The effects of Melissa officinalis (lemon balm) pretreatment on the resistance of the heart to myocardial injury

Context: The antihyperlipidemic, antiarrhythmic, neuroprotective and hepatoprotective effects of Melissa officinalis L. (Lamiaceae) have been reported. However, no study has examined its effects on the resistance of the heart to stressful conditions.

Objective: The objective of this study is to evaluate the effects of aqueous extract of M. officinalis aerial parts on Wistar rat heart with/without cardiac injury.

Materials and methods: Animals were grouped as control, isoproterenol (ISO), M. officinalis without (M50, M100, and M200) and with isoproterenol (M50?+?ISO, M100?+?ISO, and M200?+?ISO). The aqueous extract of M. officinalis was orally administered at dosages of 50, 100, and 200?mg/kg/d, respectively, for 7 consecutive days. On the 6th and 7th day, ISO, M50?+?ISO, M100?+?ISO, and M200?+?ISO groups received 85?mg/kg of isoproterenol for myocardial injury induction. On day 8, hemodynamic parameters were recorded and samplings were done.

Results: The extract (50, 100, and 200?mg/kg) significantly reduced the heart rate (264?±?5, 259?±?5 and 281?±?3 versus 377?±?13 in control group, p?<?0.01). Blood pressure was significantly decreased in M50?+?ISO (75?±?5) versus M50 (110?±?6) and M100?+?ISO (72?±?6) versus M100 (105?±?5?mmHg, p?<?0.01). The malondialdehyde levels of the injured hearts were lower in M50?+?ISO and M100?+?ISO groups than in the ISO group (p?<?0.05). Serum cardiac troponin I was higher in the M200?+?ISO group (5.1?±?1.7) than in the ISO group (2.7?±?0.7?ng/ml, p?<?0.05).

Conclusion: The lower dose of extract, by improving the balance of the redox system and by reducing the heart rate, may increase the heart resistance to injury. However, the higher doses of extract may intensify the injury of ischemic heart.     

Role of GABAB receptors and p38MAPK/NF-κB pathway in paclitaxel-induced apoptosis of hippocampal neurons

Context: The effects of the anticancer drug paclitaxel on learning and memory are rarely studied.

Objective: This study investigated changes in GABA_B receptor expression during paclitaxel-induced apoptosis of hippocampal neurons and the role of the p38MAPK/NF-κB pathway in this process.

Materials and methods: Hippocampal neurons isolated from neonatal Sprague–Dawley rats were divided into six groups: Control (C), SB (10?µL of 10-µmol/L SB203580), SN (53?µg/mL SN50), N (1?µmol/L paclitaxel), SB?+?N (10?µmol/L SB203580?+?1?µmol/L paclitaxel) and SN?+?N (53?µg/mL SN50?+?1?µmol/L paclitaxel). Cells in different groups were treated with corresponding agents for 24?h at 37?°C. The apoptosis rate and protein levels of GABA_B1 receptors and NF-κB p65 were evaluated. Rat models of neuropathic pain was induced by paclitaxel and were divided into four groups such as N, B?+?N, SN?+?N and SN?+?B?+?N groups. Rats in the N group received intrathecal injections of normal saline solution. Rats in the B?+?N group received intrathecal injections of 10?μL baclofen (0.05?μg/μL). Rats in the SN?+?N and SN?+?B?+?N groups received intrathecal injections of SN50 and SN50 plus baclofen, respectively. Spatial learning and memory were evaluated in rat models based on the escape latency and the number of crossings over the platform and protein levels of GABA_B1 receptors, NF-κB, IL-1β and TNFα were measured by immunohistochemistry assay and western blot.

Results: The neuronal apoptosis rate was significantly increased in N (49.16?±?3.12)%, SB?+?N (31.18?±?3.02)% and SN?+?N (28.47?±?3.75)% groups, accompanied by increased levels of GABA_B1 receptors and NF-κB p65 (p?p?B1:9.0?±?1.6, NF-κB p65:29.6?±?2.4, IL-1β: 30.4?±?3.4, TNFα: 31.0?±?3.4), B?+?N, SN?+?N and SN?+?B?+?N groups evidently increased levels of GABA_B1 receptor (B?+?N:SN?+?N:SN?+?B?+?N?=?19.4?±?2.1:20.8?±?1.9:28.0?±?1.9) but significantly decreased levels of NF-κB p65 (B?+?N:SN?+?N:SN?+?B?+?N?=?21.2?±?1.5:18.6?±?2.1:12.6?±?1.5), IL-1β (B?+?N:SN?+?N:SN?+?B?+?N?=?22.0?±?1.0:19.6?±?1.8:14.6?±?1.5) and TNF α (B?+?N:SN?+?N:SN?+?B?+?N?=?23.0?±?1.6:22.2?±?0.8:16.6?±?1.7). Similar findings were found in western blot analysis.

