Preventive effect of S-allyl cysteine sulfoxide (alliin) on lysosomal hydrolases and membrane-bound ATPases in isoproterenol-induced myocardial infarction in Wistar rats

In this study, S-allyl cysteine sulfoxide (SACS) was used to evaluate its preventive effect in isoproterenol (ISO)-induced myocardial ischemia in male Wistar rats. Rats were pretreated with SACS (40 and 80 mg kg(-1)) orally for 5 weeks. After the treatment period, ISO (150 mg kg(-1)) was administered subcutaneously to rats at an interval of 24 h for 2 days. The activities of beta-D-N-acetyl-glucosaminidase, beta-galactosidase, beta-glucosidase, and acid phosphatase increased in serum and heart in ISO-induced rats. In addition, these rats showed a significant (p < 0.05) increase in the activities of beta-glucuronidase and cathepsin-D in serum and heart and a significant (p < 0.05) decrease in their activities in lysosomal fraction of the heart. The activity of Na(+)K(+)-ATPase declined, while those of Ca(2+)- and Mg(2+)-ATPases significantly (p < 0.05) elevated in the heart of ISO-induced rats. Pretreatment with SACS (40 and 80 mg kg(-1)) showed a significant (p < 0.05) effect in all the biochemical parameters studied. The effect at a dose of 80 mg kg(-1) body weight was more effective than that at 40 mg kg(-1) body weight and brought back all the biochemical parameters to near normal levels. Hereby, our study shows the membrane-stabilizing as well as antioxidant effects of SACS in ISO-induced rats.     

Hepatoprotective activity of ellagic acid against carbon tetrachloride induced hepatotoxicity in rats

Administration of CCl4 to normal rats and consequent oral feeding with ellagic acid (50 mg/kg) provided a significant protection against the biochemical alterations in serum and liver produced by CCl4. In vitro experiments showed that liver microsomes from animals treated with ellagic acid and CCl4, decreased lipid peroxidation compared to microsome prepared from rats exposed to CCl4 alone.     

Grape seed proanthocyanidins ameliorates isoproterenol-induced myocardial injury in rats by stabilizing mitochondrial and lysosomal enzymes: an in vivo study

This study was designed to examine the effects of grape seed proanthocyanidins (GSP) against myocardial injury (MI) induced by isoproterenol (ISO), in a rat model. Induction of rats with ISO (85 mg/kg body weight, subcutaneously) for 2 days resulted in a significant decrease in the activities of heart mitochondrial enzymes (isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase and alpha-ketoglutarate dehydrogenase) and respiratory chain enzymes (NADH dehydrogenase and cytochrome c oxidase). The activities of lysosomal enzymes (alpha-d-glucuronidase, alpha-d-N-acetylglucosaminidase, cathepsin-D, acid phosphatases and alpha-d-galactosidase) were increased significantly in the heart and serum of ISO-induced rats. The prior administration of GSP for 6 days a week for 5 weeks significantly increased the activities of mitochondrial and respiratory chain enzymes and significantly decreased the activities of lysosomal enzymes in the heart tissues of ISO-induced rats, which proves the stress stabilizing action of GSP. Oral administration of grape seed proanthocyanidins alone (50, 100 and 150 mg/kg) to normal rats did not show any significant effect in all the parameters studied. These biochemical functional alterations were supported by the macroscopic enzyme mapping assay of ischemic myocardium. Thus, this study shows that 100 and 150 mg/kg of GSP gives protection against ISO-induced MI and demonstrates that GSP has a significant effect in the protection of heart.     

