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PubMed1987

Synthesis of N-(3,6-dihydro-1(2H)-pyridinyl)benzamides with hyperglycemic-hypoglycemic activity.

A group of N-(3,6-dihydro-1(2H)-pyridinyl)benzamides 7 were synthesized to determine the effect that the position and physicochemical properties of substituents attached to the heterocyclic ring have on blood glucose levels. 5-Methyl-N-(3,6-dihydro-1(2H)-pyridinyl)benzamide 7b was the most active hyperglycemic agent, elevating blood glucose 124% and 116% at 2 and 4 h, respectively, after a 100 mg/kg po dose. The most active hypoglycemic agent was the 4-acetyl analogue 7o, which was about 50% as active as chlorpropamide, lowering blood glucose 19% at 4 h after a 100 mg/kg po dose. A correlation between blood glucose levels and the partition coefficient P was not observed.

Animals↗

PubMed1987

Resolution of (+/-)-2-tetradecyloxiranecarboxylic acid. Absolute configuration and chiral synthesis of the hypoglycemic R enantiomer and biological activity of enantiomers.

The resolution of the hypoglycemic agent (+/-)-2-tetradecyloxiranecarboxylic acid (3) as its d- and l-ephedrine salts is presented. The active enantiomer (R)-(+)-3 was also synthesized by the Sharpless chiral epoxidation procedure and its methyl ester (R)-(+)-4 was shown to be identical with the corresponding ester from the resolved acid. Single-crystal X-ray structure analysis of the diastereomeric salt of (+)-3 and (-)-ephedrine allowed assignment of (+)-3 as the R configuration. The effects on fatty acid oxidation and glucose tolerance of the racemic and enantiomeric forms of 3, 4, and the CoA ester of 3 are presented. A postulated mechanism of action for the active enantiomer as an enantioselective, active-site-directed, irreversible inhibitor of carnitine palmitoyl transferase is suggested.

Animals↗

PubMed1998

Substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones as hypoglycemic agents.

A series of substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones was synthesized from amino alcohols or amino thiols and keto acids. A pharmacological model based on the results obtained with these compounds led to the synthesis and evaluation of a series of isoxazoles and other monocyclic compounds. These were evaluated for their ability to enhance glucose utilization in cultured L6 myocytes. The in vivo hypoglycemic efficacy and potency of these compounds were evaluated in a model of type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus), the ob/ob mouse. 25a(2S) (SDZ PGU 693) was selected for further pharmacological studies.

Animals↗

PubMedDate not supplied

Isolation and hypoglycemic activity of eleutherans A, B, C, D, E, F, and G: glycans of Eleutherococcus senticosus roots.

Intraperitoneal injection of an aqueous extract of the crude drug "shigoka" (Siberian ginseng), Eleutherococcus senticosus roots, remarkably diminished plasma-sugar level in mice. Fractionation of the extract by monitoring the activity yielded seven glycans, eleutherans A, B, C, D, E, F, and G, which exerted marked hypoglycemic effects in normal and alloxan-induced hyperglycemic mice.

Animals↗

PubMed1997

Hypoglycemic activity of some triterpenoid glycosides.

Four triterpenoid glycosides isolated from the rhizomes of Polygala senega var. latifolia, senegins II-IV (1-3) and desmethoxysenegin II (4), were tested for hypoglycemic activity in normal and KK-Ay mice. Compounds 1 and 2 reduced the blood glucose of normal mice 4 h after intraperitoneal administration and also significantly lowered the glucose level of KK-Ay mice under similar conditions. Compounds 3 and 4, as well as senegose A (5), an oligosaccharide ester, were inactive when tested against normal mice.

Animals↗

PubMed2002

Modeling the pharmacokinetics and pharmacodynamics of a unique oral hypoglycemic agent using neural networks.

