Evaluation of hepatoprotective activity of aerial parts of Tephrosia purpurea L. and stem bark of Tecomella undulata

Ethnopharmacological relevance

The aerial parts of Tephrosia purpurea (L.) pers. (Fabaceae) and stem bark of Tecomella undulata seem. (Bignoniaceae) are used for liver disorders in the traditional system of medicine.

Aim of the study

To evaluate the hepatoprotective activity of aerial parts of Tephrosia purpurea and stem bark of Tecomella undulata against thioacetamide-induced hepatotoxicity.

Materials and methods

Hepatotoxicity was induced in albino rats of either sex by subcutaneous injection of thioacetamide. Aqueous–ethanolic extract of aerial parts of Tephrosia purpurea (100, 300 and 500 mg/kg/day and ethanolic extract of stem bark of Tecomella undulata (200, 500 and 1000 mg/kg/day were evaluated.

Results

Oral administration of Tephrosia purpurea at 500 mg/kg and Tecomella undulata at 1000 mg/kg resulted in a significant reduction in serum aspartate aminotransaminase (35% and 31%, respectively), alanine aminotransaminase (50% and 42%, respectively), gamma glutamyl transpeptidase (56% and 49%, respectively), alkaline phosphatase (46% and 37%, respectively), total bilirubin (61% and 48%, respectively) and liver MDA levels (65% and 50%, respectively), and significant improvement in liver glutathione (73% and 68%, respectively) when compared with thioacetamide damaged rats. Histology of the liver sections of the animals treated with the extracts also showed dose-dependent reduction of necrosis.

Conclusions

The present study demonstrates the hepatoprotective activity of the aerial parts of Tephrosia purpurea and stem bark of Tecomella undulata against thioacetamide-induced hepatotoxicity.     

Role of human liver cytochrome P4503A in the metabolism of etoricoxib, a novel cyclooxygenase-2 selective inhibitor.

Etoricoxib, a potent and selective cyclooxygenase-2 inhibitor, was shown to be metabolized via 6'-methylhydroxylation (M2 formation) when incubated with NADPH-fortified human liver microsomes. In agreement with in vivo data, 1'-N'-oxidation was a relatively minor pathway. Over the etoricoxib concentration range studied (1-1300 microM), the rate of hydroxylation conformed to saturable Michaelis-Menten kinetics (apparent K(m) = 186 +/- 84.3 microM; V(max) = 0.76 +/- 0.45 nmol/min/mg of protein; mean +/- S.D., n = 3 livers) and yielded a V(max)/K(m) ratio of 2.4 to 7.3 microl/min/mg. This in vitro V(max)/K(m) ratio was scaled, with respect to yield of liver microsomal protein and liver weight, to obtain estimates of M2 formation clearance (3.1-9.7 ml/min/kg of b.wt.) that agreed favorably with in vivo results (8.3 ml/min/kg of b.wt.) following i.v. administration of [(14)C]etoricoxib to healthy male subjects. Cytochrome P450 (P450) reaction phenotyping studies-using P450 form selective chemical inhibitors, immunoinhibitory antibodies, recombinant P450s, and correlation analysis with microsomes prepared from a bank of human livers-revealed that the 6'-methyl hydroxylation of etoricoxib was catalyzed largely (approximately 60%) by member(s) of the CYP3A subfamily. By comparison, CYP2C9 (approximately 10%), CYP2D6 (approximately 10%), CYP1A2 (approximately 10%), and possibly CYP2C19 played an ancillary role. Moreover, etoricoxib (0.1-100 microM) was found to be a relatively weak inhibitor (IC(50) > 100 microM) of multiple P450s (CYP1A2, CYP2D6, CYP3A, CYP2E1, CYP2C9, and CYP2C19) in human liver microsomes.     

