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Selenite and organoselenium compounds have been examined at supranutritional levels for their ability to influence the activity and mRNA levels of chemoprotective enzymes in the livers of selenium-sufficient mice and the changes compared to those elicited by oltipraz. Compounds investigated included novel selenocysteine prodrugs that have previously been evaluated for their ability to reduce the tumorigenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mice. Following seven daily doses (i.g.), all compounds except 2-methylselenazolidine-4(R)-carboxylic acid (MSCA) increased thioredoxin reductase activity (43-92%) but only for 2-oxoselenazolidine-4(R)-carboxylic acid (OSCA) was there an accompanying increase in mRNA. No compound enhanced glutathione peroxidase activity, although sodium selenite significantly elevated the mRNA of this enzyme. Oltipraz was an efficacious inducer of both thioredoxin reductase and glutathione peroxidase mRNAs. Sodium selenite, selenazolidine-4(R)-carboxylic acid (SCA), and OSCA elevated NAD(P)H-quinone oxidoreductase mRNA but only for OSCA was the elevation in mRNA accompanied by an increase in enzyme activity. L-Selenocystine significantly increased this activity without increasing mRNA levels. Sodium selenite, L-selenocystine, L-selenomethionine, and Se-methyl-L-selenocysteine all enhanced glutathione S-transferase activity. The increased activity with sodium selenite was accompanied by increases in mRNAs of Gst alpha, Gst mu and Gst pi classes, while for L-selenocystine and Se-methyl-L-selenocysteine, only an elevation in the mRNA for the Gst alpha class was observed. Gst alpha and Gst mu class mRNAs were elevated by OSCA without a significant elevation in enzyme activity. SCA and MSCA both elevated a Gst pi mRNA and MSCA elevated Gst mu in addition. By comparison, oltipraz only significantly elevated the mRNA of Gst mu, adding to the conclusion that across the entire study, no selenium compound appears to be acting purely through the antioxidant response typified by oltipraz. Despite their chemical similarity, the three cysteine prodrugs, SCA, MSCA, and OSCA, each produced its own unique pattern of effects on protective enzymes and none was identical to the pattern elicited by sodium selenite, L-selenocystine, L-selenomethionine, and Se-methyl-L-selenocysteine. The study also shows that after 7 days of administration, there was only occasional concordance between elevations in mRNA and enzyme activity for any selenium compound and for any protective enzyme, there was no response in common for all selenium compounds.

Ribose cysteine (2(R,S)-D-ribo-(1',2',3',4'-tetrahydroxybutyl)thiazolidine-4(R)-carboxylic acid) protects against acetaminophen-induced hepatic and renal toxicity. The mechanism for this protection is not known, but may involve inactivation of the toxic electrophile via enhancement of glutathione (GSH) biosynthesis. Therefore, the goal of this study was to determine if GSH biosynthesis was required for the ribose cysteine protection. Male CD-1 mice were injected with either acetaminophen or acetaminophen and ribose cysteine. The ribose cysteine cotreatment antagonized the acetaminophen-induced depletion of non-protein sulfhydryls in liver as well as GSH in kidney. Moreover, ribose cysteine cotreatment significantly increased the concentration of acetaminophen-cysteine, hepatic acetaminophen-mercapturate in liver and renal acetaminophen-GSH metabolites in kidney 4 hr after acetaminophen. To determine whether protection against acetaminophen-induced liver and kidney damage involved ribose cysteine dependent GSH biosynthesis, buthionine sulfoximine was used to selectively block gamma-glutamylcysteine synthetase (gamma-GCS). Plasma sorbitol dehydrogenase (SDH) activity and blood urea nitrogen from mice pretreated with buthionine sulfoximine and challenged with acetaminophen indicated that both liver and kidney injury had occurred. While co-treatment with ribose cysteine had previously protected against acetaminophen-induced liver and kidney injury, it did not diminish the acetaminophen-induced damage to either organ in the buthionine sulfoximine-treated mice. In conclusion, ribose cysteine serves as a cysteine prodrug that facilitates GSH biosynthesis and protects against acetaminophen-induced target organ toxicity.

