The anti-hyperalgesic and anti-inflammatory profiles of p-cymene: Evidence for the involvement of opioid system and cytokines

Abstract

Context: Pain corresponds to the most frequent reason for visits to physicians, and its control by conventional drugs is accompanied by several side effects, making treatment difficult. For this reason, new chemical entities derived from natural products still hold great promise for the future of drug discovery to pain treatment.

Objective: The objective of this study was to evaluate the antinociceptive and anti-inflammatory profiles of p-cymene (PC), a monocyclic monoterpene, and its possible mechanisms of action.

Materials and methods: Mice treated acutely with PC (25, 50, or 100?mg/kg, i.p.) were screened for carrageenan-induced hyperalgesia and the inflammatory components of its cascade (30–180?min), carrageenan-induced pleurisy (4?h), and tail-flick test (1–8?h). Also, we observed the PC effect on the generation of nitric oxide by macrophages and the activation of neurons in the periaqueductal gray (PAG) by immunofluorescence.

Results: PC reduced (p?<?0.001) the hyperalgesia induced by carrageenan, TNF-α, dopamine, and PGE₂. PC decrease total leukocyte migration (100?mg/kg: p?<?0.01), neutrophils (50 and 100?mg/kg: p?<?0.05 and 0.001), and TNF-α (25, 50, and 100?mg/kg: p?<?0.01, 0.05, and 0.001, respectively), besides reducing NO production (p?<?0.05) in vitro. PC produced antinociceptive effect in tail-flick test (p?<?0.05), which was antagonized by naloxone, naltrindole, nor-BNI, and CTOP, and increased (p?<?0.001) the number of c-Fos-immunoreactive neurons in PAG.

Discussion and conclusion: These results provide information about the anti-hyperalgesic and anti-inflammatory properties of PC suggesting a possible involvement of the opioid system and modulating some pro-inflammatory cytokines.     

Alteration of pentylenetetrazole-induced seizure threshold by chronic administration of ginger (Zingiber officinale) extract in male mice

Abstract

Context: Zingiber officinale Roscoe (Zingiberaceae), or ginger, used in traditional Chinese medicine, has antioxidant activity and neuroprotective effects. The effects of this plant on clonic seizure have not yet been studied.

Objective: The present study evaluated the anticonvulsant effect of ginger in a model of clonic seizures induced with pentylenetetrazole (PTZ) in male mice.

Materials and methods: The anticonvulsant effect of Z. officinale was investigated using i.v. PTZ-induced seizure models in mice. Different doses of the hydroethanolic extract of Z. officinale (25, 50, and 100?mg/kg) were administered intraperitonal (i.p.), daily for 1 week before induction of PTZ. Phenobarbital sodium (30?mg/kg), a reference standard, was also tested for comparison. The effect of ginger on to the appearance of three separate seizure endpoints, e.g., myoclonic, generalized clonic, and tonic extension phase, was recorded.

Results: Hydroethanolic extract of Z. officinale significantly increased the onset time of myoclonic seizure at doses of 25–100?mg/kg (55.33?±?1.91 versus 24.47?±?1.33?mg/kg, p?<?0.001) and significantly prevented generalized clonic (74.64?±?3.52 versus 47.72?±?2.31?mg/kg, p?<?0.001) and increased the threshold for the forelimb tonic extension (102.6?±?5.39 versus 71.82?±?7.82?mg/kg, p?<?0.01) seizure induced by PTZ compared with the control group.

Discussion and conclusion: Based on the results, the hydroethanolic extract of ginger has anticonvulsant effects, possibly through an interaction with inhibitory and excitatory systems, antioxidant mechanisms, and oxidative stress inhibition.     

