Novel Aryl-bis-quinolines with Antimalarial Activity In-vivo

Three rationally designed isomeric aryl-bridged bis-quinolines, N¹,N^x-bis(7-chloroquinolin-4-yl)phenylene-1,x-diamines, where x = 2, 3 or 4, i.e. o-, m- and p-substituted analogues respectively, were synthesized and evaluated against Plasmodium berghei in-vivo. The compound with x = 2 had an ID50 of 30 mg kg^?1, whereas the p-substituted analogue (x = 4) was not statistically schizonticidal at either of the two dose levels tested in olive oil-dimethylsulphoxide (5 and 25 mg kg^?1, ID50 = 60 mg kg^?1 approx.). When the delivery vehicle was changed to saline-DMSO, antimalarial potency increased for the p-substituted compound (ID50 17mg kg^?1). In contrast, the m-substituted analogue had marked antimalarial activity (ID50 1.2 mg kg^?1), which compares favourably with that of chloroquine diphosphate (ID50 = 4.3 mg kg^?1). The data presented show that the amino-methylene side chain in amodiaquine can be successfully replaced by a 7-halo-4-aminoquinoline, establishing that carbon bridges containing less than four contiguous carbon atoms can be present within highly active aryl-substituted 4-aminoquinoline antimalarials. These results confirm that the presence of an OH group in the aryl bridge is not necessary for antimalarial activity and substantiate the view that, despite the appearance of resistant strains, new and existing aminoquinolines still have an important role in treating malaria.     

Do antidiarrhoeal opiates accumulate in the rat intestinal lumen?

Abstract— The opiate antidiarrhoeal drugs loperamide (0·6 mg kg^?1, i.p.) or difenoxin (0·77 mg kg^?1, s.c), were administered in an anaesthetic mixture (pentobarbitone 60 mg kg^?1) to rats. A length of jejunum (approx. 30 cm) was cannulated, washed and then perfused with iso-osmotic saline for 20 min. The perfusion commenced 50 min after drug administration and continued for 20 min. The perfusates were collected for analysis of fluid transport rates and antidiarrhoeal drug content. These doses of the antidiarrhoeals caused marked inhibition of intestinal fluid secretion induced by intra-arterial infusion of vasoactive intestinal peptide. However, neither of the antidiarrhoeal drugs were detected in the intestinal perfusates (< 0·5 ng by HPLC). The results indicate that loperamide and difenoxin have a different pharmacokinetic profile compared with that previously found for morphine under the same conditions.     

Evaluation of antinociceptive and antidiarrhoeal properties of Manilkara zapota leaves in Swiss albino mice

Context Manilkara zapota (L.). P. Royen. (Sapotaceae) has been used in folk medicine to treat pain, diarrhoea, inflammation, arthralgia, and other disorders.

Objective Screening of Manilkara zapota leaves ethanol extract and its different solvent soluble fractions for possible antinociceptive and antidiarrhoeal activities in Swiss albino mice.

Materials and methods The extract and various fractions (200 and 400?mg/kg body weight; p.o.) were tested for peripheral and central antinociceptive activity by acetic acid-induced writhing and radiant heat tail-flick method, respectively; castor oil-induced diarrhoeal model was used to evaluate antidiarrhoeal activity at both doses. All the samples were administered once in a day and the duration of study was approximately 5?h.

Results Ethanol extract (400?mg/kg), petroleum ether fraction (400?mg/kg), and ethyl acetate fraction (400?mg/kg) showed significant peripheral antinociceptive activity having 59.89, 58.24, and 46.7% (p?<?0.001) of writhing inhibition, respectively, which is comparable with that of standard diclofenac (59.34% inhibition). The ethanol extract (400?mg/kg) and petroleum ether fraction (400?mg/kg) also showed promising central analgesic activity having 74.15 and 82.15% (p?<?0.001) elongation of reaction time, respectively, at 90?min after administration of sample which is also similar to that obtained by morphine (85.84% elongation). In antidiarrhoeal activity screening, ethanol extract (200 and 400?mg/kg) showed significant inhibition of defecation by 53.57 and 60.71%, respectively (p?<?0.001) compared with that of loperamide (71.42%).