Acetaminophen (APAP) nephrotoxicity has been observed both in humans and research animals. Recent studies suggest a contributory role for glutathione (GSH)-derived conjugates of APAP in the development of nephrotoxicity. Inhibitors of either gamma-glutamyl transpeptidase (gamma-GT) or the probenecid-sensitive organic anion transporter ameliorate APAP-induced nephrotoxicity but not hepatotoxicity in mice and inhibition of gamma-GT similarly protected rats from APAP nephrotoxicity. Protection against APAP nephrotoxicity by disruption of these GSH conjugate transport and metabolism pathways suggests that GSH conjugates are involved. APAP-induced renal injury may involve the acetaminophen-glutathione (APAP-GSH) conjugate or a metabolite derived from APAP-GSH. Acetaminophen-cysteine (APAP-CYS) is a likely candidate for involvement in APAP nephrotoxicity because it is both a product of the gamma-GT pathway and a probable substrate for the organic anion transporter. The present experiments demonstrated that APAP-CYS treatment alone depleted renal but not hepatic glutathione (GSH) in a dose-responsive manner. This depletion of renal GSH may predispose the kidney to APAP nephrotoxicity by diminishing GSH-mediated detoxification mechanisms. Indeed, pretreatment of male CD-1 mice with APAP-CYS before challenge with a threshold toxic dose of APAP resulted in significant enhancement of APAP-induced nephrotoxicity. This was evidenced by histopathology and plasma blood urea nitrogen (BUN) levels at 24 h after APAP challenge. APAP alone was minimally nephrotoxic and APAP-CYS alone produced no detectable injury. By contrast, APAP-CYS pretreatment did not alter the liver injury induced by APAP challenge. These data are consistent with there being a selective, contributory role for APAP-GSH-derived metabolites in APAP-induced renal injury that may involve renal-selective GSH depletion.

Novel selenazolidine prodrugs of selenocysteine are being developed as potential selenium delivery agents for cancer chemoprevention and other clinical uses. The 2-unsubstituted compound, selenazolidine-4(R)-carboxylic acid (L-SCA), and the 2-oxo- and 2-methyl analogues possessing D-stereochemistry (D-OSCA and D-MSCA, respectively) were synthesized and chemically characterized. L/D pairs, along with other organoselenium compounds and common inorganic forms, were studied in cultured V79 cells to understand their inherent toxicity and their ability to induce selenium-dependent glutathione peroxidase (GPx) activity, which indicates the provision of biologically available selenium. All of the selenazolidines were much less toxic to the cells than was sodium selenite (IC(50) approximately 17 microM) or the parent selenolamines, L- or D-selenocystine (IC(50) approximately 34 or 39 microM, respectively); OSCA was less toxic than MSCA. The stereoisomers of OSCA produced very different IC(50) values (L-OSCA, approximately 451 microM; D-OSCA,3000 microM), while the IC(50) values derived for the stereoisomers of MSCA were of the same order of magnitude (L-MSCA, approximately 79 microM; D-MSCA, approximately 160 microM). Compounds possessing L-stereochemistry were at least as active with respect to GPx induction as was sodium selenite (2.2-fold increase at 15 microM). L-Selenocystine produced a 4.2-fold increase in GPx activity at 30 microM, while L-SCA produced a 5.9-fold increase, followed by L-OSCA (4.6-fold) and L-MSCA (2.1-fold), all at 100 microM. Compounds possessing D-stereochemistry showed minimal ability to induce GPx activity (D-selenocystine, 1.0-fold increase; D-OSCA, 1.4-fold increase; D-MSCA, 1.3-fold increase).

Experiments have been performed to document the in vitro binding of cocaine, benzoylecgonine (BE), amphetamine, and N-acetylamphetamine (N-AcAp) to synthetic melanin subtypes. The two predominant melanin types in hair are the black eumelanins and the reddish-brown pheomelanins. The melanins included in this study are two black eumelanin subtypes [5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) derived melanins], a reddish-brown pheomelanin [from 5-cysteinyl-S-Dopa (5-CysDOPA)], and two mixed eu-/pheomelanin copolymers. Results indicate that the basic drugs cocaine and amphetamine bind to eumelanins and mixed eu-/pheomelanins to varying degrees, but not to pure pheomelanin. BE and N-AcAp, net neutral molecules, do not bind to any type of melanin. As a model of which eumelanin chemical functional groups bind drugs, amphetamine was shown, using tandem mass spectrometry, to form a noncovalent adduct with dimerized oxidized catechol. Similar functional groups on the eumelanin polymer may represent an important drug-binding site. Overall, these findings show that basic drugs have a greater affinity for melanin than their net neutral analogues, reveal that melanin types differ when it comes to drug binding, help elucidate what properties of melanin are important for drug binding, and help explain why hair color biases exist.

Tea (Camellia sinensis) contains numerous polyphenolic flavonoid-derived compounds known as catechins, which have shown interesting protective activity against cancer and cardiovascular disease. Numerous products based on tea are commercially available, many of which claim to contain specific amounts of the bioactive catechins. The catechin content of seven commercial green tea products (encapsulated extracts or tea bags) was quantified by HPLC and, where possible, compared to that claimed on the label. Wide variability was observed in the catechin content between green tea products, even those that appear outwardly similar to consumers. Measured catechin content ranged from 9% to 48% of label claims; all values were significantly lower than those claims (P < 0.05). These results continue to demonstrate the problems that exist with quality control in the dietary supplement and herbal medicine industry and, there, for consumers of nutraceuticals.