Antidiarrheal,antisecretory, and bronchodilatory activities of Hypericum perforatum

This study describes the antidiarrheal, antisecretory, and bronchodilatory activities of Hypericum perforatum Linn. (Hypericaceae), commonly known as St. John’s wort, to justify its traditional use in the hyperactivity of the gastrointestinal and respiratory systems. The crude extract of Hypericum perforatum (Hp.Cr) at a dose of 500?mg/kg caused 20% protection against castor oil-induced diarrhea in mice and 60% at 1000?mg/kg (p?<?0.05 vs. saline). Hp.Cr at 300 and 1000?mg/kg reduced the castor oil-induced fluid accumulation in mice to 107.0?±?3.3?g (p?<?0.01) and 84.0?±?4.2?g (p?<?0.001) respectively, whereas in the castor oil-treated group, it was 126.9?±?3.9?g. When tested against carbachol (CCh)-mediated bronchoconstriction in rats under anesthesia, Hp.Cr dose-dependently (3–?30?mg/kg) suppressed the CCh (1?μmol/kg)-induced increase in the inspiratory pressure. Thus this study rationalizes the Hypericum perforatum usefulness in overactive gut and airways disorders, such as diarrhea and asthma.     

Prevention of arsenic-mediated reproductive toxicity in adult female rats by high protein diet

Abstract

Context: The detrimental effects of arsenic on female reproductive functions may involve overt oxidative stress. Casein and pea [Pisum sativum Linn. (Fabaceae)] proteins have antioxidant properties.

Objective: To investigate the role of casein- and pea-supplemented high-protein diet (HPD) in utero-ovarian protection from arsenic toxicity.

Materials and methods: Adult female Wistar rats were orally gavaged with vehicle (Gr-I) or arsenic at 3?ppm/rat/d (Gr-II and Gr-III) for 30 consecutive days, when they were maintained on either regular diet containing 18% protein (Gr-I and Gr-II), or HPD containing 27% protein in the form of casein (20%) and pea (7%) (Gr-III). Reproductive functions were evaluated using a battery of biochemical and histological techniques.

Results: As compared to Gr-I, the Gr-II rats suffered from loss of estrous cyclicity, reduction in weight (mg/100?g body weight) of ovary (Gr-I: 54.3?±?4.2 versus Gr-II: 35.8?±?1.6; p?<?0.001) and uterus (Gr-I: 161.7?±?24.6 versus Gr-II: 94.44?±?13.2; p?<?0.05), utero-ovarian degeneration, attenuated ovarian activities (unit/mg tissue/h) of Δ⁵, 3β-hydroxysteroid dehydrogenase (Gr-I: 3.41?±?0.12 versus Gr-II: 2.31?±?0.09; p?<?0.01) and 17β-hydroxysteroid dehydrogenase (Gr-I: 3.82?±?0.57 versus Gr-II: 1.24?±?0.19; p?<?0.001), and decreased serum estradiol level (pg/ml) (Gr-I: 61.5?±?2.06 versus 34.1?±?2.34; p?<?0.001). Ovarian DNA damage was preponderant with blatant generation of malondialdehyde (nM/mg tissue; Gr-I: 15.10?±?2.45 versus Gr-II: 29.51?±?3.44; p?<?0.01) and attenuated superoxide dismutase activity (unit/mg tissue) (Gr-I: 2.18?±?0.19 versus Gr-II: 1.33?±?0.18; p?<?0.05). The Gr-III rats were significantly protected from these ill effects of arsenic.

Discussion and conclusion: HPD, by way of antioxidant properties, may find prospective role in the protection of reproductive damage caused by arsenic.     

The importance of brain PGE2 inhibition versus paw PGE2 inhibition as a mechanism for the separation of analgesic and antipyretic effects of lornoxicam in rats with paw inflammation