Discussions and conclusions: Paclitaxel may reduce cognitive function in rats through the p38MAPK/NF-κB pathway and GABA_B1 receptors.     

Co-administration of walnut (Juglans regia) prevents systemic hypertension induced by long-term use of dexamethasone: a promising strategy for steroid consumers

Context: The long-term consumption of glucocorticoids (GCs) may induce serious adverse effects such as hypertension. There is sufficient evidence related to the benefit of walnuts on the cardiovascular system.

Objective: This study assesses the effect of methanol extract of walnut [Juglans regia L. (Juglandaceae)] on dexamethasone-induced hypertension and the possible mechanisms in Wistar rats.

Material and methods: Animals were randomized into control, kernel extract (100 and 200?mg/kg/d, orally), dexamethasone (0.03?mg/kg/d, subcutaneously), dexamethasone?+?kernel (100 and 200?mg/kg/d, separately), and dexamethasone?+?captopril (25?mg/kg/d, orally) groups. Animals were treated with water, kernel extract or captopril by gavage 4 d before and during 11 d of saline or dexamethasone treatment. On the 16th day, blood pressure (BP) was recorded and blood samples were collected to measure nitric oxide (NO). Animal hearts were frozen for measurement of malondialdehyde (MDA) and glutathione peroxidase (GPX).

Results: Dexamethasone increased the diastolic BP and MDA/GPX ratio in comparison with control group (128?±?7 vs. 105?±?3?mmHg, p?p?p?p?Conclusion: Similar to captopril, walnut extract normalized dexamethasone-induced hypertension. A part of this beneficial effect apparently involves maintaining balance of the redox system and NO production.     

The effect of aqueous extract of Rosa damascena on formaldehyde-induced toxicity in mice testes

Context: Rosa damascena L. (Rosaceae) (RD) essential oil and extracts are commonly used as a flavour in herbal medicine which increase libido. Previous studies have shown inhalation of RD flower’s oil increases libido and causes protective effects in formaldehyde (FA)-induced testicular damage.

Objective: The protective effects of aqueous extract of RD on the male reproductive system of mice were examined following FA-induced damage.

Materials and methods: Forty-eight adult NMRI male mice were randomly assigned to six groups (n?=?8): control (normal saline, 10?mg/kg); RD40 (40?mg/kg, p.o.); FA treated (10?mg/kg of 10%, i.p.) and FA?+?RD treated at 10, 20 and 40?mg/kg (FA?+?RD10), (FA?+?RD20) and (FA?+?RD40), respectively, for 40 days. At the end of treatment regimes, serum testosterone (T) level and the reproductive activity, viz. body/organ weights, testicular structure and sperm characteristics were studied.

Results: Formaldehyde administration significantly decreased serum T level (p?p?p?Discussion and conclusions: We may conclude that RD flower extract can withstand effects of FA in the male reproductive system of mice possibly due to its antioxidative properties.     

Antidepressant and anxiolytic activity of Lavandula officinalis aerial parts hydroalcoholic extract in scopolamine-treated rats

Context: Anxiety and depression are common in Alzheimer’s disease (AD). Despite some evidence, it is difficult to confirm Lavandula officinalis Chaix ex Vill (Lamiaceae) as an anxiolytic and antidepressant drug.

Objective: The effects of L. officinalis extract were studied in scopolamine-induced memory impairment, anxiety and depression-like behaviour.

Materials and methods: Male NMRI rats were divided into control, scopolamine alone-treated group received scopolamine (0.1?mg/kg) intraperitoneally (i.p.), daily and 30?min prior to performing behavioural testing on test day, for 12 continuous days and extract pretreated groups received aerial parts hydro alcoholic extract (i.p.) (100, 200 and 400?mg/kg), 30?min before each scopolamine injection. Memory impairment was assessed by Y-maze task, while, elevated plus maze and forced swimming test were used to measure anxiolytic and antidepressive-like activity.

Results: Spontaneous alternation percentage in Y maze is reduced by scopolamine (36.42?±?2.60) (p?≤?0.001), whereas lavender (200 and 400?mg/kg) enhanced it (83.12?±?5.20 and 95?±?11.08, respectively) (p?≤?0.05). Also, lavender pretreatment in 200 and 400?mg/kg enhanced time spent on the open arms (15.4?±?3.37 and 32.1?±?3.46, respectively) (p?≤?0.001). On the contrary, while immobility time was enhanced by scopolamine (296?±?4.70), 100, 200 and 400?mg/kg lavender reduced it (193.88?±?22.42, 73.3?±?8.25 and 35.2?±?4.22, respectively) in a dose-dependent manner (p?≤?0.001).

