Role of the Rosa canina L. leaf extract as an antidiarrheal drug in rodents

Objectives:

The objective of the study was to investigate the effect of the leaf extract of Rosa canina L. against experimental diarrhea induced by castor oil in rodents.

Materials and Methods:

The methanol extract of Rosa canina L. (30 and 60 mg/kg body weight) was administered orally to two groups of mice (five animals per group) in order to evaluate the activity of the extract against the castor oil-induced diarrhea model in mice. Two other groups received normal saline and diphenoxylate (5 mg/kg) as positive control. The effect of the extract on intestinal transit and castor oil-induced intestinal fluid accumulation (enteropooling) was assessed. The effects of the extract on the isolated rabbit jejunum and on the isolated rat ileum were studied.

Results:

The preliminary phytochemical screening of the leaf extract of Rosa Canina L. revealed the presence of alkaloids, flavonoids, glycosides, saponins, and volatile oil. Intraperitoneal LD50 of the extract was found to be 455.19 ± 23 mg/kg in mice. The antidiarrheal effect of the methanolic extract exhibited a concentration-dependent inhibition of the spontaneous pendular movement of the isolated rabbit jejunum and inhibited acetylcholine-induced contraction of the rat ileum. A dose-dependent decrease in gastrointestinal transit was observed with extracts (30 and 60 mg/kg), which also protected mice against castor oil-induced diarrhea and castor oil-induced fluid accumulation, respectively.

Conclusions:

The presence of some of the phytochemicals in the leaf extract may be responsible for the observed effects, and also the basis for its use in traditional medicine as an antidiarrheal drug.     

Antidiarrheal activity of extracts and compound from Trilepisium madagascariense stem bark

Objective:

The present study was performed to evaluate the preventive and curative antidiarrheal effects of the methanol extract, fractions and compound from the stem bark of Trilepisium madagascariense in rats.

Materials and Methods:

The methanol extract from the stem bark of T. madagascariense, its fractions (n-hexane, ethyl acetate, n-butanol and aqueous residue) and compound (obtained from further column chromatography of the ethyl acetate fraction) were evaluated for the antidiarrheal activity in rats. These test samples (at 100, 200 and 400 mg/kg for the extract and fractions and 2.5 mg/kg for compound) were assayed on the latent periods, purging indices and fecal frequencies in castor oil-induced diarrhea. Gastrointestinal transit and castor oil-induced enteropooling assays were conducted. Shigella-induced diarrhea was assayed. Blood chemistry and fecal Shigella load were examined.

Results:

The fractionation of the ethyl acetate fraction from the methanol extract of T. madagascariense afforded a known compound [isoliquiritigenin (1)]. Compound 1 increased the latent period of diarrhea induction (179.40 min) compared to the saline control (60.80 min). The purging indices, fecal frequencies and intestinal enteropooling decreased with an increase in the dose of test samples. The blood cell counts, sera creatinine and fecal Shigella load decreased significantly (P ≤ 0.05) in the plant extract-treated rats compared to the saline control.

Conclusion:

The results of our study, being reported for the first time, provide clear evidence that the methanol extract, fractions and isoliquiritigenin from T. madagascariense stem bark possess antidiarrheal activities.     

Antisecretory and antimotility activity of Aconitum heterophyllum and its significance in treatment of diarrhea

Aim:

The roots of the plant Aconitum heterophyllum (EAH) are traditionally used for curing hysteria, throat infection, dyspepsia, abdominal pain, diabetes, and diarrhea. Therefore, the present study was undertaken to determine the mechanism involved in the anti-diarrheal activity of roots of A. heterophyllum.

Materials and Methods:

Ant-diarrheal activity of ethanol extract at 50, 100, and 200 mg/kg p.o. was evaluated using fecal excretion and castor oil-induced diarrhea models, while optimized dose, that is, 100 mg/kg p.o. was further subjected to small intestinal transit, intestinal fluids accumulation, PGE₂-induced enteropooling and gastric emptying test. To elucidate the probable mechanism, various biochemical parameters and Na⁺, K⁺ concentration in intestinal fluids were also determined. Further, antibacterial activity of extract along with its standardization using aconitine as a marker with the help of HPLC was carried out.