Two new classes of selenazolidine-4(R)-carboxylic acids (2-oxo and 2-methyl-SCAs) were synthesized and characterized. Both were designed as latent forms of selenocysteine, intended to provide a chemically superior delivery form for selenium. The prodrugs may be clinically useful when selenium supplementation at supranutritional levels is indicated, such as in cancer chemoprevention.

Representatives of two classes of thiazolidine prodrug forms of the well-known radioprotective agents L-cysteine, cysteamine, and 2-[(aminopropyl)amino]ethanethiol (WR-1065) were synthesized by condensing the parent thiolamine with an appropriate carbonyl donor. Inherent toxicity of the prodrugs was assessed in V79 cells using a clonogenic survival assay. Protection against radiation-induced cell death was measured similarly after exposure to 0--8 Gy gamma ((137)Cs) radiation. Antimutagenic activity was determined at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus. All thiazolidine prodrugs exhibited less toxicity than their parent thiolamines, sometimes dramatically so. Protection against radiation-induced cell death was observed for the 2-alkylthiazolidine, 2(R,S)-D-ribo-(1',2',3',4'-tetrahydroxybutyl)thiazolidine (RibCyst), which produced a protection factor at 8 Gy of 1.8; the cysteine analogue, 2(R,S)-D-ribo-(1',2',3',4'-tetrahydroxybutyl)thiazolidine-4(R)-carboxylic acid (RibCys), was less active. RibCyst also exhibited excellent antimutational activity, rivaling that of WR-1065. The 2-oxothiazolidine analogues showed little activity in either determination under the conditions tested, perhaps due to their enhanced chemical and biochemical stability.

The effect of nonprotein thiol (NPT) free radical scavengers WR-1065 (SH) and WR-33278 (SS), the active thiol and disulfide metabolites of amifostine, N-acetylcysteine (NAC; both L- and D- isomers), mesna, captopril, and dithiothreitol (DTT) on NFkappaB activation in human microvascular endothelial cells (HMEC) was investigated and contrasted to TNFalpha. The use of each of these NPTs at millimolar concentrations independent of oxidative damage-inducing agents resulted in a marked activation of NFkappaB, with the maximum effect observed between 30 min and 1 h after treatment. Only the SH and SS forms of amifostine, however, were effective in activating NFkappaB when administered at micromolar levels. Using a supershift assay, SH and SS equally affected the p50-p65 heterodimer, but not homodimers or heterodimers containing p52 or c-Rel subunits of NFkappaB. Neither catalase nor pyruvate when added to the culture medium to minimize hydrogen peroxide production had an effect on NFkappaB activation by SH. Thus, while oxidative damage is known to activate NFkappaB, the intracellular redox environment may also be affected by the addition of free radical scavenging agents such as NPT, and these in turn are capable of activating the redox sensitive transcription factor NFkappaB. There does not appear to be a significant role, if any, for the production of H(2)O(2) as an intermediate step in the activation of NFkappaB by either the SH or the SS form of amifostine. Rather, the underlying mechanism of action, especially for the SS form, may be related to the close structural and functional similarities of these agents to polyamines, which have been reported to be capable of activating NFkappaB. In contrast to TNFalpha, exposure of cells to either 40 microM or 4 mM of SH for 30 min did not induce intercellular adhesion molecule-1 (ICAM-1) gene expression, but did increase manganese superoxide dismutase (MnSOD) gene expression. MnSOD expression rose by 2-fold and remained elevated from 4 to 22 h following SH exposure.

Methods not only for characterizing but also for quantitating melanin subtypes from the two types of melanin found in hair—eumelanin and pheomelanin—have been established. In relation to testing for drugs of abuse in hair, these methods will allow for correction of drug binding to specific melanin subtypes and will serve to improve drug measurement in hair. 5,6-Dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) make up the majority of the eumelanin polymer while benzothiazene units derived from 2-cysteinyl- S -Dopa (2-CysDopa) and 5-cysteinyl- S -Dopa (5-CysDopa) compose the majority of the pheomelanin polymer. Our results show that: (1) pyrrole-2,3-dicarboxylic acid (PDCA) and pyrrole-2,3,5-tricarboxylic acid (PTCA), markers for DHI and DHICA units, respectively, are produced in 0.37 and 4.8% yields, respectively, when melanins are subjected to alkaline hydrogen peroxide degradation, (2) 3-aminotyrosine (3AT) and 4-amino-3-hydroxyphenylalanine (AHP), markers for 2-CysDopa and 5-CysDopa, respectively, are produced in 16 and 23% yield, respectively, when subjected to hydriodic acid hydrolysis, and (3) that black human hair contains approximately 99% eumelanin and 1% pheomelanin, brown and blond hair contain 95% eumelanin and 5% pheomelanin; and red hair contains 67% eumelanin and 33% pheomelanin. These data will allow deeper investigation into the relationship between melanin composition and drug incorporation into hair.