Objectives Lornoxicam is a non‐selective cyclooxygenase inhibitor that exhibits strong analgesic and anti‐inflammatory effects but a weak antipyretic effect in rat models. Our aim was to investigate the mechanism of separation of potencies or analgesic and antipyretic effecls of lornoxicam in relatioin to its effect on prostaglandin E₂ (PGE₂) production in the inflammatory paw and the brain. Methods A model of acute or chronic paw inflammation was induced by Freund's complete adjuvant injection into the rat paw. Lornoxicam (0.01–1 mg/kg), celecoxib (0.3–30 mg/kg) or loxoprofen (0.3–30 mg/kg) was administered orally to the rats and the analgesic and antipyretic effects were compared. The paw hyperalgesia was assessed using the Randall–Selitto test or the flexion test. Dorsal subcutaneous body temperature was measured as indicator of pyresis. After the measurement of activities, the rats were sacrificed and the PGE₂ content in the paw exudate, cerebrospinal fluid or brain hypothalamus was measured by enzme‐immunoassay. Key findings In a chronic model of arthritis, lornoxicam, celecoxib and loxoprofen reduced hyperalgesia with an effective dose that provides 50% inhibition (ED50) of 0.083, 3.9 and 4.3 mg/kg respectively, whereas the effective dose of these drugs in pyresis was 0.58, 0.31 and 0.71 mg/kg respectively. These drugs significantly reduced the PGE₂ level in paw exudate and the cerebrospinal fluid. In acute oedematous rats, lornoxicam 0.16 mg/kg, celecoxib 4 mg/kg and loxoprofen 2.4 mg/kg significantly reduced hyperalgesia to a similar extent. On the other hand, lornnoxicam did not affect the elevated body temperature, whereas celecoxib and loxoprofen siginificantly reduced the pyrexia to almost the normal level. These drugs significantly reduced the PGE₂ level in inflamed paw exudate lo almost the normal level. On the other hand, lornoxicam did not change PGE₂ level in the brain hypothalamus, whereas celecoxib and loxoprofen strongly decreased it. Conclusions Lornoxicam exhibits strong analgesic but weak antipyretic effects in rats with paw inflammation. Such a separation of effects is related to its efficacy in the reduction of PGE₂ levels in the paw and brain hypothalamus.     

Bioactive peptide carnosin protects against lead acetate-induced hepatotoxicity by abrogation of oxidative stress in rats

Context Oxidative stress is a common mechanism of liver injury. Carnosine is a dipeptide having strong antioxidant effects.

Objectives We investigated the effects of carnosine on lead-induced hepatotoxicity and oxidative stress in rats.

Materials and methods Animals received an aqueous solution of lead acetate (500?mg Pb/L in the drinking water) and/or daily oral gavage of carnosine (10?mg/kg) for 8 weeks. Rats were then weighed and used for the biochemical (commercial kits), molecular (standard chemical methods) and histological (microscopic) evaluations.

Results Lead-induced oxidative stress in liver tissue was indicated by a significant increase in the level of malondialdehyde (MDA) (8.25?±?0.15?nmol/mg) as well as decrease in the level of total antioxidant capacity (TAC) (1.72?±?0.25?μmol/g) and total thiol (SH) groups) 1.9?±?0.22?μmol/g). Carnosine treatment decreased MDA (4?±?0.08?nmol/mg), whereas it increased the contents of total thiol (3.25?±?0.04?μmol/g) and TAC (3.44?±?0.32?μmol/g) in the lead group. Carnosine also prevented the decreased body weight (p?<?0.001), albumin (p?<?0.05) and total protein levels (p?<?0.001) and increased liver weight (p?<?0.05) and activates of hepatic enzymes (p’s?<?0.001) (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and lactate dehydrogenase) in the lead group. Furthermore, histopathological study showed that carnosine attenuates liver damage by decreasing necrosis and infiltration of inflammatory cells.

Conclusion Carnosine prevented lead-induced hepatotoxicity, indicated by molecular, biochemical and histopathological analyses through inhibiting lipid peroxidation and enhancing antioxidant defence systems. Therefore, carnosine makes a good candidate to protect against the deleterious effect of chronic lead intoxication.     

Protective effects of Osbeckia octandra against paracetamol-induced liver injury

1. Osbeckia octandra is a plant used in traditional medicine to treat jaundice and other liver disorders. In this study, the effects of Osbeckia leaf extract on paracetamol-induced liver injury were investigated both in vivo in mice and in rat hepatocytes in vitro.

2. Oral administration of Osbeckia extract (330?mg/kg) at the same time as paracetamol (450?mg/kg) to mice, resulted in a significant protection (p<0.05) against liver damage, as assessed by improvements in the blood Normotest (39.1 ± 1.9 versus 46.3 ± 2.0?s), total liver glutathione (730 ± 39 versus 574 ± 27 μg/250?mg liver), plasma aspartate aminotransferase level (916 ± 225 versus 1965 ± 291 iu/l), and liver histopathology at 24?h after paracetamol administration.