Results:

The results depicted a significant (P < 0.05) reduction in normal fecal output at 100 and 200 mg/kg p.o. of extract after 5^th and 7^th h of treatment. Castor oil-induced diarrhea model demonstrated a ceiling effect at 100 mg/kg p.o. with a protection of 60.185% from diarrhea. EAH at 100 mg/kg p.o. also showed significant activity in small intestinal transit, fluid accumulation, and PGE₂-induced enteropooling models, which also restored the altered biochemical parameters and prevented Na⁺ and K⁺ loss. The extract with 0.0833% w/w of aconitine depicted a potential antibacterial activity of extract against microbes implicated in diarrhea.

Conclusion:

The study concluded antisecretory and antimotility effect of A. heterophyllum, which mediates through nitric oxide path way.KEY WORDS: Aconitum heterophyllum, antibacterial activity, ant-diarrheal activity, castor oil-induced diarrhea, fecal excretion, nitric oxide, PGE₂, small intestinal transit     

Evaluation of antidiarrheal potential of trichodesma indicum root extract in rats

Trichodesma indicum is found as a weed throughout the greater part of India. The decoction of the root is used for diarrhea, dysentery, and fever in Indian traditional medicine. However, the traditional claims need to be validated by suitable experimental animal models. Therefore, this study was undertaken to evaluate its antidiarrheal potential in several animal models. The extract significantly inhibited the castor oil-induced diarrhea and decreased propulsion of charcoal meal through the gastrointestinal tract; it also reduced the castor oil-induced small intestinal fluid accumulation (enteropooling). The ethanol extract of T. indicum root has significant antidiarrheal activity and substantiates the use of this herbal remedy as a nonspecific treatment for diarrhea in folk medicine.     

Evaluation of Caesalpinia bonducella flower extract for anti-inflammatory action in rats and its high performance thin layer chromatography chemical fingerprinting

Objective:

The study is aimed to evaluate anti-inflammatory activity of Caesalpinia bonducella Fleming (Caesalpiniaceae) flower extract (CBFE) and to study its effect on radiographic outcome in adjuvant induced arthritis and authentication by high performance thin layer chromatography (HPTLC) chemical fingerprinting.

Materials and Methods:

CBFE was administered orally (30, 100, and 300 mg/kg b.wt.) and tested for its anti-inflammatory activity in carrageenan-induced inflammation, cotton pellet induced chronic granulomatous inflammation and autacoids-induced inflammation. Effect on radiographic outcome was tested in adjuvant-induced arthritis. CBFE was HPTLC fingerprinted in suitable solvent system.

Result:

In carrageenan-induced inflammation, CBFE produced significant inhibition in edema volume at all the doses (30, 100 and 300 mg/kg b.wt.) and percentage of inhibition was 28.68, 31.00, and 22.48, respectively as compared to control at 5 h of its administration. In cotton pellet granuloma assay, CBFE significantly decreased the granuloma weight at 300 mg/kg dose level by 22.53%. CBFE (300 mg/kg) caused significant inhibition by 37.5, 44.44, and 35.29% edema volume, at ½, 1 and 3 h after 5-hydroxytryptamine injection, respectively. Radiographic score of animals treated with 300 mg/kg CBFE was significantly decreased when compared to arthritic control animals.

Conclusion:

The extract was found to possess significant anti-inflammatory activity. CBFE treatment improved the bony architecture in adjuvant-induced arthritis in rats. The developed HPTLC fingerprint would be helpful in the authentication of C. bonducella flower extract.KEY WORDS: 5-hydroxy tryptamine, Caesalpinia bonducella, carrageenan-induced inflammation, cotton pellet granuloma, high performance thin layer chromatography, radiography     

The role of Cortistatin-14 in the gastrointestinal motility in mice

Background

This study aimed to investigate the functional roles of Cortistatin-14 (CST-14) in the gastrointestinal (GI) motility.