Highly organized polymeric structures known as Starburst™ dendrimers have been subjected to qualitative structural evaluation using molecular modeling tools. These molecules are becoming increasingly important in several different fields ranging from drug delivery to applications in selective adsorption and catalysis, and even as chromatographic materials and adsorbents. Our studies suggest that low generation dendrimers are somewhat asymmetric and that the modification of the dendrimers with molecules such as porphyrins, may lead to the reduced accessibility of other surface groups thus limiting further modification.

Thiazolidine prodrugs of L-cysteine constructed with aldose monosaccharides as the carbonyl donor offer powerful protection against acetaminophen (APAP)-induced hepato-toxicity, but require large doses to be effective. Using disaccharides in prodrug synthesis produces a thiazolidine ring form with a cyclic sugar moiety present. This structural motif may allow the delivery of the prodrug to specific carbohydrate receptors, such as the asialoglycoprotein receptor (ASGPR) of hepatocytes, thus reducing the required dose of prodrug and enhancing the effectiveness of cytoprotection. The bio-distribution of [35S]-labeled prodrugs was investigated in Swiss-Webster mice, both in the presence and absence of APAP, and compared to labeled L-cysteine itself. Accumulation of radioactivity in liver appeared to be stimulated by the presence of APAP in some cases, but organ levels after prodrug administration were much lower than after the administration of L-cysteine itself. These studies identified differences in the biodistribution of L-cysteine prodrugs of different structural types, as well as effects of the hepatotoxin on localization, but the occurrence of targeted delivery to hepatocytes remains speculative. Copyright © 1999 John Wiley & Sons, Ltd.

Novel thiazolidine prodrugs were prepared by the condensation of L-cysteine with aldose disaccharides. Using a disaccharide in prodrug construction allows for a terminal cyclic sugar moiety to be present on the prodrug, which may allow the delivery of the agent to specific receptors, such as the asialoglycoprotein receptor (ASGPR) of hepatocytes, that require specific structural motifs for recognition. Three L-cysteine prodrugs were synthesized with a pendant cyclic galactose moiety; two related glucose-bearing prodrugs were synthesized for comparison. The prodrugs were designed to release L-cysteine, which is then available to support glutathione (GSH) biosynthesis and provide cytoprotection against a variety of toxic insults. Protection studies in Swiss-Webster mice used acetaminophen (575 mg/kg), a well-documented hepatotoxin which depletes GSH at overdose. Three prodrugs performed exceptionally well against acetaminophen-induced hepatotoxicity, as measured by increased survival and improved histological profiles of liver tissue after 48 h. In further experimentation, two of the disaccharide-based prodrugs, prepared from alpha- and beta-lactose, were compared with the monosaccharide-based compound prepared from ribose. Co-administration of the selected prodrugs with a 400 mg/kg dose of acetaminophen to Swiss-Webster mice prevented the short-term depletion in hepatic GSH and also reduced hepatotoxicity as determined by histological damage and serum levels of alanine aminotransferase. A single dose of the prodrugs alone had no effect on hepatic drug metabolizing enzymes [glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase (QOR), UDP-glucuronosyltransferase (UGT), and cytochrome P450], but, concordant with the reduction of hepatotoxicity, the latentiated forms prevented the significant elevation in QOR activity and mRNA and GST mRNA elicited by acetaminophen itself. GST activity, UGT activity and mRNA, and cytochrome P450 concentration were all unaffected by acetaminophen or the prodrugs. These studies identified novel L-cysteine prodrugs with potentially useful hepatoprotective activity. However, no structure-activity relationships were obvious. In addition, the occurrence of targeted delivery to hepatocytes remains ambiguous.

The radiation protective effect of thiol compounds is unequivocal and their use is only limited by their toxic effects. We used the principle of alpha alkylation, which renders amino acids unmetabolizable, to reduce the toxicity of homocysteine. This product, alpha-methyl-homocysteine thio-lactone, was tested for toxicity and radiation protective effect along with known protectors L-cysteine, cysteamine and WR 1065 in cell culture using V79-4 Chinese hamster lung cells. The three-day growth curve assays, useful to measure overall effects on cell growth, revealed lowest toxicity for alpha-methyl-homocysteine thiolactone (GL-2). Clonogenic survival tests, used to evaluate the retention of reproductive integrity, were carried out and revealed that GL-2 had no adverse effects in this test system. Radiation protection tests showed that GL-2 exhibited protective activity against radiation induced lethality above that seen with cysteine and cysteamine, but below WR 1065. However, GL-2 showed little or no negative effects toward the cell itself, in direct contrast to WR 1065. Our findings show a potentially important tool and principle to reduce toxicity of radiation protectors with analogous structures.