3. In experiments to assess the direct effects of Osbeckia extract, significant protection was also found in freshly isolated rat hepatocytes against damage induced by 185 μM 2,6-dimethyl N-acetyl p-quinoneimine (2,6-diMeNAPQI, an analogue of NAPQI, the toxic metabolite of paracetamol) in vitro. When Osbeckia extract (500 μg/ml) was added to the incubation medium at the same time as 2,6-diMeNAPQI significant changes in cell viability (78.4 ± 3.3 versus 47.2 ± 5.8% of control, p<0.001), cell reduced glutathione (GSH) level (35.0 ± 3.1 versus 23.8 ± 1.5%, p = 0.009), and reduced release of lactate dehydrogenase (129.9 ± 6.6 versus 224.6 ± 12.1%, p<0.001) were demonstrated after 1?h incubation as compared with 2,6-diMeNAPQI alone.

4. Significant protection was still obtained against 2,6-diMeNAPQI in vitro when addition of Osbeckia extract was delayed by 20?min. These results indicate that Osbeckia extract can protect against paracetamol-induced liver injury.     

The kinin antagonist hoe 140 reduces acute paw oedema in rats caused by carrageenan, bradykinin and kaolin

The present study aimed to evaluate the effect of Hoe 140, a BK receptor B₂ antagonist, on acute oedema induced by carrageenan, BK and kaolin in male Wistar Kyoto rats. Hoe 140 (0.2 mg/kg and 20 mg/kg) given ip caused significant (p<0.05 and p<0.01) inhibition of carrageenan and BK-induced paw oedema. This suggests that BK is the prime inflammatory mediator of carrageenan oedema, and that it is also a specific blocker of oedema caused by BK. Furthermore, Hoe 140 was found to be less effective in reducing kaolin-induced oedema in rats. This might reflect that BK is not a prime inflammatory mediator of kaolin-induced oedema. The possible significance of these findings is discussed.     

Effect of pramlintide as an adjunct to basal insulin on markers of cardiovascular risk in patients with type 2 diabetes

ABSTRACT

Objective: Intensification of insulin therapy in patients with type 2 diabetes, while improving glycemic control, often leads to an increase in body weight and other markers of cardiovascular risk. The effects of pramlintide as an adjunct to basal insulin titration (without mealtime insulin) on glycemia and cardiovascular risk markers were examined.

Research design and methods: This was a post hoc analysis of a 16-week, double-blind, placebo-controlled study in patients with type 2 diabetes (N?=?211) using insulin glargine (without mealtime insulin)?±?oral agents. Patients were randomized to treatment with placebo or pramlintide (60 or 120?µg with major meals), and insulin glargine was titrated to target a fasting plasma glucose concentration of ≥70 to <100?mg/dL.

Main outcome measures: Endpoints included the change from baseline to Week 16 in body weight, high sensitivity C-reactive protein (hsCRP), triglycerides, HDL, LDL, and blood pressure.

Results: Pramlintide-treated patients lost weight and placebo-treated patients gained weight during 16 weeks of treatment (?1.6?±?0.3?kg vs. +0.7?±?0.3?kg, p?<?0.001; mean?±?SE). hsCRP was reduced in pramlintide-treated versus placebo-treated patients (?0.8?±?0.2?mg/L vs. 0.1?±?0.2?mg/L, p?<?0.01; mean?±?SE). Patients with baseline hsCRP?>?3?mg/L (high cardiovascular risk) demonstrated greater hsCRP reductions with pramlintide versus placebo treatment at Week 16 (p?<?0.05). Patients with baseline triglycerides ≥150?mg/dL or ≥200?mg/dL (high cardiovascular risk) showed significant reductions from baseline in triglyceride concentrations with pramlintide (?43?±?14?mg/dL or ?59?±?19?mg/dL; p?<?0.05; mean?±?SE) but not with placebo (1?±?29?mg/dLor ?3?±?54?mg/dL; mean?±?SE). No significant differences between pramlintide and placebo were observed for changes in HDL, LDL, or blood pressure. Pramlintide treatment was generally well tolerated. The most frequent adverse event related to pramlintide was mild-to-moderate nausea (31% pramlintide vs. 10% placebo). Pramlintide added to basal insulin did not increase the incidence of hypoglycemia. A limitation of the study was its relatively short duration.