Discussion and conclusion The findings of the studies demonstrated antinociceptive and antidiarrhoeal activities of M. zapota leaves which could be the therapeutic option against pain and diarrhoeal disease.     

Anti-diabetic activity of Emblica officinalis in animal models

The aqueous extract of Emblica officinalis Gaertn. (syn: Phyllanthus emblica L.) (Euphorbiaceae) seeds was investigated for its anti-diabetic activity in animal models. Streptozotocin (STZ)-induced type 2 diabetes models were used for the study. The standardized doses of 100, 200, 300, and 400?mg kg^?1 body weight of the extract were administered orally to normal and diabetic rats in order to define its glycemic potential. The maximum fall of 27.3% (p?<?0.001) in the blood glucose level of normal rats was observed at 6?h during fasting blood glucose studies, with the dose of 300?mg kg^?1 identified as the most effective dose. The same dose produced a fall of 25.3% (p?<?0.001) in the same models during the glucose tolerance test (GTT) at 3?h after glucose administration. However, the dose of 300?mg kg^?1 of aqueous seed extract in sub- and mild-diabetic animals produced a maximum fall of 34.1 and 41.6% (p?<?0.01), respectively, during the GTT at 3?h after glucose administration. This evidence clearly indicates that the aqueous extract of E. officinalis seeds has definite hypoglycemic potential as well as anti-diabetic activity.     

Acute toxicity of some nerve agents and pesticides in rats

Objectives: Highly toxic organophosphorus compounds (V- and G-nerve agents) were originally synthesized for warfare or as agricultural pesticides. Data on their acute toxicity are rare and patchy. Therefore, there is a need for integrated summary comparing acute toxicity of organophosphates using different administration routes in the same animal model with the same methodology. Based on original data, a summary of in vivo acute toxicity of selected V- and G-nerve agents (tabun, sarin, soman, VX, Russian VX) and organophosphates paraoxon (POX) and diisopropyl fluorophosphate (DFP) in rats has been investigated. Materials and methods: Male Wistar rats were exposed to organophosphates in several administration routes (i.m., i.p., p.o, s.c., p.c.). The acute toxicity was evaluated by the assessment of median lethal dose (LD₅₀, mg?kg^?1) 2, 4, and 24 hours post exposure. Results: V-agents were the most toxic presented with LD₅₀ ranged from 0.0082?mg?kg^?1 (VX, i.m.) to 1.402?mg?kg^?1 (Russian VX, p.o.), followed by G-agents (LD₅₀?=?0.069?mg?kg^?1/soman, i.m./ – 117.9?mg?kg^?1/sarin, p.c./), organophosphate POX and DFP (LD₅₀?=?0.321?mg?kg^?1/POX, i.m./ – 420?mg?kg^?1/DFP, p.c./). Generally, i.m. administration was the most toxic throughout all tested agents and ways of administration (LD₅₀?=?0.0082?mg?kg^?1/VX/ – 1.399?mg?kg^?1/DFP/) whereas p.c. way was responsible for lowest acute toxicity (LD₅₀?=?0.085?mg?kg^?1/VX/ – 420?mg?kg^?1/DFP/). Conclusion: The acute toxicity of selected organophosphorus compounds is summarized throughout this study. Although the data assessed in rats are rather illustrative prediction for human, it presents a valuable contribution, indicating the toxic potential and harmfulness of organophosphates.     

Pharmacokinetics and first-pass effects of ϵ-acetamidocaproic acid after administration of zinc acexamate in rats

1. Zinc acexamate (ZAC) is ionized to zinc and ?-acetamidocaproic acid (AACA). Thus, the pharmacokinetics and tissue distribution of zinc and AACA after intravenous (50?mg kg^?1) and oral (100?mg kg^?1) administration of ZAC were evaluated in rats. Also the pharmacokinetics of AACA after intravenous (10, 20, 30, and 50?mg kg^?1) and oral (20, 50, and 100?mg kg^?1) administration of ZAC and the first-pass extractions of AACA at a ZAC dose of 20?mg kg^?1 were evaluated in rats.

2. After oral administration of ZAC (20?mg kg^?1), approximately 0.408% of the oral dose was not absorbed, the F value was approximately 47.1%, and the hepatic and gastrointestinal (GI) first-pass extractions of AACA were approximately 8.50% and 46.4% of the oral dose, respectively. The incomplete F value of AACA was mainly due to the considerable GI first-pass extraction in rats.

