Months Of Oral Administration Research Articles

Studies on the glycemic and lipidemic effect of Murraya koenigii in experimental animals

Diabetes is often accompanied by lipid abnormalities, which contribute significantly to cardiovascular morbidity and mortality in diabetic patients. Previously, we have demonstrated potent hypoglycemic activity of lyophilized aqueous extract of Murraya koenigii leaves in normal and alloxan induced diabetic rabbits for short duration of 6 h. In this study, we examined the effect of 1 month oral administration of Murraya koenigii aqueous leaves extract in normal and STZ induced severe diabetic rats, at the dose of 300 mg/kg bw, on various biochemical parameters, viz., fasting blood glucose (FBG), total cholesterol (TC), HDL-cholesterol (HDL), triglyceride (TG), alkaline phosphatase (ALKP), serum glutamate oxaloacetate and pyruvate transaminases (SGOT and SGPT) and serum creatinine. In case of diabetic animals fasting blood glucose (FBG) levels of treated animals reduced by 48.2% after 30 days treatment with the aqueous leaves extract. A fall of 19.2 and 30.8% in TC and 22.97 and 37.1% in TG levels were also observed in the case of treated normal as well as diabetic rats, respectively. Feeding the extract increased the HDL-cholesterol level by 16 and 29.4% in normal and diabetic rats, respectively, as compared with their initial values. In the normal rats after 1 month of oral administration of the extract SGOT and SGPT levels were decreased by 21.7 and 25.0%. Serum alkaline phosphatase values of the treated normal animals were also reduced by 33% while negligible change was observed in the normal control animals. In the case of diabetic rats, SGOT and SGPT levels were reduced by 36.7 and 32.2%, respectively, whereas ALKP levels decreased by 39.7% after 1 month oral administration of the extract. The serum creatinine levels decrease in normal as well as in the diabetic animals by 17.75 and 18.2%, respectively, as compared to initial values. In the diabetic control animals the urinary sugar remains at +4 level but there was a decrease of 75% in urine sugar in the case of treated diabetic rats. This indicates that the aqueous extract of Murraya koenigii has favorable effect in bringing down the severity of diabetes.

S4-04-06: Thiadiazolidindiones, selective glycogen synthase kinase-3 inhibitors as potential therapeutic agents for Alzheimer’s disease and other tauopathies

GSK–3 is a serine/threonine kinase with an astoundingly diverse number of actions in intracellular signalling systems. It plays crucial roles in several human diseases having great potential for therapeutic intervention. Currently, GSK–3 inhibitors arise as promising drugs for the pharmacotherapy of several acute pathologies as cancer, diabetes, stroke, mood disorders, inflammation or Alzheimer′s disease (AD), among others. Recently, a large body of evidence has accumulated linking GSK–3 with tau hyperphosphorylation, and more recently, Aβ production, the two pathological hallmarks of AD. The small heterocyclic thiadiazolidindiones (TDZDs) represent the first non–ATP competitive GSK3 inhibitors reported to date and have been proposed as new disease–modifying agents for the effective treatment of neurodegenerative disorders where tau phosphorylation plays a key role, such as AD. TDZDs have favourable ADME–Tox drugable properties and their therapeutic potential has been proved using different animal models. A prolonged oral administration of a TDZD compound to the GSK3β conditional transgenic mice (Tet/GSK3β) produces a significant decrease on tau phosphorylation both in the hippocampus and cortex areas where the transgene is expressed. Moreover, this TDZD compound is able to improve cognition (by object recognition test), and diminish the cortex and hippocampus amyloid plaque load in an APP–PS1 double transgenic mouse after 2 months of oral administration. The positive observed effects in these studies together with some other neuroprotective properties found on this family of compounds, confirm the potential of TDZDs as new therapeutic agents for the inhibition of GSK3 and tau phosphorylation in AD and other tauopathies.