Conclusions: Pramlintide, as an adjunct to basal insulin, was associated with improvements in several cardiovascular risk markers, warranting long-term clinical studies to determine its potential effects on cardiovascular risk.     

Pharmacological properties of lichen Cladonia clathrata

Cladonia clathrata Ahti & L. Xavier-Filho (Cladoniaceae) is a lichen; several Cladonia species extracts have been used for various remedies in folk medicine. In order to evaluate the actions of this lichen, studies were performed on antinociceptive, anti-inflammatory, and antioxidant activities. The hydroalcoholic extract (HE) of C. clathrata stems was used in the following experiments. Oral treatment with the HE of C. clathrata elicited inhibitory activity (p?<?0.001) on acetic acid-induced abdominal writhes at 100 (47.2%), 200 (47.2%), and 400?mg/kg (86.4%), and reduced the formalin-induced nociception on both the neurogenic (400?mg/kg, p?<?0.01) and inflammatory phases (200 and 400?mg/kg, p?<?0.01). It was not associated with non-specific effects, such as muscle relaxation or sedation. The HE reduced the carrageenan-induced edema formation at 100, 200, and 400?mg/kg (p?<?0.05) and inhibited neutrophil migration into the peritoneal cavity at 400?mg/kg (p?<?0.001). The HE of C. clathrata reacted with the DPPH radical and reduced the same by 50.19%, and exhibited an IC₅₀ value of 69.25?±?0.65 μg/mL. The HE of C. clathrata stems shows antinociceptive and anti-inflammatory activities, with a moderate antioxidant potential.     

GABAA and GABAC (GABAA0r) Receptors Affect Ocular Growth and Form-Deprivation Myopia

Abstract

Roles of γ-aminobutyric acid (GABA) antagonists on the chick model of form-deprivation myopia (FDM) were investigated. Bicuculline (GABA_A) or TPMPA (GABA_A0r) was injected intravitreally (1 or 10 mg/mL) into the right eyes of chicks with or without FDM for 13 days. The contralateral eyes served as the control. The eye weight (EW), equatorial diameter (ED), ocular length (OL), axial length (AL), and refraction (RFN) were measured. Histological sections of the retina and sclera were measured, and changes in tissue thickness were compared. The EW, ED, OL, and AL of the FDM eyes went up by 13.1±2.0% (n = 24, p < 0.001), 18.7±2.0% (n = 24, p < 0.001), 7.2±1.9% (n = 24, p < 0.001) and 5.1±1.5% (n = 11, p < 0.05), respectively. Bicuculline and TPMPA significantly reversed these changes (p < 0.05) but not the OL at either concentration used. The RFN measurements confirmed this (n = 2–8, p < 0.01). The drugs have no effect on the retinal thickness but significantly reduced the thickness of cartilaginous scleral layer of chicks with or without FDM (n = 9–120, p < 0.05). Bicuculline and TPMPA reduced form-deprived as well as normal ocular growth. GABAergic-mediated mechanism may directly influence the growth, shape, and refractive state of the developing eye.     

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.     

Metabolism of low-dose paracetamol in patients with chronic neurological disease

1. Low dose (500 mg) paracetamol (acetaminophen) was administered to patients with Parkinson's disease, motor neurone disease and to age-matched controls.

2. At this low dose level the controls excreted proportionately more sulphate and less glucuronide conjugate than has been reported for administration of 1000 mg of paracetamol.

3. Both groups of patients with chronic neurological disease excreted decreased amounts of paracetamol sulphate (control mean 11.2±5.4% dose; Parkinson's disease 3.9±3.7%; motor neurone disease, 5.0±4.1%).

4. The mean ratio of excretion of paracetamol sulphate/paracetamol glucuronide was 5.6±11.7 in controls, but 1.1±1.7 and 1.2±1.7 in Parkinson's disease and motor neurone disease respectively. These differences are statistically significant (p<0.001).     

