PubMed Health⌕ Search

Biomedical subjects

C Orvig

Publications and source records attributed to C Orvig.

34 records · Page 2Linked to original sources
PubMed1996

Effects of low and high dose administration of bis(maltolato)oxovanadium(IV) on fa/fa Zucker rats.

The fatty Zucker rat, characterized by obesity, hyperinsulinemia, hyperlipidemia, and mild hyperglycemia, has been suggested as an animal model of non-insulin-dependent diabetes mellitus. The present study examined the chronic dose-dependent effect of bis(maltolato)oxovanadium(IV), a potent insulin mimetic, in this animal model of diabetes. Chronic (6 weeks) oral administration of bis(maltolato)oxovanadium(IV) (0.06 mmol.kg-1.day-1, low dose study) was effective in reducing the hyperinsulinemia associated with the fatty Zucker rat model (termination insulin: lean, 82.8 +/- 21.6; fatty, 732 +/- 89.4; fatty treated, 336 +/- 126.6 pmol/L; p < 0.05). Pancreatic perfusion data indicated a significant improvement in insulin secretory function in the fatty rats. The dose dependency of this relationship was observed in the high dose study (0.128 mmol.kg-1.day-1 for 14 weeks), wherein bis(maltolato)oxovanadium(IV) treatment restored plasma insulin levels in the fatty rats to lean levels (termination insulin: lean, 199.2 +/- 17.4; fatty 660.6 +/- 12.6; fatty treated, 153.6 +/- 9.6 pmol/L; p < 0.05) and significantly improved insulin response to a glucose challenge. In addition, bis(maltolato)oxovanadium(IV) treatment (high dose study) ameliorated the age-dependent increase in blood pressure observed in fatty Zucker rats (systolic blood pressure: lean, 127 +/- 10; fatty, 176 +/- 5; fatty treated, 156 +/- 9 mmHg (1 mmHg = 133.3 Pa)). These data indicate that chronic oral administration of bis(maltolato)oxovanadium(IV) in the drinking water was effective in reducing hyperinsulinemia, insulin resistance, glucose intolerance, and hypertension in the fatty Zucker rat.

Animals↗
PubMed1995

Evidence for energy-dependent transport of aluminum out of brain extracellular fluid.

Aluminum (Al) can cause CNS toxicity. The mechanism of its blood-brain barrier (BBB) permeation is poorly understood. In this study, microdialysis was used to determine extracellular fluid (ECF) unbound aluminum distribution between frontal cortex (FC) and blood during steady-state aluminum concentrations. The brain/blood aluminum ratio was determined. Over a 16-fold range of aluminum concentrations (dosed as aluminum citrate), brain/blood aluminum ratios were 0.10-0.15, consistently and significantly < 1. Aluminum diffusion cannot account for these results, suggesting the presence of a carrier that moves aluminum out of brain extracellular fluid. These aluminum brain/blood ratios (BBRs) were not significantly different over the range of concentrations studied, suggesting an inability to saturate the carrier. Brain/blood aluminum ratios obtained with four aluminum-hydroxypyridinones were also significantly < 1 (0.1-0.3), and were generally significantly different among themselves and from the aluminum citrate BBR. Movement of a BBB permeability marker from blood into brain extracellular fluid suggested partial BBB opening. The aluminum BBRs obtained (all << 1), in the presence of a partially opened BBR, suggest an efficient carrier moving aluminum out of brain ECF. Addition of cyanide to the brain microdialysis probe solution significantly increased the Al (citrate) BBR to 1. These results suggest the presence of an efficient, energy-dependent carrier that removes aluminum from brain ECF, either into brain cells or blood.

Aluminum↗
PubMed1995

Comparison of the glucose-lowering properties of vanadyl sulfate and bis(maltolato)oxovanadium(IV) following acute and chronic administration.