The synthetic porphyrins N-benzyl-5,10,15,20-tetrakis(4-carboxyphenyl)porphine (N-bzHTCPP) and N-4-nitrobenzyl-5-(4-carboxyphenyl)-10,15,20-tris(4-sulfophenyl)porphine (NbzHCS3P) represent excellent radiocopper chelating agents that may find utility in antibody-mediated diagnosis and/or therapy. Detailed analyses were performed to explore the effect of the chemical modification strategy on the characteristics of immunoconjugates prepared from the anti—renal cell carcinoma monoclonal antibody A6H and N-bzHCS3P. The parameters included in the study were antibody type [intact A6H and two of its fragments, half A6H and A6H-F(ab’)2], chemical linkage type and site, the presence or absence of intermediate linker molecules, and the nature of the chemical modification steps employed. The immunoconjugate synthesized by directly coupling N-bzHCS3P to whole antibody retained 75–85% of the immunoreactivity of the unmodified antibody. In general, however, immunoconjugates prepared using the fragments or the in...

PAMAM Starburst™ dendrimers are spherical macromolecules composed of repeating polyamidoamino units. They can be produced in successive “generations,” each with a defined size, molecular weight, and number of terminal amino groups. Because of these well-defined characteristics, PAMAMs are finding utility in a variety of applications, many of which are biological in nature. Little is known, however, about the biological behavior of the PAMAMs, which is critical to their use in vivo. Generation 3 (G3; MW = 5,147; 24 terminal amines), 5 (G5; MW = 21,563; 96 amines), and 7 (G7; MW = 87,227; 384 amines) PAMAMs were studied in V79 cells or in Swiss-Webster, mice for a number of biological properties, including (1) in vitro toxicity, (2) in vivo toxicity, (3) immunogenicity, and (4) biodistribution. Potential biological complications were observed only with G7 at the highest level tested. No evidence of immunogenicity was seen. The biodistribution properties of the Starburst™ dendrimers were rather unusual. G3 showed the highest accumulation in kidney tissue (∼15% ID/g over 48 h); G5 and G7 appeared to preferentially localize in the pancreas (peak levels ∼32% ID/g at 24 h, and ∼20% ID/g at 2 h, respectively). In addition, G7 showed extremely high urinary excretion, with values of 46 and 74% ID/g at 2 and 4 h, respectively. In general, the dendrimers did not exhibit properties that would preclude their use in biological applications. Depending on the situation (desired endpoint, dose, and generation used), however, the biodistribution of biological preparations should be carefully studied. © 1996 John Wiley & Sons, Inc.

PURPOSE: A variety of adjuvant treatments and cytoprotective agents have been proposed to lessen the toxicity of radiation therapy. The following study was designed to evaluate the benefit of six agents or combinations using anastomotic bursting strength as a measure of transmural radiation injury. METHODS: The 40-Gy study consisted of the following. Seventy-two male Sprague-Dawley rats were divided into eight equal groups: nonradiated control, radiated untreated control, and six radiated treated groups. The radioprotective treatments included ribose-cysteine (RibCys), WR-2721, glutamine, vitamin E, MgCl2/adenosine triphosphate, and RibCys/glutamine in combination. Radiated animals received 40 Gy to the abdomen. Two weeks after radiation, all animals underwent small bowel and colonic resection with primary anastomosis. Animals were sacrificed one week postoperatively, at which time anastomoses were evaluated and bursting strengths determined. The 70-Gy study consisted of the following. The same protocol was repeated for five groups of nine rats divided into nonradiated, radiated untreated, and three radiated treated groups receiving RibCys (8 mmol/kg), RibCys (20 mmol/kg), and WR-2721. All radiated animals received 70-Gy doses. RESULTS: In the 40-Gy group, there were 10 radiation-related deaths and 6 anastomotic leaks among 70 rats studied. None of the differences between groups were significant. Nonradiated control group small bowel and large bowel anastomotic bursting pressures were significantly elevated compared with all radiated groups. Compared with radiated controls, there were significant improvements in small bowel bursting strength in the RibCys, WR-2721, RibCys-glutamine, and vitamin E groups and significant improvement in colonic bursting strength in MgCl2/adenosine triphosphate, WR-2721, and RibCys groups. In the 70-Gy group, all nine nonradiated control rats survived. All eight untreated radiated control rats died, four of eight WR-2721 animals died (P=0.03), all RibCys (8 mmol/kg) animals died (P=0.03), and three of nine treated with RibCys (20 mmol/kg) survived (P=0.08). CONCLUSIONS: WR-2721 and RibCys gave consistent protection against large and small bowel radiation injury. The lower incidence of treatment-related toxicity and potentially equal or greater radioprotective effects may make RibCys more clinically useful than WR-2721.