3. Affinity of rat tissues to zinc and AACA was low—the tissue-to-plasma (T/P) ratios were less than unity. The equilibrium plasma-to-blood cells partition ratios of AACA were independent of initial blood ZAC concentrations of 1, 5, and 10?µg ml^?1—the mean values were 0.481, 0.490, and 0.499, respectively. The bound fractions of zinc and AACA to rat plasma were 96.6% and 39.0%, respectively.

     

In vivo anti-inflammatory properties of aerial parts of Nasturtium officinale

Context: Nasturtium officinale R. Br. (watercress) has long been used in Iranian folk medicine to treat hypertension, hyperglycemia, and renal colic. Moreover, anticancer, antioxidant, and hepatoprotective properties of N. officinale have been reported.

Objective: In this study, anti-inflammatory activity of the hydro-alcoholic extract from aerial parts of N. officinale was investigated.

Materials and methods: Oral administration of the hydro-alcoholic extract of N. officinale (250, 500 and 750?mg?kg^?1) was investigated on two well-characterized animal models of inflammation, including carrageenan- or formalin-induced paw edema in rats. Then, the topical anti-inflammatory effect of N. officinale (2 and 5?mg/ear) was studied on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema. Finally, biopsy of the paw or ear was performed for pathological evaluation.

Results: Acute toxicity tests of N. officinale in rats established an oral LD₅₀ of >5?g?kg^?1. The extract of watercress (250, 500 and 750?mg?kg^?1) significantly inhibited carrageenan-induced paw edema 1, 2, 3 and 4?h after carrageenan challenge (p??1) also showed considerable activity against formalin-evoked paw edema over a period of 24?h (p?N. officinale (5?mg/ear) reduced TPA-induced ear edema (p?Discussion and conclusion: Our findings indicate potent anti-inflammatory activity of N. officinale in systemic and topical application and propose its potential as an anti-inflammatory agent for treatment of inflammatory conditions.     

Influence of 1,8-dihydroxyanthraquinone and loperamide on the paracellular permeability across colonic mucosa

Administration of 1,8-dihydroxyanthraquinone (DHA) markedly increases the permeability of guinea-pig colonic mucosa. In 1 h 25% of the administered dose of^99m Tc-EDTA complex leaks through the mucosa. Orally administered loperamide blocks the^99m Tc-EDTA transfer after DHA administration. Loperamide injected in situ in the ligated colon segment shows the same blocking properties of the transfer rate of the complex. These findings suggest that the opposing action on fluid transport of the laxative DHA and the antidiarrhoeal loperamide could be due to these drugs affecting the permeability of the colonic mucosa. The minimal dose of loperamide, able to restore normal permeability, was as low as 0·01 mg kg^?1.     

Evaluation of the anti-inflammatory activity of N,N′-bis(3-dimethylamino-1-phenyl-propylidene)hydrazine dihydrochloride

This study investigated the anti-inflammatory effect of N, N′-bis(3-dimethylamino-1-phenyl-propylidene)hydrazine dihydrochloride, D1, on carrageenan-induced edema. In addition, its effect on hyaluronidase-induced vascular permeability was also tested. D1 was synthesized, and anti-inflammatory activity was determined by carrageenan-induced hind paw edema in rats (n?=?30) at 50, 100, and 200?mg kg^?1 doses of D1 and also a 25?mg kg^?1 dose of indomethacin. The effects of D1 and indomethacin on hyaluronidase-induced capillary permeability were investigated in rabbits (n?=?18) at a 100?mg kg^?1 dose of D1 and 25?mg kg^?1 dose of indomethacin. D1 inhibited carrageenan-induced inflammation by 40, 20, and 10% at 50, 100, and 200?mg kg^?1 doses after 1?h. The inhibitions were 22.5, 32.7, 28.6% and 15.6, 33.4, 8.9% at 2?h and 3?h, respectively. The inhibitions due to indomethacin (25?mg kg^?1 dose) were 67.5, 87.8, and 91.1%, at 1?h, 2?h, and 3?h, respectively. The subcutaneous spreading areas of Trypan blue at 1, 5, 30, and 60?min after subcutaneous injection of hyaluronidase were 172.6?±?41.6, 210.2?±?39.7, 363?±?50, and 400.2?±?46.7?mm² in the D1 (100?mg kg^?1) treated group. The spreading areas at these time periods were 38.8?±?3.7, 48.2?±?4.5, 100.6?±?6.9, and 119.8?±?22.5?mm² in the indomethacin treated group. Our results showed that D1 inhibits carrageenan-induced inflammation in rats. A tendency to decrease the capillary permeability suggested that the mechanism of action of the anti-inflammatory effect of D1 may partly depend on inhibition of the hyaluronidase enzyme.     