Protective effect of ethyl acetate fraction of Rhododendron arboreum flowers against carbon tetrachloride-induced hepatotoxicity in experimental models

Objective:

To evaluate the hepatoprotective potential of ethyl acetate fraction of Rhododendron arboreum (Family: Ericaceae) in Wistar rats against carbon tetrachloride (CCl₄)-induced liver damage in preventive and curative models.

Materials and Methods:

Fraction at a dose of 100, 200, and 400 mg/kg was administered orally once daily for 14 days in CCl₄-treated groups (II, III, IV, V and VI). The serum levels of glutamic oxaloacetic transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase (SALP), γ-glutamyltransferase (γ -GT), and bilirubin were estimated along with activities of glutathione S-transferase (GST), glutathione reductase, hepatic malondialdehyde formation, and glutathione content.

Result and Discussion:

The substantially elevated serum enzymatic activities of SGOT, SGPT, SALP, γ-GT, and bilirubin due to CCl₄ treatment were restored toward normal in a dose-dependent manner. Meanwhile, the decreased activities of GST and glutathione reductase were also restored toward normal. In addition, ethyl acetate fraction also significantly prevented the elevation of hepatic malondialdehyde formation and depletion of reduced glutathione content in the liver of CCl₄-intoxicated rats in a dose-dependent manner. Silymarin used as standard reference also exhibited significant hepatoprotective activity on post-treatment against CCl₄-induced hepatotoxicity in rats. The biochemical observations were supplemented with histopathological examination of rat liver sections. The results of this study strongly indicate that ethyl acetate fraction has a potent hepatoprotective action against CCl₄-induced hepatic damage in rats.     

Antioxidant and antidiarrheal activities of ethanol extract of Ardisia elliptica fruits

Context: Ardisia elliptica Thunb Lam. (Myrsinaceae) is widely used traditionally in the treatment of diarrhea related health disorders in Bangladesh.

Objective: The crude ethanol extract of Ardisia elliptica fruits (EFA) was evaluated for its antioxidant and antidiarrhoeal activities.

Materials and methods: DPPH radical scavenging, nitric oxide scavenging, reducing power and Fe⁺⁺ ion chelating ability were used for determining antioxidant activities and animal models were used for antidiarrheal activities such as the castor oil and magnesium sulfate-induced diarrhea, enteropooling induced by the administration of castor oil and magnesium sulfate at the doses of 250 and 500?mg/kg.

Results: The extract possessed a significant DPPH free radical scavenging activity with an IC₅₀ value of 30.75?μg/ml compared to ascorbic acid (IC₅₀: 7.89?μg/ml). The IC₅₀ values of the extract and ascorbic acid were 51.72 and 38.68?μg/ml, respectively, in nitric oxide scavenging assay. The IC₅₀ value of the extract for Fe⁺⁺ ion chelating ability (41.30?μg/ml) was also found to be significant compared to the IC₅₀ value of EDTA (22.57?μg/ml). The EFA also showed a significant protection (p?Conclusion: Therefore, the obtained results confirm the antioxidant and antidiarrheal activity of EFA and thus support the traditional uses of this plant as a modality for antioxidant and antidiarrheal activity.     

Pharmacological investigations of Punica granatum in glycerol-induced acute renal failure in rats

Objective:

The present study was designed to investigate the ameliorative potential and possible mechanism of hydroalcoholic extract of flowers of P. granatum in glycerol-induced acute renal failure (ARF) in rats.

Materials and Methods:

The rats were subjected to rhabdomyolytic ARF by single intramuscular injection of hypertonic glycerol (50% v/v; 8 ml/kg) and the animals were sacrificed after 24 hours of glycerol injection. The plasma creatinine, blood urea nitrogen, creatinine clearance, and histopathological studies were performed to assess the degree of renal injury.

Results:

Pretreatment with hydroalcoholic extract of flowers of P. granatum (125 and 250 mg/kg p.o. twice daily for 3 days) significantly attenuated hypertonic glycerol-induced renal dysfunction in a dose-dependent manner. BADGE (Bisphenol-A-diglycidyl ether) (30 mg/kg), a peroxisome proliferator-activated receptor (PPAR)-γ antagonist, and N(omega)-nitro-l-arginine-methyl ester (L-NAME) (10, 20, and 40 mg/kg), nitric oxide synthase inhibitor, were employed to explore the mechanism of renoprotective effects of Punica granatum. Administration of BADGE (30 mg/kg) and L-NAME (40 mg/kg) abolished the beneficial effects of P. granatum in glycerol-induced renal dysfunction.