PURPOSE: To develop a predictive population pharmacokinetic/ pharmacodynamic (PK/PD) model for repaglinide (REP), an oral hypoglycemic agent, using artificial neural networks (ANNs). METHODS: REP, glucose concentrations, and demographic data from a dose ranging Phase 2 trial were divided into a training set (70%) and a test set (30%). NeuroShell Predictor was used to create predictive PK and PK/PD models using population covariates: evaluate the relative significance of different covariates; and simulate the effect of covariates on the PK/PD of REP. Predictive performance was evaluated by calculating root mean square error and mean error for the training and test sets. These values were compared to naive averaging (NA) and randomly generated numbers (RN). RESULTS: Covariates found to have an influence on PK of REP include dose, gender. race, age, and weight. Covariates affecting the glucose response included dose, gender, and weight. These differences are not expected to be clinically significant. CONCLUSIONS: We came to the following three conclusions: 1) ANNs are more precise than NA and RN for both PK and PD; 2) the bias was acceptable for ANNs as compared with NA and RN; and 3) neural networks offer a quick and simple method for predicting, for identifying significant covariates, and for generating hypotheses.

Blood Glucose↗

PubMed2003

Blackgram fiber (Phaseolus mungo): mechanism of hypoglycemic action.

The effect of the administration of blackgram fiber (Phaseolus mungo) on the metabolism of carbohydrates was studied in rats fed 30% NDF (neutral detergent fiber) diet. The experimental group showed a significant increase in liver glycogen level and a significant decrease in blood glucose. Significant increases in the activities of glycogen phosphorylase, hexokinase, fructose-1, 6-diphosphatase, glucose-6-phosphate dehydrogenase and isocitrate dehydrogenase were observed in the experimental group. The activities of phosphoglucomutase and glucose-6-phosphatase were significantly lower in rats fed the fiber diet. The study showed that blackgram fiber exhibits significant hypoglycemic action in experimental animals.

Animals↗

PubMed2003

Effects of sulfonylurea hypoglycemic agents and adenosine triphosphate dependent potassium channel antagonists on ventricular arrhythmias in patients with decompensated heart failure.

Hypoglycemic sulfonylureas block cardiac ATP-sensitive potassium channels (K(ATP)). The opening of these channels in cardiomyocytes can induce arrhythmias. In animal studies, sulfonylureas exert an antiarrhythmic effect on the ischemic myocardium, but data on human arrhythmic events are lacking. The study population included 207 patients (age 61 +/- 14 years) admitted for decompensated CHF. The severity of ventricular arrhythmias was assessed by 24-hour Holter monitoring. None of the patients were on parenteral vasoactive therapy or antiarrhythmics during Holter recording. Diabetic patients comprised 48% of the study population, and 34% of diabetic patients were prescribed sulfonylureas. The mean hourly ventricular pairs (3.6 +/- 0.5 vs 1.8 +/- 0.3, P = 0.03), the mean hourly repetitive ventricular beats (5.7 +/- 1.0 vs 2.6 +/- 0.1, P = 0.03), and the frequency of ventricular tachycardia episodes per 24 hours (4.7 +/- 0.8 vs 2.2 +/- 0.4, P = 0.03) were significantly lower in patients with diabetes who were receiving sulfonylureas compared with nondiabetics. No significant difference occurred between patients with diabetes who were not receiving sulfonylureas and nondiabetic patients. Multivariate regression revealed a negative independent relationship between sulfonylurea therapy and hourly ventricular pairs (P = 0.03), the mean hourly repetitive ventricular beats (P = 0.03), and ventricular tachycardia episodes (P = 0.04). In a multiple logistic regression, sulfonylurea therapy was a negative predictor of repetitive ventricular beats (P = 0.01, adjusted OR, 0.31; 95% CI, 0.12-0.78). Concomitant sulfonylurea therapy may reduce the occurrence of complex ventricular ectopy in the setting of severe CHF. These results suggest that cardiac K(ATP) channel activation may be involved in the genesis of ventricular arrhythmias in CHF.

