Investigation of in vitro absorption, distribution, metabolism, and excretion and in vivo pharmacokinetics of paromomycin: Influence on oral bioavailability.

OBJECTIVE: The objective of this study is to investigate in vitro Caco2 permeability, metabolism and in vivo pharmacokinetic (PK) properties of paromomycin to develop an efficient dosage form with improved oral bioavailability. MATERIALS AND METHODS: For the purpose, Caco2 permeability assay, mouse microsomal stability assay and in vivo PKs in male BALB/c mice were performed. RESULTS: In Caco-2 permeability assay, paromomycin showed negligible permeability in the apical to basolateral (A-to-B) direction and vice versa (B-to-A). Marginal increase in permeability with the use of P-glycoprotein (P-gp) inhibitor, namely, verapamil suggesting paromomycin could be a P-gp substrate. Paromomycin was unstable in liver microsomes of mouse. Paromomycin showed good PK properties after intravenous dose in male BALB/c mice which included low plasma clearance, i.e., <10% of hepatic blood flow in mice, high volume of distribution (Vd), and half-life (T½) of 2.6 h. Following per oral dose, it exhibits low oral bioavailability (0.3%) with carboxymethyl cellulose formulation. Oral plasma exposure increased in mice by 10% and 15% after pretreatment with P-gp inhibitor verapamil and CYP inhibitor 1-Aminobenztriazole, respectively. CONCLUSION: Comparatively significant increase in oral plasma exposure of paromomycin was observed with an alternative oral formulation approach, use of P-gp and CYP inhibitors resulting in improved oral bioavailability up to 16%.

Neuroprotective and nootropic activity of Clitorea ternatea Linn.(Fabaceae) leaves on diabetes induced cognitive decline in experimental animals.

PURPOSE: Ethanol extract of Clitorea ternatea (EECT) was evaluated in diabetes-induced cognitive decline rat model for its nootropic and neuroprotective activity. MATERIALS AND METHODS: Effect on spatial working memory, spatial reference memory and spatial working-reference memory was evaluated by Y maze, Morris water maze and Radial arm maze respectively. Neuroprotective effects of EECT was studied by assaying acetylcholinesterase, lipid peroxide, superoxide dismutase (SOD), total nitric oxide (NO), catalase (CAT) and glutathione (GSH) levels in the brain of diabetic rats. RESULTS: The EECT (200 and 400 mg/kg) was found to cause significant increase in spatial working memory (P < 0.05), spatial reference memory (P < 0.001) and spatial working-reference (P < 0.001) in retention trials on Y maze, Morris water maze and Radial arm maze respectively. Whereas significant decrease in acetylcholinesterase activity (P < 0.05), lipid peroxide (P < 0.001), total NO (P < 0.001) and significant increase in SOD, CAT and GSH levels was observed in animals treated with EECT (200 and 400 mg/kg) compared to diabetic control group. CONCLUSIONS: The present data indicates that Clitorea ternatea tenders protection against diabetes induced cognitive decline and merits the need for further studies to elucidate its mode of action.

Protective effect of diosmin against diabetic neuropathy in experimental rats.

OBJECTIVE: The present study was undertaken to evaluate the effect of diosmin in diabetic neuropathy in type 2 diabetic rats. METHODS: Type 2 diabetes was induced in male Sprague-Dawley rats by single intraperitoneal injection of streptozotocin (35 mg/kg) and high-fat diet. Four weeks after the confirmation of diabetes, diabetic rats were treated with diosmin (50 and 100 mg/kg, p.o.) for next 4 weeks. Rats were evaluated for biochemical, behavioral and oxidative stress parameters. Eddy's hot plate and tail immersion test were performed on 6th, 7th, 8th, 9th and 10th weeks of experiment to assess thermal hyperalgesia and cold allodynia respectively. Further, the walking function test was performed for assessing the motor responses at the end of the treatment schedule. RESULTS: Rats were fed with high-fat diet throughout the experiment schedule and administration of low-dose streptozotocin induced significant elevation in blood glucose level and insulin resistance which was confirmed by oral glucose tolerance test. Treatment with diosmin at doses of 50 and 100 mg/kg significantly restored the reduced body weight, elevated blood sugar and lipid profiles. Further the dose-dependent improvement was observed in thermal hyperalgesia, cold allodynia and walking function in diabetic rats treated with diosmin. Elevated levels of malondialdehyde, and nitric oxide and decreased glutathione levels and superoxide dismutase activity in diabetic rats were restored significantly after the 4 weeks of diosmin treatment. CONCLUSION: Diosmin has shown beneficial effect in preventing the progression of early diabetic neuropathy in rats.

