Kinetics,safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects

Induction of mild states of hyperketonemia may improve physical and cognitive performance. In this study, we determined the kinetic parameters, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone monoester administered in the form of a meal replacement drink to healthy human volunteers. Plasma levels of β-hydroxybutyrate and acetoacetate were elevated following administration of a single dose of the ketone monoester, whether at 140, 357, or 714 mg/kg body weight, while the intact ester was not detected. Maximum plasma levels of ketones were attained within 1–2 h, reaching 3.30 mM and 1.19 mM for β-hydroxybutyrate and acetoacetate, respectively, at the highest dose tested. The elimination half-life ranged from 0.8–3.1 h for β-hydroxybutyrate and 8–14 h for acetoacetate. The ketone monoester was also administered at 140, 357, and 714 mg/kg body weight, three times daily, over 5 days (equivalent to 0.42, 1.07, and 2.14 g/kg/d). The ketone ester was generally well-tolerated, although some gastrointestinal effects were reported, when large volumes of milk-based drink were consumed, at the highest ketone monoester dose. Together, these results suggest ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a safe and simple method to elevate blood ketone levels, compared with the inconvenience of preparing and consuming a ketogenic diet.     

Olvanil,a non-pungent vanilloid enhances the gastrointestinal toxicity of cisplatin in the ferret

Pungent transient receptor potential vanilloid (TRPV1) channel activators have been shown to have broad inhibitory anti-emetic activity against centrally- and peripherally acting challenges but only at doses that have adverse effects on the cardiovascular system and on temperature homeostasis. In the present studies, we investigated the anti-emetic potential of the non-pungent TRPV1 activator, olvanil (0.05–5 mg/kg, s.c., 3 times per day, for 3 days) to antagonise the acute and delayed emesis induced by cisplatin (5 mg/kg, i.p.) in ferrets that had been implanted with radiotelemetry devices to enable an analysis of heart rate and temperature. Cisplatin induced an acute (day 1: 48.0 ± 18.3 retches + vomits) and delayed (day 2: 111.7 ± 35.5; day 3: 147.5 ± 20.2 retches + vomits) emetic response that was associated with reduced food (−98.7% at day 3, P < 0.001) and water consumption (−70.2% at day 3, P < 0.001) and progressive weight loss (−12.0% at day 3, P < 0.001). Olvanil did not prevent either emesis or the weight loss and negative effects on food and water consumption (P > 0.05); the effect on food consumption appeared potentiated by a further 21.2% at 0.05 mg/kg (P < 0.05) and 19.9% at 0.5 mg/kg (P < 0.05). Cisplatin did not alter body temperature (basal: 37.7 ± 0.1 °C) or heart rate (basal: 233.7 ± 5.5 beats per min (BPM); P > 0.05), but hypothermia (−1.6 °C) and increases in locomotor activity (50–90%) were recorded in animals concomitantly treated with olvanil (P < 0.05). These data indicate that non-pungent activators as exemplified by olvanil are unlikely to be useful clinically for the control of the gastrointestinal side effects induced by cisplatin.     

Antiviral activity of tenofovir against Cauliflower mosaic virus and its metabolism in Brassica pekinensis plants

The antiviral effect of the acyclic nucleoside phosphonate tenofovir (R)-PMPA on double-stranded DNA Cauliflower mosaic virus (CaMV) in Brassica pekinensis plants grown in vitro on liquid medium was evaluated. Double antibody sandwich ELISA and PCR were used for relative quantification of viral protein and detecting nucleic acid in plants. (R)-PMPA at concentrations of 25 and 50 mg/l significantly reduced CaMV titers in plants within 6-9 weeks to levels detectable neither by ELISA nor by PCR. Virus-free plants were obtained after 3-month cultivation of meristem tips on semisolid medium containing 50 mg/l (R)-PMPA and their regeneration to whole plants in the greenhouse. Studying the metabolism of (R)-PMPA in B. pekinensis revealed that mono- and diphosphate, structural analogs of NDP and/or NTP, are the only metabolites formed. The data indicate very low substrate activity of the enzymes toward (R)-PMPA as substrate. The extent of phosphorylation in the plant’s leaves represents only 4.5% of applied labeled (R)-PMPA. In roots, we detected no radioactive peaks of phosphorylated metabolites of (R)-PMPAp or (R)-PMPApp.     