Preventive effect of naringin on lipids, lipoproteins and lipid metabolic enzymes in isoproterenol-induced myocardial infarction in Wistar rats

This study was designed to evaluate the preventive effect of naringin in isoproterenol (ISO)-induced myocardial infarction (MI) in rats. Rats were pretreated with naringin (10, 20, and 40 mg/kg body weight) orally for a period of 56 days. After the treatment period, ISO (85 mg/kg body weight) was administered subcutaneously to rats at an interval of 24 h for 2 days. There was a significant increase in the levels of total, ester, and free cholesterol, triglycerides (TG), and free fatty acids (FFA) in serum and heart and decrease in heart phospholipids (PL) in ISO-induced rats. Altered levels of lipoproteins and activities of 3-hydroxy-3-methylglutaryl-Coenzyme reductase A in liver and heart, lecithin cholesterol acyl transferase and lipoprotein lipase in plasma were also observed in ISO-induced rats. Pretreatment with naringin (10, 20, and 40 mg/kg) for a period of 56 days significantly decreased the levels of total, ester, and free cholesterol, TG, FFA in serum and heart and increased PL in heart. It also minimized the alterations in serum lipoproteins and lipid metabolic enzymes in ISO-induced rats. Thus, naringin has a lipid-lowering effect in ISO-induced MI rats.     

Protective effects of N-acetyl cysteine on lipid peroxide metabolism on isoproterenol-induced myocardial infarcted rats

The present study was designed to evaluate the preventive effects of N-acetyl cysteine on lipid peroxide metabolism in isoproterenol (ISO) induced myocardial infarcted rats. Male albino Wistar rats were pretreated with N-acetyl cysteine (5 and 10 mg/kg) daily for a period of 14 days. After the pretreatment period, ISO (100 mg/kg) was subcutaneously injected to rats twice at an interval of 24 h. Increased activities of serum creatine kinase, creatine kinase-MB, lactate dehydrogenase, and increased intensities of serum lactate dehydrogenase-isoenzyme bands (LDH-1, LDH-2) were observed in ISO-induced rats. The heart lipid peroxidation products were significantly increased, and the antioxidant system was significantly reduced in ISO-induced rats. Pretreatment with N-acetyl cysteine (5 and 10 mg/kg) to ISO-induced rats showed significant effects on all the biochemical parameters studied. Histopathological findings of the myocardium also showed the protective role of N-acetyl cysteine in ISO-induced rats. Furthermore, in vitro study confirmed the potent-free radical scavenging activity of N-acetyl cysteine. The effect at a dose of 10 mg/kg of N-acetyl cysteine was more pronounced than the dose, 5 mg/kg. The results of our study show that N-acetyl cysteine protects the heart against ISO-induced myocardial infarction by its free radical scavenging effect.     

Preventive effect of naringin on cardiac mitochondrial enzymes during isoproterenol-induced myocardial infarction in rats: a transmission electron microscopic study

Dietary flavonoids intake has been reported inversely related to the incidence of cardiovascular diseases (CVD). The present study is undertaken to evaluate the preventive role of naringin on mitochondrial enzymes in isoproterenol (ISO)-induced myocardial infarction in male albino Wistar rats. Rats subcutaneously injected with ISO (85 mg/kg) at an interval of 24 h for 2 days, resulting in significant (p < 0.05) increase in the levels of mitochondrial lipid peroxides. ISO-induction also showed significant (p < 0.05) decrease in the activities of mitochondrial tricarboxylic acid cycle enzymes (isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, and alpha-ketoglutarate dehydrogenase) and respiratory chain enzymes (NADH dehydrogenase and cytochrome c oxidase). Oral pretreatment with naringin (10, 20, and 40 mg/kg) to ISO-induced rats daily for a period of 56 days significantly (p < 0.05) minimized the alterations in all the biochemical parameters and restored the normal mitochondrial function. Transmission electron microscopic (TEM) observations also correlated with these biochemical findings. Thus, our findings demonstrate that naringin prevents the mitochondrial dysfunction during ISO-induced myocardial infarction in rats.     

