Phenolics-rich fraction of Khaya senegalensis stem bark: Antitrypanosomal activity and amelioration of some parasite-induced pathological changes

Abstract

Context: The stem bark of Khaya senegalensis A. Juss (Meliaceae) is currently used for the treatment of trypanosomiasis by traditional practitioners in Nigeria.

Objectives: The present study investigated the anti-Trypanosoma brucei brucei activity of phenolics-rich fraction of K. senegalensis (pfks) and its ameliorative effects on trypanosome-induced pathological changes.

Materials and methods: The fraction was initially analyzed by gas chromatography-mass spectrometry (GC-MS). A 60?min time course experiment was conducted with various concentrations of the fraction using a 96-well microtiter plate technique and was further used to treat T. brucei infected rats at 100, 200 and 300?mg/kg body weight (BW). Indices of anemia as well as hepatic and renal functions were analyzed in all experimental animals at the end of the experiment.

Results: The GC-MS analysis of the pfks revealed that the most abundant phytochemicals are phloroglucinol (40.56%) and 3,4-(dihydroxyphenyl) acetic acid (41.76%). The fraction showed a concentration dependent in vitro antitrypanosomal activity. Interestingly, the fraction completely eliminated the parasites from the bloodstream of infected rats without relapse during the experimental period at the dose of 300?mg/kg BW and also kept the parasites consistently lower at 100 and 200?mg/kg BW than that was recorded in the untreated infected rats. Furthermore, the severity of T. brucei-induced anemia and hepatic damage was significantly (p?<?0.05) ameliorated in the 300?mg/kg BW treatment group whereas the parasite-induced renal damage was significantly (p?<?0.05) ameliorated in all treatment groups.

Conclusion: Data from this study may suggest that phenolics play an important role in the antitrypanosomal activity of K. senegalensis.     

Sedative and anticonvulsant effects of an alcoholic extract of Capparis decidua

Capparis decidua (frock) Edgew (family Capparidaceae) is a xerophytic shrub, commonly known as karrel or ker, whose bark and shoot are used as analgesic, anti-inflammatory, hypolipidemic, and antidiabetic agents. The plant contains generous quantities of alkaloids. An alcoholic extract of aerial parts of C. decidua, including flowers and fruits, was screened for central nervous system (CNS) activity using conventional behavioral animal models. In the open field test all doses of C. decidua extract tested decreased the number of rearings, grooming, and fecal bolus (P < 0.001) when compared with control. In the barbiturate-induced sleeping test a significant (P < 0.001) a decrease in latency of sleeping and increase in sleeping time were observed at all doses (100, 200, and 300 mg/kg). C. decidua extract increased the percentage of animals exhibiting motor deficit in the rotarod test. In the pentylenetetrazole-induced seizures test the C. decidua extract dose-dependently decreased (P < 0.05) the number of animals with convulsions and increased convulsion latency (P < 0.001); none of the animals treated with extract died in the test. C. decidua extract decreased the duration of tonic hind leg extension in maximal electroshock-induced seizures (P < 0.001) when compared with control. The findings of the present animal study suggested that C. decidua has CNS depressant and anticonvulsant activities.     

Gemfibrozil and its combination with metformin on pleiotropic effect on IL-10 and adiponectin and anti-atherogenic treatment in insulin resistant type 2 diabetes mellitus rats

Aim

Gemfibrozil is a PPAR-α ligand that inhibits the progression of atherosclerosis in insulin resistance type 2 diabetes mellitus (IR type 2 DM). Gemfibrozil, poor anti-hyperglycemic combined with metformin, evaluated for MMP-9, IL-10 and adiponectin beyond glycemic control.

Essential methods

IR type 2 DM induced by administering streptozotocin (90 mg/kg, i.p.) in neonatal rat model. IR type 2 DM rats at 6-week age treated for 8 weeks with (1) gemfibrozil (140 mg/kg od) and (2) gemfibrozil (70 mg/kg bid) + metformin (60 mg/kg bid). At the end, risk parameters like MMP-9, IL-10 and adiponectin were evaluated by ELISA kits.