Improved haemorrheological properties by Ginkgo biloba extract (Egb 761) in type 2 diabetes mellitus complicated with retinopathy

Background & Aims: Abnormal haemorrheological property changes in erythrocyte deformability, plasma and blood viscosity, and blood viscoelasticity may play very important roles in the development of microangiopathies in diabetes mellitus (DM). In this study, we demonstrate the improvement in abnormal haemorrheological parameters in DM with ingestion of Ginkgo biloba extract 761 (Egb 761). Methods: Haemorrheological parameters before and 3 months after Egb 761 oral ingestion were determined in 25 type 2 DM patients with retinopathy. These parameters included lipid peroxidation stress of erythrocytes, erythrocyte deformability, plasma and blood viscosity, blood viscoelasticity, and retinal capillary blood flow velocity. Results: After taking Egb 761 orally for 3 months, the blood viscosity was significantly reduced at different shear rates, by 0.44±0.10 ( γ=400), 0.52±0.09 ( γ=150) and 2.88±0.57 ( γ=5). Viscoelasticity was significantly reduced in diabetic patients by 3.08±0.78 (0.1 Hz). The level of erythrocyte malondialdehyde (MDA) was reduced by 30%; however, the deformability of erythrocyte was increased by 20%. And lastly, retinal capillary blood flow rate was increased from 3.23±0.12 to 3.67±0.24 cm min −1. Conclusion: In this preliminary clinical study, 3 months of oral administration of Egb 761 significantly reduced MDA levels of erythrocytes membranes, decreased fibrinogen levels, promoted erythrocytes deformability, and improved blood viscosity and viscoelasticity, which may facilitate blood perfusion. Furthermore, it effectively improved retinal capillary blood flow rate in type 2 diabetic patients with retinopathy.

Complete remission of multiple hepatocellular carcinomas associated with hepatitis C virus-related, decompensated liver cirrhosis by oral administration of enteric-coated tegafur/uracil

We report a case of complete remission of multiple hepatocellular carcinomas after oral administration of enteric-coated tegafur/uracil. A 77-yr-old woman was diagnosed as having recurrent hepatocellular carcinoma associated with decompensated liver cirrhosis. We administered enteric-coated tegafur/uracil to this patient. After 1 month of oral administration, there was a decrease in tumor markers. An image analysis showed disappearance of hepatocellular carcinoma. No recurrence of the hepatocellular carcinoma was recognized for 18 months up to the time of the patient’s death, which was due to massive bleeding from a hemorragic rectal ulcer. At autopsy, the tumor lesion had necrotized. Oral administration of enteric-coated granules containing tegafur/uracil may provide an effective treatment for hepatocellular carcinoma.

Effect of chronic angiotensin converting enzyme inhibition on sympathetic nerve traffic and baroreflex control of the circulation in essential hypertension.

Human studies have shown that the blood pressure lowering effects of angiotensin converting enzyme inhibitors are accompanied by a reduction in plasma norepinephrine levels. Whether this is due to central or peripheral mechanisms is unknown, however. To evaluate the effects of chronic interference with the renin-angiotensin system on sympathetic nerve traffic and baroreflex control of vagal and adrenergic cardiovascular drive. In 18 untreated mild to moderate essential hypertensive patients aged 48.5+/-1.9 years (mean+/-SEM), we measured mean arterial pressure (Finapres), heart rate (electrocardiogram), plasma renin activity (radioimmunoassay), plasma norepinephrine (high-performance liquid chromatography) and postganglionic muscle sympathetic nerve activity (microneurography at a peroneal nerve). In nine patients, measurements were performed before and after 2 months of oral administration of lisinopril (10 mg/day), while in the remaining nine patients they were performed before and after a 2 month observation period, without the drug administration. Measurements were performed at rest and during baroreflex stimulation and deactivation elicited by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Lisinopril induced a marked increase in plasma renin activity (from 1.1+/-0.2 to 6.4+/-1.3 ng/ml per h, P< 0.01) and a reduction in mean arterial pressure (from 109.6+/-3.1 to 98.7+/-2.9 mmHg, P < 0.01) without affecting the heart rate. Plasma norepinephrine and muscle sympathetic nerve activity values were not significantly different before and after lisinopril treatment (plasma norepinephrine values changed from 290.4+/-39.2 to 308.1+/-67.1 pg/ml; muscle sympathetic nerve activity changed from 56.4+/-5.3 to 50.6+/-6.6 bursts/100 heart beats). Neither the sympathoinhibitory nor the sympathoexcitatory responses to phenylephrine and nitroprusside were affected by lisinopril, nor the concomitant bradycardia and tachycardia. The curves relating mean arterial pressure to heart rate and muscle sympathetic nerve activity values during baroreceptor manipulation were shifted to the left, indicating a resetting of the baroreflex to the lower blood pressure values achieved during treatment. CONCLUSIONS In essential hypertension, sympathetic nerve traffic is not affected by chronic angiotensin converting enzyme inhibitor treatment that effectively interferes with the renin-angiotensin system and lowers the elevated blood pressure. The baroreflex ability to modulate heart rate and central sympathetic outflow is also unaffected. These data argue against the existence of a central sympathoexcitatory effect of angiotensin II in this condition. They also indicate that antihypertensive treatment with an angiotensin converting enzyme inhibitor preserves autonomic reflex control, with favorable consequences for cardiovascular homeostasis.