TRILINOLEIN INHIBITS THE ADHESION OF NEUTROPHILS TO ENDOTHELIAL CELLS

1. Trilinolein is a triacylglycerol with linoleic acid as the only type of fatty acid in all three esterified positions of glycerol. It was recently reported to have a myocardial protective effect in coronary ligated rats. We now study its effect on the adhesion of human neutrophils to cultured bovine endothelial cells. 2. Pretreatment of an endothelial monolayer with trilinolein at concentrations ranging from 10^-10 to 10^-6 mol/L significantly inhibited neutrophil adhesion to endothelial cells. Trilinolein was less potent than sodium nitroprusside in inhibiting neutrophil adhesion. 3. The inhibitory effect of trilinolein was antagonized by methylene blue and N^G-nitro-L-arginine methyl ester. The inhibitory effect of trilinolein was not mediated through linoleic acid because linoleic acid did not inhibit neutrophil adhesion. 4. Pretreatment of neutrophils with trilinolein did not reduce neutrophil adhesion. However, in neutrophils activated with N-formyl-methionyl-leucyl-phenylalanine, trilinolein inhibited the neutrophil adhesion to endothelial cells. 5. We conclude that trilinolein inhibits neutrophil adhesion to the endothelial monolayer by stimulating the nitric oxide and cyclic GMP pathways in endothelial cells. It may also inhibit neutrophil adhesion by scavenging free radicals. The inhibitory effect of trilinolein on neutrophil adhesion may play a role in its myocardial protective activity.     

Flt3 ligand: a novel cytokine prevents allergic asthma in a mouse model

Flt-3 ligand (FL), a recently described growth factor affecting early hematopoietic progenitor cells, can also support the expansion of dendritic cells secreting IL-12. Since type 2 T cells predominate in asthma and IL-12 prevents the differentiation of naive T lymphocytes to a type 2 phenotype, we hypothesized that FL could prevent the development of asthma-like conditions in the ovalbumin mouse model. We found that co-administration of FL during ovalbumin sensitization abrogated late allergic responses, but had no effect on early allergic responses. Airway hyperresponsiveness to methacholine was also blocked by FL treatment. Analysis of bronchoalveolar lavage (BAL) fluid demonstrated a significant reduction in eosinophils, with concomitant decreases in IL-5 and increases in IFN-gamma levels. However, there was no change in BAL fluid IL-4 and serum IgE levels. These data suggest that FL treatment prevents ovalbumin-induced asthma in the mouse and may provide a useful adjuvant in the treatment of human asthma.     

Suppression of ovarian function in combination with an aromatase inhibitor as treatment for advanced breast cancer in pre-menopausal women

Trials have shown superiority of aromatase inhibitors (AIs) over tamoxifen for post-menopausal oestrogen receptor-positive advanced breast cancer (ER + ABC). We previously reported the use of goserelin plus anastrozole (G + A) as second-line endocrine therapy for pre-menopausal ER + ABC. We report clinical and endocrine data from G + A as first-line systemic therapy.Thirty-six patients (median age = 44 years) with metastatic (N = 28) and locally advanced disease were administered G + A for ?6 months (unless progressed prior). Some (N = 13) received further therapy with goserelin plus another AI (steroidal), exemestane (G + E). Serial serum hormone assays (oestradiol, dehydroepiandrosterone sulphate, testosterone, follicle stimulating hormone and luteinising hormone) were performed.Twenty-four patients (67%) derived clinical benefit (CB) (5% complete response, 31% partial response, 31% stable disease for ?6 months) with median time to progression and duration of CB of 12 (2–47) and 24 + (7–78+) months respectively. Ten patients were still receiving first-line G + A at analysis. Amongst 13 patients who went onto receive G + E, 38% achieved CB with a mean duration of 13+(7–32) months. Therapy was well tolerated with no withdrawals. The combination of G + A resulted in 98% reduction (from pre-treatment to 6-month) in median levels of oestradiol (from 574.5 pmol/L; inter-quartile range (IQR) = 209–1426; (N = 6) to 13.45 pmol/L; IOQ = 5.5–31.5 (N = 4) whilst the levels of other hormones had minimal fluctuations during therapy.The combinations of ovarian function suppression (using G) and AIs produce sustained CB and minimal side effects in pre-menopausal ER + ABC with significant reduction in oestradiol levels. Within the limitations of being a non-randomised study, they should be considered in appropriate patients with hormone-sensitive ABC.     