Main results

Gemfibrozil reduced the MMP-9 levels (?25.740 %) (106.772 ± 7.201 ng/ml vs. 80.231 ± 7.023 ng/ml, P < 0.01); increased adiponectin (68.321 %) (8.781 ± 1.111 μg/ml vs. 14.782 ± 1.055 μg/ml) and IL-10 (155.687 %) (334.208 ± 26.307 pg/ml vs. 853.472 ± 23.172 pg/ml, P < 0.001), but poor glycemic control (?6.169 %) (167.5 ± 16.037 vs. 157.167 ± 3.911, P = ns), hence combined with metformin showed synergistic activity, reduced the MMP-9 levels (?16.992 %) (106.772 ± 7.201 ng/ml vs. 89.941 ± 8.636 ng/ml, P < 0.05) and increased adiponectin (39.870 %) (8.781 ± 1.111 μg/ml vs. 12.282 ± 0.782 μg/ml) and, IL-10 (80.136 %) (334.208 ± 26.307 pg/ml vs. 602.029 ± 39.668 pg/ml, P < 0.01) had good glycemic control (?28.856 %) (167.5 ± 16.037 mg/dl vs. 129.167 ± 4.214 mg/dl, P < 0.05).

Overall conclusions

Gemfibrozil plus metformin decrease MMP-9, increase IL-10 and adiponectin acting as anti-atherogenic, anti-inflammatory and immunomodulatory in IR type 2 DM.     

Potential protective effect of sunitinib after administration of diclofenac: biochemical and histopathological drug–drug interaction assessment in a mouse model

Sunitinib is a tyrosine kinase inhibitor for GIST and advanced renal cell carcinoma. Diclofenac is used in cancer pain management. Coadministration may mediate P450 toxicity. We evaluate their interaction, assessing biomarkers ALT, AST, BUN, creatinine, and histopathological changes in the liver, kidney, heart, brain, and spleen. ICR mice (male, n?=?6 per group/dose) were administered saline (group A) or 30 mg/kg diclofenac ip (group B), or sunitinib po at 25, 50, 80, 100, 140 mg/kg (group C) or combination of diclofenac (30 mg/kg, ip) and sunitinib (25, 50, 80, 100, 140 mg/kg po). Diclofenac was administered 15 min before sunitinib, mice were euthanized 4 h post-sunitinib dose, and biomarkers and tissue histopathology were assessed. AST was 92.2?±?8.0 U/L in group A and 159.7?±?14.6 U/L in group B (p?<?0.05); in group C, it the range was 105.1–152.6 U/L, and in group D, it was 156.0–209.5 U/L (p?<?0.05). ALT was 48.9?±?1.6 U/L (group A), 95.1?±?4.5 U/L (p?<?0.05) in group B, and 50.5–77.5 U/L in group C and 82.3–115.6 U/L after coadministration (p?<?0.05). Renal function biomarker BUN was 16.3?±?0.6 mg/dl (group A) and increased to 29.9?±?2.6 mg/dl in group B (p?<?0.05) and it the range was 19.1–33.3 mg/dl (p?<?0.05) and 26.9–40.8 mg/dl in groups C and D, respectively. Creatinine was 5.9 pmol/ml in group A; 6.2 pmol/ml in group B (p?<?0.01), and the range was 6.0–6.2 and 6.2–6.4 pmol/ml in groups C and D, respectively (p?<?0.05 for D). Histopathological assessment (vascular and inflammation damages) showed toxicity in group B (p?<?0.05) and mild toxicity in group C. Damage was significantly lesser in group D than group B (p?<?0.05). Spleen only showed toxicity after coadministration. These results suggest vascular and inflammation protective effects of sunitinib, not shown after biomarker analysis.     

Antinociceptive and pronociceptive effect of levetiracetam in tonic pain model

Background

Levetiracetam (LEV) is a novel anticonvulsant with proven antinociceptive properties. However, the antinociceptive and pronociceptive effect of this drug has not yet been fully elucidated in a tonic pain model.