Conclusion:

Hydroalcoholic extract of flowers of P. granatum has ameliorative potential in attenuating myoglobinuric renal failure and its renoprotective effects involve activation of PPAR-γ and nitric oxide-dependent signaling pathway.     

Radioprotective and cytoprotective activity of Tinospora cordifolia stem enriched extract containing cordifolioside-A

Objectives:

The present study was undertaken to evaluate the radioprotective and cytoprotective potential of cordifolioside-A, a primary active constituent of n-butanol fraction of Tinospora Cordifolia (NBTC) against 4 Gy-γ radiation in mice and cyclophosphamide induced genotoxicity.

Materials and Methods:

Presence of cordifolioside-A in NBTC stem ethanolic extract was confirmed by high performance thin layer chromatography (HPTLC) analysis. Radioprotective activity was evaluated at 80 and 120 mg/kg, intraperitoneal (i.p.) dose of NBTC administered 15 days prior to whole body radiation exposure by observing survival rate, change in body weight, hematology, spleen colony forming unit (CFU), and micronucleus (MN) expression. Cytoprotective activity of NBTC was evaluated at 5, 10, and 15 mg/ml concentrations on Allium cepa root meristem growth against cyclophosphamide.

Results:

HPTLC analysis of standard cordifolioside A, and NBTC confirmed the presence of cordifolioside-A in NBTC with the retention factor value of 0.86. Administration of NBTC (120 mg/kg, i.p.) produced significant protection against radiation in terms of increased survival rate, body weight retention, hematological parameters, spleen CFU assay (P < 0.01), and decreased MN expression (P < 0.01). Cytoprotectivity was observed maximally at 10 mg/ml NBTC concentration with significant increase in root growth (P < 0.01), non-toxic mitotic index (MI) (65.9%) and lesser chromosomal aberrations (15.4%). NBTC at 10 mg/ml concentration showed very few C-anaphase compared to aberrations like fragmentation, C-anaphase, multipolarity and sticky chromosome in cyclophosphamide alone.

Conclusion:

The results suggest that enriched NBTC containing cordifolioside-A has a potential in vivo radioprotective effect as well as in vitro cytoprotective activity.KEY WORDS: Cordifolioside-A, cytoprotective activity, radioprotective activity, Tinospora cordifolia     

Preliminary studies on local anesthetic and antipyretic activities of Spilanthes acmella Murr. in experimental animal models

Objective:

Spilanthes acmella Murr. (Family: Compositae) is a herb that grows throughout the tropics. It is used in the treatment of rheumatism, fever, sore throat, and hemorrhoids. A tincture of the flowers is used to relieve toothache. The leaves and flowers produce numbness of the tongue when eaten as salad. The present study was undertaken to evaluate the local anesthetic and antipyretic activities of S. acmella in experimental animal models.

Materials and Methods:

Aqueous extract of S. acmella Murr. (SAM) was tested for local anesthetic action by (i) intracutaneous wheal in guinea pigs and (ii) plexus anesthesia in frogs. In both the models, 2% xylocaine was used as the standard drug. The anti-pyretic activity was determined by yeast-induced pyrexia in rats. Aspirin 300 mg/kg was used as the standard drug.

Result:

The test drug in concentrations of 10% and 20% produced 70.36% and 87.02% anesthesia respectively by the intracutaneous wheal compared to 97.22% anesthetic effect produced by 2% xylocaine (P<0.001). The mean onset of anesthesia with the test drug was 5.33±0.57 min compared to 2.75±0.31 min (P<0.001) for the standard drug in the plexus anesthesia model. In the anti-pyretic model, ASA in doses of 100, 200, and 400 mg produced dose-dependent reduction in mean temperature at various hours of observation.