Respiratory effects of buprenorphine/naloxone alone and in combination with diazepam in naive and tolerant rats

Respiratory depression has been attributed to buprenorphine (BUP) misuse or combination with benzodiazepines. BUP/naloxone (NLX) has been marketed as maintenance treatment, aiming at preventing opiate addicts from self-injecting crushed pills. However, to date, BUP/NLX benefits in comparison to BUP alone remain debated. We investigated the plethysmography effects of BUP/NLX in comparison to BUP/solvent administered by intravenous route in naive and BUP-tolerant Sprague-Dawley rats, and in combination with diazepam (DZP) or its solvent. In naive rats, BUP/NLX in comparison to BUP significantly increased respiratory frequency (f, P < 0.05) without altering minute volume (V_E). In combination to DZP, BUP/NLX significantly increased expiratory time (P < 0.01) and decreased f (P < 0.01), tidal volume (V_T, P < 0.001), and V_E (P < 0.001) while BUP only decreased V_T (P < 0.5). In BUP-tolerant rats, no significant differences in respiratory effects were observed between BUP/NLX and BUP. In contrast, in combination to DZP, BUP/NLX did not significantly alter the plethysmography parameters, while BUP increased inspiratory time (P < 0.001) and decreased f (P < 0.01) and V_E (P < 0.001). In conclusion, differences in respiratory effects between BUP/NLX and BUP are only significant in combination with DZP, with increased depression in naive rats but reduced depression in BUP-tolerant rats. However, BUP/NLX benefits in humans remain to be determined.     

Evaluation of the direct systemic and cardiopulmonary effects of diesel particles in spontaneously hypertensive rats

Recent data suggest that ultrafine pollutant particles (diameter <0.1 μm) may pass from the lung into the systemic circulation. However, the systemic and cardiorespiratory effects of translocated particles are not well known. In this study, we determined the direct acute (24 h) effect of the systemic administration of 0.01 mg/kg and 0.02 mg/kg diesel exhaust particles (DEP) on systolic blood pressure, heart rate, and both systemic and pulmonary inflammation in spontaneously hypertensive rats (SHR). Compared to the blood pressure in control group, rats exposed to DEP exhibited a dose-dependent increase in systolic blood pressure, at 0.01 mg/kg (P < 0.05) and 0.02 mg/kg (P < 0.01). Likewise, the heart rate was also dose-dependently increased at 0.01 mg/kg (P:NS) and 0.02 mg/kg (P < 0.01) compared to control SHR. DEP exposure (0.02 mg/kg) significantly elevated the number of leukocytes in blood (P < 0.05), interleukin-6 (IL-6, P < 0.005), tumor necrosis factor alpha (P < 0.05) and leukotriene B4 (LTB4, P < 0.005) concentrations in plasma. Moreover, in SHR given 0.02 mg/kg, the number of platelet was significantly reduced (P < 0.05), whereas the tail bleeding time was prolonged (P < 0.05). Pulmonary inflammations were confirmed by the presence of a significant increase in the number of macrophages (0.02 mg/kg) and neutrophils (0.01 and 0.02 mg/kg) and protein contents (0.02 mg/kg) in bronchoalveolar lavage (BAL) compared to saline-treated SHR. Also, IL-6 (0.01 mg/kg; P < 0.05 and 0.02 mg/kg; P < 0.01), LTB4 (0.02 mg/kg; P < 0.05) concentrations in BAL and the superoxide dismutase activity (0.02 mg/kg; P = 0.01) were significantly elevated compared to control group. We conclude that, in SHR, the presence of DEP in the systemic circulation leads not only to cardiac and systemic changes, but also triggers pulmonary inflammatory reaction involving IL-6, LTB4 and oxidative stress.     

Differential inhibitory effects of drugs acting at the noradrenaline and 5-hydroxytryptamine transporters in rat and human neocortical synaptosomes

Background and purpose:

Although the amino acid sequences of rat and human 5-hydroxytryptamine (5-HT) and noradrenaline (NA) transporters (i.e. SERT and NET) are highly homologous, species differences exist in the inhibitory effects of drugs acting at these transporters. Therefore, comparison of the potencies of drugs acting at SERT and NET in native human and rat neocortex may serve to more accurately predict their clinical profile.

