No description available.

No description available.

No description available.

No description available.

A series of 2-alkyl-3-arylpyrido[2,3-d]pyrimidones were synthesized for testing as potential antiepileptic drugs. The goal was to achieve better neurological activity and/or lower toxicity than displayed by a series of 2-alkyl-3-aryl-4(3H)-quinazolinones prepared previously in our research group. From the pharmacological testing data of these target compounds, we have found that the additional nitrogen at the C-8 position of the quinazolinone framework increased the anticonvulsant activity. However, the neurological toxicity increased as well. The anticonvulsant and neurotoxic activity seen in the variuos 2-alkyl side chains and 3-aryl substituents incorporated into these new pyridopyrimidones was consistent with the activity observed with the same substituents on the 4(3H)-quinazolinones. The 3-aryl group consists of various ortho-substituted phenyl rings, while the 2-alkyl chain consists of a 2-(2-aryl-2-oxo)ethyl or 2-arylethenyl group. / Master of Science

An increased demand by consumers for more prescription drug information has resulted in many consumer-oriented books on the subject. Fourteen such books were identified and assessed for readability, completeness, and accuracy. Ten drugs were randomly selected for review from among the 225 most frequently prescribed brand name and generic drugs for 1980. The Caylor formula was selected to evaluate readability. The thirteen points from ASHP's "Statement on Pharmacist-Conducted Patient Counseling" served as the basis by which completeness was measured. The United States Pharmacopeia Dispensing Information (USP DI) served as the standard professional reference for counseling patients about their medicines. It was used to test the completeness and accuracy of each book. Descriptive statistics (means and standard deviations) were selected for the readability and completeness sections. Readability means ranged from ninth grade to college level. The intrabook readability range width ranged from less than one grade level to over four grade levels. Completeness ranged from less than 30% to over 75% of the information provided by the USP DI. All test books achieved a minimum accepatble level of accuracy relative to the USP DI. Finally, the books were rated and ranked by various factors related to their readability and completeness.

The medium offering the greatest resistance to heat transfer from the freeze-drying shelf to the moving and subliming surface is the space between the flat shelf top and the concave vial bottom. The resistance to heat transfer can be greatly reduced by improving the thermal conductivity of the intervening space. Several heat transfer augmentation devices, including a multilayered corrugated aluminum quilt and a conformable fluid cushion device, which fill this gap are described. The devices are inexpensive and easy to use. Experimental data show that the resistance of the intervening space is reduced appreciably and the drying rate is greatly increased. The fluid cushion device is superior to the aluminum quilt as it reduces the consequences of spillage of solution and provides greater intervial uniformity among the same batch of vials. Drying times obtained in experiments with and without the fluid cushion device are compared here for different sizes and different types of vials. Product evaluation is conducted by measuring the reconstitution time and observing the product under a microscope. The solubilities of two univalent electrolytes, sodium chloride and potassium chloride, have been measured in eight cosolvent-water binary systems. The solubility of both the solutes has been found to be adequately described by the log-linear solubility equation, log S(m) = log S(w) + fσ. The rank order of the desolubilization slopes obtained for the electrolyte solutes is compared with the solubilization of nonelectrolyte solutes. These results indicate that a cosolvent which is most effective in solubilizing a nonelectrolyte is also most effective in desolubilizing an electrolyte. The solubility of oxacillin sodium in methanol-water mixtures has been determined at various temperatures ranging from +21 to -26 degrees centigrade. The data has been fitted to the log-linear relationship as proposed by Yalkowsky et. al. The heat of solution is determined using the van't Hoff equation and was found to be nearly constant at 1.2 Kcal/mole. There appears to be no dependency of the slope of the log S(m) vs. fraction cosolvent plot to the temperature. The data suggests that there is a polymorphic or amorphic transition of oxacillin at -14.5 degrees centigrade.

No description available.

No description available.

Accurate identification of small-molecule compound substrates and effectors, within specific tissues, represents a highly relevant yet equally elusive objective. Accomplishing this goal would have major implications on the assessment of compound efficacy and potential toxicity with significant impact on drug discovery and development. Computationally, there are no methods to elucidate a compound mechanisms of action (MoA) in cell-context-specific and genome-wide fashions. Experimental approaches are equally limited in that they are effective in identifying only specific drug substrate classes (e.g., high-affinity substrates of kinase inhibitors) rather than the full repertoire of proteins that effect compound activity in a specific tissue, including those that may cause undesired toxicity. They are costly, laborious, and the relevant mechanistic assays can only be performed in vitro. Here I introduce DeMAND, a novel algorithm for the regulatory network-based elucidation of compound Mechanisms of Action. The algorithm interrogates a context-specific regulatory network using at least six gene-expression profiles representative of in vitro or in vivo compound perturbation to identify compound dysregulated sub-networks as well as substrates and effector proteins. In experimental tests, the algorithm correctly identified proteins in the established MoA of over 90% of the tested compounds, including protein such as SIK1, a private effector of doxorubicin responsible for its cardiac toxicity, which is however not affected by less toxic topoisomerase inhibitors, such as camptothecin. Using gene expression profiles following perturbation of diffuse large B cell lymphoma cells with 14 and 92 compounds, respectively, at different concentrations and time points, I identified and validated several novel effector proteins. These include RPS3A (ribosomal protein S3A), VHL (von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase), and CCNB1 (cyclin B1) as effectors of the mitotic spindle inhibitor vincristine, all of which significantly affected microtubule architecture and/or modulated vincristine activity when silenced, as well as JAK2 (Janus kinase 2) as a novel effector/modulator of mitomycin C, which desensitizes cells to mitomycin C treatment when silenced. Finally, I used DeMAND to evaluate compound similarity by comparing the proteins in their MoA. I tested the similarity of altretamine, a compound with currently unknown substrates, and sulfasalazine, which were predicted to have similar MoA and in particular to be inhibitors of the GPX4 (glutathione peroxidase 4) protein. Experimental validation confirmed this prediction as well as increase in lipid reactive oxygen species (ROS) levels, a recently established downstream effector of sulfasalazine. Critically, DeMAND suggests that regulatory networks reverse engineered de novo form large molecular profile datasets can provide novel mechanistic insight into drug activity, thus providing a significant novel contribution to our search for highly specific and non-toxic small-molecule inhibitors.