Aged↗

PubMed2002

The hypoglycemic effect of Nigella sativa oil is mediated by extrapancreatic actions.

A plant mixture containing extracts of Nigella sativa possesses blood glucose lowering effects, but the direct antidiabetic effect of Nigella sativa is not yet established. Therefore, the effect of Nigella sativa oil (NSO) on blood glucose concentrations was studied in streptozotocin diabetic rats. In addition, the effect of NSO, nigellone and thymoquinone were studied on insulin secretion of isolated rat pancreatic islets in the presence of 3, 5.6 or 11.1 mM glucose. NSO significantly lowered blood glucose concentrations in diabetic rats after 2, 4 and 6 weeks. The blood lowering effect of NSO was, however, not paralleled by a stimulation of insulin release in the presence of NSO, nigellone or thymoquinone. The data indicate that the hypoglycemic effect of NSO may be mediated by extrapancreatic actions rather than by stimulated insulin release.

Animals↗

PubMed1994

Hypoglycemic activity of juniper "berries".

This work studies the hypoglycemic activity of a decoction from juniper "berries" (Juniperus communis) both in normoglycemic and in streptozotocin-diabetic animals. Juniper decoction decreases glycemic levels in normoglycemic rats at a dose of 250 mg/kg. This effect can be achieved through: a) an increase of peripheral glucose consumption; b) a potentiation of glucose-induced insulin secretion. The administration of the decoction (125 mg total "berries"/kg) to streptozotocin-diabetic rats for 24 days results in a significant reduction both in blood glucose levels and in the mortality index, as well as the prevention of the loss of body weight. This effect seems to be mediated by the peripheral action of juniper.

Animals↗

PubMed1994

Hypoglycemic action of the rhizomes of Polygonatum officinale in normal and diabetic mice.

The hypoglycemic effect of the rhizomes of Polygonatum officinale (Liliaceae) was investigated in both normal and streptozotocin-induced diabetic mice. The methanol extract of rhizomes of Polygonatum officinale (PO) (800 mg/kg) reduced the blood glucose of normal mice from 170 +/- 3 to 136 +/- 5 mg/100 ml 4 hours after intraperitoneal administration (P < 0.001), and also significantly lowered the blood glucose of streptozotocin-induced diabetic mice from 696 +/- 60 to 407 +/- 35 mg/100 ml under similar conditions (P < 0.01). PO also suppressed epinephrine-induced hyperglycemia in mice. In addition, the n-butanol fraction of the methanol extract elicited a significant decrease in the blood glucose level of streptozotocin-induced diabetic mice after 4 hours (P < 0.05).

Animals↗

PubMed1990

Anti-complementary and hypoglycemic activities of the glycans from the seeds of Malva verticillata.

Seven polysaccharides and peptidoglycans obtained from the seeds of Malva verticillata were tested for anti-complementary activity. Remarkable activities were observed for MVS-I and MVS-IIA. The former is mainly composed of beta-1,3-linked D-glucan and of alpha-1,5-linked L-arabino-beta-3,6-branched D-galactan, and the latter is essentially alpha-1,5-linked L-arabino-beta-3,6-branched D-galactan. Further, considerable activities were observed for MVS-IIIA and MVS-IVA. Both glycans possess arabino-3,6-galactan moieties accompanying alpha-1,3-linked L-arabinopyranosyl, beta-1,4-linked D-xylosyl, and alpha-1,4-linked D-galacturonic acid units. In addition, the major neutral polysaccharide (MVS-I), the major peptidoglycan (MVS-V), and the polysaccharide-rich fraction (MVS-V-CH) obtained from MVS-V were tested for hypoglycemic activity. MVS-I especially showed remarkable activity, and MVS-V-CH also exhibited significant activity. From the viewpoint of structural features, the latter belongs to pectic substances.