Discussion and conclusion: Lavender extracts improved scopolamine-induced memory impairment and also reduced anxiety and depression-like behaviour in a dose-dependent manner.     

GC-MS analysis and hepatoprotective activity of the n-hexane extract of Acrocarpus fraxinifolius leaves against paracetamol-induced hepatotoxicity in male albino rats

Context: In Egypt, the burden of liver diseases is exceptionally high.

Objective: To investigate the components of the n-hexane extract of Acrocarpus fraxinifolius Arn. (Leguminosae) and its hepatoprotective activity against paracetamol (APAP)-induced hepatotoxicity in rats.

Material and methods: TRACE GC ultra gas chromatogaphic spectrometry was used for extract analysis. Thirty albino rats were divided into six groups (five rats in each). Group 1 was the healthy control; Groups 2 and 3 were healthy treated groups (250 and 500?mg/kg b.w. of the extract, respectively) for seven days. Group 4 was hepatotoxicity control (APAP intoxicated group). Groups 5 and 6 received APAP?+?extract 250 and APAP?+?extract 500, respectively.

Results: Chromatographic analysis revealed the presence of 36 components. Major compounds were α-tocopherol (18.23%), labda-8 (20)-13-dien-15-oic acid (13.15%), lupeol (11.93%), phytol (10.95%) and squalene (7.19%). In the acute oral toxicity study, the mortality rates and behavioural signs of toxicity were zero in all groups (doses from 0 to 5?g/kg b.w. of A. fraxinifolius). LD₅₀ was found to be greater than 5?g/kg of the extract. Only the high dose (500?mg/kg b.w.) of extract significantly alleviated the liver relative weight (4.01?±?0.06) and biomarkers, as serum aspartate aminotransferase (62.87?±?1.41), alanine aminotransferase (46.74?±?1.45), alkaline phosphatase (65.96?±?0.74), lipid profiles (180.39?±?3.51), bilirubin profiles (2.30?±?0.06) and hepatic lipid peroxidation (114.20?±?2.06), and increased body weight (11.58?±?0.20), serum protein profile (11.09?±?0.46) and hepatic total antioxidant capacity (23.78?±?0.66) in APAP-induced hepatotoxicity in rats.

Conclusion: Our study proves the antihepatotoxic/antioxidant efficacies of A. fraxinifolius hexane extract.     

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.     

Beneficial effect of Citrus limon peel aqueous methanol extract on experimentally induced urolithic rats

Context: Citrus limon (L.) Burm.f. (Rutaceace) is a commonly available fruit variety with high medicinal and industrial values.

Objective: Lemon peel (LP) extract was studied as a potent preventive and curative agent for experimentally induced hyperoxaluric rats.

Materials and methods: Gas chromatography–mass spectrometry (GC–MS) analyses and toxicity study were performed for aqueous methanol LP extract. Twenty-four Wistar rats were segregated into four groups. Group 1: Control; Group 2: Urolithic (ethylene glycol (EG) – 0.75%); Group 3: Preventive study (EG?+?LP extract administration from 0th to 7th week); Group 4: Curative study (EG?+?LP extract administration from 4th to 7th week). Animals received LP extract daily by oral administration (100?mg/kg body weight) for 7 weeks.

Results and discussion: GC–MS analyses revealed that compound 6 was abundant in the LP extract (32%) followed by compound 1 (～21%). The LD₅₀ value of LP extract was found to be >5000?mg/kg of body weight. Urolithic rats showed significantly higher urinary calcium and oxalate (4.47?±?0.44 and 18.86?±?0.55?mg/24 h, respectively) excretion compared with control and experimental rats. Renal function parameters like urea (84?±?8.5 and 96.1?±?3.6?mg/dL), creatinine (1.92?±?0.27 and 1.52?±?0.22?mg/dL), and urinary protein (2.03?±?0.02 and 2.13?±?0.16?mg/24 h) were also reduced by LP extract (p?<?0.001) and corroborated with tissue analyses (SOD, catalase, and MDA levels) and histological studies in normal and experimental animals. Immunohistochemical staining of THP and NF-κB in urolithic animals showed elevated expression than the control, while LP extract suppressed the expression of these proteins.

Conclusion: In conclusion, lemon peel is effective in curing kidney stone disease and also can be used to prevent the disease and its recurrence.     