Education seems to be in America the only commodity of which the customer tries to get as little he can for his money. (1) The Scottish social philosopher Adam Smith, who gave us the concept of the "invisible hand" as a force in society, is often credited with articulating the importance of the unintended consequences of actions, especially those taken on a societal scale. History is replete with examples of public policy that, while intended to address a societal need, has given rise to long-term, unanticipated negative consequences. For example, the generous donation of clothing to certain regions of Africa has decimated the local textile industry, exacerbating rather than relieving poverty. (2) In the healthcare arena, 1 of the commonly cited unintended consequences of our educational and practice efforts is the lack of innovation in health care and healthcare delivery. The Institute of Medicine Roundtable on Value & Science-Driven Health Care, whose purpose is "the development of a learning healthcare system that is designed ... to drive the process of discovery as a natural outgrowth of patient care; and to ensure innovation, quality, safety, and value in health care," has noted that "although medical care in the United States has the capability to be the world's best, it currently falls short. Far too often, care that is important is not delivered, and care that is delivered is not important." (3) The Roundtable was referring to health care in general, but we believe that their concerns are especially applicable to pharmacy practice and education. Over the past 2 decades, pharmacy education has undergone a major transformation with the shift to a doctor of pharmacy degree for entry-level practice. This change was made because of the prevailing belief at the time that pharmacy practice and pharmaceutical science were advancing to the point where additional education was required to ensure that the pharmacy profession maintained its leadership role in medication therapy management and ensuring the safety of drug therapy. (4) The result of this educational shift was a number of changes in how we recruit, educate, and place our students. While each measure enacted has been intended to advance our education of new professionals, it is legitimate to ask if these well-intentioned actions are giving rise to inadvertent negative consequences. In particular, we suggest that pharmacy educational programs are at risk of producing not the leaders and innovators needed to change health care but rather followers who will inappropriately tend to preserve the status quo in health care and pharmacy practice. We believe there are several trends promoting this concern. These are widespread and affect our key processes: admissions/recruitment, curricular design, programmatic evaluation, and preparation/advising for career placement. Our concerns begin with how we select students for admission to our programs. There is significant research published on the various admission processes used in colleges and schools of pharmacy. The research indicates that our quantitative measures (eg, Pharmacy College Admissions Test scores, prepharmacy grade-point average [GPA], math/science grades) are good predictors of academic success, defined as professional program GPA, graduation rates, and success on national board examinations. (5-9) Although most schools use these measures as key predictors for admittance, there appears to be little research on how good these measures are at predicting applicants' future leadership potential or their likelihood of becoming change agents for the profession. Fortunately, the requirement of the Accreditation Council for Pharmacy Education (ACPE) that all potential enrollees be interviewed enables us to combine these quantitative criteria with qualitative assessments. Interview approaches appear to vary widely and the ability of these approaches to predict students' academic performance or, more importantly, their potential for leadership or innovation is not clear. …

Buthionine sulfoximine (BSO) is widely used for its ability to deplete glutathione (GSH). However, BSO also induces key drug metabolizing enzymes, potentially complicating the interpretation of experimental results. The prothionine and hexathionine analogs of BSO were synthesized and evaluated as alternative agents which might offer an advantage over BSO by depleting GSH without inducing the enzyme activities.

There is little consistency in the literature regarding the procedures for sample preparation employed for the measurement of glutathione (GSH) in biological tissues. Most procedures use an acid to homogenize tissue samples to precipitate proteins from the mixture and to minimize oxidative changes. Others employ 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) in the homogenization, which serves only to block thiol groups. The present studies were undertaken to critically compare the two methods of sample preparation on resulting GSH values determined by the Tietze method in numerous organs of mice. It was found that kidney, liver, and pancreas GSH levels were seriously underestimated when DTNB was used instead of acid to prepare the tissue samples. This discrepancy was eliminated when the animals were pretreated with AT-125, confirming the participation of gamma-glutamyltranspeptidase, the enzyme responsible for the first step in the degradation of GSH. GSH added to kidney homogenates in DTNB was degraded rapidly and continuously in a time-dependent fashion. In contrast, GSH added to acid homogenates produced stable GSH values up to 8 h after sample preparation in most cases. Storage of acid homogenates at -70 degrees C for 12 months gave results identical to original measurements, within 10% error, for 9 of 10 samples tested.