Immune Suppression During Preclinical Drug Development Mitigates Immunogenicity-Mediated Impact on Therapeutic Exposure

In the clinical setting, anti-drug antibodies (ADA) against biotherapeutics can influence patient safety and interfere with product efficacy. High immunogenicity has been addressed in clinic by concomitant immune suppression, such as co-administration of methotrexate with enzyme replacement therapy (ERT) and combination tacrolimus/sirolimus treatment for prophylaxis against organ transplant rejection. This study investigates the use of such immune suppressants in mitigating ADA responses to a fully human monoclonal antibody (mAb1) in preclinical animal studies. Three groups of Sprague Dawley rats (n?=?18) were treated with low (0.01 mg/kg), moderate (50 mg/kg), or high (300 mg/kg) doses of mAb1. Experimental groups also received either methotrexate or tacrolimus/sirolimus immune suppressive regimens. ELISA-based methods were utilized to measure and characterize ADA and mAb1 pharmacokinetics (PK). Results demonstrated a stepwise increase in immunogenicity with mAb1 dosage. Methotrexate significantly lowered incidence of anti-variable region antibodies at moderate mAb1 dose (P?<?0.05), while tacrolimus/sirolimus did likewise at moderate and high doses (P?<?0.01) of mAb1. Except for low-dose mAb1 + methotrexate, all immunosuppressed groups displayed more than a 70-fold decrease in ADA magnitude (P?<?0.05). This abrogation in ADA response correlated with more mAb1 in circulation by week 4 for moderate- and high-dosed mAb1 groups. These data provide an approach to mitigate preclinical immunogenicity by the use of immunosuppressant regimens. Such preconditioning can support preclinical drug development of human therapeutics that are antigenic to animals. Similar approaches could be investigated for wider application to novel therapeutics.     

In vivo recovery effect of silibinin treatment on streptozotocin-induced diabetic mice is associated with the modulations of sirt-1 expression and autophagy in pancreatic β-cell

Improper adjustments of autophagy and silent information regulator 1 (Sirt-1) expression were reported to be closely associated with metabolic disorders. In this study, we examined the roles of Sirt-1 and autophagy in streptozotocin-induced diabetes mellitus, assessed the relationship between autophagy and Sirt-1, and investigated the protective mechanism of silibinin. Diabetes was induced in 6-week-old mice by intravenous injection of streptozotocin (150 mg/kg/day, for 2 weeks). In the treatment groups, silibinin (50 mg/kg/day, intramuscular injection, for 8 weeks) or inhibitors (50 mg/kg/day, subcutaneous injection, for 8 weeks) were given. Diabetic control animals received vehicle for the same time. Compared with diabetic controls, silibinin or autophagy inhibitor, 3-methyladenine, treated mice showed decreased levels of glycosylated hemoglobin A1C (P < 0.01), serum triglyceride (P < 0.01), cholesterol (P < 0.01), blood glucose (P < 0.05), autophagy (P < 0.05), and apoptosis ratio (P < 0.05) of pancreatic β-cells. Systemic administration of silibinin reversed streptozotocin-induced downregulation of Sirt-1 expression. Sirt-1 may play a role in regulating the physiological level of autophagy and is associated with loss of pancreatic β-cells and metabolic biochemical disorders. Through promoting Sirt-1 expression and recovering autophagy physiologically, silibinin may reverse hyperglycemia and repair damaged pancreatic β-cells.     

Asenapine effects in animal models of psychosis and cognitive function

Rationale

Asenapine, a novel psychopharmacologic agent in the development for schizophrenia and bipolar disorder, has high affinity for serotonergic, α-adrenergic, and dopaminergic receptors, suggesting potential for antipsychotic and cognitive-enhancing properties.

Objectives

The effects of asenapine in rat models of antipsychotic efficacy and cognition were examined and compared with those of olanzapine and risperidone.

