No description available.

No description available.

The present research is focused on the topic of inflammation-drug interaction. Inflammation complicates many human diseases and conditions ranging from obesity to cancer. Therefore, the study of the effect of inflammation on drug pharmacokinetics and pharmacodynamics is pivotal. First, we tested the hypothesis that controlling inflammation using valsartan can restore the previously reported altered verapamil pharmacokinetics and pharmacodynamics. Such an effect is expected due to the anti-inflammatory properties of angiotensin II inhibition. Inflammation resulted in L-type calcium channel target protein (Cav1.2) downregulation and reduced verapamil potency in pre-adjuvant arthritis rat model. Valsartan treatment reversed the observed downregulation of L-type calcium channels thereby enhancing verapamil potency. This beneficial interaction, once proven in humans, may be of value in cardiac patients with superimposing inflammatory diseases. Second, we investigated whether the response to verapamil is reduced in experimentally induced acute myocardial injury (AMI) in rats. AMI caused a 75% reduction in verapamil potency and Cav1.2 target protein downregulation. If extrapolated to humans, our observations may suggest that L-type calcium channel downregulation can contribute, at least in part, to the poor outcome in myocardial infarction patients treated with calcium channel blockers (CCBs). Third, we studied the effect of obesity on the pharmacological response of CCBs in children with renal disease. Our data indicated that obese children are less responsive to CCBs than non-obese ones. Therefore, obesity should be considered when initiating antihypertensive drug therapy in children. Last, we were interested in finding out if the expression of other target genes is also altered by inflammation. We used real time polymerase chain reaction, after determination of the best housekeeping gene to be used as an internal control. Inflammation resulted in significant alterations of several molecular targets and transporters affecting the pharmacokinetics and pharmacodynamics of drugs. These findings may provide an insight into the effect of inflammation on drug targets and modulators of disease pathogenesis. In conclusion, inflammation is a missed ring in the chain of therapy. The research presented in this thesis will add to the inflammation-drug interaction field important findings that will help understanding the role of inflammation in pharmacotherapy outcomes. / pharmaceutical sciences

Thesis (Ph. D.)--University of Wisconsin--Madison, 1985. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 178-200).

No description available.

The purpose of this study was to examine exercise responses during acute and chronic administration of BB, Beta Blockade. Twenty-eight healthy males performed maximal treadmill exercise tests after 1 day and 9 days of 3 double-blind, randomized conditions: a placebo (Pl), propanolol (Pr) 80 mg bid, and atenolol (At) 100 mg daily. Maximal heart rate (HR), oxygen consumption (VO₂), ventilation (VE), and treadmill time (TT) were significantly reduced by Pr and At after an acute and chronic dose. An acute dose of Pr and At caused a greater decrease in maximal HR compared to chronic administration (143.1 ± 5.0 b min⁻¹ at day 1 vs. 147.7 ± 4.2 b min⁻¹ at day 9). However, the overall exercise response was not effected by the change in HR in either the TR or UT subjects. These data indicate that there is no difference in exercise response to acute and chronic BB in young healthy males. (Abstract shortened with permission of author.)