Conclusion:

The present study shows that SAM has significant local anesthetic and antipyretic activities.     

Hypoglycemic effect of aqueous extract of Parthenium hysterophorus L. in normal and alloxan induced diabetic rats

Objectives:

To study the effects of Parthenium hysterophorus L. flower on serum glucose level in normal and alloxan induced diabetic rats.

Materials and Methods:

Albino rats were divided into six groups of six animals each, three groups of normal animals receiving different treatments consisting of vehicle, aqueous extract of Parthenium hysterophorus L. flower (100 mg/kg) and the standard antidiabetic drug, glibenclamide (0.5 mg/kg). The same treatment was given to the other three groups comprising alloxan induced diabetic animals. Fasting blood glucose level was estimated using the glucose oxidase method in normal and alloxan induced diabetic rats, before and 2 h after the administration of drugs.

Results:

Parthenium hysterophorus L. showed significant reduction in blood glucose level in the diabetic (P<0.01) rats. However, the reduction in blood glucose level with aqueous extract was less than with the standard drug glibenclamide. The extract showed less hypoglycemic effect in fasted normal rats, (P<0.05).

Conclusion:

The study reveals that the active fraction of Parthenium hysterophorus L. flower extract is very promising for developing standardized phytomedicine for diabetes mellitus.     

Evaluation of Antidiarrheal Potential of Emblica officinalis.

ABSTRACT

The antidiarrheal potential of the methanol extract of the fruit of Emblica officinalis. Gaertn. Euphorbiaceae was evaluated using several experimental models of diarrhea in Wistar albino rats. The methanol extract showed a significant inhibitory effect on rats with diarrhea induced by castor oil and magnesium sulfate. The methanol extract produced a significant reduction in gastrointestinal motility in charcoal meal tests in rats. It also significantly inhibited PGE₂-induced enteropooling as compared to control animals. The results obtained establish the efficacy and substantiate the use of this herbal remedy as a nonspecific treatment for diarrhea in folk medicine.     

Antiproliferative and antioxidant activity of Aegle marmelos (Linn.) leaves in Dalton's Lymphoma Ascites transplanted mice

Objective:

The present investigation was performed to evaluate the antiproliferative and antioxidant activity of Aegle marmelos leaves in Dalton''s Lymphoma Ascites (DLA)-bearing mice.

Materials and Methods:

The DLA cells maintained in vivo in Swiss albino mice were used for developing ascitic tumor in mice by intraperitoneal transplantation. The standardized 50% ethanolic extract of A. marmelos leaves (AMEE) was administered intraperitoneally in dose levels 200 and 400 mg/kg, after 24 hours of tumor inoculation in mice for two weeks.

Results:

The AMEE treatment significantly prevented (P<0.001) the increase in body weight due to tumor cell growth and increased the mean survival time of the tumor-bearing mice as compared to the untreated DLA control mice. The treatment of DLA-bearing mice brought down the Alanine Aminotransferase (ALAT), Aspartate Aminotransferase (ASAT), and alkaline phosphatase to normal levels. The extract decreased the levels of hepatic lipid peroxidation and increased the levels of hepatic antioxidants Glutathione, Superoxide Dismutase (SOD), and catalase. All the changes observed with AMEE treatment were dose dependent.

Conclusion:

The hydroalcoholic extract of A. marmelos exhibits strong antitumor and antioxidant activities in DLA-bearing mice.KEY WORDS: Aegle marmelos, antioxidant activity, antiproliferative activity, Dalton''s Lymphoma Ascites     

Experimental evaluation of analgesic and anti-inflammatory potential of Oyster mushroom Pleurotus florida

Background:

Edible mushrooms have been used as flavorful foods and as health nutritional supplements for several centuries. A number of bioactive molecules have been identified in numerous mushroom species

Objective:

To evaluate the analgesic and anti-inflammatory potential of Oyster Mushroom Pleurotus florida using various experimental models in Wistar rats.

Materials and Methods:

Acute toxicity studies were performed whereby dose of 250 mg/ kg and 500 mg/kg was selected for present study, Analgesic activity was determined using hot plate method, tail flick method, acetic acid induced writhing and formalin induced pain in rats, while carrageenan was used to induce inflammation and anti-inflammatory studies were performed.