S-allylcysteine ameliorates isoproterenol-induced cardiac toxicity in rats by stabilizing cardiac mitochondrial and lysosomal enzymes

This study was aimed to evaluate the preventive role of S-allylcysteine (SAC) on mitochondrial and lysosomal enzymes in isoproterenol (ISO)-induced rats. Male albino Wistar rats were pretreated with SAC (50, 100 and 150 mg/kg) daily for a period of 45 days. After the treatment period, ISO (150 mg/kg) was subcutaneously injected to rats at an interval of 24 h for two days. The activities of heart mitochondrial enzymes (isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase and alpha-ketoglutarate dehydrogenase) and respiratory chain enzymes (NADH dehydrogenase and cytochrome C oxidase) were decreased significantly (p<0.05) in ISO-induced rats. The activities of lysosomal enzymes (beta-glucuronidase, beta-N-acetyl glucosaminidase, beta-galactosidase, cathepsin-D and acid phosphatase) were increased significantly (p<0.05) in serum and heart of ISO-induced rats. Pretreatment with SAC (100 mg/kg and 150 mg/kg) for a period of 45 days increased significantly (p<0.05) the activities of mitochondrial and respiratory chain enzymes and decreased the activities of lysosomal enzymes significantly (p<0.05) in ISO-induced rats. Oral administration of SAC (50, 100 and 150 mg/kg) for a period of 45 days to normal rats did not show any significant (p<0.05) effect in all the parameters studied. The altered electrocardiogram (ECG) of ISO-treated rats was also restored to near normal by treatment with SAC (100 and 150 mg/kg). These results confirm the efficacy of SAC in alleviating ISO-induced cardiac damage.     

Effect of ursolic acid treatment on apoptosis and DNA damage in isoproterenol-induced myocardial infarction

The present study was designed to evaluate the protective effect of ursolic acid (UA) against isoproterenol-induced myocardial infarction. Myocardial infarction was induced by subcutaneous injection of isoproterenol hydrochloride (ISO) (85 mg/kg BW), for two consecutive days. ISO-induced rats showed elevated levels of cardiac troponins T (cTn T) and I (cTn I) and increased activity of creatine kinase-MB (CK-MB) in serum. Lipid peroxidative markers (thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD) and lipid hydroperoxides (HP)) elevated in the plasma and heart tissue whereas decreased activities of enzymatic antioxidants (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and glutathione reductase (GR)) in erythrocytes and heart tissue of ISO-induced rats. Non-enzymatic antioxidants (vitamin C, vitamin E and reduced glutathione (GSH)) levels were decreased significantly in the plasma and heart tissue of ISO-induced rats. Furthermore, ISO-induced rats showed increased DNA fragmentation, upregulations of myocardial pro-apoptotic B-cell lymphoma-2 associated-x (Bax), caspase-3, -8 and -9, cytochrome c, tumor necrosis factor-α (TNF-α), Fas and down-regulated expressions of anti-apoptotic B-cell lymphoma-2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL). UA-administered rats showed decreased levels/activity of cardiac markers, DNA fragmentation and the levels of lipid peroxidative markers in the plasma and heart tissue. Activities of enzymatic antioxidants were increased significantly in the erythrocytes and heart tissue and also non-enzymatic antioxidants levels were increased significantly in the plasma and heart tissue in UA-administered rats. UA influenced decreased DNA fragmentation and an apoptosis by upregulation of anti-apoptotic proteins such as Bcl-2, Bcl-xL and down-regulation of Bax, caspase-3, -8 and -9, cytochrome c, TNF-α, Fas through mitochondrial pathway. Histopathological observations were also found in line with biochemical parameters. Thus, results of the present study demonstrated that the UA has anti-apoptotic properties in ISO-induced rats.     