Animals↗

PubMed1989

Isolation and hypoglycemic activity of trichosans A, B, C, D, and E: glycans of Trichosanthes kirilowii roots.

The non-dialyzable portion of the water extract of the Oriental crude drug "karokon", the roots of Trichosanthes kirilowii, was found to reduce the plasma glucose level in mice. Activity-guided fractionation of this non-dialyzable portion led to the isolation of five glycans termed as trichosans A, B, C, D and E, showing hypoglycemic actions in normal mice. The main glycan, trichosan A, also exhibited activity in alloxan-induced hyperglycemic mice.

Animals↗

PubMed1992

The beta cell function in NIDDM patients with secondary failure: a three year follow-up of combined oral hypoglycemic and insulin therapy.

Eleven Type 2 (non-insulin-dependent) diabetic patients, islet cell autoantibodies negative, nonobese with secondary failure to oral hypoglycemic agents (OHA) [glyburide (7.5 mg/day) and phenformin (75 mg/day)] and HbA1c 10.2 +/- 0.6% were studied. Insulin receptors on circulating monocytes, glucose utilization at supraphysiological insulin concentrations, and plasma C-peptide after i.v. glucagon were evaluated before and after 2 months of combined therapy with OHA and insulin (Ultratard HM Novo). A significant improvement was demonstrated in HbA1c and glycemia after two months of treatment. Glucose MCR was increased after two months of treatment whilst basal C-peptide was decreased as well as receptor binding to monocytes. After three years of combined therapy, body weight, glycemia and HbA1c did not increase. After three years the C-peptide basal values were significantly increased with respect to values found after 2 months of therapy. These results demonstrate that insulin treatment may restore insulin sensitivity in NIDDM patients resistant to OHA treatment and that after three years there is no exhaustion of B-cell function.

Administration, Oral↗

PubMed1984

Hydrazonopropionic acids, a new class of hypoglycemic substances, 3. Inhibition of jejunal glucose uptake in the rat and guinea pig.

Recently hydrazonopropionate derivatives have been recognized as a new group of compounds with strong hypoglycemic effects in various laboratory animals. The hypoglycemia probably has several causes of which an inhibition of gluconeogenesis and of intestinal glucose uptake could be identified. In the present report, the influence of phenylethylhydrazonopropionate, cyclohexylethylhydrazonopropionate, methylcinnamylhydrazonopropionate and their corresponding hydrazine derivatives on the glucose uptake of rat and guinea pig jejunum has been compared with the well known effects caused by phenformin. All substances tested inhibited the jejunal glucose uptake, phenelzine, methylcinnamylhydrazine and cyclohexylhydrazonopropionate more effective, the other compounds less effective than phenformin. The hydrazine derivatives appeared more effective than the hydrazone compounds used. The cellular ATP/ADP ratio was not influenced by the hydrazonopropionate compounds.

Adenosine Diphosphate↗

PubMed1980

Hydrazonopropionic acid, a new class of hypoglycemic substances. 2. Influence of 2-(phenylethylhydrazono)- and 2-(2-cyclohexyl-ethylhydrazono)-propionic acid on redox systems, acid base status and monoamino oxidase activity.

Phenylethylhydrazono-propionic acid (PEHP) and cyclohexyl-ethylhydrazono-propionic acid (CHEHP) has been shown to lower blood glucose concentrations in various laboratory animals after intraperitoneal or oral application. The present study has been conducted to investigate, if these hydrazones may induce lactic acidosis like the biguanides or may cause unwanted side reactions due to an inhibition of monoamino oxidase like the corresponding hydrazines. It was found that intramitochondrial and cytoplasmatic redox ratios were not influenced at a hypoglycemic effective dosage (145 mumol/kg body weight) of these substances in fasted guinea pigs. An effect on the acid base status was not observed. Both substances lowered the concentration of ketone bodies in fasted guinea pigs. In vitro the activity of monoamino oxidase purified from guinea pig liver was much less inhibited by the hydrazones than by one of the corresponding hydrazines (phenelzine). Furthermore CHEHP (145 mumol/kg body weight) did not influence the serum activity of various liver enzymes and the concentration of triglycerides, cholesterol and uric acid in plasma of fasted guinea pigs. It is concluded that CHEHP meets basic requirements for a potential oral antidiabetic agent.

