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Biomedical subjects

V Jagadeesan

Publications and source records attributed to V Jagadeesan.

At least 19 recordsLinked to original sources
PubMed2006

Nonclinical toxicology study of recombinant-plasmid DNA anti-rabies vaccines.

The absence of standard guidelines from National and International regulatory agencies for the safety evaluation of biotechnology products challenges the ingenuity of toxicologists. At present, the development of standard pre-clinical toxicology protocols for such products is on an individual case basis. The present investigation is an attempt to evaluate the safety profile of the first indigenously developed DNA based anti-rabies vaccine in India. The test compounds were DNA rabies vaccine [DRV (100 microg)] and combination rabies vaccine (CRV (100 microg DRV and 1/50 dose of cell culture vaccine)), intended for clinical use by intramuscular route on 1, 7, 14 and 28 day. As per the regular mandatory requirements, the study has been designed to undertake acute (single dose--10 days), sub-chronic (repeat dose--28 days) and chronic (intended clinical dose--120 days) toxicity tests using three dose levels viz. therapeutic, average (2 x therapeutic dose) and highest dose (10 x therapeutic dose) exposure in Swiss Albino mice. The selection of the rodent model viz. Swiss Albino mice is based on affinity and rapid higher antibody response during the efficacy studies. Apart from physical, physiological, clinical, hematological and histopathology profiles of all target organs, the tier-I immunotoxicity parameters have also been monitored. There were no observational adverse effects even at levels of 10x therapeutic dose administration of DRV and CRV. The procedure also emphasizes on the designing of protocols for the products developed by recombinant technique.

Animals↗
PubMed2002

Role of red cell selenium in recurrent pregnancy loss.

Selenium is an essential trace mineral required for normal human health and reproduction. In recent years selenium deficiency in humans has been implicated as a risk factor for recurrent pregnancy loss. So far the selenium status in recurrent pregnancy loss (RPL) has been evaluated only in plasma and serum samples showing discrepancies of selenium deficiency as a cause for RPL. The present pilot study from India has evaluated selenium status in red cells (as they are the better indicators of selenium levels) in 20 women with three or more unexplained recurrent pregnancy losses compared to similar number of controls. The mean+/-SD red cell selenium levels in the study group was found to be 119.55+/-32.94 ng/ml (range 55-170 ng/ml), which was significantly lower compared to the control group with a mean+/-SD of 150.85+/-37.63 ng/ml (range 87-225 ng/ml). The difference was statistically significant at the 1% level ( P <0.01). Since selenium supplementation resulted in successful pregnancy outcome in veterinary practice, we conclude that large randomised studies are needed to assess the contribution of selenium in the aetiology of RPL and the potential benefits of its supplementation.

Abortion, Habitual↗
PubMed1996

Lipid peroxidation and activities of antioxidant enzymes in iron deficiency and effect of carcinogen feeding.

Iron deficiency has been implicated in increasing the risk of GI tract cancers in humans. Among various mechanisms of carcinogenesis, oxidative damage to DNA is well known and, hence, the present experimental study was undertaken to investigate lipid peroxidation and activities of different antioxidant enzymes in iron deficiency to explain the higher risk of tumorigenesis. Two groups of male weanling Fischer rats maintained on iron sufficient (C) or iron deficient (D) diets for a period of 32 weeks were subdivided, from 3 weeks onwards, into two subgroups each. The carcinogen, dimethyl hydrazine was fed at a dose of 30 mg/kg/week IG for a period of 9 weeks to groups that were designated as (C+) and (D+). The other two subgroups (C-) and (D-) served as controls. After the experimental period, hepatic assays for lipid peroxidation (MDA production) and activities of various antioxidant enzymes were carried out. The results showed that MDA production was elevated by 50% and activity of superoxide dismutase significantly depressed in carcinogen-fed, iron-deficient group (D+) by 28% compared to deficient (D-) group. There was an increase in hepatic selenium-dependent glutathione peroxidase activity in iron-deficient and iron-deficient, carcinogen-treated groups to the extent of 57 and 59%, respectively, as compared to controls; however, induction of enzyme in response to carcinogen feeding, observed in the control group, was not evident in iron deficiency. Liver catalase was not altered between control and deficient groups. These results suggest that prolonged iron deficiency superimposed with carcinogen ingestion may render the host susceptible to a greater risk of tumorigenesis through oxidative stress.