Experimental approach:

Synaptosomes prepared from fresh human and rat neocortical tissues were used for [³H]-5-HT and [³H]-NA saturation and competition uptake experiments. The drugs tested included NA reuptake inhibitors (desipramine, atomoxetine and (S,S)-reboxetine), 5-HT reuptake blockers (citalopram, fluoxetine and fluvoxamine) and dual 5-HT/NA reuptake inhibitors (duloxetine and milnacipran).

Key results:

In saturation experiments on synaptosomal [³H]-5-HT and [³H]-NA uptake, the dissociation constants did not indicate species differences although a smaller density of both SERT and NET was observed in human tissues. In competition experiments with the various drugs, marked species differences in their potencies were observed, especially at SERT. The rank order of selectivity ratios (SERT/NET) in human neocortex was as follows: citalopram ≥ duloxetine = fluvoxamine ≥ fluoxetine > milnacipran > desipramine = atomoxetine > (S,S)-reboxetine. Significant species differences in these ratios were observed for duloxetine, atomoxetine and desipramine.

Conclusions and implications:

This study provides the first compilation of drug potency at native human neocortical SERT and NET. The significant species differences (viz., human vs. rat) in drug potency suggest that the general use of rodent data should be limited to predict clinical efficacy or profile.     

Filicene obtained from Adiantumcuneatum interacts with the cholinergic, dopaminergic, glutamatergic, GABAergic, and tachykinergic systems to exert antinociceptive effect in mice

In the present study, we describe the antinociceptive effect of filicene, a triterpene isolated from Adiantumcuneatum (Adiantaceae) leaves, in several models of pain in mice. When evaluated against acetic acid-induced abdominal constrictions, filicene (10, 30 and 60 mg/kg, i.p.) produced dose-related inhibition of the number of constrictions, being several times more potent [ID₅₀ = 9.17 (6.27-13.18) mg/kg] than acetaminophen [ID₅₀ = 18.8 (15.7-22.6) mg/kg], diclofenac [ID₅₀ = 12.1(9.40-15.6) mg/kg] and acetylsalicylic acid [ID₅₀ = 24.0(13.1-43.8) mg/kg] in the same doses as those used for the standard drugs. Filicene also produced dose-related inhibition of the pain caused by capsaicin and glutamate, with mean ID₅₀ values of 11.7 (8.51-16.0) mg/kg and < 10 mg/kg, respectively. Its antinociceptive action was significantly reversed by atropine, haloperidol, GABA_A and GABA_B antagonists (bicuculline and phaclofen, respectively), but was not affected by L-arginine-nitric oxide, serotonin, adrenergic and the opioid systems. Together, these results indicate that the mechanisms involved in its action are not completely understood, but seem to involve interaction with the cholinergic, dopaminergic, glutamatergic, GABAergic and tachykinergic systems.     

Resiniferatoxin antagonizes cisplatin-induced emesis in dogs and ferrets

We evaluated the antiemetic activity of resiniferatoxin, an ultrapotent capsaicin analogue, on cisplatin- and apomorphine-induced emesis in dogs, and on cisplatin-induced acute and delayed emesis in ferrets. In the dog, resiniferatoxin (10 microg/kg, s.c.) 30 min before the injection of cisplatin markedly prevented acute emesis induced by cisplatin. When animals were given resiniferatoxin (10 microg/kg, s.c.) 24 h prior to cisplatin, the emesis was still inhibited, but not significantly. Resiniferatoxin (10 microg/kg, s.c.) 30 min before the administration of apomorphine also significantly reduced the emetic responses induced by apomorphine in dogs. In the ferret, resiniferatoxin (10 microg/kg, s.c.) 30 min prior to cisplatin completely inhibited acute emesis caused by cisplatin (10 mg/kg, i.p.). When ferrets were given resiniferatoxin (10 microg/kg, s.c.) 16 h prior to cisplatin, the emesis was still significantly inhibited. Cisplatin (5 mg/kg, i.p.) induced both acute (0-24 h) and delayed (24-72 h) phase emesis, and a single injection of resiniferatoxin (10 microg/kg, s.c.) at 36 h after cisplatin significantly reduced subsequent emetic responses during the 36-72 h period. These results suggest that resiniferatoxin-related vanilloids may be useful drugs against both acute and delayed emesis induced by cancer chemotherapy.     