Materials and methods

Amphetamine-stimulated locomotor activity (Amp-LMA; 1.0 or 3.0 mg/kg s.c.) and apomorphine-disrupted prepulse inhibition (Apo-PPI; 0.5 mg/kg s.c.) were used as tests for antipsychotic activity. Delayed non-match to place (DNMTP) and five-choice serial reaction (5-CSR) tasks were used to assess short-term spatial memory and attention, respectively. Asenapine doses varied across tasks: Amp-LMA (0.01–0.3 mg/kg s.c.), Apo-PPI (0.001–0.3 mg/kg s.c.), DNMTP (0.01–0.1 mg/kg s.c.), and 5-CSR (0.003–0.3 mg/kg s.c.).

Results

Asenapine was highly potent (active at 0.03 mg/kg) in the Amp-LMA and Apo-PPI assays. DNMTP or 5-CSR performance was not improved by asenapine, olanzapine, or risperidone. All agents (P?<?0.01) reduced DNMTP accuracy at short delays; post hoc analyses revealed that only 0.1 mg/kg asenapine and 0.3 mg/kg risperidone differed from vehicle. All active agents (asenapine, 0.3 mg/kg; olanzapine, 0.03–0.3 mg/kg; and risperidone, 0.01–0.1 mg/kg) significantly impaired 5-CSR accuracy (P?<?0.05).

Conclusions

Asenapine has potent antidopaminergic properties that are predictive of antipsychotic efficacy. Asenapine, like risperidone and olanzapine, did not improve cognition in normal rats. Rather, at doses greater than those required for antipsychotic activity, asenapine impaired cognitive performance due to disturbance of motor function, an effect also observed with olanzapine and risperidone.     

Protective effect of flavonoid extract from Chinese bayberry (Myrica rubra Sieb. et Zucc.) fruit on alcoholic liver oxidative injury in mice

To evaluate the beneficial effects of Chinese bayberry (Myrica rubra Sieb. et Zucc.) flavonoid extract (CBFE) on chronic alcohol-induced liver oxidative injury in mice, experimental mice were pretreated with different doses of CBFE (50–200 mg/kg) for 4 weeks by gavage feeding. Biochemical markers and enzymatic antioxidants from serum, liver tissue, mitochondria and microsomes were examined. Our results showed that the activities of TC, TG, L-DLC in serum, the activity of CYP2E1 in microsomes, and the levels of MDA in liver tissue and mitochondria, decreased significantly (P < 0.05) in the CBFE-treated group compared with the alcohol group. On the contrary, the activities of ALT, AST, and H-DLC in serum, enzymatic antioxidants GSH-Px, SOD and GST in liver tissue and mitochondria, and HO-1 in microsomes rose markedly (P < 0.05). Histopathological examination revealed that CBFE (200 mg/kg) pretreatment noticeably prevented alcohol-induced hepatocyte apoptosis and fatty degeneration. It was suggested that the hepatoprotective effects exhibited by CBFE on alcohol-induced liver oxidative injury may be due to its potent antioxidant properties.     

Preventive and curative effects of Artemisia absinthium on acetaminophen and CCl4-induced hepatotoxicity

• 1.1. Effect of aqueous-methanolic extract of Artemisia absinthium (Compositae) was investigated against acetaminophen- and CCl₄-induced hepatic damage.
• 2.2. Acetaminophen produced 100% mortality at the dose of 1 g/kg in mice while pretreatment of animals with plant extract (500 mg/kg) reduced the death rate to 20%.
• 3.3. Pretreatment of rats with plant extract (500 mg/kg, orally twice daily for two days) prevented (P < 0.01) the acetaminophen (640 mg/kg) as well as CCl₄ (1.5 ml/kg)-induced rise in serum transaminases (GOT and GPT).
• 4.4. Post-treatment with three successive doses of extract (500 mg/kg, 6 hr) restricted the hepatic damage induced by acetaminophen (P < 0.01) but CCl₄-induced hepatotoxicity was not altered (P > 0.05).
• 5.5. Plant extract (500 mg/kg) caused significant prolongation (P < 0.05) in pentobarbital (75 mg/kg)-induced sleep as well as increased strychnine-induced lethality in mice suggestive of inhibitory effect on microsomal drug metabolizing enzymes (MDME).
• 6.6. These results indicate that the crude extract of Artemisia absinthium exhibits hepatoprotective action partly through MDME inhibitory action and validates the traditional use of plant in hepatic damage.