Pulmonary Inflammation by Ambient Air Particles is Mediated by Superoxide Anion

Lung inflammation is a key response to increased levels of particulate air pollution (PM); however, the cellular mechanisms leading to this response remain poorly understood. We have previously shown that oxidants are critical mediators of the inflammatory response elicited by inhalation of ambient air particles. Here we tested the possible role of a specific oxidant, superoxide anion, by using the membrane-permeable analog of superoxide dismutase, Mn(III) tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP). Adult Sprague-Dawley rats were instilled with either urban air particles (UAP) or saline. MnTBAP-treated rats received 10 mg/kg (ip) MnTBAP 2 h prior to exposure to UAP. Recruitment of inflammatory cells into bronchoalveolar lavage was evaluated 4 h after instillation. Rats exposed to UAP showed significant increases in the total cell number (8.9 ± 0.6× 10⁶; sham: 5.1 ± 0.6 × 10⁶, p < .02), the numbers of polymorphonuclear leukocytes (26 ± 4%; sham: 6 ± 1%, p < .0001), protein levels (1.2 ± 0.5 mg/ml, sham:0.4 ± 0.1 mg/ml, p < .001), and a trend of increase in myeloperoxidase levels (5 ± 1; sham: 2 ± 1 mU/ml) in bronchoalveolar lavage (BAL). Pretreatment with MnTBAP at a dose that prevented UAP-induced increases in oxidants effectively prevented increase in BAL cells (2.7 ± 0.6 × 10⁶, p < .0001 vs. UAP), PMN influx into the lungs (4 ± 3%, p < .0001 vs. UAP), and increase in myeloperoxidase (2 ± 1 mU/ml) and protein levels in BAL (0.1 ± 0.1 mg/ml). These data indicate that superoxide anion is a critical mediator of the inflammatory response elicited by PM deposition in the lung.     

Effectiveness of simvastatin therapy in raising HDL-C in patients with type 2 diabetes and low HDL-C

SUMMARY

Objective: To evaluate the efficacy of high and moderate doses of simvastatin (80 and 40?mg), for raising high density lipoprotein-cholesterol (HDL-C), improving HDL sub-fractions, and affecting other parameters, including high sensitivity C-reactive protein (hs-CRP), in patients with type 2 diabetes mellitus (DM) and low HDL-C.

Research design and methods: This double-blind, placebo-controlled, randomized, 3-period, complete block, 6-week crossover study examined the efficacy of simvastatin in adult men and women (N = 151) with stable type 2 DM (HbA_1C < 9%), low density lipoprotein-cholesterol (LDL-C) > 100?mg/dL (2.6?mmol/L), HDL-C < 40?mg/dL (< 1?mmol/L), and fasting triglyceride level > 150 (> 1.7?mmol/L) and < 700?mg/dL (< 7.9?mmol/L). This study included adult men (71%) and women (29%) of various races (89% white, 6% black, 1% Asian, 3% other) enrolled from 29 practice-based sites in the United States.

Main outcome measures: Percentage change in HDL-C from baseline at the end of each 6-week treatment interval.

Results: Both simvastatin 80 and 40?mg significantly increased total HDL-C from baseline (mean increases of 8% ± 1 [SE] and 5% ± 1, respectively; p < 0.001) compared with placebo, and significantly reduced plasma concentrations of LDL-C (?p < 0.001), triglycerides (?p < 0.001), apolipoprotein B (?p < 0.001), and hs-CRP (?p ≤ 0.012). Compared with simvastatin 40?mg, the 80?mg dose provided additional efficacy. Simvastatin 80?mg also significantly (?p < 0.001) increased HDL₂ from baseline (14% ± 3[SE]) and placebo phases (10 ± 3). An exploratory analysis showed 87% (simvastatin 80?mg) and 82% (simvastatin 40?mg) of patients reached the NCEP ATP III treatment goals for LDL-C compared with 14% on placebo.

Conclusions: Both simvastatin 80 and 40?mg raise HDL-C and improve other measures associated with elevated coronary risk in patients with type 2 DM and low HDL-C.     