Numerous studies, both in vitro and in vivo, have demonstrated the insulin-mimetic properties of vanadium. Chronic oral administration of inorganic and organic compounds of both vanadium(IV) and vanadium(V) reduced plasma glucose levels and restored plasma lipid levels in streptozotocin-diabetic rats. We investigated the acute effects of both vanadyl sulfate and bis(maltolato)oxovanadium(IV) (BMOV), an organic vanadium compound, on plasma glucose levels by several routes of administration. Previous studies have shown that chronic administration of vanadyl sulfate has resulted in a sustained euglycemia following withdrawal of the drug. This effect was not observed following the chronic administration of BMOV; therefore, we investigated the effect of increasing the concentration of BMOV on the production of a sustained euglycemic response. An acute plasma glucose lowering effect was obtained with both vanadyl sulfate and BMOV when administered as a single dose by either oral gavage or intraperitoneal injection. In those animals that responded to vanadium treatment, plasma glucose levels were within the normal range within 2 to 6 h when given by i.p. injection or within 4 to 8 h when given by oral gavage. BMOV-treated rats that responded to treatment maintained the euglycemic effect for extended periods, ranging from 1 to 14 weeks following administration. However, vanadyl sulfate treated rats reverted to hyperglycemia within 12 to 24 h, depending on the route of administration. Intravenous administration of BMOV was effective in lowering plasma glucose levels only when administered by continuous infusion. An oral dose-response curve showed that BMOV was 2 to 3 times as potent as vanadyl sulfate. This difference in potency was observed with both oral and intraperitoneal administration, which suggests that the increase in potency with BMOV cannot be totally attributed to increased gastrointestinal absorption. Organic chelation of vanadium may facilitate uptake into vanadium-sensitive tissues. Chronic oral administration of higher concentrations of BMOV did not result in a sustained reduction in plasma glucose following withdrawal of the drug. All diabetic rats eventually responded to increased concentrations of BMOV with a restoration of plasma glucose levels to normal values; however, reversion to the hyperglycemic state occurred within 2 days of withdrawal of treatment. Chronic oral administration of BMOV did not produce a sustained euglycemic effect following withdrawal, but acute administration of the compound by either oral gavage or intraperitoneal injection did produce a long-term reduction in plasma glucose levels. Rats treated chronically with vanadyl sulfate remained euglycemic even after the drug was withdrawn. However, acute treatment produced only a transient euglycemia.

Administration, Oral↗
PubMed1995

Vanadium compounds as insulin mimics.

That vanadium compounds act in an insulin-mimetic fashion both in vitro and in vivo has been well established. Both inorganic and organic vanadium compounds have been shown to lower plasma glucose levels, increase peripheral glucose uptake, improve insulin sensitivity, decrease plasma lipid levels, and normalize liver enzyme activities in a variety of animal models of both type I and type II diabetes. Vanadium treatment of diabetic animals does not restore plasma insulin levels but may spare pancreatic insulin. Elucidation of the mechanism(s) of action and potentiation of vanadium's insulin-mimetic effect by appropriate ligand binding would seem to be the highest priorities for future investigation.

Animals↗
PubMed1994

Pharmacokinetics of aluminum 3-hydroxypyridin-4-one complexes: implications for aluminum redistribution subsequent to chelation therapy.

The pharmacokinetics of selected aluminum-hydroxypyridinone (Al-HP complexes were determined in rats to better understand the relationship between their disposition and elimination parameters and the safety of HPs in the chelation therapy of Al intoxication. Five complexes were administered as i.v. bolus doses of Al-HP (0.25 mmol/kg Al-0.75 mmol/kg HP). The Al-HP steady state volumes of distribution ranged from 220 to 871 ml/kg, suggesting that each complex distributed out of the vascular compartment (which should have been approximately 65 ml/kg). Systemic clearances ranged from 189 to 906 ml/h per kg. Elimination half-lives (t1/2) and mean residence times ranged from 0.36 to 0.84 and 0.52 to 1.20 h, respectively. The Al-CP20 complex had a short t1/2 and a midrange volume of distribution. It demonstrated no apparent toxicity, whereas myoclonic seizures were observed after Al-CP22, Al-CP24 and Al-CP94 administration. The most appropriate choice for Al chelation among the HPs tested may be CP20. Characterization of the distribution and elimination of Al-HP complexes improves the understanding of potential toxicity that may be associated with HP therapy of Al intoxication.