Protective effect of diosmin against diabetic neuropathy in experimental rats / 中西医结合学报

The present study was undertaken to evaluate the effect of diosmin in diabetic neuropathy in type 2 diabetic rats.

Antihyperglycemic and antioxidant activity of Clitorea ternatea Linn. on streptozotocin-induced diabetic rats.

Ethanol extract of Clitorea ternatea Linn. (EECT) was evaluated for its antihyperglycemic and antioxidative activity in normal and streptozotocin-induced diabetic rats. Antihyperglycemic activity of EECT was studied in normal fasted and glucose fed hyperglycemic and epinephrine induced hyperglycemic rats by estimating fasting serum glucose (FSG) by glucose oxidisae or peroxidase enzymatic method. Antioxidant activity of EECT was studied by assaying lipid peroxide/Thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), total nitric oxide, catalase (CAT) and glutathione levels in diabetic rats. The EECT (200 and 400 mg/kg) showed significant antihyperglycemic activity by decreasing FSG in all hyperglycemic models except epinephrine induced hyperglycemic rats; in which improvement in FSG was observed only with EECT in 400 mg/kg dose, whereas significant decrease in TBARS (P < 0.001), nitric oxide (P < 0.001) and significant increase in SOD (P < 0.001), CAT (P < 0.01) and reduced glutathione levels (P < 0.001) was observed in animals treated with EECT (200 and 400 mg/kg) compared to diabetic control group. The results indicated that EECT has remedial effects on hyperglycemia and oxidative stress in diabetic rats.

Proteomic analysis of glycated proteins from streptozotocin-induced diabetic rat kidney.

Glycation of proteins leading to formation of advanced glycation end products (AGEs) has been considered as one of the important causes of diabetic nephropathy. Therefore, in this study, glycated proteins were detected by anti-AGE antibodies from kidney of streptozotocin-induced diabetic rat showing nephropathic symptoms, by using two dimensional electrophoresis and western blot analysis. These glycated proteins were identified and characterized by using combination of peptide mass finger printing and tandem mass spectrometric approaches. Glycated proteins identified included proteins from metabolic pathways, oxidative stress, cell signaling, and transport. Several of the proteins modified by glycation were involved in glucose metabolism. The extent of glycation was higher in diabetes compared to control, in the glycated proteins that were common to both control and diabetic kidney. Two dimensional electrophoresis proteins profiling of glycated proteins suggest that four of the glycated proteins were significantly up regulated in diabetes.

Effect of aqueous extracts of Achyranthes aspera Linn. on experimental animal model for inflammation.

BACKGROUND: Achyranthes aspera is known as Chirchita (Hindi), Apamarga (Sanskrit), Aghedi (Gujarati), Apang (Bengali), Nayurivi (Tamil), Kalalat (Malyalam) and Agadha (Marathi) in our country. It possesses valuable medicinal properties and used in treatment of cough, bronchitis and rheumatism, malarial fever, dysentery, asthma, hypertension and diabetes in Indian folklore. Present study was designed to evaluate anti-inflammatory activity of an aqueous extracts of Achyranthes aspera (AEAA). MATERIALS AND METHODS: AEAA leaves and whole plant (i.e. Aqueous extracts of Achyranthes aspera leaves (AEAAL)/Aqueous extracts of A. aspera whole plant (AEAAW) were studied in albino mice using carrageenan induced left hind paw edema. Both extracts were subjected to preliminary phytochemical analysis and acute toxicity of the extracts was also studied using Organization for Economic Co-operation and Development OECD guidelines 423. RESULTS: Acute toxicity study confirmed toxic dose of AEAA to be more than 2,000 mg/kg. Flavonoids, alkaloids, saponins and triterpenoids were the major constituents found in extracts. AEAA reduced the edema induced by carrageenan by 35.71-54.76% on intraperitoneally administration of 400 mg/kg and 800 mg/kg as compared to the untreated control group. Diclofenac sodium at 10 mg/kg inhibited the edema volume by 42.85%. The results indicated that the AEAA 800 mg/kg body weight shows more significant (P < 0.01, P < 0.001) anti-inflammatory activity when compared with the standard and untreated control respectively. CONCLUSION: Both AEAA exhibit promising anti-inflammatory activity attributed to flavonoids, alkaloids, saponins and triterpenoids phytoconstituents.