Crataegus Aronia protects and reverses vascular inflammation in a high fat diet rat model by an antioxidant mechanism and modulating serum levels of oxidized low-density lipoprotein

Context: Crataegus aronia (Willd.) Bosc (Rosaceae) (syn. Azarolus L) is traditionally used to treat cardiovascular disorders.

Objectives: To investigate C. aronia protection against a high-fat diet (HFD)-induced vascular inflammation in rats.

Materials and methods: Wistar Male rats (180–220?g) were divided (n?=?10/group) as control fed a standard diet (STD), STD + C. aronia (200?mg/kg, orally), HFD, HFD + C. aronia and HFD post-treated with C. aronia. Simvastatin (20?mg/kg) was co- or post-administered as a positive control drug. HFD was given for 8?weeks, and all other treatments were administered for 4?weeks.

Results: Most significantly, co-administration of C. aronia to HFD-fed rats reduced the thickness of aorta tunica media (90?±?5 vs. 160?±?11.3?µm) and adventitia (54.3?±?3.8 vs. 93.6?±?9.4?µm). It also lowered protein levels of TNF-α (0.51?±?0.15 and 0.15?±?0.16 vs. 0.1?±?0.09%) and IL-6 (0.52?±?0.19 vs. 1.0?±?0.2%) in their aorta or serum (5.9?±?0.91 vs. 12.98?±?1.3?ng/mL and 78.1?±?6.7 vs. 439?±?78?pg/mL, respectively). It also lowered all serum lipids and increased aorta levels of GSH levels (70.4?±?4.0 vs. 40.7?µM) and activity of SOD (5.7?±?0.7 vs. 2.9?±?0.6?U/mg) and decreased serum levels of ox-LDL-c (566.7?±?46 vs. 1817?±?147?ng/mL). Such effects were more profound than all other treatments.

Conclusions: C. aronia inhibits the HFD-induced vascular inflammation and its use in clinical trials is recommended.     

Effect of pregabalin on fear-based conditioned avoidance learning and spatial learning in a mouse model of scopolamine-induced amnesia

Objectives: Cognitive deficits are one of the frequent symptoms accompanying epilepsy or its treatment.

Methods: In this study, the effect on cognition of intraperitoneally administered antiepileptic drug, pregabalin (10?mg/kg), was investigated in scopolamine-induced memory-impaired mice in the passive avoidance task and Morris water maze task. The effect of scopolamine and pregabalin on animals’ locomotor activity was also studied.

Results: In the retention phase of the passive avoidance task, pregabalin reversed memory deficits induced by scopolamine (p?p?p?p?Discussion: In passive avoidance task, pregabalin reversed learning deficits induced by scopolamine. In the Morris water maze, pregabalin did not influence spatial learning deficits induced by scopolamine. These results are relevant for epileptic patients treated with pregabalin and those who use it for other therapeutic indications (anxiety, pain).     

Effectiveness and safety of vildagliptin and vildagliptin add-on to metformin in real-world settings in Egypt – results from the GUARD study

Objective: The GUARD study evaluated the effectiveness, safety, and tolerability of vildagliptin treatment with or without metformin in patients with type 2 diabetes mellitus (T2DM) in real-life settings. Here we present the results of the GUARD study for the patient subset from Egypt.

Research design and methods: This was a 24?±?6 weeks, prospective, non-interventional study that enrolled adult patients with T2DM receiving vildagliptin or vildagliptin?+?metformin combination therapy as per local prescribing information.

Main outcome measures: The primary effectiveness endpoint was change in HbA1c levels from baseline to week 24?±?6 endpoint. Safety was assessed by reporting of adverse events and serious adverse events (SAEs).

Results: Of 2786 patients enrolled from Egypt, 655 received vildagliptin and 2131 received vildagliptin?+?metformin. Overall, at baseline, mean (± standard deviation [SD]) age was 49.5?±?9.49 years, BMI was 31.5?±?4.85?kg/m², HbA1c was 8.4?±?0.86%, and duration of T2DM was 2.3?±?3.78 years. At week 24, significant reductions in mean (±SD) HbA1c were observed in the vildagliptin (?1.47?±?0.79%) and vildagliptin?+?metformin (?1.62?±?0.82%) groups (both p?Conclusion: In a real-world setting, vildagliptin, with or without metformin, resulted in significant reductions in HbA1c and was well tolerated in patients with T2DM from Egypt. Limitations of the study include non-randomization and the open-label, observational nature of the study.     