1,2-Dimethylhydrazine↗
PubMed1995

Effect of long term iron deficiency on the activities of hepatic and extra-hepatic drug metabolising enzymes in Fischer rats.

Male Fischer rats were maintained for a period of 17 weeks on an iron-deficient diet along with suitable controls. The effect of long term deprivation of iron on xenobiotic metabolism was studied by the activities of various drug metabolising enzymes in both liver as well as extra-hepatic tissues like lungs, kidneys and intestinal mucosa (I.M.). The results show that among the Phase I (activating) enzymes, the hepatic activities of benzo(a)pyrene hydroxylase (AHH) and microsomal epoxide hydrolase (mEH) are significantly reduced in iron deficiency. The other parameters of the activating system, namely cytochrome P450, aminopyrene demethylase (ADM) and aniline hydroxylase (AH), are not altered. Of the two Phase II (conjugating) enzymes studied, only uridine diphospho glucuronyl transferase (UDPGT) is found to be depressed, but not glutathione S-transferase (GST) in liver in iron deficiency. Activities of Phase I enzymes are markedly lowered in extra-hepatic tissues compared to liver; such depression is not observed in conjugating enzymes. Iron deficiency does not seem to make much impact on the enzyme activities of extra-hepatic tissues. Overall, the hepatic results suggest a defect in detoxification mechanisms in iron deficiency. Such impairment may very well predispose an iron-deficient host to an increased risk of carcinogenesis.

Aminopyrine N-Demethylase↗
PubMed1995

Development of a rat model for iron deficiency and toxicological studies: comparison among Fischer 344, Wistar, and Sprague Dawley strains.

We carried out a comparative study to develop iron deficiency in three strains of rats: Fischer 344, Wistar, and Sprague Dawley. Considering that certain ingredients in the diet, such as sucrose, may inhibit enzymes of drug metabolism, which we planned to study during an iron deficiency state, the diet was modified to contain 35% each of sucrose and starch. Results of hematologic studies at the end of 6 weeks of iron deprivation clearly indicated that all clinical signs of iron deficiency anemia--hemoglobin concentration, protoporphyrin-to-heme ratio, and serum and liver iron concentrations--were affected in the three strains. However, the deficiency was less pronounced in Sprague Dawley than in Wistar and Fischer 344 strains. Results of this study suggest that rat strains respond differently to dietary iron inadequacy; this variability could be exploited to suit specific experimental needs.

Anemia, Iron-Deficiency↗
PubMed1994

Effect of iron deficiency on DMH-induced gastrointestinal tract tumors and occurrence of hepatocyte abnormalities in Fischer rats.

The relationship between iron deficiency and carcinogenesis was studied using the carcinogen dimethylhydrazine to induce gastrointestinal tumors in Fischer 344 control and iron-deficient rats. Dimethylhydrazine (30 mg/body wt) was administered by gastric intubation 10 times over nine weeks. After 32 weeks, rats were sacrificed, and tumor incidence was assessed. The overall incidence of gastrointestinal tract tumors (colonic and duodenal) was higher in the iron-deficient (66%) than in the control group (46%). Whereas the incidence of colonic tumors was identical in control and iron-deficient groups, the duodenal tumor incidence was significantly elevated in iron deficiency. Five of 15 rats, i.e., 33.3%, in the iron-deficient group developed duodenal tumors; in the control group, only 1 of 15 rats developed a tumor (i.e., 6.6%). Also, iron-deficient rats had multiple tumors. Histological examination of the colon and duodenum revealed that the tumors were adenocarcinomatous in nature. Another notable feature in the iron-deficient group was the presence of atypical cells in the livers of carcinogen-treated iron-deficient rats. This study thus suggests that there is a greater incidence of tumors in iron deficiency and that the proximal part of the intestines seems to be the preferred site. The presence of atypical cells in the liver suggests that in iron deficiency, besides gastrointestinal tract tumors, the liver may also be a favored site for abnormalities.

1,2-Dimethylhydrazine↗
PubMed1993

Effects of riboflavin deficiency and riboflavin administration on carcinogen-DNA binding.

