THE DIRECT AND INDIRECT EFFECTS OF HERBAL PRODUCTS ON COMMON DRUG METABOLIZING ENZYMES AND DRUG TRANSPORTERS

The increase in the use of herbal products, particularly in patients taking conventional medicine, has increased the likelihood of drug-herb interactions. Herbal products sold to the public are often not a single chemical compound, but rather a complex mixture of hundreds of different constituents. Human microsomal systems have been employed as a cost and time efficient approach to prospectively evaluate individual constituents for the potential for interactions with drug metabolizing enzymes. In fact, it has been shown that certain herbal constituents are capable of direct inhibition of drug metabolizing enzymes in this system. However, extrapolation of the drug interaction potential to cellular systems or whole organisms is often difficult because the preparation of microsomes necessitates the destruction of the integrity of the living cell and the physiologically relevant processes within. The primary goal of this dissertation research was to investigate the effect of herbal products on human hepatic drug metabolizing enzymes and transporters using primary cultures of human hepatocytes.Cultured hepatocytes were exposed to the various herbal constituents acutely, to evaluate the direct effect on enzyme activity, or chronically, to evaluate the indirect effect on enzyme expression and subsequent activity. Additionally, in order to assess to scalability of our in vitro UGT1A results to humans, healthy human subjects were administered acetaminophen, a general UGT1A probe, before and after a 7-day course of milk thistle. These data demonstrate that herbal constituents can directly inhibit enzyme activity but also influence activity by indirectly modulating gene expression. In the case of St. John's wort, human hepatocytes showed that while constituents were capable of enzyme induction, inhibition also occurred. However, in vivo, it is the former that predominates over the latter. Furthermore, our predictions of interactions in vivo for St. John's wort have been validated through a number of clinical studies. The case of milk thistle, however, proved more complex. While our in vitro data showed the possibility of drug interactions with several drug metabolizing enzymes, little effect was found in vivo. The latter demonstrates the value of consideration of the entire pharmacologic profile of an herb before conclusions about clinical relevance are made

7Li NMR of Normal Human Erythrocytes

Lithium has been known to be an effective medication for people with bipolar disorder. The mechanisms of action of lithium in the brain is not very well understood. NMR spectroscopy and imaging are effective both in determining lithium levels in tissue and brain. We have monitored lithium levels in red blood cells. We have been able to separate intra- and extracellular compartments of lithium using shift reagents, thereby obtaining T^1 \u27s of both the compartments. Lithium uptake as a function of hematocrit was monitored weekly over a 3 week period. The time constant of 50 mM lithium uptake at 25°C and 85% hematocrit was found to be 16.5 hrs. The time constant of 1.8 mM lithium uptake at 37 °C and 45% hematocrit was found to be 11.6 hrs. Experiments on the visibility of the quadrupolar nuclei indicate that it is only 74-90% visible and the visibility decreased with decreasing concentrations

A study of the acid etch pretreatment used with the Nuva-seal dental process

Nuva-Seal, a bisphenol-A-glycidyl-methacrylate polymer, is applied to the occlusal surface of teeth to prevent tooth decay. Before application of the sealant, the enamel surface is etched for one minute by a 50 percent by weight solution of phosphoric acid containing seven percent by weight of zinc oxide. This treatment renders the tooth surface more porous and surface active to insure a strong bond between tooth and sealant. Past studies at Union College have shown that the etching treatment removes much of the enamel from the tooth. In the current work the amount of tooth removed by acid etching was determined gravimetrically. Seven teeth were etched in vitro using an etchant solution similar to that recommended for use with Nuva-Seal. The total time of etching was one minute. Measurements of the weight losses for each tooth were made after every 20 seconds of acid attack. The maximum amount of etch appears to occur between 20 and 40 seconds of acid etching. The results of an extensive literature search are also included

Women at Bryant : a History, 1863 - Present

This paper highlights the history of influential women at Bryant and Bryant\u27s contribution to the education of women from 1863 to 2009. Bryant students Jillian Emberg \u2712 and Jessica Komoroski \u2711, \u27honors’ students in Professor Judy Barrett Litoff’s American Women’s History Class, presented this paper at Bryant\u27s Celebrate Women event held November 10, 2009 at Bryant University commemorating the 40th anniversary of Women\u27s Studies programs

Method to Correct the Voxel Size in PRESS Localized NMR Stereoscopy

Two techniques commonly used on human magnetic resonance spectroscopy systems to obtain spectra from localized volumes in the brain are point resolved spectroscopy (PRESS) and stimulated echo acquisition mode (STEAM) spectroscopy. PRESS gives a signal twice as large as that obtained with STEAM, but suffers from longer minimum echo times. While STEAM must be used to detect species with short spin-spin relaxation times, PRESS can be used for species with longer relaxation times to give a spectrum with a better signal to noise ratio. Only STEAM was provided for the GE Omega 4.7 T small animal imager used in this laboratory. Therefore, a PRESS pulse program was written for this instrument. With the standard sequence, the sampled voxel is smaller than the prescribed voxel. A larger voxel can be prescribed to increase the sampled volume. A different approach, involving the modification of the gradient strength, has been used in this laboratory. The resulting pulse sequence, with representative profiles, is discussed

Solid State NMR of Hydrogen in Thin Film Synthetic Diamond

Thin film synthetic diamond promises to be the next semiconductor material, if the manufacturing processes which produce it can be controlled. Solid state nuclear magnetic resonance (NMR) using magic angle spinning (MAS) is used to measure the content of hydrogen in diamond which controls the resistivity of the diamond thin films. Spectral results are presented for proton NMR of thin film synthetic diamond. Experimental calibration techniques using BaF2 as the hydrogen standard will be discussed, as well as acquisition times, pulsing sequences, spinning rates, and rotor composition

Dapagliflozin Monotherapy in Type 2 Diabetic Patients With Inadequate Glycemic Control by Diet and Exercise: A randomized, double-blind, placebo-controlled, phase 3 trial

OBJECTIVE - Dapagliflozin, a highly selective inhibitor of the renal sodium-glucose co-transporter-2, increases urinary excretion of glucose and lowers plasma glucose levels in an insulin-independent manner. We evaluated the efficacy and safety of dapagliflozin in treatment-naive patients with type 2 diabetes. RESEARCH DESIGN AND METHODS - This was a 24-week parallel-group, double-blind, placebo-controlled phase 3 trial. Patients with A1C 7.0-10% (n = 485) were randomly assigned to one of seven arms to receive once-daily placebo or 2.5, 5, or 10 mg dapagliflozin once daily in the morning (main cohort) or evening (exploratory cohort). Patients with A1C 10.1-12% (high-A1C exploratory cohort, it n=73) were randomly assigned 1:1 to receive blinded treatment with a morning close of 5 or 10 mg/day dapagliflozin. The primary end point was change from baseline in A1C in the main cohort, statistically tested using an ANCOVA. RESULTS - In the main cohort, mean A1C changes from baseline at week 24 were -0.23% with placebo and -0.58, -0.77 (P = 0.0005 vs. placebo), and -0.89% (P < 0.0001, vs. placebo) with 2.5, 5, and 10 mg dapagliflozin, respectively. Signs, symptoms, and other reports suggestive of urinary tract infections and genital infection were more frequently noted in the dapagliflozin arms. There were no major episodes of hypoglycemia. Data from exploratory cohorts were consistent with these results. CONCLUSIONS - Dapagliflozin lowered hyperglycemia in treatment-naive patients with newly diagnosed type 2 diabetes. The near absence of hypoglycemia and an insulin-independent mechanism of action make dapagliflozin a unique addition to existing treatment options for type 2 diabetes