Aluminum↗
PubMed1994

Pharmacokinetics and distribution of tris(maltolato)aluminum(III) into the central nervous system.

The maltolate compound of aluminum (Al), tris(maltolato)aluminum(III), has been demonstrated to be quite toxic after central administration and in cell cultures. However, reports of peripheral Al-maltolate administration in vivo demonstrated unimpressive neurological effects. We found no reports of Al-maltolate pharmacokinetics or its distribution into the central nervous system (CNS) after systemic administration. In the present study, we evaluated Al pharmacokinetics in serum and Al distribution into brain extracellular fluid (ECF) in rats following Al-maltolate administration. The pharmacokinetic studies revealed that systemic clearance, elimination half-life and mean residence time were 42 (+/- 5) ml/hr/kg, 2.2 (+/- 0.5) hr and 3.1 (+/- 0.7) hr [mean +/- SD), respectively. The steady state volume of distribution (Vss) for Al-maltolate was 130 ml/kg. This Vss suggests that Al-maltolate may exhibit limited distribution outside the vascular compartment, which is estimated to be approximately 80 ml/kg in these rats. Previously, we used microdialysis (MD) probes to assess Al-citrate distribution into the CNS. MD was utilized in the present study to evaluate the CNS distribution of Al as a result of Al-maltolate administration. MD probes were implanted into the frontal cortex (FC) and jugular vein to sample Al from brain and blood ECF, respectively. Al was not measurable in FC MD probe dialysates after a 0.5 mmol/kg Al (as maltolate) bolus, but could be measured after steady state blood and brain ECF Al concentrations had been achieved. The Al brain/blood ration calculated from Al-maltolate steady state brain and blood MD samples was 0.04, significantly less than those calculated for other Al salts at equimolar Al doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Potential 99mTc radiopharmaceuticals for renal imaging: tris(N-substituted-3-hydroxy-2-methyl-4-pyridinonato)technetium(IV) cations.

A series of monocationic complexes of N-substituted-3-hydroxy-2-methyl-4-pyridinones labeled with technetium(IV)-99m have been evaluated in vivo as potential radiopharmaceuticals. The pyridinones have different substituents at the ring nitrogen atom: ethyl, i-propyl, i-butyl, benzyl, phenyl, p-methoxyphenyl, 3-butoxypropyl and cyclohexyl. Biodistribution studies of the 99mTc complexes have been carried out in rabbits and mice. High kidney uptake and retention of the radionuclide has been shown in rabbits and mice with the cationic complexes of 3-hydroxy-1-(p-methoxyphenyl)-2-methyl-4-pyridinone and 1-(cyclohexyl)-3-hydroxy-2-methyl-4-pyridinone. These 99mTcL3+ compounds appear to be morphologic renal agents.

Animals↗
PubMed1992

Potential 67Ga radiopharmaceuticals for myocardial imaging: tris(1-aryl-3-hydroxy-2-methyl-4-pyridinonato)gallium(III) complexes.

A series of highly lipophilic complexes of 1-aryl-3-hydroxy-2-methyl-4-pyridinones with gallium(III)-67 has been evaluated in vitro and in vivo as potential radiopharmaceuticals. The pyridinones have different substituents at the para-position of the phenyl ring: R = H, CH3, OCH3 and NO2. Biodistribution studies of 67Ga complexes have been carried out in rabbits, mice, rats and a dog. High heart uptake of the radionuclide has been shown in rabbits and the dog. The different biodistribution patterns in mice and rats indicate that there is a species difference in the biodistribution of these complexes. Rabbits and the dog show rapid heart uptake and blood clearance. The speciation of the Ga3+ ion in vivo is simulated in vitro with a simple blood plasma model based on the available thermodynamic data.

Animals↗
PubMed1992

Complexation of iron with the orally active decorporation drug L1 (3-hydroxy-1,2-dimethyl-4-pyridinone).