A study was conducted to assess the effects of riboflavin deficiency and riboflavin supplementation on carcinogen-DNA binding. After 12 wk on a riboflavin-sufficient or a riboflavin-deficient diet male Wistar rats were administered 3H-labelled benzo[a]pyrene (BP) ip. [3H]BP was given either at a uniform dose of 450 muCi/rat irrespective of body weight or at a dose adjusted to body weight. After 17 hr the animals were killed, various organs were dissected and the level of [3H]BP bound to DNA was quantified in organs that are known to be the seats of drug metabolism (i.e. the liver, lungs and intestinal mucosa). In a separate experiment, the effect of riboflavin supplementation on BP-DNA binding was also investigated. When [3H]BP was administered at 450 microCi/rat, BP-DNA binding was markedly increased in the livers and intestinal mucosae of the pair-fed and deficient groups compared with controls. With the administration of [3H]BP adjusted to body weight, no differences in BP-DNA binding between groups were observed in any tissue. However, on administration of riboflavin there was a decrease in the level of [3H]BP bound to DNA in almost all tissues, especially in the lungs, where the reduction was significant. The results suggest that undernutrition/riboflavin deficiency may increase the risk of carcinogenesis by way of an increase in carcinogen binding, which however can be reversed by riboflavin supplementation.

Animals↗
PubMed1991

Effect of administration of Aroclor 1254 on the activities of hepatic drug metabolizing enzymes in zinc deficiency.

In order to understand the mechanisms of carcinogenesis in zinc deficiency, a study was conducted in experimental animals to investigate the effect of administration of an inducer. After the production of zinc deficiency in NIN/Wistar strain of rats by feeding an egg albumin-starch based diet almost devoid of zinc, the animals were administered a potent inducer of mixed-function oxidases: Aroclor 1254 and various Phase I and Phase II enzymes of drug metabolism like benzo[a]pyrene hydroxylase, microsomal epoxide hydrolase, cytosolic epoxide hydrolase, and cytosolic glutathione-S-transferase studied in liver tissues. Control and pair-fed groups were also run alongside. The results showed that while the activities of various enzymes studied were low in the uninduced basal condition, these activities increased many-fold after induction. This induction was observed not only in the control group, but in the pair-fed and deficient groups as well. These results suggest that the ability to respond to a carcinogenic insult, though initially present in zinc deficiency, may not be adequate to counteract an excess or chronic exposure to carcinogen in the long run.

Animals↗
PubMed1989

Effect of food restriction on benzo(a)pyrene binding to DNA in Wistar rats.

A study was carried out to assess the binding of the carcinogen benzo[a]pyrene to DNA in different tissues under in vivo and in vitro conditions in Wistar rats which have been subjected to different levels of food restriction. The results showed that there was a significant increase in the binding of benzo[a]pyrene to hepatic DNA in food restricted animals in in vivo experimentation although this was not observed under in vitro conditions. There was a decrease in binding to pulmonary DNA and no change for renal DNA.

Animals↗
PubMed1989

Study of activating and conjugating enzymes of drug metabolism in zinc deficiency.

A study was undertaken to investigate the activities of certain enzymes of drug metabolism in zinc deficiency. For this purpose, an experimental model for zinc deficiency was produced in a NIN/Wistar strain of rats by feeding an egg albumin-starch based diet. Of the two enzymes of Phase I pathway of drug metabolism studied, Benz (alpha) pyrene hydroxylase was altered in zinc deficiency and food restriction; the other one microsomal epoxide hydrolase was unchanged. The activity of glutathione-S-transferase, a key enzyme in conjugation reaction was significantly lowered in zinc deficiency as well as food restriction. These alterations in the activities of xenobiotic metabolising enzymes are discussed with reference to toxicity manifestation in zinc deficiency.

Animals↗
PubMed1988

Serum complement levels in normal pregnancy and pregnancy-induced hypertension.

Serum complement assay (CH50) was carried out in urban low-income women belonging to the following groups: (i) non-pregnant and non-lactating women; (ii) pregnant women in different periods of gestation; (iii) women suffering from pregnancy-induced hypertension. Serum CH50 titers showed significant increase in the second and third trimester pregnancies as compared to non-pregnant, non-lactating women. There were no differences in CH50 levels between women suffering from pregnancy-induced hypertension and those with normal pregnancy of comparable period of gestation. Nutritional status did not seem to have any influence on complement titers.