Dexmedetomidine is α2-adrenergic agent and commonly used in the intensive care setting. It is used primarily to sedate critically ill patients in various surgical, endoscopic and radiologic procedures. This medication gained superiority with other sedatives with a distinct advantage of less depression of the respiratory system. Although dexmedetomidine is often administered to septic patients, the vascular effect has not been fully studied in this clinical setting. In this thesis, rats were administered saline or bacterial lipopolysaccharide (LPS) 1, 10 and 20 mg/kg. Aortic rings were obtained after two, 24 and 72 hours exposure and dexmedetomidine-induced contractions were investigated. Rats could not tolerate prolonged exposure to 20 mg/kg LPS and died during the process. Systolic, diastolic and mean arterial pressures were reduced after LPS exposure while heart rates were elevated. Body temperatures were elevated after LPS administration (all doses and time), except a reduction at two hours with 1 mg/kg LPS. LPS increased the plasma levels of tissue necrosis factor-α and interleukin-6 after two hours LPS administration but not at 24 and 72 hours. In aortic rings with functional endothelium from rats with or without LPS exposure, dexmedetomidine had no effect on resting tension. Dexmedetomidine produced concentration-dependent contractions (10 nM to 10 μμM) after incubation with endothelial nitric oxide synthase (NOS) inhibitor L-NAME or removal of endothelium in rings without and with exposure to LPS for two, 24, 72 hours. LPS administration dose-dependently attenuated dexmedetomidine-induced contractions. In the presence of 1400W (inducible NOS inhibitor) the contractile response to dexmedetomidine was potentiated suggesting a role of NO produced by iNOS. Treatment with MnTMPyP attenuated dexmedetomidine-induced contractions indicating that the superoxide dismutase mimetic might increase NO availability by reducing superoxide. A significant role of iNOS was further supported by the detection of iNOS expression in aortic rings after LPS exposure at two, 24, and 72 hours when compared to non-LPS exposed group. Use of selective α2A and α2B receptor antagonists (BRL44408 and ARC239 respectively) showed that dexmedetomidine-induced contractions were mediated mostly via α2A receptor subtype as the former but not the latter agent significantly reduced contractions. Serotonin (5-HT, 10 nM to 100 μμM) and phenylephrine (1 nM to 100 μμM) produced concentration-dependent contractions in aortic rings with and without LPS exposure. The maximal responses to 5-HT and phenylephrine were increased at 10 mg/kg LPS as compared to a reduction in contractions by dexmedetomidine with LPS exposure at 1 and 10 mg/kg supporting alterations in α2 receptors occurred after LPS administration. In conclusion, the present study demonstrated that the vascular contractile responses of dexmedetomidine in the absence of endothelium or in the presence of eNOS inhibition were reduced in the presence of LPS at different time points and at different doses in aortic rings while two other receptor mediated vasoconstrictors, 5-HT and phenylephrine were affected. Our findings suggest that LPS may preferentially reduce the vascular contractile responses of dexmedetomidine and it is essential to exercise caution when the drug is administered to critically ill patients or with endothelial dysfunction. / published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy

Thesis (M.S.)--University of Wisconsin--Madison, 1984. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 81-86).

Two investigations were conducted to examine the influence of beta-adrenergic blockade on cardiovascular, respiratory, metabolic, and thermoregulatory responses to maximal and submaximal exercise in both highly trained and untrained subjects. In both studies, subjects received randomized and double-blind oral medication with atenolol (100 mg/day), propranolol (160 mg/day), and placebo. In the first study significant reductions in HR max and ‘VO₂ max resulted during the atenolol and propranolol treatments in both the trained and untrained subjects. However, the reductions in ‘VO₂ max were significantly greater in the trained subjects and both groups experienced their greatest reduction during the propranolol treatment. In all subjects, the magnitude of reduction in HR max was significantly greater than the concomitant decrease in ‘VO₂ max. It is concluded that untrained subjects have a greater compensatory reserve than do trained subjects during maximal exercise while under beta-adrenergic blockade. In addition, significant advantages were found with the use of a selective compared to a non-selective beta blocker. Thermoregulation during prolonged exercise in the heat with beta blockade was studied in fourteen subjects. Subjects performed 90-minute cycle ergometer rides at a workload equivalent to 40% of the subjects' unblocked ‘VO₂ max. Rectal temperature was slightly higher during the atenolol trial compared to the placebo but was not different during the propranolol trial compared to the placebo. Skin blood flow was significantly lower during the propranolol trial compared to both the atenolol and placebo trials, but it did not differ significantly between the atenolol and placebo trials. Maintenance of rectal temperatures appeared to be achieved through changes in sweat rate, skin blood flow, and a reduced heat production, i.e., lower ‘VO₂ during the propranolol trial. The decrease in cutaneous blood flow reported during the propranolol trial is likely associated with the associated increase in TPR. This increase in TPR would help to compensate for the lower ‘Q and, hence, help maintain mean arterial pressure. Changes in substrate utilization, i.e., decreased lipolysis, during the beta-blocked trials may also be indicated. Lastly, the inability of two subjects to complete the 90-minute ride, the elevated RPE values, and the additional side effects reported during the propranolol trial would indicate an advantage for the use of a selective blocker.

Thesis--M.D., University of Hong Kong, 1982.