Protective Effect of Aegle marmelos Fruit in Gastrointestinal Dysfunction in rats

The effect of the ethanol extract of the unriped fruits of Aegle marmelos Correa was assessed on experimentally induced diarrhoea and gastric ulceration in rats. The extract (50, 100 and 200?mg/kg, p.o.) exhibited a dose-dependent decrease in the intestinal propulsion from 61.79–39.32% which is equivalent to 38.21–60.68% intestinal propulsion inhibition (control 58.3 ± 3.4 inhibition, P < 0.5 to P < 0.001) and caused a dose-dependent decrease in the total number of faecal matter in castor oil-induced diarrhoea (control 70, reduced to 51 and 42 at 100 and 200?mg/kg extract, p.o.). Further, yohimbine, a α₂ adrenoreceptor blocker, attenuated the antidiarrhoeal effect of the extract in a dose of 200?mg/kg to 17.14%, and diphenoxylate by 74.28%. The extract also reduced the ulcer index induced by ethanol (control 18.7 ± 4.4, 34.22–72.73% protection), aspirin (control 22.6 ± 3.4, 36.73–81.42% protection) and cold restraint stress (control 23.8 ± 3.2, 56.72% and 81.51% protection). Further study on tissue lipid peroxidation was significantly increased (P < 0.001) as evidenced by accumulation of malondialdehyde in cold restraint stress ulcers. Administration of A. marmelos (100 and 200?mg/kg), cimetidine 50?mg/kg and reduced glutathione (150?mg/kg) prior to cold restraint stress causes significant decrease in ulcer index and lipid peroxidation (P < 0.01 to P < 0.001). The result showed that A. marmelos had significant antidiarrhoeal and ulcer protective activity by scavenging the reactive oxygen species on the cold restraint stress-induced gastric damage.     

Evaluation of the antithrombotic effects of Crataegus monogyna and Crataegus davisii in the carrageenan-induced tail thrombosis model

Abstract

Context: Crataegus species are widely used as herbal medicines for preventing cardiovascular diseases (CVDs). However, there are no studies on the effects of Crataegus monogyna Jacq. (Rosaceae) and C. davisii Browicz on thrombosis, which is an important mechanism in CVDs.

Objective: The purpose of this study was to investigate the antithrombotic effects of ethanol extracts of Crataegus monogyna (CMEx) and C. davisii (CDEx) leaves by using the carrageenan-induced tail thrombosis model.

Materials and methods: The hind paw of each mouse was injected with 1% Type I carrageenan to induce thrombosis. CMEx was tested at the doses of 100, 200, and 300?mg/kg and CDEx at the dose of 50, 100, 200, and 300?mg/kg in comparison with heparin. The lengths of tail thrombosis were measured at the 24, 48, and 72?h.

Results: Does of 200 and 300?mg/kg CMEx showed significant effects (p?<?0.01; p?<?0.001) at 24?h when compared with the control group. The antithrombotic activity of 200 and 300?mg/kg CMEx showed a decrease at 48 and 72?h but the activity of 300?mg/kg dose of CMEx was still significant (p?<?0.01). The activities of 50 and 100?mg/kg doses of CDEx were significant (p?<?0.001; p?<?0.01) between 24 and 72?h whereas 200 and 300?mg/kg CDEx did not show any significance.

Discussion and conclusions: CMEx and CDEx significantly inhibited the carrageenan-induced mouse tail thrombosis. Based on these results, it was concluded that CDEx and CMEx may potentially be used as therapeutic agents or complementary treatments against thrombosis.     

Exenatide effects on diabetes,obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years

ABSTRACT

Background: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A_1c (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of?≥?3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety.

Methods: Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5?µg exenatide, or 10?µg exenatide for 30 weeks, followed by 5?µg exenatide BID for 4 weeks, then 10?µg exenatide BID for ≥3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas.