Probiotic supplementation for preventing invasive fungal infections in preterm neonates – a systematic review and meta‐analysis

Invasive fungal infections (IFI) are associated with significant health burden in preterm neonates. The objective of this study was to systematically review effect of probiotic supplementation (PS) for preventing IFI in preterm neonates. We searched Cochrane Central Register of Controlled Trials, Medline, Embase, Cumulative Index of Nursing and Allied Health Literature, and proceedings of the Pediatric Academic Society meetings in August 2014. Study selection was performed on randomised controlled trials ( RCT) of PS in neonates born <37 weeks. Primary outcome of this study was IFI (Isolation of fungus in blood/body fluids) and secondary outcome was fungal gut colonisation. Information on IFI/colonisation was available in 8 of 27 RCT. Meta‐analysis (fixed effects model) showed that PS reduced the risk of IFI (RR: 0.50, 95% CI: 0.34, 0.73, I² = 39%). Results were not significant with random effects model (RR: 0.64, 95%, CI: 0.30, 1.38, P = 0.25, I² = 39%). Analysis after excluding the study with a high baseline incidence (75%) of IFI showed that PS had no significant benefits (RR: 0.89; 95% CI: 0.44, 1.78). Of the five studies reporting on fungal gut colonisation, three reported benefits of probiotics; two did not. Current evidence is limited to derive firm conclusions on the effect of PS for preventing IFI/gut colonisation in preterm neonates.     

Synthesis, characterization and pharmacological evaluation of amide prodrugs of ketorolac

Ketorolac (KC) suffers from the general side effects of NSAIDs, owing to presence of free carboxylic acid group. The study aimed to retard the adverse effects of gastrointestinal origin. Ten prodrugs of KC were synthesized by amidation with ethyl esters of amino acids, namely, glycine, l-phenylalanine, l-tryptophan, l-valine, l-isoleucine, l-alanine, l-leucine, l-glutamic acid, l-aspartic acid and beta-alanine. Purified synthesized prodrugs were characterized by m.p., TLC, solubility, partition coefficients, elemental analyses, UV, FTIR, NMR and MS. Synthesized prodrugs were subjected for biopharmaceutical studies, analgesic, anti-inflammatory activities and ulcerogenic index. Marked reduction of ulcerogenic index and comparable analgesic, anti-inflammatory activities were obtained in all cases as compared to KC. Among synthesized prodrugs, viz. AR-11, AR-19 and AR-20 showed excellent pharmacological response and encouraging hydrolysis rate both in SIF and in 80% human plasma. Prodrugs with increased aliphatic side chain length or introduction of aromatic substituent showed enhanced partition coefficient but diminished dissolution and hydrolysis rates. Such prodrugs can be considered for sustained release purpose.     

Antibiotic prophylaxis in elective cholecystectomy: a randomized, double blinded study comparing ciprofloxacin and cefuroxime

A prospective, randomised and double blind study was undertaken to compare the prophylactic efficacy of ciprofloxacin and cefuroxime in 155 patients undergoing elective cholecystectomy. Patients with past history of jaundice or presence of jaundice, diabetes mellitus, common bile duct stones and previous biliary tract surgery were excluded. Patients were allocated to the following groups: group A-no antibiotic (n = 30); group B-ciprofloxacin (200 mg i/v before surgical incision and a second dose after 12 hrs) (n + 45); group C-ciprofloxacin given only post operatively (200 mg i/v, 12 hourly X 2 days followed by oral 500 mg twice daily X 3 days) (n = 35); group D-cefuroxime (750 mg i/v before surgical incision and a second dose after 12 hrs) (n = 45). Efficacy of the antibiotic was defined as a patient being free of post operative wound infection. Maximum numbers of infection occurred in group A (26.67%) and group C (25.71%). The incidence of wound infection was significantly lower when ciprofloxacin was used as prophylaxis (group B) than when used post operatively (group C) only (P < 0.05). Patients who received ciprofloxacin (group B) and cefuroxime (group D) as prophylaxis had significantly reduced incidence of infection (4.44% and 6/67% respectively); no statistically significant difference was found between these groups. Ciprofloxacin could be used as prophylactic antimicrobial in elective cholecystectomy in developing countries because of its effectiveness, economy and ready availability.