The cardioprotective effects of a combination of quercetin and α-tocopherol on isoproterenol-induced myocardial infarcted rats

The present study aims to evaluate the combined protective effects of quercetin and α-tocopherol on isoproterenol-treated myocardial infarcted rats. Male albino Wistar rats were pretreated with a combination of quercetin (10 mg/kg) and α-tocopherol (10 mg/kg) daily for 14 days. After the pretreatment, rats were injected isoproterenol (100 mg/kg) to induce myocardial infarction. Isoproterenol-treated rats showed increased levels of serum troponins and increased intensities of serum lactate dehydrogenase-1 and -2 isoenzyme bands. Isoproterenol treatment also showed significant decreased levels of antioxidant system and significant increased levels of plasma lipid peroxidation, plasma uric acid, and the heart calcium. Furthermore, isoproterenol-treated rat's electrocardiogram showed elevated ST segments. Combined pretreatment with quercetin and α-tocopherol normalized all the biochemical parameters and minimized the alterations in electrocardiogram. Histopathology of myocardium also confirmed the cardioprotective effects of quercetin and α-tocopherol. In vitro studies confirmed the mechanism of action of quercetin and α-tocopherol. Thus, quercetin and α-tocopherol exhibited cardioprotective effects against isoproterenol-induced cardiotoxicity due to their scavenging free radicals, improving antioxidants and maintaining Ca(2+) levels. Our study also showed that combined pretreatment (quercetin and α-tocopherol) was highly effective than single pretreatment (quercetin or α-tocopherol).     

Effects of dietary bovine lactoferrin on growth, physiological performance, iron metabolism and non-specific immune responses of Siberian sturgeon Acipenser baeri

The present experiment was carried out to investigate the effects of different levels of dietary lactoferrin (LF) on growth performance, physiological status, iron absorption and innate immune response of juvenile Siberian sturgeon Acipenser baeri. Fish were fed with six different rations including 0, 100, 200, 400, 800 and 1600 mg LF kg(-1) diet for 8 weeks. At the end of the experiment, samples were collected for estimating the physiological and immunological parameters. Dietary LF did not change the fish growth performance, hematological parameters, serum proteins or hepatic enzymes. Moreover, stress indicators (plasma cortisol, glucose and lactate) were not affected by dietary LF. The iron absorption of fish was considerably affected by LF; thus, plasma iron in LF-treatments greatly declined and the total iron binding capacity (TIBC) significantly increased in fish fed with 800 mg LF kg(-1). In addition, the liver iron content markedly increased in some LF-treatments, but the variation of muscle iron concentration in treatments was insignificant. The amount of mucus secretion and serum bactericidal activity rose in fish fed on dietary LF, although other non-specific immune responses such as mucus bactericidal activity, serum and mucus lysozyme activity, serum peroxidase, serum natural hemolytic complement activity and serum IgM were not influenced by LF. This study revealed the ability of dietary LF to sequester iron, which is an essential nutrient required for the growth of bacteria. LF was also shown to improve some physiological and immunological parameters of Siberian sturgeon, to some extent.     

Preventive effect of (-)epigallocatechin-gallate (EGCG) on lysosomal enzymes in heart and subcellular fractions in isoproterenol-induced myocardial infarcted Wistar rats

This study was aimed to evaluate the preventive role of (-)epigallocatechin-gallate (EGCG) on lysosomal enzymes in isoproterenol (ISO)-induced myocardial infarcted rats. Male albino Wistar rats were pretreated with EGCG (30 mg/kg) daily for a period of 21 days. After the treatment period, ISO (100 mg/kg) was subcutaneously injected to rats at intervals of 24h for 2 days. The activities of lysosomal enzymes (beta-glucuronidase, beta-N-acetylglucosaminidase, beta-galactosidase, cathepsin-B and cathepsin-D) were increased significantly (P<0.05) in serum and the heart of ISO-induced rats. ISO-induction also resulted in decreased stability of membranes, which was reflected by decreased activities of beta-glucuronidase and cathepsin-D in mitochondrial, nuclear, lysosomal and microsomal fractions. Pretreatment with EGCG daily for a period of 21 days to ISO-induced rats prevented the changes in the activities of these enzymes. Oral treatment with EGCG (30 mg/kg) to normal control rats did not show any significant effect in all the biochemical parameters studied. Thus, the results of our study shows that EGCG protects the lysosomal membrane against ISO-induced cardiac damage. The observed effects might be due to the free radical scavenging and membrane stabilizing properties of EGCG.     