Results: 217 patients (64% male, age 58?±?10 years, weight 99?±?18?kg, BMI 34?±?5?kg/m², A1C 8.2?±?1.0% [mean?±?SD]) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (?1.1?±?0.1% [mean?±?SEM]) were sustained to 3 years (?1.0?±?0.1%; p?<?0.0001), with 46% achieving A1C?≤?7%. Exenatide progressively reduced body weight from baseline (?5.3?±?0.4?kg at 3 years; p?<?0.0001). Patients with elevated serum alanine aminotransferase (ALT) at baseline (n?=?116) had reduced ALT (?10.4?±?1.5?IU/L; p?<?0.0001) and 41% achieved normal ALT. Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline (?6.1?±?0.6?kg vs. ?4.4?±?0.5?kg; p?=?0.03), however weight change was minimally correlated with baseline ALT (r?=??0.01) or ALT change (r?=?0.31). Homeostasis Model Assessment B (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n?=?151). Triglycerides decreased 12% (p?=?0.0003), total cholesterol decreased 5% (p?=?0.0007), LDL-C decreased 6% (p?<?0.0001), and HDL-C increased 24% (p <?0.0001). Exenatide was generally well tolerated. The most frequent adverse event was mild-to-moderate nausea. The main limitation of this study is the open-label, uncontrolled nature of the study design which does not provide a placebo group for comparison.

Conclusion: Adjunctive exenatide treatment for ≥3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.     

Riboflavin attenuates lipopolysaccharide-induced lung injury in rats

Abstract

Riboflavin (vitamin B2) is an easily absorbed micronutrient with a key role in maintaining health in humans and animals. It is the central component of the cofactors flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) and is therefore required by all flavoproteins. Riboflavin also works as an antioxidant by scavenging free radicals. The present study was designed to evaluate the effects of riboflavin against acute lungs injury induced by the administration of a single intranasal dose (20?μg/rat) of lipopolysaccharides (LPS) in experimental rats. Administration of LPS resulted in marked increase in malondialdehyde (MDA) level (p?<?0.01) and MPO activity (p?<?0.001), whereas marked decrease in glutathione (GSH) content (p?<?0.001), glutathione reductase (GR) (p?<?0.001) and glutathione peroxidase (p?<?0.01) activity. These changes were significantly (p?<?0.001) improved by treatment with riboflavin in a dose-dependent manner (30 and 100?mg/kg, respectively). Riboflavin (100?mg/kg, p.o.) showed similar protective effects as dexamethasone (1?mg/kg, p.o.). Administration of LPS showed marked cellular changes including interstitial edema, hemorrhage, infiltration of PMNs, etc., which were reversed by riboflavin administration. Histopathological examinations showed normal morphological structures of lungs tissue in the control group. These biochemical and histopathological examination were appended with iNOS and CAT gene expression. The iNOS mRNA expression was increased significantly (p?<?0.001) and levels of CAT mRNA expression was decreased significantly (p?<?0.001) in the animals exposed to LPS, while treatment with riboflavin significantly (p?<?0.01) improved expression of both gene. In conclusion, the present study clearly demonstrated that riboflavin caused a protective effect against LPS-induced ALI. These results suggest that riboflavin may be used to protect against toxic effect of LPS in lungs.     

Anti-inflammatory and antinociceptive activities of Homalium letestui

Abstract

Context. Homalium letestui Pellegr (Flacourtiaceae) is used in various decoctions traditionally by the Ibibios of the Niger Delta of Nigeria to treat stomach ulcer, malaria and other inflammatory diseases, as well as an aphrodisiac.

Objective: To investigate the anti-inflammatory and antinociceptive activities of the stem extract of the plant.

Materials and methods: The ethanol stem extract (500, 750, 1000?mg/kg, i.p.) of H. letestui was investigated for anti-inflammatory activity using carrageenan, egg albumin-induced and xylene-induced ear edema models and analgesic activity using acetic acid-induced writhing, formalin-induced paw licking and thermal-induced pain models. The ethanol extract was administered to the animals orally, 30?min to 1?h depending on the model, before induction of inflammation/pain. The LD₅₀ was also determined. GC–MS analysis of dichloromethane fraction was carried out.

Results: The extract caused a significant (p?<?0.05–0.001) reduction of inflammation induced by carrageenan (8.3–70.0%), egg albumin (10.0–71.42%) and xylene (39.39–84.84%). The extract also reduced significantly (p?<?0.05–0.001) pain induced by acetic acid (44.22–73.65%), formalin (55.89–79.21%) and hot plate (93.0–214.5%). The LD₅₀ was determined to be 4.38?±?35.72?g/kg.

Discussion and conclusion: The results of this study suggest that the ethanol stem extract of H. letestui possesses anti-inflammatory and analgesic properties which may in part be mediated through the chemical constituents of the plant as revealed by the GC–MS.