     

Identification of Brugia malayi adult worm molecules immunoreactive with sera of infected animals treated with antifilarial and re-infected with homologous infection and their role in the establishment of infection in Mastomys coucha

The present study was aimed at identifying molecules of Brugia malayi adult worm (BmA) that are immunoreactive with sera of B. malayi-infected Mastomys coucha treated with albendazole (ALB) or diethylcarbamazine (DEC) and re-exposed to infection and the effect of immunization with the molecules on the establishment of infection in M. coucha. A ～62 kDa molecule showed strong reactivity with sera of infected ALB-treated reinfected animals whereas ～32 kDa and ～45 kDa molecules strongly reacted with sera of DEC-treated reinfected animals. Two molecules (～22 kDa and ～28 kDa) reacted with sera of infected untreated and reinfected control animals. Immunization with ～62 kDa molecules reduced the adult worm recovery by 58% (P < 0.001) and microfilaremia by 32–54% (P < 0.05–0.01) of unimmunized controls. Animals immunized with the ～32 kDa molecule exhibited 63% recovery of adult worms with no effect on circulating microfilaraemia. L₃ inoculation in ～62 kDa-immunized animals upregulated cellular proliferation, interferon-γ (IFN-γ) and IgG responses (P < 0.001) but downregulated interleukin-10 (IL-10) response (P < 0.001). Animals immunized with ～22, ～28, ～32 and ～45 kDa molecules and bearing L₃-induced infection showed mixed responses. Lymph node cells of unimmunized animals exposed to ～28, ～32 and ～62 kDa molecules showed significant DNA damage (P < 0.001) as compared to untreated control; ～62 kDa molecule induced maximum damage. In conclusion, immunization with a ～62 kDa molecule suppressed the establishment of L₃-induced infection in M. coucha and this correlated with enhanced cellular proliferation and IFN-γ release, downregulation of IL-10, increased levels and DNA damage in lymph node cells.     

Ellagic acid mitigates sodium arsenite-induced renal and hepatic toxicity in male Wistar rats

Background

The aim of this study was to investigate the effect of ellagic acid (EA) on arsenic-induced renal and hepatic toxicity in rats.

N-acetyl cysteine abates hepatorenal toxicities induced by perfluorooctanoic acid exposure in male rats

Ingestion of perfluorooctanoic acid (PFOA) elicits toxicities in the hepatorenal system. We investigated the effect of PFOA and N-acetylcysteine (NAC) on the hepatorenal function of rats treated thus: control, PFOA (5 mg/kg), NAC (50 mg/kg), PFOA + NAC (5 and 25 mg/kg), and PFOA + NAC (5 and 50 mg/kg). We observed that NAC significantly (p < 0.05) reduced PFOA-induced increase in hepatic and renal function biomarkers of toxicities relative to PFOA alone and alleviated (p < 0.05) decreases in antioxidant status. Increases in oxidative stress and lipid peroxidation in PFOA-treated rats were reverted to normal by NAC and abated increased pro-inflammatory mediators, and decreased anti-inflammatory cytokine both in the hepatorenal system PFOA treated rats. Histology of the kidney and liver indicated that NAC, abated the severity of PFOA-induced damage significantly. Our findings affirm further that oxido-inflammatory mediators involved in PFOA-mediated toxicity can be effectively blocked by NAC through its antioxidant activity.     

Acute and chronic inflammation studies of Strobilanthes callosus leaves extract on rat model

Aim

To assess the protective efficacy of Strobilanthes callosus against the acute and chronic inflammation on rat model.