Results:

HEE showed significant (P < 0.01) analgesic and anti-inflammatory response against all experimental models.

Conclusion:

These studies conclude that Pleurotus florida possesses analgesic and anti- inflammatory potential which might be due to presence of myochemicals like flavonoids, phenolics and polysaccharides.KEY WORDS: Analgesic, anti-inflammatory, Pleurotus florida     

Anticataleptic and antiepileptic activity of ethanolic extract of leaves of Mucuna pruriens: A study on role of dopaminergic system in epilepsy in albino rats

Objective:

To assess the anticataleptic and antiepileptic activity of leaves of Mucuna pruriens in albino rats.

Materials and Methods:

Haloperidol-induced catalepsy (HIC), maximum electro-shock (MES) method, pilocarpine-induced Status epilepticus (PISE) and single-dose effect of M. pruriens were employed.

Results:

M. pruriens (100 mg/kg) had significant anticataleptic and antiepileptic activity in HIC, MES, and PISE.

Conclusions:

M. pruriens extract has the potential to be an anticataleptic and antiepileptic drug. Dopamine and 5-HT may have a role in such activity.     

Adverse drug reaction profile of nanoparticle versus conventional formulation of paclitaxel: An observational study

Objectives:

Conventional polyethoxylated castor oil (PCO)-based paclitaxel is associated with major adverse drug reactions (ADRs). Nanoxel, a nanoparticle-based formulation, may improve its tolerability by removing the need for PCO vehicle, and also permit its use in a higher dose. We conducted intensive monitoring of the ADR profile of Nanoxel in comparison with conventional paclitaxel in a public tertiary care set-up.

Materials and Methods:

ADR data were collected from 10 patients receiving Nanoxel and 10 age-matched controls receiving conventional paclitaxel in this longitudinal observational study, conducted in a medical oncology ward over 18 months. Severity was graded as per US National Cancer Institute Common Terminology Criteria for Adverse Events.

Results:

The groups had comparable demography at baseline. The median disease duration and per cycle median dose of paclitaxel were greater in the Nanoxel arm. Total 119 ADRs were noted with Nanoxel and 123 with conventional paclitaxel. Of these, 25 (21.0%, 95% CI 13.69–28.33%) in the Nanoxel and 20 (16.2%, 95% CI 9.74–22.78%) in paclitaxel group were of grade 3/4 severity. Common events included myalgia, nausea, anemia, paresthesia, alopecia, diarrhea, and vomiting with Nanoxel, and paresthesia, anemia, myalgia, anorexia, alopecia, vomiting, diarrhea, stomatitis, and nausea with paclitaxel. Of the less common events (<5%), grade 2 or 3 arthralgia was seen exclusively with Nanoxel while motor neuropathy with muscular weakness was more frequent and severe with conventional paclitaxel. Hypersensitivity reactions were not encountered in either arm, although no antiallergy premedication was employed for Nanoxel.

Conclusions:

Despite its ADR profile being statistically comparable to conventional paclitaxel, this observational study suggests that Nanoxel tolerability could be better, considering that a significantly higher dose was employed. This hypothesis needs confirmation through an interventional study.     

Antidepressant-like activity of anthocyanidins from Hibiscus rosa-sinensis flowers in tail suspension test and forced swim test

Aim:

Flowers of Hibiscus rosa-sinensis Linn (Malvaceae) popularly known as “China-rose flowers” contain flavonoids. Flavonoids have been found to have antidepressant activity. The aim of the present study is to evaluate the antidepressant activity of flavonoids in H. rosa-sinensis flowers with possible involvement of monoamines.

Materials and Methods:

Anti-depressant activity of methanol extract containing anthocyanins (MHR) (30 and 100 mg/kg) and anthocyanidins (AHR) (30 and 100 mg/ kg) of H. rosa-sinensis flowers were evaluated in mice using behavioral tests such as tail suspension test (TST) and forced swim test (FST). The mechanism of action involved in antidepressant activity was investigated by observing the effect of extract after pre-treatment with low dose haloperidol, prazosin and para-chlorophenylalanine (p-CPA).