Memory restorative ability of clioquinol in copper–cholesterol-induced experimental dementia in mice

Abstract

Context: Results from various studies indicate that the presence of certain heavy metals such as aluminum (Al), arsenic (As), copper (Cu), lead (Pb), and mercury (Hg) may enhance the aggregation of Aβ and oxidative stress levels leading to neuronal toxicity and Alzheimer’s disease (AD). Studies also reveal that anomalous brain copper–cholesterol (Cu–Ch) homeostasis may lead to memory deficits in Swiss albino mice.

Objective: The present study investigates the anti-amnesic potential of clioquinol (5-chloro-7-iodoquinolin-8-ol) in cognitive deficits associated with experimental dementia induced by Cu–Ch.

Materials and methods: Administration of Cu–Ch {0.21?mg/kg, per os – 2% w/v, per os for 8 weeks} was used to induce dementia in Swiss albino mice. The Morris water maze (MWM) test was performed to assess the effect on learning and memory. A battery of biochemical estimations was performed following the MWM test such as brain-reduced glutathione (GSH), superoxide dismutase (SOD), thiobarbituric acid reactive species (TBARS), acetylcholinestrase (AChE) activity, and serum cholesterol levels.

Results: Administration of Cu–Ch produced a marked decline in MWM performance measured during the acquisition (78.9?±?3.3) and retrieval trials (9.5?±?2.4), reflecting impairment of learning and memory. Cu–Ch-treated mice also exhibited a marked accentuation of AChE activity (5.8?±?0.55) and TBARS levels (9.74?±?1.9) along with a decline in the GSH level (15.4?±?3.3) and the SOD level (26?±?2.5) when compared with the untreated control group. Administration of clioquinol significantly attenuated Cu–Ch-induced memory deficits and biochemical alterations.

Discussion and conclusion: The findings demonstrate memory restorative ability of clioquinol which may be attributed to its anti-cholinesterase, antioxidative, and cholesterol-lowering potential.     

Desalted Salicornia europaea powder and its active constituent,trans-ferulic acid,exert anti-obesity effects by suppressing adipogenic-related factors

Context: Salicornia europaea (Amaranthaceae) (SE) has been shown to reduce obesity, but it remains a problem as a food supplement because of its high salt content (25–35% NaCl).

Objectives: This study investigated the anti-obesity effects and mechanism of action of desalted SE powder (DSP).

Materials and methods: Sprague–Dawley rats (n?=?50) were divided into a normal control group (NC), a high-fat diet (HFD)-induced obesity control group (HFD), and HFD groups co-administered DSP (250 and 500?mg/kg) or Garcinia cambogia (Clusiaceae) extract (GE, 200?mg/kg, standard control) orally each day for 12?weeks.

Results: The body weight was significantly reduced by co-administration of DSP (596.51?±?19.84?kg, 4.60% and 562.08?±?9.74?kg, 10.10%, respectively) and GE (576.00?±?11.29?kg, 7.88%) relative to the HFD group (625.25?±?14.02?kg) and was accompanied by reduced abdominal fat mass, and serum lipid levels, with no effects on feed intake. To find the underlying mechanism of the anti-obesity effects, trans-ferulic acid (TFA) was identified as the main ingredient and investigated with regard to whether it attenuated adipogenesity in 3T3L-1 cells. DSP-derived TFA suppressed adipocyte differentiation and accumulation of intracellular lipids. TFA also down-regulated the adipogenesis-related gene expression of sterol regulatory element-binding protein 1, peroxisome proliferator-activated receptor γ, CCAAT/enhancer binding protein-α and fatty acid synthase.

Conclusions: These findings suggest that DSP may be considered for use as a food supplement intent of controlling obesity through its antiobesity and antiadipogenic properties.     

Efficacy and safety of the single pill combination of amlodipine 10 mg plus valsartan 160 mg in hypertensive patients not controlled by amlodipine 10 mg plus olmesartan 20 mg in free combination

ABSTRACT

Background and objective: For patients with moderate hypertension (grade 2, defined as systolic blood pressure [SBP] 160–179?mmHg and/or diastolic blood pressure [DBP] 100–109?mmHg), current guidelines recommend initial combination therapy and rapid dose-adjustment to achieve blood pressure goal. In this study we investigated the efficacy and tolerability of the single pill combination of amlodipine 10?mg plus valsartan 160?mg (A?10?+?Val 160) in patients not controlled by the free combination of amlodipine 10?mg plus olmesartan 20?mg (A?10?+?O 20).

Methods: In this prospective, open-label, non-randomized trial, 257 patients with mean sitting DBP of 100–109?mmHg at trough entered a 4 week treatment phase with A?10?+?O 20 in free combination once daily. Patients in whom DBP remained uncontrolled were switched in a second 4 week treatment phase to A?10?+?Val 160. The primary efficacy variable was the reduction in DBP at week 8 compared to week 4 in the intent-to-treat population.