Immunoglobulin-containing cells in the colonic mucosa of rabbits with carrageenan-induced colitis.

Immunohistochemical analysis of immunocompetent cells in the colonic mucosa was performed with carrageenan-induced experimental colitis in rabbits. Colitis was induced by seven months of oral administration of lambda-degraded carrageenan following immunization with the same substances containing Freund's complete adjuvant. In the colonic mucosa with colitis, IgG- and IgM-containing cells were significantly increased in number (IgG: 540 +/- 94/mm2 in experimental group, vs. 120 +/- 54/mm2 in control, P less than .05, IgM: 55.0 +/- 19.7/mm2 in experimental group, vs. 6.7 +/- 2.4/mm2 in control, P less than .05). There was no significant increase of IgA-containing cells either in number or in proportion to the total mononuclear cells. These changes, induced by carrageenan in rabbits, had resembled those in human ulcerative colitis well. These observations suggested an impairment of the IgA-regulated local immune system and an abnormality in the differentiation process of immunoglobulin-secreting cells.

Cardiovascular effects of verapamil in patients with essential hypertension.

The cardiovascular effects of intravenous verapamil and 3 months of oral administration of a slow-release form of verapamil (verapamil-SR) were studied in 10 patients with mild-to-moderate essential hypertension. Intravenous verapamil reduced arterial pressure by 15% (p less than .01) through a fall in total peripheral resistance of 29% (p less than .01); provoked a reflexive rise in heart rate (by 19%, p less than .02), cardiac output (by 74%, p less than .01), and plasma catecholamines; and shifted intravascular volume toward the cardiopulmonary circulation indicating peripheral venoconstriction. Quite in contrast to the immediate effects of the intravenous drug, oral therapy with verapamil-SR for 2 to 3 months lowered arterial pressure effectively (by 15%, p less than .01) by inducing vasodilation of 15% (p less than .02), but without causing reflex tachycardia, activation of the sympathetic-adrenergic or renin-angiotensin systems, or volume expansion. Oral therapy with verapamil-SR preserved systemic and renal blood flow and slightly reduced cardiac mass (by 6%, p less than .05) and renal vascular resistance (by 25%, p less than .05). Whereas intravenous verapamil tended to depress myocardial contractility, oral verapamil-SR did not at all affect myocardial contractility or left ventricular function. These cardiovascular effects make verapamil-SR an excellent agent for long-term antihypertensive therapy.

Effects of long term intravenous administration of ethanol on rat pancreas.

Pancreatic exocrine function and morphologic changes were investigated in groups of rats receiving solutions of ethanol by oral or intravenous route, or equicaloric doses of glucose solution by intravenous route daily for a period of 4 weeks. Comparable degrees of exocrine dysfunction and morphologic changes in the pancreas at the ultrastructural level were observed in the groups given ethanol orally and in those receiving i.v. injections of ethanol, suggesting that neither intragastric ingestion nor high blood levels of alcohol is required for alcohol to exert its pancreatotoxic effects. All groups of rats receiving ethanol or glucose showed signs and pathologic findings of nutritional disorder, and at 4 weeks of treatment, electron microscopic abnormalities of the pancreas were more pronounced and higher in incidence in the groups given ethanol p.o. or i.v. than in the groups given i.v. doses of glucose. There was no microscopic evidence of protein plug or other changes in the region of origin of the pancreatic duct system in rats after 18 months of oral administration of ethanol. The present findings indicate that the cytotoxic effect of alcohol on acinar cells and nutritional disorder associated with alcohol ingestion constitute important factors in the pathogenesis of chronic alcoholic pancreatitis.