with sulphonylureas and metformin: a double-blind,cross-over,clinical trial

ABSTRACT

Objective: To compare the metabolic effects of acarbose and repaglinide in type 2 diabetic patients who are being treated with a sulphonylurea–metformin combination therapy. The primary endpoint of the study was to evaluate which add-on treatment between acarbose and repaglinide is more efficacious in reducing PPG. The second endpoint was to evaluate which of these two treatment is more efficacious in the global management of glucose homeostasis in the enrolled patients.

Research design and methods: After a 4-week run-in period with a suplonylurea–metformin combination, 103 patients were randomised to receive in addition either repaglinide, up to 6?mg/day (2?mg three times a day) or acarbose, up to 300?mg/day (100?mg three times a day) with forced titration (independently of their glycaemic control, unless side-effects developed due to the drug dosage) for 15 weeks. The treatment was then crossed-over for further 12 weeks until the 27th week. We assessed body mass index (BMI), glycosylated haemoglobin (HbA_1c), fasting plasma glucoe (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), postprandial plasma insulin (PPI), homeostatic model assesssment (HOMA) index, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (Tg), at baseline and at 1, 2, 15 and 27 weeks of treatment.

Results: Seven patients did not complete the study, comprising one patient who was lost to follow-up and a further six through side-effects (two in week 1, one in week 15 and three after cross-over) Side-effects were classified as nausea (one in acarbose group), gastrointestinal events (four in acarbose group), and hypoglycaemia (one in repaglinide group). After 15 weeks of therapy, the repaglinide-treated patients experienced a significant decrease in HbA_1c (?1.1%, p?<?0.05), FPG (?9.5%, p?<?0.05), and PPG (?14.9%, p?<?0.05), when compared to the baseline values. However, the same treatment was associated with a significant increase in body weight (+2.3%, p?<?0.05), BMI (+3.3%, p?<?0.05) and FPI (+22.5%, p?<?0.05); The increase was reversed during the cross-over phase. After 15 weeks of therapy, the acarbose-treated patients experienced a significant decrease in body weight (?1.9%, p?<?0.05), BMI (?4.1%, p?<?0.05), HbA_1c (?1.4%, p?<?0.05), FPG (?10.7%, p?<?0.05), PPG (?16.2%, p?<?0.05), FPI (?16.1%, p?<?0.05), PPI (?26.9%, p?<?0.05), HOMA index (?30.1%, p?<?0.05), when compared to the baseline values. All these changes were reversed during the cross-over study phase, except those relating to HbA_1c, FPG and PPG. The only changes that significantly differed when directly comparing acarbose- and repaglinide-treated patients were those relating to FPI (?16.1% vs. +22.5%, respectively, p?<?0.05) and HOMA index (?30.1% vs. +2.7%, p?<?0.05).

Conclusion: In addition from having a similar effect to repaglinide on PPG, acarbose appeared to have a more comprehensive positive effect on glucose metabolism compared to repaglinide in this relatively small sample of type 2 diabetic patients when used as add-on therapy to sulphonylureas and metformin.