Results: In the total cohort, baseline SBP/DBP of 164.2?±?9.8/103.6?±?2.1?mmHg decreased by 19.2?±?12.4/14.1?±?7.4?mmHg at week 4. In patients who did not achieve BP control (n?=?175), subsequent treatment with A?10?+?Val 160 for 4 weeks reduced SBP from 149.6?±?11.1 at week 4 by 7.9?mmHg at week 8 (95% CI: 6.1–9.6, p?<?0.0001) and DBP from 93.4?±?3.9?mmHg by 9.1?mmHg (95% confidence interval: 8.1–10.2, p?<?0.0001). The combination of A?10?+?Val 160 was well tolerated, and the observed adverse events (15.3% of patients in phase 2) were consistent with the known drug profiles.

Conclusions: In a study designed to reflect typical clinical practice, in patients not controlled by the free combination of A?10?+?O 20, the single pill combination of A?10?+?Val 160 produced a statistically and clinically significant additional BP reduction and was well tolerated. Potential limitations of the design (open-label, non-controlled design, short term treatment) have to be taken into account.     

Phytochemical screening and analgesic profile of the lyophilized aqueous extract obtained from Chrysobalanus icaco leaves in experimental protocols

Context: Chrysobalanus icaco L. (Chrysobalanaceae) has been used for the treatment of abdominal pain and cramps.

Objective: Assess the chemical and pharmacological profile of the lyophilized aqueous extract from C. icaco leaves (AEC).

Materials and methods: Chromatographic methods were used to assess compounds from AEC. Mice were treated with vehicle (control group) or AEC (100, 200 or 400?mg/kg, p.o.) (group with 7–8 mice) and the analgesic profile was assessed employing the acetic acid-induced writhing, formalin, hot plate tests and hyperalgesia induced by carrageenan (CG) or tumour necrosis factor-alpha. The animal motor performance was assessed using rota-rod and grip strength tests.

Results: The chromatographic profile of AEC demonstrated the presence of terpenoid compounds. The acute pretreatment with AEC, at all doses, produced a significant (p?<?0.01) inhibition of painful bahaviour (11.4?±?3.6; 10.3?±?2.8; 11.3?±?2.2) when compared to the control group (24.7?±?4.7) in acetic acid-induced writhing test. In the formalin test, AEC were effective in the second phase (p?<?0.01) (57.2?±?10.3; 56.3?±?9.2; 54.7?±?8.9) when compared to control group (121.9?±?18.5). No response was observed in the hot plate test. The higher dose of AEC produced a significant (p?<?0.01 or p?<?0.05) inhibitory effect on the mechanical hyperalgesia test. AEC did not affect the motor performance of the mice.

Discussion: The terpenoids from AEC are known for its analgesic and anti-inflammatory properties. So, these results corroborate the experiments using the AEC in inflammatory pain protocols.

Conclusion: Our results suggest that AEC act against inflammatory pain.     

Assessment of the therapeutic activity of a combination of almitrine and raubasine on functional rehabilitation following ischaemic stroke

Background and objectives: Stroke is a major cause of disability. Certain experimental studies have suggested that a combination of almitrine?+?raubasine (Duxil) increases the supply of oxygen to cerebral tissues and may be beneficial in post-stroke rehabilitation. This multicentre clinical study was carried out in order to assess the efficacy of this combination on post-stroke rehabilitation.

Methods: The trial was a randomised, double-blind, placebo-controlled study. Patients that had experienced an ischaemic cerebrovascular accident (confirmed by CT scan) were included 4-6 weeks after the acute onset and received randomised treatment of either almitrine?+?raubasine or placebo 2 tablets daily for 3 months. Before treatment, there was a 2-week washout period for stopping all other drugs, except for antihypertensive and antidiabetic drugs. We assessed the patients by Barthel Index (BI), Neurological Functional Deficit Scores (NFDS), and Hasagawa Dementia Scales (HDS) each month after treatment.