Hepatoprotective activity of Symplocos racemosa bark on carbon tetrachloride-induced hepatic damage in rats.

The present study aims to evaluate the hepatoprotective activity of ethanol extract of Symplocos racemosa (EESR) bark on carbon tetrachloride (CCl4)-induced hepatic damage in rats. CCl4 with olive oil (1 : 1) (0.2 ml/kg, i.p.) was administered for ten days to induce hepatotoxicity. EESR (200 and 400 mg/kg, p.o.) and silymarin (100 mg/kg p.o.) were administered concomitantly for fourteen days. The degree of hepatoprotection was measured using serum transaminases (AST and ALT), alkaline phosphatase, bilirubin, albumin, and total protein levels. Metabolic function of the liver was evaluated by thiopentone-induced sleeping time. Antioxidant activity was assessed by measuring liver malondialdehyde, glutathione, catalase, and superoxide dismutase levels. Histopathological changes of liver sample were also observed. Significant hepatotoxicity was induced by CCl4 in experimental animals. EESR treatment showed significant dose-dependent restoration of serum enzymes, bilirubin, albumin, total proteins, and antioxidant levels. Improvements in hepatoprotection and morphological and histopathological changes were also observed in the EESR treated rats. It was therefore concluded that EESR bark is an effective hepatoprotective agent in CCl4-induced hepatic damage, and has potential clinical applications for treatment of liver diseases.

Study of central nervous system depressant and behavioral activity of an ethanol extract of Achyranthes aspera (Agadha) in different animal models.

BACKGROUND: Achyranthes aspera Linn., an indigenous herb, has been reported to have antifertility, antihyperlipidemic, antidiabetic, immunomodulatory, anticarcinogenic, diuretic, cardiotonic, analgesic anti-inflammatory, hypnotic, antifungal, antibacterial, and central antinociceptive activities. AIMS: This study was designed to evaluate depressant effects on central nervous system (CNS) and behavioral effects of ethanol extract of A. aspera (EEAA) and to find the phytochemical responsible for these activities. MATERIALS AND METHODS: The pharmacological assays used to study CNS depressant effect in albino mice were rota rod and actophotometer performance test. Effects on behavioral activity were studied using open field test. The extract was given intraperitoneally (i.p.) at a dose of 400 mg/kg. Diazepam (2 mg/kg body weight i.p.) was used as standard. STATISTICAL ANALYSIS USED: Data were analyzed by using analysis of variance followed by Dunnett's test. P < 0.05 was considered significant. RESULTS: Phytochemical screening revealed presence of triterpenoids, saponins, alkaloids (betaine, achyranthine), and steroids as major constituents. The result of this study reflected that EEAA (400 mg/kg i.p.) decreased locomotor activity, produced muscle relaxation, and showed anxiolytic activity. CONCLUSIONS: EEAA exhibit CNS depressant and significant anxiolytic activity comparable to diazepam.

The biology and chemistry of hyperlipidemia.

Coronary arterial diseases are responsible for more deaths than all other associated causes combined. Elevated serum cholesterol levels leading to atherosclerosis can cause coronary heart disease (CHD). Reduction in serum cholesterol levels reduces the risk for CHD, substantially. Medicinal chemists all around the world have been designing, synthesizing, and evaluating a variety of new bioactive molecules for lowering lipid levels. This review summarizes the disorders associated with elevation of lipids in blood and the current strategies to control them. The emphasis has been laid in particular on the new potential biological targets and the possible treatments as well as the current ongoing research status in the field of lipid lowering agents.

Antidiabetic potential of Butea monosperma in rats.

The antihyperglycemic activity of the ethanolic extract of Butea monosperma (BMEE) was studied in glucose-loaded and alloxan-induced diabetic rats. Single dose treatment of BMEE (200 mg/kg, p.o.) significantly improved glucose tolerance and caused reduction in blood glucose level in alloxan-induced diabetic rats. Repeated oral treatment with BMEE (200 mg/kg/day) for 2 weeks significantly reduced blood glucose, serum cholesterol and improved HDL-cholesterol and albumin as compared to diabetic control group.