Synthesis and pharmacological activity of 2-(substituted)-3-{2-[(4-phenyl-4-cyano)piperidino]ethyl}-1,3-thiazolidin-4-ones

Loperamide is a well-known peripherally acting opiate used for the treatment of diarrhoea. To gain more knowledge on the structure-activity relationships of antidiarrhoeal drugs and to develop new active molecules, a series of aryl-cyano-piperidinoalkyl-thiazolidinones related to Loperamide was synthesized and screened for antidiarrhoeal activity in mice by castor oil test. To characterize the potency and toxicity of the synthesized compounds ED50 and LD50 values were also determined. The thiazolidinones 2-6 displayed antidiarrhoeal activity at doses ranging between 15 and 82 mg/kg. Although the results show that the synthesized compounds are 15- to 80-fold less active respect to the reference compound, Loperamide, they are much less toxic (> or = 1000 mg/kg and 108.9 mg/kg, respectively). Besides, to evaluate the involvement of opioid receptors in antidiarrhoeal activity, Naloxone was administered prior to test the 2-phenyl-3-{2-[(4-phenyl-4-cyano)piperidino]ethyl}-1,3-thiazolidin-4-one (2), the more active compound of this series. The results obtained by this study, suggest that the antidiarrhoeal activity of this series of thiazolidinone derivatives could involve the opioid receptors.     

Metabolism of 3-chloro-4-fluoroaniline in rat using [14C]-radiolabelling, 19F-NMR spectroscopy,HPLC-MS/MS,HPLC-ICPMS and HPLC-NMR

The metabolic fate of 3-chloro-4-fluoroaniline was investigated in rat following intraperitoneal (i.p.) administration at 5 and 50?mg?kg^?1 using a combination of HPLC-MS, HPLC-MS/MS, ¹⁹F-NMR spectroscopy, HPLC-NMR spectroscopy and high-pressure liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICPMS) with ³⁵Cl and ³⁴S detection. The metabolism of 3-chloro-4-fluoroaniline at both doses was rapid and extensive, to a large number of metabolites, with little unchanged compound excreted via the urine. Dosing at 5?mg?kg^?1 with [¹⁴C]-labelled compound enabled the comparison of standard radioassay analysis methods with ¹⁹F-NMR spectroscopy. ¹⁹F-NMR resonances were only readily detectable in the 0–12?h post-dose samples. Dosing at 50?mg?kg^?1 allowed the facile and specific detection and quantification of metabolites by ¹⁹F-NMR spectroscopy. Metabolite profiling was also possible at this dose level using HPLC-ICPMS with ³⁵Cl-specific detection. The principal metabolites of 3-chloro-4-fluoroaniline were identified as 2-amino-4-chloro-5-fluorophenyl sulfate and 2-acetamido-4-chloro-5-fluorophenyl glucuronide. N-acetylation and hydroxylation followed by O-sulfation were the major metabolic transformations observed.     

