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Potentiation of antitumor effect of cyclophosphamide and hydrazine sulfate by treatment with the antidiabetic agent, 1-phenylethylbiguanide (phenformin).

It was shown that 1-phenylethylbiguanide (phenformin) administered orally to mice at a dose of 2 mg/day potentiated the antitumor effect of cyclophosphamide on transplantable squamous cell cervical carcinoma, hepatoma-22a and Lewis lung tumor, but did not alter the effect of cyclophosphamide on sarcoma-180 and L-1210. Oral administration of phenformin (5 mg/day) to rats with transplanted Walker 256 carcinoma enhanced the antitumor effect of hydrazine sulfate.

Animals↗

Analysis of the antidiabetic drug acarbose by capillary electrophoresis.

This study describes the derivatization of the pseudooligosaccharide acarbose and its main metabolite, component 2, with 7-aminonaphthalene-1,3-disulfonic acid (ANDS) in human urine. Their efficient separation was possible by means of capillary zone electrophoresis, using a capillary tube of fused-silica containing 100 mM triethylammonium phosphate buffer, pH 1.5. On column laser-induced fluorescence allowed the detection of the pseudooligosaccharides in human urine in the nanomolar range. With this method, acarbose and component 2 were quantified in human urine after application of 300 mg of acarbose.

Acarbose↗

Effect of an antidiabetic extract of Catharanthus roseus on enzymic activities in streptozotocin induced diabetic rats.

Hypoglycemic activity was detected in dichloromethane:methanol extract (1:1) of leaves and twigs of Catharanthus roseus (family Apocynaceae), a traditionally used medicinal plant, using streptozotocin (STZ) induced diabetic rat model. Extract at dose 500 mg/kg given orally for 7 and 15 days showed 48.6 and 57.6% hypoglycemic activity, respectively. Prior treatment at the same dose for 30 days provided complete protection against STZ challenge (75 mg/kg/i.p.x1). Enzymic activities of glycogen synthase, glucose 6-phosphate-dehydrogenase, succinate dehydrogenase and malate dehydrogenase were decreased in liver of diabetic animals in comparison to normal and were significantly improved after treatment with extract at dose 500 mg/kg p.o. for 7 days. Results indicate increased metabolization of glucose in treated rats. Increased levels of lipid peroxidation measured as 2-thiobarbituric acid reactive substances (TBARS) indicative of oxidative stress in diabetic rats were also normalized by treatment with the extract.

Animals↗

Antidiabetic activity of Terminalia pallida fruit in alloxan induced diabetic rats.

Different doses of ethanolic fraction of fruits of Terminalia pallida were evaluated for hypoglycemic and antihyperglycemic activity in normal and alloxan diabetic rats. The oral administration of ethanolic extract at a dosage of 0.5 g/kg body weight exhibited a significant antihyperglycemic activity in alloxan diabetic rats, whereas in normal rats no hypoglycemic activity was observed.

Administration, Oral↗

Study of the anti-hyperglycemic effect of plants used as antidiabetics.

The purpose of this research was to study the anti-hyperglycemic effect of 28 medicinal plants used in the treatment of diabetes mellitus. Each plant was processed in the traditional way and intragastrically administered to temporarily hyperglycemic rabbits. The results showed that eight out of the 28 studied plants significantly decrease the hyperglycemic peak and/or the area under the glucose tolerance curve. These plants were: Guazuma ulmifolia, Tournefortia hirsutissima, Lepechinia caulescens, Rhizophora mangle, Musa sapientum, Trigonella foenum graceum, Turnera diffusa, and Euphorbia prostrata. The results suggest the validity of their clinical use in diabetes mellitus control, after their toxicological investigation.

Animals↗

Antidiabetic effect of Gymnema montanum leaves: effect on lipid peroxidation induced oxidative stress in experimental diabetes.

Gymnema montanum is widely used in ancient medicine for the ailment of various diseases. Oral administration of 200 mg kg(-1) (body weight) BW of the alcoholic extract of the leaf for 3 weeks resulted in a significant reduction in blood glucose and an increase in plasma insulin, whereas the effect of 50 and 100 mg kg(-1) BW was not significant. The alcoholic extract also resulted in decreased free radical formation in plasma of diabetic rats. Thus, this study shows that Gymnema montanum leaf extract (GLEt) possess antihyperglycemic and antiperoxidative effect. The decrease in lipid peroxides and increase in reduced glutathione (GSH), ascorbic acid (Vitamin C) and alpha-tocopherol (Vitamin E) clearly show the antioxidant properties of GLEt. The effect of GLEt was most prominently seen in the case of animals given 200 mg kg(-1) BW. In addition, the results suggest that GLEt was highly effective than the reference drug glibenclamide.

Animals↗

Triple oral antidiabetic therapy.