The stability constants for the Fe(III) complexes of the orally active iron decorporation drug L1 (3-hydroxy-1,2-dimethyl-4-pyridinone) have been determined by potentiometric titration [glass electrode, 25.0 degrees C, mu = 0.15 mol/L (isotonic) NaCl]. A simple computer model of blood plasma (citrate 100 mumol/L, transferrin 37 mumol/L) has been used to compare the Fe(III) binding efficacies in blood of L1 and the clinically used intravenously administered chelating agent deferoxamine.

Chelating Agents↗
PubMed1982

Chemical and in vivo studies of the anion oxo[N,N'-ethylenebis(2-mercaptoacetimido)]Technetate(V).

Studies of the anionic coordination complex 99Tc-oxo[N,N'-ethylene-bis(2-mercaptoacetimido)]technetate(V) ([TcO(ema)]-) are described. Syntheses performed both at carrier levels (10(-5)M) and with no carrier added (less than 10(-8)M) indicate that the complex is formed virtually quantitatively from pertechnetate ion over this range. Tissue distributions in normal rats are similar at both concentrations up to one hour after administration. It has been shown--using a combination of high-pressure liquid chromatography and field-desorption mass spectrometry--that the anion is excreted unchanged into both urine and bile. The effectiveness of this N2S2 donor set in sequestering Tc-99m, and the in vivo stability of the resulting complex, suggest that modified chelates of this structural class could provide a series of useful diagnostic agents.

Animals↗
PubMed1980

A survey of reducing agents for the synthesis of tetraphenylarsonium oxotechnetiumbis(ethanedithiolate) from [99Tc] pertechnetate in aqueous solution.

We have studied the effectiveness of various reducing agents in the production of the well-characterized complex [99TcO(SCH2CH2S)2]- from pertechnetate in aqueous solution. The reductants tested included sodium dithionite, hypophosphorous acid, formamidine sulfinic acid, dithiothreitol, hydrazine, and hydroxylamine. Of these, only sodium dithionite in the pH range 11--13 was found to give quantitative yields of the required technetium complex.

Arsenicals↗
PubMedDate not supplied

Increased potency of vanadium using organic ligands.

The in vivo glucose lowering effect of orally administered inorganic vanadium compounds in diabetes was first reported in our laboratory in 1985. While both vanadate and vanadyl forms of vanadium are orally active, they are still not well absorbed. We have synthesized several organic vanadium compounds and one compound, bis(maltolato)oxovanadium(lV) or BMOV, has been extensively investigated. BMOV proved effective in lowering plasma glucose and lipids in STZ-diabetic rats when administered in drinking water over a 25 week period. The maintenance dose (0.18 mmol/kg/day) was approximately 50% of that required for vanadyl sulfate (VS). Secondary complications of diabetes were prevented by BMOV and no marked toxicity was noted. Oral gavage of STZ-diabetic rats with BMOV also reduced blood glucose levels. The ED50 for BMOV was 0.5 mmol/kg, while for VS the estimated ED50 was 0.9 mmol/kg. BMOV was also effective by the intraperitoneal route in STZ-diabetic rats. The ED50 was 0.08 mmol/kg compared to 0.22 mmol/kg for VS. Some animals treated p.o. or i.p. remained euglycemic for up to 14 weeks. An i.v. infusion of BMOV of 0.05 mmol/kg over a 30 min period reduced plasma glucose levels by 50% while VS was not effective.

Animals↗
PubMedDate not supplied

Active oxygen species formation in synaptosomes exposed to an aluminum chelator.