The peripheral NK-1/NK-2 receptor antagonist MDL 105,172A inhibits tachykinin-mediated respiratory effects in guinea-pigs

1 Stimulation of sensory nerves causes release of tachykinins, including substance P (SP) and neurokinin A (NKA), which produce a variety of respiratory effects via NK-1 and NK-2 receptors, respectively. Hence, development of a compound which could potently and equivalently antagonize both receptors was pursued. 2 MDL 105,172A ((R)-1-[3-(3,4-dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-3-pyrrolidinyl]-4-phenyl-piperidine-4-morpholinecarboxamide) exhibited high affinity for NK-1 (4.34 nm ) and NK-2 (2.05 nm ) receptors. In vitro, the compound antagonized SP (pA₂ = 8.36) or NKA (pA₂ = 8.61)-induced inositol phosphate accumulation in tachykinin monoreceptor cell lines. 3 In anaesthetized guinea-pigs, MDL 105,172A inhibited SP-induced plasma protein extravasation (ED₅₀ = 1 mg kg^?1, i.v.) and [β-Ala⁸]NKA 4–10-induced bronchoconstriction (ED₅₀ = 0.5 mg kg^?1, i.v.) indicating NK-1 and NK-2 antagonism, respectively. 4 Capsaicin was used to elicit respiratory effects in anaesthetized and conscious guinea-pigs; the latter were inhibited by MDL 105,172A following i.v. (ED₅₀ = 1 mg kg^?1) or oral (ED₅₀ = 20 mg kg^?1) adminstration. Hence, MDL 105,172A can inhibit pulmonary responses to tachykinins released endogenously in the airways. 5 At doses up to 200 mg kg^?1, p.o., MDL 105,172A failed to inhibit repetitive hind paw tapping induced by i.c.v. GR 73632, an NK-1 selective agonist, in gerbils, whereas CP-99,994 (0.87 mg kg^?1, s.c.) completely ablated the effect. These data suggest that MDL 105,172A does not penetrate the central nervous system (CNS) and its tachykinin antagonism is restricted to the periphery. 6 MDL 105,172A is a non-peptide, potent, equivalent antagonist of NK-1 and NK-2 receptors. Its ability to inhibit both exogenously administered as well as endogenously released tachykinins support its use in examining the role of sensory neuropeptides in diseases associated with neurogenic inflammation including asthma.     

Effects of Two N-arylpiperazinylmethylpyrazolo [1,5-d][1,2,4]triazine Derivatives in Pain and Antidepressant Tests in Mice

The antinociceptive and antidepressant effects of two pyrazolotriazine derivatives, 2-phenyl-3,3α-dihydro-4-oxo-5-(4-phenylpiperazin-1-yl)methyl-pyrazolo[1,5-d][1,2,4]-triazine (SMI) and 2-phenyl-3,3α-dihydro-4-oxo-5-[4-(4-fluorophenyl)piperazin-1-yl]methylpyrazolo[1,5-d][1,2,4] triazine (SM3) have been investigated in mice using classical pharmacological tests. The intraperitoneal LD50 values of SMI and SM3 were 253.4 and 218.8 mg kg^? respectively. SMI and SM3 showed analgesic properties in the phenylbenzoquinone-induced abdominal constriction test (ED50 ? 10–15 mgkg^?, i.p.) and in the hot-plate test. The antinociceptive effects of the triazines were significantly reduced by administration of naloxone (1 and 3.2 mgkg^?, s.c.) and yohimbine (1 mgkg^?, p.o.). Acute intraperitoneal administration of both compounds (1 mgkg^? SMI or 1.5 mgkg^? SM3) potentiated morphine (0.15 mgkg^?, s.c.) analgesia in the phenylbenzoquinone test. Although this synergistic activity was not reversed by methysergide (0.5 mgkg^?, i.p.), the analgesic activity of both compounds was enhanced by administration of 5-hydroxytryptophan (50 mgkg^?, i.p.) in conjunction with carbidopa (25 mgkg^?, i.p.). Furthermore, neither compound (at 100 mgkg^?, i.p.) significantly reduced the duration of immobility of mice in the forced swimming test, and both (at 75 mgkg^?, i.p.) were ineffective at enhancing the toxic effects of yohimbine (30 mgkg^?, s.c). Only SM3 (ED50 = 74.5 mgkg^?, i.p.) significantly antagonized reserpine (2.5 mgkg^?, i.p.)-induced ptosis. Thus, the results suggest that SMI and SM3 have antinociceptive properties related to co-involvement of opioidergic and α₂-adrenoceptor mechanisms without associated antidepressant properties.     