Action of prostanoids on the emetic reflex of Suncus murinus (the house musk shrew)

Several prostanoids were investigated for a potential to induce emesis in Suncus murinus. The TP receptor agonist 11α,9α-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619) induced emesis at doses as low as 3 μg/kg, i.p. but the DP receptor agonist 5-(6-Carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl) hydantoin (BW245C) was approximately 1000 times less potent. The emetic action of U46619 (300 μg/kg, i.p.) was antagonized significantly by the TP receptor antagonist, vapiprost (P<0.05). EP (prostaglandin E₂, 17-phenyl-ω-trinor prostaglandin E₂, misoprostol and sulprostone), FP (prostaglandin F_2α and fluprostenol) and IP (iloprost and cicaprost) receptor agonists failed to induce consistent emesis at doses up to 300-1000 μg/kg, i.p. Fluprostenol reduced nicotine (5 mg/kg, s.c.)-but not copper sulphate (120 mg/kg, intragastric)-induced emesis; the other inconsistently emetic prostanoids were inactive to modify drug-induced emesis. The results indicate an involvement of TP and possibly DP and FP receptors in the emetic reflex of S. murinus.     

The antiemetic interaction of Delta9-tetrahydrocannabinol when combined with tropisetron or dexamethasone in the least shrew

5-HT₃ receptor antagonists (e.g. tropisetron) combined with dexamethasone are effective for the acute phase of cisplatin (CIS)-induced emesis. This study determined the possible additive or synergistic antiemetic efficacy of Δ⁹-THC when combined with tropisetron or dexamethasone (DEX). Δ⁹-THC (0-10 mg/kg i.p.) was injected in combination with tropisetron (0-5 mg/kg i.p.) or dexamethasone (0-20 mg/kg i.p.) prior to CIS (20 mg/kg i.p.) in the least shrew, and the induced emesis was recorded for 60 min. CIS-induced vomiting was dose-dependently and significantly attenuated by individual administration of Δ⁹-THC (59-97% reductions) and tropisetron (79-100% attenuation), but not dexamethasone (26-40%), although a trend (p < 0.1) towards reduced vomiting frequency following DEX was noted. Low doses of Δ⁹-THC (0.25 or 0.5 mg/kg) when combined with low doses of tropisetron (0.025, 0.1, or 0.25 mg/kg) were more efficacious in reducing emesis frequency than when given individually, but Δ⁹-THC had no antiemetic interactions with DEX. However, no tested combination provided a significantly greater effect on the number of animals vomiting than their individually-administered counterparts. The modest interaction of Δ⁹-THC with tropisetron suggests they activate overlapping antiemetic mechanisms, while the lack of interaction with dexamethasone needs further clarification.     

Protective effect of Solanum torvum on doxorubicin-induced nephrotoxicity in rats

Nephrotoxicity is one of the important side effects of anthracycline antibiotics. The aim of the study was to determine the protective effect of Solanum torvum on doxorubicin-induced nephrotoxicity in rats using biochemical and histopathological approaches. Oxidative stress is the main factor in doxorubicin (DOX) induced nephrotoxicity. Wistar rats received either DOX (67.75 mg/kg, i.v, 2 days before sacrifice) or S. torvum (100 mg/kg and 300 mg/kg, p.o.) prior to DOX treatment or S. torvum (100 mg/kg and 300 mg/kg, p.o.) extract alone for 4 weeks. Nephrotoxicity was assessed by measuring the abnormal levels of serum creatinine and blood urea nitrogen (BUN). The anti-oxidant defence enzymes superoxide dismutase (SOD) and catalase (CAT) of kidney tissue were also measured at the end of the treatment schedule. Treatment with S. torvum (100 mg/kg and 300 mg/kg) significantly (p < 0.05) decreased the levels of creatinine and BUN and significantly (p < 0.05) increased the anti-oxidant defence enzyme levels of SOD and CAT. Histopathological changes showed that DOX caused significant structural damages to kidneys like tubular necrosis, renal lesions and glomerular congestion which was reversed with S. torvum. The results suggest that S. torvum has the potential in preventing the nephrotoxicity induced by doxorubicin.     