Vanadyl Sulfate Administration Protects the Streptozotocin-Induced Oxidative Damage to Brain Tissue in Rats

Diabetes mellitus manifests itself in a wide variety of complications and the symptoms of the disease are multifactorial. The present study was carried out to investigate the effects of vanadyl sulfate on biochemical parameters, enzyme activities and brain lipid peroxidation, glutathione and nonenzymatic glycosylation of normal- and streptozotocin-diabetic rats. Streptozotocin (STZ) was administered as a single dose (65 mg/kg) to induce diabetes. A dose of 100 mg/kg vanadyl sulfate was orally administered daily to STZ-diabetic and normal rats, separately until the end of the experiment, at day 60. In STZ-diabetic group, blood glucose, serum sialic and uric acid levels, serum catalase (CAT) and lactate dehydrogenase (LDH) activities, brain lipid peroxidation (LPO) and nonenzymatic glycosylation (NEG) increased, while brain glutathione (GSH) level and body weight decreased. In the diabetic group given vanadyl sulfate, blood glucose, serum sialic and uric acid levels, serum CAT and LDH activities and brain LPO and NEG levels decreased, but brain GSH and body weight increased.The present study showed that vanadyl sulfate exerted antioxidant effects and consequently may prevent brain damage caused by streptozotocin-induced diabetes.     

The effect of chromium on parameters related to iron metabolism

The effect of chromium on some parameters related to iron metabolism was investigated. Preliminary experiments showed that this metal ion was taken up by serum proteins and was dependent on the amount of chromium present in the medium. It was also shown that the uptake of iron was reduced significantly in the presence of chromium. In vivo study showed that the serum levels of iron and total iron binding capacity (TIBC) were reduced by 28 and 11%, respectively, following daily administration of chromium (1 mg/kg) for 45 d. Serum ferritin was reduced by 22% under this condition. Hematocrit and hemoglobin levels were also affected in chromium-treated animals and were both reduced by 17%. Spectrophotometric titration of each individual amino acid located in the iron binding site of transferrin revealed that tyrosin might be the most suitable ligand for the binding of chromium to transferrin. These results suggest that chromium may compete with iron in binding to apo-transferrin, and influence iron metabolism and its related biochemical parameters.     

Combined effects of quercetin and α-tocopherol on lipids and glycoprotein components in isoproterenol induced myocardial infarcted Wistar rats

This study was aimed to evaluate the combined effects of quercetin and α-tocopherol on lipid metabolism and glycoprotein components in isoproterenol induced myocardial infarction in Wistar rats. Myocardial infarction in rats was induced by isoproterenol (100 mg/kg) at an interval of 24 h for 2 days. Quercetin (10 mg/kg) and α-tocopherol (10 mg/kg) were given to rats as pretreatment for 14 days orally using an intragastric tube. Quercetin and α-tocopherol significantly reduced the levels of cholesterol, triglycerides and free fatty acids in the serum and heart and serum phospholipids and significantly increased the levels of heart phospholipids in isoproterenol induced rats. They also significantly decreased the activity of plasma and liver 3-hydroxy-3-methylglutaryl-coenzyme-A reductase and increased the activity of plasma and liver lecithin cholesterol acyl transferase in isoproterenol treated rats. In addition to this, they also significantly reduced the levels of hexose, hexosamine, fucose and sialic acid in the serum and heart of isoproterenol treated rats. Quercetin and α-tocopherol also showed significant decrease in plasma lipid peroxidation products (thiobarbituric acid reactive substances and lipid hydroperoxides). Pretreatment with quercetin alone and α-tocopherol alone showed significant effect in all the biochemical parameters in myocardial infarcted rats. But, combined pretreatment with quercetin and α-tocopherol normalized all the above mentioned biochemical parameters in isoproterenol treated myocardial infarction in rats. Thus, the experiment clearly showed that quercetin and α-tocopherol prevented the accumulation of lipids and glycoprotein components in myocardial infarcted rats by their anti-lipid peroxidative effect. This study also showed that combined pretreatment was better than single pretreatment.     