Acetoacetates↗

PubMed1998

The effect of the new oral hypoglycemic agent A-4166 on glucose turnover in the high fat diet-induced and/or in the hereditary insulin resistance of rats.

A-4166, a phenylalanine derivative, is a hypoglycemic agent, which has been shown to improve blood glucose levels mainly due to the rapid and short term stimulation of insulin release. Nevertheless, a possible extrapancreatic action of A-4166 has not yet been investigated. Therefore, insulin action (euglycemic hyperinsulinemic 6.4 mU.kg-1.min-1 clamp plus 3H-2-deoxyglucose tracer administration) was studied after 3 weeks on either standard (BD) or high fat (HF) diet in normal control (C) or in hereditary insulin resistant (hHTg) rats which were given a single dose of A-4166 (10 mg per kg BW, i.v.) 60 min after clamp commencement. HF feeding reduced the glucose infusion rate (GIR) required to maintain euglycemia to about 50% of C (p < 0.001). In hHTg rats, HF did not further pronounce the pre-existing decrease of GIR of hHTg animals fed BD. A-4166 changed GIR neither in C, nor in the hHTg group. The estimated glucose disposal (Rd) (C-BD: 32.3 +/- 1.9 vs C-HF: 25.5 +/- 1.9 mg.kg-1.min-1, p < 0.001) and glucose metabolic index (Rg') in skeletal muscles (Q. femoris: C-BD: 25.6 +/- 1.5 vs C-HF: 12.3 +/- 1.1 mmol.100 g-1.min-1, p < 0.001) were reduced by HF in control rats but were not restored by a concomitant bolus of A-4166. Nevertheless, in hHTg rats fed the HF diet a single dose of A-4166 brought back their Rd (hHTg-HF: 23.5 +/- 1.3 vs hHTg-HF plus A-4166: 31.0 +/- 3.5 p < 0.03) and Rg' (Soleus muscle: hHTg-HF: 29.2 +/- 3.2 vs hHTg-HF plus A-4166: 41.3 +/- 4.0) to values of the control group on BD. In summary, a) a single bolus administration of A-4166 to the control or to the insulin resistant hHTg rats, fed either the BD or HF diets, did not abolish the reduction of GIR required to maintain euglycemia during hyperinsulinemic clamps; b) nevertheless, A-4166 caused a significant increase of the estimated plasma glucose disposal (Rd) and skeletal muscle glucose metabolic index (Rg') of hHTG rats fed the HF diet; c) we suggest that A-4166 may have an extrapancreatic action but this needs to be proven using a long-term administration plan of A-4166.

Animals↗

PubMed2001

Hypoglycemic and antihyperglycemic activity of Syzygium alternifolium (Wt.) Walp. seed extracts in normal and diabetic rats.

Aqueous, ethanolic and hexane fractions of Syzygium alternifolium seeds were prepared and given different doses of these extracts individually to different batches of rats (both normal and alloxan diabetic rats) after an overnight fast. The blood glucose levels were measured at 0, 1, 3, 5 and 7 hours after the treatment. The aqueous extract of Syzygium alternifolium at a dosage of 0.75 g/kg b.w. is showing maximum blood glucose lowering effect in both normal and alloxan diabetic rats. The ethanol and hexane fractions are also showing hypoglycemic and antihyperglycemic activity, but the effect is significantly less than that of aqueous extract. The antihyperglycemic activity of Syzygium alternifolium seed was compared with the treatment of Glibenclamide.

Alloxan↗