Anti-peroxidative and anti-hyperlipidemic nature of Ulva lactuca crude polysaccharide on d-Galactosamine induced hepatitis in rats

To find whether pretreatment of Ulva lactuca polysaccharide (ULP) extract could be effective against d-Galactosamine (500 mg/kg body weight, i.p.) induced anomaly in rat. Serum total cholesterol (TC), triglycerides (TG), free fatty acid (FFA), phospholipids (PL), high density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoprotein (VLDL), tissue lipoperoxides (LPO), hepatic protein thiols, non-enzymatic anti-oxidants glutathione (GSH) and vitamins (E and C) were examined using spectrophotometer. The ultra structural changes of liver during d-Galactosamine and protection offered by ULP were examined by electron microscopy. Seaweed histology and chemical composition of polysaccharides in seaweed were examined. Alcian blue staining showed the presence of sulphated polysaccharide with total sugar (65.4%), sulphate (17.4%), and uronic acid (17.2%) content. d-Galactosamine intoxicated rats showed significant (p < 0.01) liver damage with acute aberration in serum lipid profile, hepatic protein thiols and tissue non-enzymatic anti-oxidants. Assorted deposits of lipid droplets and abnormal appearance of mitochondria was observed in electron microscopy study. Rats pretreated with ULP (30 mg/kg body weight/day/for 21 days) showed a significant inhibition (p < 0.05) against abnormality induced by d-Galactosamine. U.lactuca exhibit anti-peroxidative and anti-hyperlipidemic property.     

N-Methanocarbathymidine is more effective than acyclovir for treating neonatal herpes simplex virus infection in guinea pigs

The outcome of neonatal herpes simplex (HSV) infection, even after therapy with high dose acyclovir (ACV), is not optimum. We therefore evaluated N-Methanocarbathymidine ((N)-MCT) using the guinea pig model of neonatal herpes. Treatment with ACV (60 mg/kg/day) was compared to doses of 1, 5, and 25 mg/kg/day of (N)-MCT initiated 1, 2, or 3 days postinoculation (dpi). Both ACV and (N)-MCT significantly improved survival, but only (N)-MCT significantly reduced the number of animals with symptoms when begun at 1 dpi. When therapy was begun at 2 dpi, only (N)-MCT (1, 5, or 25 mg/kg/day) significantly increased survival. In fact, (N)-MCT improved survival up to 3 dpi, the last time point evaluated. (N)-MCT was highly effective and superior to high dose ACV therapy for the treatment of neonatal herpes in the guinea pig model.     

Inhibiting NF-κB activation and ROS production are involved in the mechanism of silibinin's protection against D-galactose-induced senescence

Aging is featured by intelligence decline, behavioral disorders and cognitive disability. Autophagy is related to senescent development. In this study, we investigated the roles of NF-κB and autophagy in hippocampal neurons of d-galactose-induced senescent mice, and examined the protective roles of silibinin. Senescence was induced in 6-month-old mice by subcutaneous injection of d-galactose (150 mg/kg/d, for 6 weeks). Silibinin (50 mg/kg/d, intramuscular injection, for 6 weeks) or inhibitors (PDTC, 3-MA or rapamycin, 50 mg/kg/d, subcutaneous injection, for 6 weeks) were given 1 h before d-galactose exposure. Senescent control animals received vehicle for the same time. Ethological analysis, immunofluorescence staining, flow cytometric analysis, western blot and enzyme activity assays were used. Compared with senescent controls, silibinin, PDTC or rapamycin-treated mice showed upregulations of spatial recognition memory (P < 0.05), cellular oxidoreductase activities (P < 0.05) and autophagy (P < 0.05) as well as downregulations of MDA (P < 0.05) and ROS (P < 0.05) levels. We propose in d-galactose-induced murine senescence, autophagy is inhibited by NF-κB, inducing the deactivations of celluar oxidoreductases and upregulation of ROS level. The protection by autophagy and the promotion of cellular oxidoreductase activities via inhibiting NF-κB activation and ROS production are involved in the mechanism of silibinin's protection against d-galactose-induced senescence.     