Complement System Proteins↗
PubMed1988

Effects of dietary zinc deficiency on the activity of enzymes associated with phase I and II of drug metabolism in Fischer-344 rats: activities of drug metabolising enzymes in zinc deficiency.

A study was undertaken to assay the various phase I and phase II drug metabolising enzymes in zinc deficiency. Male weanling Fischer rats were subjected to zinc deficiency for a period of 7 weeks. Zinc levels in the control and deficient diets were 30 mg and 1.1 mg/kg diet, respectively. At the end of the experimental period, the activities of various hepatic cytosolic and microsomal enzymes were estimated. It was observed that the activities of microsomal epoxide hydrolase (with benz(a)pyrene 4-5 oxide as substrate), uridine diphospho glucuronyl transferase (with 1-naphthol as substrate) and cytosolic glutathione-S-transferase (with chlorodinitrobenzene as substrate) were altered exclusively due to zinc deficiency. There was a change in the activities of the following enzymes, which could be due either to zinc deficiency and/or food restriction: 1) aryl hydrocarbon hydroxylase; 2) cytochrome b; 3) cytochrome c; and 4) cytochrome b5. Other enzymes studied, i.e., cytosolic epoxide hydrolases, microsomal EHSTO, and UDPGT testosterone were not different in the control and experimental groups. The results are discussed in relation to the activation of carcinogens and neoplastic formation in zinc deficiency.

Animals↗
PubMed1985

Drug binding in the undernourished: a study of the binding of propranolol to alpha 1-acid glycoprotein.

The binding of propranolol, a drug commonly used in cardiovascular disorders, to alpha 1-acid glycoprotein (AGP) was studied in vitro in malnutrition. Compared to normal and hospital controls, the level of AGP was found to be elevated in undernourished subjects with and without infection. In the same patients the free drug percentage was significantly diminished. A significant inverse relationship was observed between the percentage of free drug and the level of AGP. The finding suggests that there may be need for an altered dosage regimen in the undernourished.

Humans↗
PubMed1982

Immune studies with T-2 toxin: effect of feeding and withdrawal in monkeys.

Ingestion of T-2 toxin, a product of Fusarium fungi, has been reported to have a variety of effects leading to morbidity and mortality in animals and humans. Semi-purified T-2 toxin was given to monkeys by gastric intubation at a level of 100 microgram/kg body weight/day for 4-5 wk and the haematological and immune parameters were studied before and after the treatment. Leucocyte counts were depressed at the end of wk 4 of treatment. The immunological studies studies showed suppression of the bactericidal activity of neutrophils, of cell-mediated immune status as assessed by T-cell number and lymphocyte transformation, and of humoral immunity as reflected in B-cell number and IgG and IgM levels. However serum complement (CH50) did not show any change. Investigations carried out 5 months after withdrawal of the toxin indicated that these parameters had returned almost to the initial, pretreatment levels. These data suggest that the greater incidence of infection seen in mycotoxin-ingesting animals may be due to immune suppression. Withdrawal of the mycotoxin results in improvement of haematological and immune functions.

Animals↗
PubMed1980

Plasma tocopherol and lipid levels in pregnancy and oral contraceptive users.

Plasma tocopherol (vitamin E), cholesterol and triglycerides were estimated to normal non pregnant women and in women throughout pregnancy. All three constituents were increased in the later stages of pregnancy. There was a significant statistical correlation between tocopherol and cholesterol levels, but not between the vitamin and triglycerides. The data suggest that the increase in tocopherol may be associated with a corresponding increase in cholesterol since both are known to share a common transport system, but the association was evident only during pregnancy. Compared to controls, plasma vitamin E levels were not altered in pre-eclampsia nor in oral contraceptive users.

Cholesterol↗
PubMed1980

Plasma tocopherol and lipid levels in mother and umbilical cord; influence on birth weight.

Levels of tocopherol, cholesterol and triglycerides were estimated in paired maternal and umbilical cord plasma samples. All three constituents were significantly lower in cord plasma than in maternal plasma. Since tocopherol and lipid share a common lipoprotein carrier system, the present data suggests that the reduction observed in cord circulation could be due to the inability of the fetus to synthesise these carrier proteins. There was no relation between maternal vitamin E concentrations and infant birth weights.

Birth Weight↗