Methods

Inflammation was induced by carrageen and Freund’s complete adjuvant in plantar surface of the rats. The ethanol, chloroform and petroleum ether extracts in three divided doses (100, 200 and 400 mg/kg) were administered orally. Diclofenac sodium (10 mg/kg), prednisolone (5 mg/kg) and methotrexate (0.5 mg/kg) were used as standard. The statistical significance between means was analyzed using a one-way analysis of variance followed by Tukey’s multiple comparison test. A p <0.005 was considered as statistically significant.

Results

Pet. ether (200 and 400 mg/kg) and ethanol extract (100 and 400 mg/kg) showed statistically significant (p < 0.001) effect in analgesic activity. In a carrageen-induced model, only pet. ether extract (100 and 400 mg/kg) confirmed statistically significant effect (p < 0.001) at every interval (four in all) of 1 h. In Freund’s adjuvant model, Pet ether and ethanol extract (200 and 400 mg/kg) have shown statistically significant effect (p < 0.001) and in case of chloroform extract only single dose (400 mg/kg) were observed statistically significant results considered to be anti-arthritic effects. The histopathology pictures showed there was positive inhibition of arthritis at a certain level in different groups compared to positive control group.

Conclusion

Pet. ether and ethanol extracts of S. callosus were observed to have a promising efficacy against acute and chronic inflammation.     

Potential antidiabetic effect of the Semecarpus anacardium in a type 2 diabetic rat model

Semecarpus anacardium Linn. nut milk extract (SA) was evaluated for its antidiabetic role in type 2 diabetic rats. Type 2 diabetes was induced in rats by feeding high-fat diet for 2 weeks followed by single intraperitoneal injection of streptozotocin 35 mg/kg body weight. Diabetic rats were treated with SA orally at a dosage of 200 mg/kg body weight daily for 30 days. Metformin (500 mg/kg body weight, orally) was used as a reference drug. SA significantly (p < 0.05) reduced the blood glucose levels and decreased the levels of HbA1c and the glucose intolerance. SA treatment significantly (p < 0.05) decreased the increase in lipid profile. The levels of urea, uric acid and creatinine were restored to near normal levels when compared with control diabetic rats. The histopathological abnormalities were also found to be normalized after treatment with SA nut milk extract. The potential antihyperglycemic action of SA is plausibly due to its underlying antioxidant role.     

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.     

Febuxostat exerts dose-dependent renoprotection in rats with cisplatin-induced acute renal injury

The aim of the present study was to investigate possible renoprotective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against cisplatin (CIS)-induced acute kidney injury in rats. Male Sprague Dawley rats were randomly assigned into four groups of six rats each, as follows: normal control; CIS, received a single intraperitoneal injection of CIS (7.5 mg/kg); [febuxostat 10 + CIS] and [febuxostat 15 + CIS], received febuxostat (10 and 15 mg/kg/day, respectively, orally) for 14 days, starting 7 days before CIS injection. At the end of experiment, 24-h urine output was collected and serum was separated for biochemical assessments. Kidney tissue homogenate was prepared for determination of oxidative stress-related parameters, nitric oxide (NO), and tumor necrosis factor-α (TNF-α). Moreover, histological alterations of kidney tissues were evaluated. Serum creatinine, blood urea, and urinary total protein were significantly elevated, while serum albumin and creatinine clearance were significantly reduced, in CIS-intoxicated rats, indicating depressed renal function. CIS administration also elicited renal oxidative stress, evidenced by increased malondialdehyde content and depleted levels of reduced glutathione and superoxide dismutase activity. Moreover, enhancement of renal levels of the pro-inflammatory TNF-α indicated renal inflammation. CIS-administered rats also showed increased serum lactate dehydrogenase activity and reduced renal NO bioavailability. Febuxostat dose-dependently improved or restored these changes to near-normal (e.g., mean ± SD of serum creatinine levels in control, CIS, [febuxostat 10 + CIS] and [febuxostat 15 + CIS] groups were 0.78 ± 0.19, 3.28 ± 2.0 (P < 0.01 versus control group), 1.03 ± 0.36 (P < 0.01 versus CIS group), and 0.93 ± 0.21 (P < 0.01 versus CIS group) mg/dl, respectively, and blood urea levels for the different groups were 36.80 ± 4.36, 236.10 ± 89.19 (P < 0.0001 versus control group), 114.50 ± 78.63 (P < 0.05 versus CIS group), and 60.91 ± 14.30 (P < 0.001 versus CIS group) mg/dl, respectively). Histological analysis of renal tissues also demonstrated that febuxostat offered a dose-dependent renoprotection. The present study suggests that antioxidant, anti-inflammatory, and cytoprotective mechanisms potentially mediate the renoprotective effects of febuxostat in CIS-administered rats, presenting febuxostat as a promising combinatorial strategy for cancer patients undergoing CIS chemotherapy.     