Results: A total of 83 patients were entered into the study and data were available for 74. Of these, 38 patients received almitrine?+?raubasine and 36 received placebo. The baseline characteristics were comparable between both groups. Almitrine?+?raubasine was significantly more effective than placebo at increasing BI at 1, 2 or 3 months (14.6?±?13.8 versus 3.3?±?13.2, p?=?0.01; 19.3?±?13.6 versus 8.8?±?14.0, p?=?0.02; 22.6?±?14.7 versus 10.7?±?17.0, p?=?0.02 respectively) and reducing NFDS at 1 month (3.6?±?3.2 versus 1.9?±?3.5, p?=?0.034) after treatment. More almitrine?+?raubasine-treated patients' NFDS had improved compared with placebo-treated patients at 2 and 3 months (97 versus 78%, p?=?0.013; 100 versus 86%, p?=?0.023 respectively). Compared with pre-treatment, there was a strong tendency towards an improvement of HDS with almitrine + raubasine. The number of adverse events reported was low for the almitrine + raubasine-treated group and the placebo group and all events were mild, of short duration and resolved without treatment. Almitrine + raubasine had no clinically significant effect on blood pressure, heart rate or other laboratory tests.

Conclusion:The results indicate that almitrine + raubasine can accelerate neurological function recovery after stroke to some degree and is well tolerated.     

Dihydromyricetin improves vascular hyporesponsiveness in experimental sepsis via attenuating the over-excited MaxiK and KATP channels

Context: Dihydromyricetin (DMY) has oxidation resistance, anti-inflammatory and free radical scavenging capabilities. The preventive effects of DMY for vascular hyporeactivity remain unclear.

Objective: This study investigates the preventive effects of DMY in vascular hyporeactivity.

Materials and methods: The experimental sepsis was induced by transvenous administration of lipopolysaccharide (LPS) to Sprague–Dawley (SD) rats. DMY-treated rats received daily administration of DMY, 5?μg/kg dissolved in DMSO through the tail vein for 7?days. The invasive mean arterial pressure (MAP) of the caudal ventral artery was measured. Dose-response curves for norepinephrine (NE, doses from 10^?9 to 10^?6?M) were obtained in isolated thoracic aorta in a cumulative manner. The function of MaxiK and K_ATP channels were investigated using whole-cell patch clamp recording. The Elisa was adopted to measure the serum concentration of NO, MDA, 3-NT, IL-1β and TNF-α.

Results: The increased MAP in septic rats induced by vasopressor agents was smaller than that in control rats. However, the % of increased MAP induced by vasopressor agents was raised by DMY injection (NE: 20.4?±?8.495 vs. 15.16?±?5.195%; AVP: 14.05?±?2.459 vs. 9.583?±?2.982%, p??6?M) in vitro. was increased by 51% in LPS?+?DMY group compared with that in LPS?+?Con group (2.74?±?0.81 vs. 1.82?±?0.92?g, p?ATP channel blocker) pretreatment, instead of 4-aminopyridine (4-AP) and BaCl₂, could diminish the DMY-induced improvement of vasoconstrictor hyporeactivity (ChTX: 73.2?±?11.8 vs. 71.8?±?13.5%; Glib: 63.1?±?12.5 vs. 58.1?±?13.7%, p?>?0.05). DMY blunted the highly sensitized MaxiK and K_ATP channels of arterial smooth muscle cells isolated from the thoracic aorta of LPS rats. DMY decreased the serum level of NO, MDA, IL-1β and TNF-α, which had increased in LPS rats.

Discussion and conclusions: Our results indicate that DMY administration ameliorated the impaired contractility of the rat aorta in experimental sepsis. Such an effect is mediated by normalization of the over-excited MaxiK and K_ATP, channels possibly via oxidative stress inhibition.     

Antidiabetic,antihyperlipidaemic, and antioxidant activity of Syzygium densiflorum fruits in streptozotocin and nicotinamide-induced diabetic rats

Context Syzygium densiflorum Wall. ex Wight & Arn (Myrtaceae) has been traditionally used by local tribes of the Nilgiris, Tamil Nadu, India, for the treatment of diabetes, however, no definitive experimental studies are available.

Objective This study investigates the antidiabetic, antihyperlipidaemic and antioxidant activities of ethanol extract of S. densiflorum (EFSD) fruits in streptozotocin (STZ) and nicotinamide (NA)-induced diabetic rats.

Materials and methods Acute oral toxicity and oral glucose tolerance were assessed in normal rats. The antidiabetic, antihyperlipidaemic and antioxidant activities were investigated in STZ???NA-induced diabetic rats. Diabetic rats were orally administered with glibenclamide (10?mg/kg b.wt), EFSD (200, 400 and 800?mg/kg b.wt) for 28 d. Further, changes in the blood glucose level (BGL), biochemical parameters, antioxidants were observed and histology of pancreas was performed.