Amelioration of alcohol-induced oxidative stress by Emblica officinalis (amla) in rats

The present study was aimed at investigating the ameliorative effect of Emblica (Phyllanthus Emblica L) fruit extract (EFE) against alcohol-induced oxidative changes in plasma biochemical profile in rats. Alcohol administration (5 g/kg body wt/day) for 60 days resulted in significantly (P<0.05) higher levels of plasma nitrite/nitrate (NOx), total bilirubin, creatinine, and abnormalities in lipid and lipoproteins. Moreover, alcohol receiving rats showed significantly (P<0.05) lowered plasma total protein, albumin/globulin (A/G) ratio and uric acid, with no significant change in glucose level. The EFE administration (250 mg/kg body wt/day) to alcohol-administered rats significantly modulated plasma lipids and lipoprotein patterns and also decreased nitrite/nitrate, total bilirubin and creatinine levels. EFE administration to alcohol receiving rats showed a significant (P<0.05) increase in plasma total protein, A/G ratio and uric acid levels. Total cholesterol (r = 0.466), triglycerides (r = 0.574), VLDL-C (r = 0.578), LDL-C (r = 0.225) and total bilirubin (r = 0.419) showed a stronger positive correlation with that of NOx in alcohol-treated rats. The concentration of nitric oxide (NOx) was negatively correlated with HDL-C (r = -0.285) and uric acid (r = 0.392) in alcohol-treated rats. The amelioration of alcohol-induced oxidative stress might be due to the combined effect of phytophenols, such as tannins and flavonoid compounds and vitamin C.     

Effect of vitamin E therapy on serum uric acid in DOCA-salt-treated rats

Uric acid is considered as an antioxidant in the blood. Despite its proposed protective properties, elevated plasma uric acid has been associated with hypertension in a variety of disorders. The purpose of this study was to investigate the relationship between the increase of arterial blood pressure and the changes in serum uric acid, measured during the gradual development of experimental hypertension in deoxycorticosterone (DOCA)-salt-treated rats. Blood pressure was monitored by tail-cuff method, urinary and plasma uric acid was measured by autoanalyzer during the induction of hypertension in 1-, 2-, 3- and 4-week DOCA-salt-treated Sprague-Dawley rats. Vitamin E (200 mg/kg/day/gavage) was co-administered with DOCA-salt for 4 weeks. From the first week of DOCA-salt treatment, rats exhibited marked increases in blood pressure. DOCA-salt treatment also resulted in a significant increase in serum uric acid and a significant decrease in urinary uric acid at the end of the first week. These changes in serum and urinary uric acid remained until the 4th week of DOCA-salt treatment but blood pressure continued to increase throughout the study. Vitamin E treatment increased urinary excretion of uric acid and decreased blood pressure and serum uric acid in DOCA-salt-treated rats. These data suggest that enhanced serum uric acid may be a contributing factor to the onset of hypertension in DOCA-salt-treated rats. A uricosuric effect is suggested for vitamin E in the treatment of hypertension.     