Pharmacokinetic profiles of glycyrrhizin in patients with chronic hepatitis

The pharmacokinetics of glycyrrhizin (G) in eight patients with chronic hepatitis receiving chronically i.v. administration of 120 mg dose of G was investigated. The plasma concentration of G in the patients after dosing declined in a monophasic manner. However, the pharmacokinetic profiles varied among patients. The mean elimination half-life (t_1/2) and the total body clearance (CL_tot) were 6.0 h (range 4.3–10.7 h) and 7.9 ml h^?1 kg^?1 (4.5–12.7 ml h^?1 kg^?1), respectively. The variation of the CL_tot for G was closely related to that of aspartate aminotransferase (r = ?0.739, p <0.05) and alanine aminotransferase (r = ?0.783, p <0.05) activities in the plasma.     

Preclinical assessment of the ADME,efficacy and drug-drug interaction potential of a novel NAMPT inhibitor

1. GNE-617 (N-(4-((3,5-difluorophenyl)sulfonyl)benzyl)imidazo[1,2-a]pyridine-6-carboxamide) is a potent, selective nicotinamide phosphoribosyltransferase (NAMPT) inhibitor being explored as a potential treatment for human cancers.

2. Plasma clearance was low in monkeys and dogs (9.14?mL min^?1?kg^?1 and 4.62?mL min^?1?kg^?1, respectively) and moderate in mice and rats (36.4?mL min^?1?kg^?1 and 19.3?mL min^?1?kg^?1, respectively). Oral bioavailability in mice, rats, monkeys and dogs was 29.7, 33.9, 29.4 and 65.2%, respectively.

3. Allometric scaling predicted a low clearance of 3.3?mL min^?1?kg^?1 and a volume of distribution of 1.3?L kg^?1 in human.

4. Efficacy (57% tumor growth inhibition) in Colo-205 CRC tumor xenograft mice was observed at an oral dose of 15?mg/kg BID (AUC?=?10.4?µM h).

5. Plasma protein binding was moderately high. GNE-617 was stable to moderately stable in vitro. Main human metabolites identified in human hepatocytes were formed primarily by CYP3A4/5. Transporter studies suggested that GNE-617 is likely a substrate for MDR1 but not for BCRP.

6. Simcyp^® simulations suggested a low (CYP2C9 and CYP2C8) or moderate (CYP3A4/5) potential for drug-drug interactions. The potential for autoinhibition was low.

7. Overall, GNE-617 exhibited acceptable preclinical properties and projected human PK and dose estimates.

     

Testing of different plants to determine influence of physico–chemical properties and contaminants content on municipal sewage sludges phytotoxicity

This study attempts to evaluate the Phytotoxkit? as a tool for measuring the toxicity of municipal sewage sludges using 10 common plants: mustard, turnip, cress, red clover, cucumber, tomato, radish, sorrel, and spinach. The results were used to determine a germination index (GI) and a median effective concentration (EC) value for each plant. The trace metal and polycyclic aromatic hydrocarbon (PAH) contaminant content and the physical–chemical properties were examined. Most sewage sludges were characterized by an unfavorable electrical conductivity value of about 5.2 mS/cm^?1. The most abundant trace metals were zinc (Zn) at 871–1680 mg kg^?1, manganese (Mn) at 245–661 mg kg^?1, and copper (Cu) at 88.2–161.0 mg kg^?1. The lowest values were determined for cobalt (Co) at 2.9–3.8 mg kg^?1 and cadmium (Cd) at 0.7–3.7 mg kg^?1. The PAH sum was based on 10 individual compounds (USE EPA), and the PAH content ranged from 4.76 to 27.95 mg kg^?1, most of the sewage sludges showing a predomination by carcinogenic PAHs. The GI values, based on seed germination and root growth inhibition bioassays, showed increasing plant sensitivity to the tested sewage sludges in the following order: cress > turnip > mustard > sorrel > tomato > sorgo > red clover > radish > cucumber > spinach. The EC50 sewage sludge values lay in the range 31–404 g/kg of soil, and significant relationships were found for most of the plants between EC50 and the magnesium content (Mg²⁺: α = 0.888–0.924, P = 0.05), calcium content (Ca²⁺: α = 0.813–0.911, P ≤ 0.05), and pH (α = ?0.913–0.948, P = 0.05). In the case of sewage sludge pollutants, significant relationships were found for trace metals such as: strontium (Sr: α = 0.851–0.948, P ≤ 0.05), chromium (Cr: α = 0.858, P ≤ 0.05), and nickel (Ni: α = 0.955, P = 0.05), as well as pyrene (PAHs). © 2009 Wiley Periodicals, Inc. Environ Toxicol, 2010.     