While the accreditation of higher education institutions and their programs is voluntary in the United States, students' opportunities are hindered substantially if they attend or earn degrees from nonaccredited programs. For example, federal financial aid is available only to those students enrolled in institutions that have been accredited by an agency recognized by the US Department of Education. In the health professions, graduation from an accredited program is generally a prerequisite for sitting for state board examinations required for licensure as a practitioner. Accreditation is an important external certification that a program provides an educational experience that is consistent with producing graduates prepared to enter the workforce with the expected knowledge and abilities of entry-level practitioners. Recognizing that practice environments vary substantially, an accreditation agency must ensure that the educational programs it accredits are based on current and emerging standards of practice. Accrediting agencies must, however, strike a balance between ensuring minimal competencies of a program's graduates and allowing sufficient programmatic flexibility to support educational experimentation and innovation. Reaccreditation of educational programs can be a healthy process that provides an opportunity for programs to assess carefully and strategically their progress, opportunities, and challenges. It is also a time- and resource-intensive process; programs commonly devote 12 to 18 months to the development of a self-study and programmatic assessment in light of Accreditation Council for Pharmacy Education (ACPE) standards. During this period, widespread engagement in the self-study by faculty members, students, and staff members is necessary. The time and resources devoted to this process often delay the implementation of other important initiatives; thus, the frequency of reaccreditation itself can slow or minimize the ability of a program to implement educational advances. There is a need for a healthy tension between a frequency of reaccreditation that ensures that the quality of programs does not decline and a frequency that does not affect programmatic advancement adversely. As deans of pharmacy programs at institutions affiliated with the Committee on Institutional Cooperation (CIC, encompassing the Big Ten institutions and the University of Chicago), the authors collectively represent some of the longest established pharmacy programs in the nation, each with a program history dating between 120 and 150 years. Each of our programs has achieved continuous accreditation since the inception of accreditation of pharmacy programs and has a long history of leadership in educational innovation and advances in the profession of pharmacy. In our annual meetings as a group of deans, we have devoted significant time to discussing the accreditation process for doctor of pharmacy (PharmD) programs. Each of us has experienced the forestalling of important initiatives within our colleges/schools during a period of self-study for reaccreditation. Our shared experiences have convinced us that it is time to reconsider the period for which PharmD programs are accredited. It is informative to compare the accreditation cycles for PharmD programs with those for other health professions. Table ​Table11 provides a comparison of the maximum length of accreditation for compliant programs for 10 different health professions, all but 2 of which (nurses and physician assistants) require a doctorate-level first professional degree. As shown by this data, ACPE provides the shortest maximum accreditation period of any agency accrediting a health professions program. Table 1 Comparison of Maximum Accreditation Length for Compliant Programs (n = 10) Are there rational reasons for a shorter accreditation period for PharmD programs compared to other professions? One reasonably could not argue that the complexity of practice in pharmacy exceeds that of other professions, such as medicine and optometry. It would also be indefensible to assert that the pace of change within pharmacy exceeds that of other health professions. In short, we see no reasonable justification for the period of accreditation for established PharmD programs being shorter than that of any other health professions program. We suggest that the current ACPE policy of awarding well-established programs the same maximal period of accreditation awarded to new programs be modified. Programs with a long history of continuous accreditation are granted the same accreditation length as programs that have gone through only 1 accreditation cycle. We recommend implementation of a tiered system in which programs with a significant history of successful accreditation be granted longer periods between reaccreditation. What are the risks associated with lengthening the period of accreditation for well-established PharmD programs? The obvious risk is that a program could become non-compliant with accreditation standards between review periods. No evidence exists, however, that shows programmatic compliance is impacted by length of time between review periods. Other health professional programs are managed acceptably with longer periods of time between accreditation visits. In addition, the ACPE's notification requirement in the event of a substantive change in the program or its associated resources provides a process for the council to trigger an earlier programmatic review if concerns about continued compliance with the standards arise as a result of meaningful changes. Recognizing the resources (time, energy, and dollars) required to conduct a self-study and reaccreditation site visit, the benefits for institutions of an extended period of accreditation should be obvious. In addition, it would reduce the burden on ACPE, which has been recognizably stretched with the substantial growth of new programs. An extension of the accreditation length for established programs would allow the council to focus more carefully on at-risk or noncompliant programs. All programs operate in an increasingly resource-constrained environment. This includes reduced budgets and increased demands on faculty time and energy. Balancing the competing demands on human and fiscal capital is imperative to sustain forward momentum within the profession. The time has come to reassess the time span between reaccreditation as a component of this balancing process. The authors advocate for an extension in the period of maximal accreditation for well-established pharmacy programs (perhaps defined as 3 or more continuous full-accreditation cycles). We believe that such an extension, perhaps combined with an approval process for specific proposed mid-cycle innovations in a program, will allow programs to redirect the resources required for routine reaccreditation into educational innovations, and thus accelerate the pace of change in pharmacy education.

Two new classes of selenazolidine-4(R)-carboxylic acids (2-oxo and 2-methyl-SCAs) were synthesized and characterized. Both were designed as latent forms of selenocysteine, intended to provide a chemically superior delivery form for selenium. The prodrugs may be clinically useful when selenium supplementation at supranutritional levels is indicated, such as in cancer chemoprevention.

Starburst dendrimers, spherical polymers constructed from methyl acrylate and ethylenediamine, were successfully used to covalently couple synthetic porphyrins to antibody molecules. The dendrimers, as linker molecules, have great potential for increasing the specific activity of radiolabeled antibodies for tumor therapy and diagnosis.