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.     

Effects of chlorpromazine and atropine on acetaminophen absorption in rabbits

The effects of chlorpromazine and atropine on the gastrointestinal absorption of acetaminophen were investigated in rabbits. Two doses of chlorpromazine and atropine were injected intraperitoneally 30 min prior to the oral administration of acetaminophen. Blood samples were collected before and 0.25,0.5,0.75, 1.0,1.5,2,3,4,5 and 6 h after acetaminophen administration and were analyzed for acetaminophen contents using a HPLC method. Chlorpromazine at a 10 mg/kg dose significantly reduced the maximum plasma concentration (C_max) of acetaminophen from 64.2 ± 2.8 to 40.0 ± 6.3 μgg/ml(P < 0.05). In addition, chlorpromazine at 5 and 10 mg/kg doses significantly increased the time taken to reach the maximum plasma concentration (T_max) of acetaminophen from 0.29 ± 0.04 to 0.67 ± 0.15 and 0.96 ± 0.21h, respectively (P < 0.05). Atropine at 0.5 and 1.0 mg/kg doses also significantly reduced the C_max of acetaminophen from 69.6 ± 4.7 to 45.6 ± 3.7 and 45.9 ± 6.7 μg/ml, respectively (P < 0.05). However, atropine has little effect on T_max of acetaminophen. Both chlorpromazine and atropine did not seem to affect the area under the plasma concentration-time curve and the elimination half-life of acetaminophen. It was concluded that chlorpromazine and atropine affect the rate but not the extent of acetaminophen absorption, by delaying the gastric emptying.     

Neurological activities of lapachol and its furano derivatives from Kigelia africana

This study was carried out to investigate some neurological activities of lapachol and other chemical constituents isolated from Kigelia africana in male albino mice using elevated plus-maze (EPM) test, open-field test (OFT), and forced swimming test (FST). The anxiolytic-like and antidepressant effects of these constituents were compared to known active anxiolytic (diazepam, 2 mg/kg) and antidepressant (imipramine, 15 mg/kg) reference drugs. The compounds 1 [50 mg/kg, intraperitoneally (i.p.)] and 3 (100 mg/kg, i.p.) significantly increased the number of lines crossed in the OFT and the duration of immobility in the FST, indicating a possible antidepressant activity, but no significant effect was observed in the EPM test. The compound 4 (100 mg/kg, i.p.) significantly increased the time spent on the open arms, but the increase in number of open arms entries was not significant in the EPM test. Meanwhile, the duration of the immobility time was significant and quite close to that of the standard drug, imipramine used in the FST. The compound 5 (100 mg/kg, i.p.) substantially increased the time spent and entries into open arms of the EPM, and reduced the time spent and entries into closed arms, when compared with saline controls (P < 0.05). This compound also increased the exploratory activity of the mice as well as the swimming duration in the OFT and FST, respectively. These results indicate that among the compounds tested, quinones displayed significant anxiolytic and/or antidepressant effects at all doses tested. Kojic acid, a fungal metabolite whose structure was unambiguously confirmed by single-crystal X-ray studies, is also isolated for the first time from K. africana, suggesting that it is a possible taxonomic marker in the biogenesis of the quinone skeleton.