This study evaluates the potential of two chelators, 1,2-dimethyl-3-hydroxypyridine-4-one (Hdpp) and 1-n-butyl-2-methyl-3-hydroxypyridin-4-one (Hnbp), to modulate cerebral rates of free radical production. The fluorometric assay for 2',7'-dichlorofluorescein, which is formed by oxidation of a nonfluorescent precursor (2',7'-dichlorofluorescein diacetate), was used to assay reactive oxygen species (ROS) production. The chelator Hdpp alone and the aluminum complexes of each chelator, Al (dpp)3 and Al (nbp)3, all inhibited basal rates of generation of ROS within a rat cerebral synaptosomal fraction. In the presence of an iron salt (1 microM FeSO4), a major enhancement of synaptosomal ROS formation was apparent. However, with the addition of an equimolar concentration of Hdpp, Al(dpp)3, or Al(nbp)3, this stimulation was completely abolished. The N-substituted-3-hydroxy-4-pyridinones have been proposed to be of clinical utility for the removal of iron or aluminum from tissues. The clinical potential of this class of chelator may be enhanced by their ability to inhibit iron-related oxidative events.

Aluminum↗
PubMedDate not supplied

Glucose-lowering effects of a new organic vanadium complex, bis(maltolato)oxovanadium(IV).

Inorganic vanadium has been shown, both in vivo and in vitro, to have insulin-mimetic properties. A new organic vanadium complex, bis(maltolato)oxovanadium(IV) (BMOV), was developed to increase the absorption of vanadium from the gastrointestinal tract, thereby reducing the dose of vanadium necessary to produce glucose-lowering effects. BMOV was administered in the drinking water for 25 weeks to control and streptozotocin-induced diabetic, male Wistar rats. BMOV treatment produced a stable euglycemic state in 70% of diabetic treated animals. The other 30% of the diabetic treated animals demonstrated fluctuations in glucose control over the entire study period. The initial effective dose of BMOV was 0.45 mmol/kg, which decreased to an effective maintenance dose of 0.18 mmol/kg, significantly lower than the dose of inorganic vanadium salts used in previous studies. BMOV treatment did significantly reduce fluid consumption levels in control treated animals after 10 weeks of therapy; however, the food consumption for control treated animals was only intermittently lower than that for controls. Plasma cholesterol and triglyceride levels were normalized with BMOV treatment for all diabetic treated animals, without a concomitant increase in plasma insulin levels. An oral glucose tolerance test demonstrated that glucose homeostasis in control-treated animals occurred at significantly lower plasma insulin levels than in control animals. BMOV effectively produced the glucose-lowering effects at significantly lower dose than previously used for inorganic vanadium salts, without any overt signs of toxicity.

Animals↗
PubMedDate not supplied

Improvement in cardiac dysfunction in streptozotocin-induced diabetic rats following chronic oral administration of bis(maltolato)oxovanadium(IV).

Decreased cardiac function in streptozotocin-diabetic rats has been used as a model of diabetes-induced cardiomyopathy, which is a secondary complication in diabetic patients. The present study was designed to evaluate the therapeutic effect of a new organic vanadium complex, bis(maltolato)oxovanadium(IV), (BMOV), in improving heart function in streptozotocin-diabetic rats. There were four groups of male, Wistar rats: control (C), control treated (CT), diabetic (D), and diabetic treated (DT). Treatment consisted of BMOV, 0.5 mg/mL (1.8 mM) for the first 3 weeks and 0.75 mg/mL (2.4 mM) for the next 22 weeks, in the drinking water of rats allowed ad libitum access to food and water. BMOV lowered blood glucose to < 9 mM in 70% of DT animals without any increase in plasma insulin levels, and mean blood glucose and plasma lipid levels were significantly lower in DT vs. D rats. Tissue vanadium levels were measured in plasma, bone, kidney, liver, muscle, and fat of BMOV-treated rats. Plasma vanadium levels averaged 0.84 +/- 0.07 microgram/mL (16.8 microM) in CT rats and 0.76 +/- 0.05 microgram/mL (15.2 microM) in DT animals. The highest vanadium levels at termination of this chronic feeding study were in bone, 18.3 +/- 3.0 micrograms/g (0.37 mumol/g) in CT and 26.4 +/- 2.6 micrograms/g (0.53 mumol/g) in DT rats, with intermediate levels in kidney and liver, and low, but detectable levels in muscle and fat. There were no deaths in either the CT or DT group, and no overt signs of vanadium toxicity were present. Tissue vanadium levels were not correlated with the glucose-lowering effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