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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Effects of obesity on cholinergic and noncholinergic endpoints of organophosphate toxicity following chlorpyrifos exposure in standard and high fat diet fed animals

Kondakala, Sandeep Reddy 25 November 2020 (has links)
Obesity is a prevalent disease in which, when compared to individuals of normal weight, obese individuals have noted pathophysiological alterations including increased adiposity and fat mass which may alter toxicokinetics of xenobiotics and therefore alter their toxicities. However, the effects of obesity and the altered pathophysiology accompanying this condition on the toxicity of many widely utilized pesticides have not been established. Organophosphate (OP) pesiticides, including chlorpyrifos (CPS), have historically been widely used for agricultural purposes. CPS and several other notable OPs are no longer registered for household use but still used mainly in agriculture by registered users. CPS is bioactivated to form chlorpyrifos-oxon (CPO) in liver by cytochrome P450 isozymes. Acute toxicity of CPS exposure is inhibition of acetylcholinesterase (AChE) in the central and peripheral nervous systems. The other targets following CPS exposure are the noncholinergic serine hydrolase enzymes: carboxylesterase (CES), fatty acid amide hydrolase (FAAH), and monoacylglycerol lipase (MAGL). Therefore the current study was designed to: 1) determine the time and concentration-dependent effects of CPS on noncholinergic endpoints of OP toxicity utilizing hepatoma cells under normal and steatotic conditions 2) determine if obese phenotype altered the toxicity of CPS, including both cholinergic and non-cholinergic endpoints and 3) determine the effects of high fat diet on CPS bioaccumulation and detoxication by determining CPS and 3,5,6-trichloro-2-pyridinol (TCP) levels at different time points. The current in vitro studies determined that CES is more sensitive to CPS mediated inhibition in normal and steatotic conditions compared to FAAH and MAGL. The in vivo studies determined that CPS (2 mg/kg) exposure produced a greater inhibitory effect on hepatic CES and FAAH in obese animals compared to lean animals which indicates that the obese animals may be at greater risk for CPS mediated alterations in hepatic lipid metabolism upon chronic exposure. Our toxicokinetic studies using a higher dose of CPS (25 mg/kg) did not inhibit AChE in CNS and did not alter the overall CPS levels between normal and obese animals. Peak levels of TCP were decreased in liver of obese animals at 3 hours and overall hepatic TCP levels were significantly decreased in obese animals.
2

The Pharmacodynamics and Toxicodynamics of Inotropic Drugs in Calves With Natural and Artificial Hearts

Everett, Scott D. 01 May 1994 (has links)
Inotropic support for the failing myocardium as the therapy for xi congestive heart failure (CHF) is intended to achieve an increase in cardiac output via positive responses in myocardial contractility and vasodilation. A novel approach to differentiate these two responses is the use of an animal with an implanted total artificial heart (TAH). Three inotropic drugs, dobutamine, enoximone, and pimobendan, were tested in eight animals with their natural heart intact and five animals implanted with a TAH. Baseline values of the TAH and natural heart (NH) were compared to determine their hemodynamic similarities. Each of the three drugs was given randomly to the animals in dosages similar to human clinical doses. Peak responses were recorded and analyzed. All three drugs caused an increase in contractility and cardiac output in the NH animals. Dobutamine and pimobendan also caused a significant increase in heart rate at higher dosages whereas enoximone did not. Dobutamine caused an increase in left ventricle work, as did pimobendan at the first dose given; at higher doses of pimobendan, the left ventricular work returned to baseline. However, at the doses tested, the left ventricular stroke work during enoximone administration decreased. Vasodilation (the only drug stimulation response in the TAH model) was also observed with the administration of the drugs in T AH animals, and all three caused decreases in systemic and pulmonary vascular resistance. Dobutamine and pimobendan caused an increase in left and right atrial pressures (because of the mechanical heart not being adjusted to compensate the increased return). There was also a reduction in systemic and pulmonary resistance. Enoximone caused severe pulmonary hypertension in the TAH animals, possibly due to stimulus of platelets to release vasoconstrictive substances. Thus, dobutamine, enoximone, and pimobendan significantly contribute to increases in output by vasodilation in animals with a natural heart. Similarly, dobutamine and pimobendan's vasodilatory action is identified in an animal with a TAH. However, enoximone's hypertensive action on the pulmonary vasculature of a TAH animal may offer an insight to the toxicity of enoximone when used after recent surgery.

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