Results No toxicity and lethality were observed. Results of the following parameters are represented by treated versus disease control (STZ?+?NA) groups. BGL (161.33?±?22.8 versus 476.17?±?56.58?mg/dl), glycosylated haemoglobin (5.285?±?0.19 versus 8.05?±?0.55%), urea (40.32?±?1.96 versus 75.37?±?2.91?mg/dl), uric acid (1.2?±?0.07 versus 2.16?±?0.05?mg/dl), total cholesterol (89.3?±?5.14 versus 139.7?±?5.95?mg/dl) and triglycerides (79.65?±?2.52 versus 108.9?±?3.61?mg/dl) were significantly decreased, whereas haemoglobin (11.75?±?0.73 versus 7.95?±?0.42?g/dl), high‐density lipoprotein cholesterol (14.2?±?1.11 versus 6.97?±?0.84?mg/dl), total protein (45%) and liver glycogen (87%) were significantly increased in EFSD-treated diabetic group. Significant changes were observed in the enzymatic and non-enzymatic antioxidants in EFSD-treated groups (p?<?0.001). Histopathological examination showed the regeneration of β-cells in Islets of Langerhans.

Conclusion This study confirms the antidiabetic, antihyperlipidaemic and antioxidant activities of S. densiflorum fruits.     

Rutin ameliorates oxidative stress and preserves hepatic and renal functions following exposure to cadmium and ethanol

Context: Rutin (RUT) is an antioxidant flavonoid with well-known metal chelating potentials.

Objective: This study was designed to evaluate the protective effects of RUT against cadmium (Cd)?+?ethanol (EtOH)-induced hepatic and renal toxicity in rats.

Materials and methods: Wistar rats were treated with Cd (50?mg/kg) alone or in combination with EtOH (5?mg/kg) and RUT (25, 50 and 100?mg/kg) for 15?days. After treatment, the liver, kidney and serum were removed for biochemical assays by spectrophotometric methods.

Results: Serum, hepatic and renal malondialdehyde (MDA) levels were highest in the Cd?+?EtOH group and lowest in Cd?+?EtOH animals co-treated with the highest dose of RUT (2.98?±?0.34, 10.08?±?2.32, 4.99?±?1.21 vs. 1.69?±?0.33, 6.13?±?0.28, 3.66?±?1.12?μmol MDA/mg protein, respectively). The serum level of Cd was increased in the Cd?+?EtOH treated animals compared to Cd?+?EtOH animals co-treated with 100?mg/kg RUT (2.54?±?0.08 vs. 1.28?±?0.04?ppm). Furthermore, RUT at the highest dose protected against Cd?+?EtOH-induced elevation of bilirubin and uric acid levels as well as activities of lactate dehydrogenase and γ-glutamyl transferase (62.86?±?2.74 vs. 122.52?±?6.35?µmol/L; 1.77?±?0.35 vs. 3.23?±?0.55?mmol/L; 9.56?±?1.22 vs. 16.21?±?1.64?U/L; 288.92?±?40.12 vs. 159.8?±?18.01?U/L). The histo-pathological changes in the liver and kidney were also reduced in the Cd?+?EtOH animals co-treated with RUT in a dose-dependent manner.

Discussion and conclusion: RUT protected against the combined effects of Cd?+?EtOH on hepatic and renal functions and improved the antioxidant defence system in the blood.     

Antioxidant capacity of Typha angustifolia extracts and two active flavonoids

Context: The pollen of Typha angustifolia L. (Typhaceae) has been used as a traditional Chinese medicine for improving the microcirculation and promoting wound healing. Flavonoids are the main constituent in the plant, but little is known about the antioxidant activity of the principal constituent of the pollen in detail.

Objectives: To assess the antioxidant activities of ethanol and water extracts and two constituents of the pollen.

Materials and methods: Plant material (1?g) was extracted by 95% ethanol and water (10?mL?×?2, 1?h each), respectively. The extracted activities (0.8–2.6?mg/mL) were measured by DPPH and the reducing activity of ferric chloride (1.7–2.6?mg/mL). Typhaneoside and isorhamnetin-3-O-neohesperidoside (I3ON) (2.8–70?μmol/L) were investigated on the relationship between NO, MDA and SOD in HUVECs treated with 100?μg/mL of LPS for 24?h.

Results: Nine compounds were identified by UPLC-MS. Ethanol extract showed IC₅₀ values in DPPH (39.51?±?0.72) and Fe³⁺ reducing activity (82.76?±?13.38), higher than the water extract (50.85?±?0.74) and (106.33?±?6.35), respectively. Typhaneoside and I3ON promoted cell proliferation at the respective concentration range of 2.8 to 70?μmol/L (p?p?p?p?Conclusions: The constituents from Typha angustifolia could be a novel therapeutic strategy for LPS-induced inflammation.