Chemopreventive potential of Epoxy clerodane diterpene from <Emphasis Type="Italic">Tinospora cordifolia</Emphasis> against diethylnitrosamine-induced hepatocellular carcinoma

Summary  Medicinal plants are a promising source for identification of lead molecules for cancer therapy. In our continuous search to discover bioactive compounds from natural products, we isolated (5R, 10R)-4R, 8R-dihydroxy-2S, 3R:15, 16-diepoxycleroda-13(16), 17, 12S:18,1S-dilactone (ECD), a diterpenoid from Tinospora cordifolia and studied its chemopreventive potential in diethylnitrosamine (DEN) induced hepatocellular carcinoma (HCC) rats. Fifty male Wistar rats were divided into five groups. Group I served as normal control. Group II–IV were given DEN (0.01% in drinking water) for twenty weeks. In addition, Group III (preventive treatment) received ECD (10 mg/kg body weight) throughout the study. Group IV (curative treatment) received ECD (10 mg/kg body weight) for the last 8 weeks. Group V received ECD alone (10 mg/kg body weight) throughout the experimental period. At the end of the experimental period all the animals were sacrificed and analyzed for biochemical end points to assess the effect of ECD treatment in DEN induced HCC. The animals treated with DEN showed a decrease in the activities of antioxidant (SOD, CAT) and detoxification enzymes (GSH, GPx) with increase in the activities of the hepatic markers (SGOT, SGPT, LDH). Treatment of ECD in both preventive and curative DEN induced animals increased the level of antioxidants and detoxification enzymes, and decreased serum transaminase level and hepatic marker enzymes to near normal. Histopathological and nodular incidence also confirmed that ECD remarkably reduced tumor incidence and reversed damaged hepatocytes to normal. Our findings confirm that ECD exhibits preventive effect against chemically induced HCC in rats. ECD can be a potent chemopreventive drug for HCC.     

Higher than recommended amikacin loading doses achieve pharmacokinetic targets without associated toxicity

Antibiotic therapy improves the outcome of severe sepsis and septic shock, however pharmacokinetic properties are altered in this scenario. Amikacin (AMK) is an option to treat community or nosocomial infections, although standard doses might be insufficient in critically ill patients. The aim of this study was to evaluate two AMK dosage regimens in comparison with standard therapy with regard to efficacy in achieving adequate plasma levels as well as safety. In total, 99 patients with severe sepsis or septic shock were randomised to different AMK dose protocols: Group 1, 25 mg/kg/day; Group 2, 30 mg/kg/day; and Group 3, historical standard dose (15 mg/kg/day). Peak plasma concentrations at 1 h (C_max) were determined. Pharmacokinetics was determined and renal function was monitored to evaluate toxicity. Groups were compared using bilateral T-test. Demographic characteristics of the three groups were comparable. AMK C_max values were 57.4 ± 9.8, 72.1 ± 18.4 and 35.2 ± 9.4 μg/mL, respectively (P < 0.001 between Groups 1 and 2 versus Group 3, and P < 0.01 between Group 1 versus Group 2). A C_max > 60 μg/mL was reached by 39%, 76% and 0% of patients in Groups 1, 2 and 3, respectively (P < 0.001) and creatinine clearance at Day 28 was 95.6 ± 47.4, 89.7 ± 26.6 and 56.4 ± 18.4 mL/min, respectively. In conclusion, a 30 mg/kg daily dose of AMK presents significantly higher C_max compared with the other groups, with 76% of patients reaching recommended peak plasma levels with no association with higher nephrotoxicity. Standard doses are insufficient in critically ill patients to reach the recommended C_max.     

Potential analgesic,anti-inflammatory and antioxidant activities of hydroalcoholic extract of Areca catechu L. nut

The hydroalcoholic extract of Areca catechu L. (ANE) nut was screened for its analgesic, anti-inflammatory and in vitro antioxidant potential. Three doses of ANE (250, 500 and 1000 mg/kg orally) were tested for analgesic and anti-inflammatory activities. Evaluation of analgesic activity of ANE was performed using hot plate and formalin test in mice. ANE showed maximum increase in hot plate reaction time (56.27%, p < 0.01), while reduced the duration of licking/biting behaviors in first (39.45%, p < 0.05) and second (92.71%, p < 0.01) phases of the formalin test indicating significant analgesic activity. ANE reduced the paw edema considerably (86.79% inhibition after 24 h, p < 0.01) in dose-dependent manner compared to carrageenan-induced rat. In addition, in vitro antioxidant activity of ANE was investigated by total phenolic content (TPC) and hydrogen peroxide assay. The IC₅₀ observed in hydrogen peroxide assay was 83.14 μg/ml and TPC 120.56 ± 21.09 mg QE/g. Altogether, these results suggest that the hydroalcoholic extract of Areca catechu could be considered as a potential analgesic, anti-inflammatory and antioxidant agent.     