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.     

Analgesic activity of Eugenia jambolana leave constituent: A dikaempferol rhamnopyranoside from ethyl acetate soluble fraction

Context: Eugenia jambolana Lam. (Myrtaceae) is a medicinal plant used in folk medicine for the treatment of diabetes, inflammation, and pain.

Objective: We investigated the antinociceptive effect of kaempferol-7-O-α-l-rhamnopyranoside]- 4′-O-4′-[kaempferol-7-O-α-l-rhamnopyranoside (EJ-01), isolated from the E. jambolana leaves.

Materials and methods: EJ-01 (3, 10, and 30?mg?kg^?1, orally) was assessed for peripheral (formalin-nociception and acetic acid-writhing) and central (hot plate and tail flick test) analgesic activity in mice and the in vitro anti-inflammatory activity (25, 50, and 100?µg?mL^?1) in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells.

Results and discussion: EJ-01 (10 and 30?mg?kg^?1) significantly inhibited mean writhing counts (37.74 and 36.83) in acetic acid writhing and paw licking time (55.16 and 45.66?s) in the late phase of the formalin test as compared with the respective control (60.66 and 104.33?s). EJ-01 did not show analgesic activity in central pain models. Significant reduction in the tumor necrosis factor (TNF)-α (295.48, 51.20, and 49.47?pg?mL^?1) and interleukin (IL)-1β (59.38, 20.08, and 15.46?pg?mL^?1) levels were observed in EJ-01-treated medium (25, 50, and 100?µg?mL^?1) as compared with vehicle-treated control values (788.67 and 161.77?pg?mL^?1), respectively. Significant reduction in total nitrite plus nitrate (NO_x) levels (70.80?nmol) was observed in the EJ-01-treated medium (100?µg?mL^?1) as compared with the vehicle-treated value (110.41?nmol).

Conclusion: EJ-01 is a valuable analgesic constituent of E. jambolana leaves and this study supports the pharmacological basis for the use of this plant in traditional medicine for curing inflammatory pain.     

Pharmacological Activity of DC−015, a Novel Potent and Selective α1-Adrenoceptor Antagonist

The pharmacological activity of 3?((4?(2?methoxyphenyl)piperazin?1?yl)methyl)?2,3?dihydroimidazo(1,2?c)quinazolin?5(6H)-one (DC?015), a newly synthesized quinazoline derivative, was determined in rat isolated thoracic aorta and pressor responses were determined in spontaneously hypertensive rats (SHR). Experimental results indicated that DC?015 is an α₁-adrenoceptor-blocking agent in rat thoracic aorta as revealed by its competitive antagonism of phenylephrine-induced vasocontraction (pA₂ = 10m?54 ± 0m?55). These effects still persisted in denuded aorta. It was as potent as prazosin (pA₂ = 10m?04 ± 0m?63). At higher concentrations (1m?0 μM), DC?015 also expressed 5?hydroxytryptamine (5?HT) receptor competitive antagonism, but this 5?HT blocking effect was not found in the prazosin-administration group. [³H]Inositol monophosphate formation stimulated by phenylephrine (30 μM) in rat thoracic aorta was diminished by DC?015 (3 and 10 nM) and prazosin (10 nM); whereas the cAMP content of rat thoracic aorta was not altered by DC?015 and prazosin. Furthermore, intravenous administration of DC?015 and prazosin (both at 0m?01, 0m?05 and 0m?1 mg kg¹¹) induced a dose-dependent reduction of mean arterial pressure which reached a maximal effect at 5 min after injection and persisted over 2 h in SHR. A higher dose of DC?015 (0m?1 mg kg^?1, i.v.) did not cause any significant changes in heart rate, whereas, the same dose of prazosin (0m?1 mg kg^?1, i.v.) produced a decrease which seems to parallel the time course of the hypotensive response. We can conclude that the DC?015 is a potent, highly selective α₁-adrenoceptor antagonist in vascular smooth muscle.