Results:

Present study exhibited significant decrease in immobility time in TST and FST, similar to that of imipramine (10 mg/kg, i.p.) which served as a positive control. The extract significantly attenuated the duration of immobility induced by Haloperidol (50 μg/ kg, i.p., a classical D₂-like dopamine receptor antagonist), Prazosin (62.5 μg/kg, i.p., an α₁-adrenoceptor antagonist) and p-chlorophenylalanine (100 mg/kg, i.p., × 3 days; an inhibitor of serotonin synthesis) in both TST and FST.

Conclusion:

It can be concluded that MHR and AHR possess potential antidepressant activity (through dopaminergic, noradrenergic and serotonergic mechanisms) and has therapeutic potential in the treatment of CNS disorders and provides evidence at least at preclinical levels.KEY WORDS: Anthocyanidins, dopamine, flavonoids, quercetin, serotonin     

Reduced exposure of imatinib after coadministration with acetaminophen in mice

Purpose:

Imatinib is an efficacious drug against chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST) due to selective inhibition of c-KIT and BCR-ABL kinases. It presents almost complete bioavailability, is eliminated via P450-mediated metabolism and is well tolerated. However, a few severe drug-drug interactions have been reported in cancer patients taking acetaminophen.

Materials and Methods:

Male ICR mice were given 100 mg/kg single dose of imatinib orally or imatinib 100 mg/kg (orally) coadministered with acetaminophen intraperitoneally (700 mg/kg). Mice were euthanized at predetermined time points, blood samples collected, and imatinib plasma concentration measured by HPLC.

Results:

Imatinib AUC_0-12 was 27.04 ± 0.38 mg·h/ml, C_max was 7.21 ± 0.99 mg/ml and elimination half-life was 2.3 hours. Acetaminophen affected the imatinib disposition profile: AUC_0-12 and C_max decreased 56% and 59%, respectively and a longer half-life was observed (5.6 hours).

Conclusions:

The study shows a pharmacokinetic interaction between acetaminophen and imatinib which may render further human studies necessary if both drugs are administered concurrently to cancer patients.     

Rimonabant reduces keratinocyte viability by induction of apoptosis and exerts topical anti-inflammatory activity in mice

BACKGROUND AND PURPOSE

There is growing evidence that the cannabinoid CB₁ receptor antagonist, rimonabant (SR141716) exerts potential anti-proliferative and anti-inflammatory actions. Here, we have assessed the effects of rimonabant in vitro in murine immortalized keratinocytes and in vivo by assaying the topical anti-inflammatory activity.

EXPERIMENTAL APPROACH

Cell viability and death in a keratinocyte cell line (C5N cells) were measured by Trypan blue exclusion assay and cytotoxicity by sulphorhodamine B test. Cell cycle progression was assessed by flow cytometry and the expression of apoptotic and anti-apoptotic markers, cyclins, pathways of signal transduction and CB1 receptor levels were evaluated by Western blot. The topical anti-inflammatory properties of rimonabant were analysed by inhibition of croton oil-induced ear dermatitis in mice.

KEY RESULTS

Rimonabant reduced cell viability and induced apoptosis as shown by the enhanced number of cells in the subG0 phase of the cell cycle, the expression of Bax and reduced levels of Bcl-2 and X-inhibitor of apoptosis protein. In addition, reduced levels of phosphorylated serine/threonine protein kinase Akt and nuclear factor-kappa B were detected associated with regulation of total nuclear factor-kappa B and inhibitor of kappa B-α, phosphorylated inhibitor of kappa B-α, cyclins D1, E and A. In croton oil-induced ear dermatitis, rimonabant significantly reduced oedema and leukocyte infiltrate.

CONCLUSIONS AND IMPLICATIONS

Rimonabant reduced cell viability, inducing cell death in keratinocytes and decreased croton oil-induced ear dermatitis. Our findings suggest a potential application of rimonabant as a topical anti-inflammatory drug. We did not assess the involvement of CB₁ receptors in these effects of rimonabant.