Our objective was to determine the efficacy of adding acarbose to the combination of metformin and a sulfonylurea in the treatment of type II diabetes mellitus. Acarbose was added to the treatment regimen of 11 type II diabetic patients who were not adequately controlled on the combination of a sulfonylurea and metformin. Glycosylated hemoglobin before and after the addition of acarbose was compared to assess the efficacy of this additional therapy. One patient did not tolerate acarbose therapy. Of the remaining ten patients, the mean improvement in glycosylated hemoglobin with the addition of acarbose was 1.4 percentage points, p = 0.01. Eight patients had improvements in glycosylated hemoglobin; mean improvement, 2.0 percentage points. Two patients' glycohemoglobin values worsened. Thus, the addition of acarbose to the treatment regimen of type II diabetic patients presently on a combination of a sulfonylurea and metformin improves glycemic control.

Acarbose↗

CoMFA and docking studies on glycogen phosphorylase a inhibitors as antidiabetic agents.

Glycogen phosphorylase (GP(a)) is a specific target for the design of inhibitors and may prevent glycogenolysis under high glucose conditions in type II diabetes. The carboxamides first reported by Hoover D. J. et al. (J. Med. Chem. 1998, 41, 2934-2938) are one of the major classes of GP(a) inhibitors other than glucose derivatives. The recent, X-ray crystallographic analyses (Oikonomakos et al. Biochim. Biophys. Acta 2003, 1647, 325-332) have revealed a distinct mechanism of action for these inhibitors, which bind at a new allosteric site away from the inhibitory and catalytic sites. To elucidate the essential structural and physicochemical requirements responsible for binding to the GP(a) enzyme and to develop predictive models, CoMFA and docking studies have been carried out on a series of indole-2-carboxamide derivates. The CoMFA model developed using pharmacophoric alignments and hydrogen-bonding fields demonstrated high predictive ability against the training (r2 = 0.98, q2 = 0.68) and the test set (r2pred = 0.85). Further the superimposition of PLS coefficient contour maps from CoMFA with the GP(a) active site (PDB: 1lwo) has shown a high level of compatibility.

Binding Sites↗

Antidiabetic activity of red wine polyphenolic extract, ethanol, or both in streptozotocin-treated rats.

A polyphenol extract from a Corbières (France) red wine (P, 200 mg/kg), ethanol (E, 1 mL/kg), or a combination of both (PE) was administered by daily gavage for 6 weeks to healthy control or streptozotocin (60 mg/kg i.v.)-induced diabetic rats (180-200 g). Treatment groups included C or D (untreated control or diabetic) and CP, CE, or CPE (treated control) or DP, DE, or DPE (treated diabetic). P treatment induced a reduction in body growth, food intake, and glycemia in both CP and DP groups. In DP, hyperglycemia was reduced when measured 1 h after daily treatment but not at sacrifice (no treatment on that day). The hyperglycemic response to the oral glucose tolerance test (OGTT) and plasma insulin at sacrifice were impaired similarly in DP and D groups. In contrast, in DE or DPE, body growth was partially restored while hyperglycemia was reduced both during treatment and at sacrifice. In addition, hyperglycemia response to OGTT was reduced and plasma insulin was higher in DE or DPE than in D animals, indicating a long-term correction of diabetes in ethanol-treated animals. Morphometric studies showed that ethanol partially reversed the enlarging effect of diabetes on the mesenteric arterial system while the polyphenolic treatment enhanced it in the absence of ethanol. In summary, our study shows that (i). a polyphenol extract from red wine ("used at a pharmacological" dose) reduces glycemia and decreases food intake and body growth in diabetic and nondiabetic animals and (ii). ethanol ("nutritional" dose) administered alone or in combination with polyphenols is able to correct the diabetic state. Some of the effects of polyphenols were masked by the effects of ethanol, notably in diabetic animals. Further studies will determine the effect of "nutritional" doses of polyphenols as well as their mechanism of action.

Animals↗

Synthesis and alpha-D-glucosidase inhibitory activity of N-substituted valiolamine derivatives as potential oral antidiabetic agents.

Various kinds of N-substituted valiolamine derivatives, including compounds 23a, 24a, and 34a, which are structurally analogous to the key pseudodisaccharides (25a and 26a) of naturally occurring oligosaccharide alpha-D-glucosidase inhibitors, have been synthesized and estimated by the measure of inhibitory activity against porcine sucrase and maltase. The N-substituted valiolamine derivatives evaluated in this study have been found to be more potent than the corresponding N-substituted valienamine derivatives as well as the parent valiolamine. It is noteworthy that even simple N-substituted valiolamine derivatives such as N-[2-hydroxy-1-(hydroxymethyl)ethyl]-, N-[(1R,2R)-2-hydroxycyclohexyl]-, and N-[(R)-(-)-beta-hydroxyphenethyl]valiolamine (6, 8a, and 9a) have the stronger alpha-D-glucosidase inhibitory activity against porcine intestinal maltase and sucrase than naturally occurring oligosaccharide alpha-D-glucosidase inhibitors.

Animals↗