Liquid chromatography/tandem mass spectrometry study of anti-inflammatory activity of Plantain (Plantago L.) species

To evaluate anti-inflammatory activity of selected Plantago species (P. lanceolata L. and P. major L.) an optimized in vitro test for determination of cyclooxygenase-1 (COX-1) and 12-lipoxygenase (12-LOX) inhibition potency was undertaken. By using intact cell system (platelets) as a source of COX-1 and 12-LOX enzymes and highly sensitive and specific LC–MS/MS technique for detection of main arachidonic acid metabolites formed by COX-1 and 12-LOX, this test provides efficient method for evaluation of anti-inflammatory potential of plant extracts and isolated compounds. Our results validated the well-known COX-1 inhibitory activity of P. lanceolata and P. major methanol extracts (concentration required for 50% inhibition (IC₅₀) was 2.00 and 0.65 mg/ml, respectively). Furthermore, 12-LOX inhibitory activity of examined extracts was reported for the first time (IC₅₀ = 0.75 and 1.73 mg/ml for P. lanceolata and P. major, respectively). Although renowned inhibitors, such as acetylsalicylic acid and quercetin showed higher activity, this study verifies P. lanceolata and P. major as considerable anti-inflammatory agents.     

Influence of GSTs, CYP2E1 and mEH polymorphisms on 1, 3-butadiene-induced micronucleus frequency in Chinese workers

1,3-butadiene (BD) has been classified as a human carcinogen, however, the relationship between chromosomal damage and its metabolic polymorphisms is not clear. The present study used the CBMN assay to detect chromosomal damage in the peripheral lymphocytes of 166 exposed workers and 41 non-exposed healthy individuals. PCR and PCR-RFLP were applied to detect GSTT1, GSTM1, CYP2E1 c1c2 and mEH Tyr113His, His139Arg polymorphisms. The results demonstrated that the micronucleus (MN) frequency of the exposed workers was significantly higher than controls (P < 0.01). Among the exposed workers, the individuals with high BD exposures are more susceptible to chromosomal damage than those with low exposures (FR = 1.30, 95% CI 1.14-1.53; P < 0.05). Gender-difference was also found in our study: males got lower micronucleus frequency than females. Workers who carried the genotypes of GSTM1 (+), CYP2E1 (c1c2/c2c2) and mEH intermediate (I) group had significantly higher MN frequency than those carrying the genotypes of GSTM1 (−) (FR = 1.29, 95% CI 1.05-1.59; P < 0.05), CYP2E1 (c1c1) (FR = 1.55, 95% CI 1.24-1.93; P < 0.01) or mEH high (H) group (FR = 1.57, 95% CI 1.08-2.34; P < 0.05), respectively. Our data indicated that the current BD exposure level could cause significantly higher MN frequency in workers than controls. Polymorphisms of GSTM1, CYP2E1 and mEH are susceptible to altered chromosome damage.     

Effects of Thai Musa species on prevention of UVB-induced skin damage in mice

The effects of oral administration of Musa sapientum and Musa suerier on prevention of UVB induced skin damages were investigated in male ICR mice. Animals were orally administered 50 mg/day ascorbic acid, or M. sapientum or M. suerier’s fruit pulps at dose of 0.5, 1 or 1.5 mg/g body weight/day for 12 weeks. Concurrently, the shaved backs of animals were irradiated with UVB for 12 weeks. The intensity of irradiation was progressively increased, from 54 mJ/cm² per exposure at week 1–126 mJ/cm² at week 11. A significant decrease (p < 0.05) in skin elasticity (from 0.82 ± 0.02 to 0.42 ± 0.09) and total glutathione (from (193.6 ± 18.7 to 152.7 ± 7.8 ng/mg protein) as compared with the control group (water-administered UVB-irradiated mice) was observed after 12 weeks of UVB exposure. When l-ascorbic acid (0.72 ± 0.01) or 1 mg/g body weight/day M. suerier (0.84 ± 0.06) were administered to UVB-irradiated mice, the reduction in skin elasticity was significantly inhibited (p < 0.05). Moreover, the significant increase (p < 0.05) in level of total glutathione was found in these groups (220.8 ± 13.3 ng/mg protein for l-ascorbic acid and 224.9 ± 20.1 ng/mg protein for M. suerier). These findings suggest the potential effect of daily consumption of M. suerier on prevention of skin damage from repeated UVB exposure.