Synergistic interactions of Ferulic acid with Ascorbic acid: Its cardioprotective role during isoproterenol induced myocardial infarction in rats

Studies on the lipid peroxidation and antioxidant changes and their significance during myocardial injury have provided a new insight into the pathogenesis of heart disease. The heart failure subsequent to myocardial infarction may be associated with an antioxidant deficit as well as increased myocardial oxidative stress. The present study was designed to evaluate the effect of the combination of ferulic acid and ascorbic acid on antioxidant defense system and lipid peroxidation against isoproterenol (ISO)-induced myocardial infarction in rats. Induction of rats with isoproterenol (150 mg/kg body weight daily, i.p.) for 2 days resulted in a marked elevation in lipid peroxidation, serum marker enzymes (LDH, CPK, GOT, and GPT), and a significant decrease in activities of endogenous antioxidants (SOD, GPx, GST, CAT, and GSH). Pre-co-treatment with the combination of ferulic acid (20 mg/kg body weight/day) and ascorbic acid (80 mg/kg body weight/day) orally for 6 days, significantly attenuated these changes when compared to the individual treatment groups. Histopathological observations were also in correlation with the biochemical parameters. Thus, ferulic acid and ascorbic acid significantly counteracted the pronounced oxidative stress effect of ISO by the inhibition of lipid peroxidation, restoration of antioxidant status, and myocardial marker enzymes levels. In conclusion, these findings indicate the synergistic protective effect of ferulic acid and ascorbic acid on lipid peroxidation and antioxidant defense system during ISO-induced myocardial infarction and associated oxidative stress in rats.     

Is Berlina grandiflora (Leguminosae) toxic in rats?

The toxicity profile of the aqueous methanolic extract of Berlina grandiflora (BG) stem bark was studied in rats. The rats were administered graded doses (125-500 mg/kg p.o) of the extract daily for 21 days and the effects on body weight, organ weight, clinical signs, gross pathology, hematology, histology and serum biochemical parameters were measured. The relative weights of the heart, liver, kidneys and lungs of treated rats were unaffected but there were significant changes in the relative weights of the spleen and testes. The packed cell volume and hemoglobin concentrations were slightly reduced whereas total leucocytes counts were increased remarkably. Alkaline phosphatase and Creatine Kinase levels were reduced in all the groups but Glutamate oxaloacetate was significantly elevated. Total proteins and albumin levels remained normal. BG elicited a significant increase in gamma glutamyl transferase concentrations at 250 mg/kg. No significant changes occurred in urea, uric acid and BUN concentrations but calcium levels shot up remarkably. Histological findings did not reveal any treatment-related effects. The acute toxicity LD50 was estimated to be >2000 mg/kg but dose-related mortality rates of 16.7, 33.4 and 50% were observed during the sub-acute toxicity studies. These findings have once more highlighted the limitations of acute toxicity LD50 testing and suggest that BG may exert varied toxicological effects when administered orally in rats.     

Pharmacokinetics, safety and immunomodulatory effects of human recombinant interleukin-1 receptor antagonist in healthy humans.

A phase I study of human recombinant interleukin-1 receptor antagonist (IL-1ra) was conducted in healthy males between the ages of 18 and 30. Twenty-five volunteers received a single, 3 h continuous intravenous infusion of doses ranging between 1 mg/kg and 10 mg/kg IL-1ra. At 3 h into the infusion, plasma IL-1ra levels were 3.1 micrograms/ml and 29 micrograms/ml for the 1 mg/kg and 10 mg/kg doses, respectively. Post-infusion plasma IL-1ra levels declined rapidly, exhibiting an initial half-life of 21 min and a terminal half-life of 108 min. Clinical, hematological, biochemical, endocrinological and immunomodulatory effects were monitored over 72 h and compared to those of four subjects receiving a 3 h infusion of saline. There were no clinically significant differences between the drug and saline groups in symptoms, physical examinations, complete blood counts, mononuclear cell phenotypes, blood chemistry profiles, serum iron and serum cortisol levels. Peripheral blood mononuclear cells (PBMC) obtained after completion of the IL-1ra infusion synthesized significantly less interleukin 6 ex vivo than PBMC from saline-injected controls. These data suggest that transient blockade of interleukin 1 receptors is safe and does not significantly affect homeostasis.