AACP President Marilyn Speedie chose to appoint an Educating Clinical Scientists Task Force (Task Force) instead of the AACP Research and Graduate Affairs Committee to explore how academic pharmacy can increase its capacity for training clinical scientists to expand pharmacy's involvement, given the national emphasis on clinical and translational research, in bench to bedside and bedside to patient care research. President Speedie noted that academic pharmacy presently has at least five models for educating clinical scientists in our colleges/schools, but the output from the programs is relatively low. These graduates are in demand for academic positions, and are highly sought by other private-sector employers. By clarifying the competencies required and pathways needed to attain those competencies, President Speedie postulated that academic pharmacy will be more prepared to attract students to these programs, and better able to communicate with federal agencies that might fund our training programs. She asked the Task Force to: Define the various career opportunities for clinical scientists. Define the competencies and outcomes required for each type of position. Explore the demand for such individuals. Examine the state of clinical scientist preparation (models, capacity, demand). Make recommendations for unifying the way clinical scientists are trained for various positions. Is one model sufficient for all; if not, can two models suffice? What are the advantages of having one or two models with clearly defined outcomes? Discuss the collaborations (between schools, across professional boundaries) needed in order for us to expand our graduation of clinical scientists. Explore how we can best obtain further funding to allow us to expand our numbers of graduates. The Task Force met October 18-19, 2006 in Washington, DC, discussed the charges, and came to consensus on a Policy Statement for the Association on the education and training of a “new” Pharmacist Clinical Scientist. The Task Force report presents academic pharmacy's previous deliberations on these charges to provide a context for the Task Force's Policy Statement.

Murine (Hepa1c1c7) hepatoma cells are a suitable in vitro system for investigating the regulation of chemoprotective enzymes by selenazolidines, novel l-selenocysteine prodrugs developed as potential chemopreventive agents. They are less sensitive to the cytotoxic effects of both selenite and the less toxic selenazolidines than rat hepatoma (H4IIE) cells. All four selenazolidine 4-carboxylic acid (SCA) derivatives examined elevated thioredoxin reductase (Txnrd1), alpha-class glutathione transferases (Gsta), and UDP-glucuronosyltransferase (Ugt)1a6 mRNAs. NAD(P)H-quinone oxidoreductase (Nqo1) was induced by the three 2-alkyl derivatives (2-cyclohexylSCA, 2-butylSCA, and 2-methylSCA) but not SCA itself. Transcripts of mu- and pi-class glutathione transferases were induced only by 2-cyclohexylSCA and 2-butylSCA. Only Gsta and Txnrd1 transcripts were elevated by l-selenomethionine, l-selenocystine, or Se-methyl-l-selenocysteine. Txnrd1, Gsta, Nqo1, and Gstp responses to selenazolidines were all abolished by actinomycin D while Ugt1a6 responses were not. Induction responses to the selenazolidines were also eliminated (most) or reduced (Txnrd1 by 2-methylSCA) by cycloheximide, with the exception of Ugt1a6. The Ugt1a6 mRNA levels in the presence of SCAs and cycloheximide were similar to those with cycloheximide alone, and were almost double those of vehicle-treated cells. Thus, Hepa1c1c7 cells appear to provide a viable platform for the study of protective enzyme regulation by selenocompounds, and with the exception of Ugt1a6, the mRNA elevations from selenazolidines are transcriptionally dependent.

Novel selenazolidines, designed as l -selenocysteine prodrugs and potential cancer chemopreventive agents, were examined for their ability to affect the transcription of murine hepatic chemoprotective enzymes. Compounds investigated were selenazolidine-4( R )-carboxylic acid (SCA) and six 2-substituted derivatives that cover a C log P range of −0.512 to −3.062. Their biological effects were compared with those of l -selenocystine. Gene transcripts were examined 24 h after a single dose, administered i.p. and i.g., and covered a range of chemoprotective enzymes; alpha, mu and pi class glutathione transferases (Gsts), UDP-glucuronosyltransferases (Ugts) 1a1, 1a6, 1a9, and 2b5, glutathione peroxidase 1 (Gpx), thioredoxin reductase (Tr), NAD(P)H-quinone oxidoreductase 1 (Nqo), and microsomal epoxide hydrolase (Meh). When given i.g., 2-butyl SCA (BSCA) resulted in elevations in alpha, mu and pi class Gsts, Ugt1a6, Tr, and Gpx, and 2-phenyl SCA (PhSCA) elevated GstP, Ugt1a9, Tr, Gpx (3 kb), and Meh. Other derivatives with C log P values both lower [2-(2′-hydroxy)phenyl SCA (PhOHSCA) and 2-methyl SCA (MSCA)] and higher [2-cyclohexyl SCA (ChSCA) and 2-oxo SCA (OSCA)] than BSCA and PhSCA elevated far fewer transcripts; PhOHSCA (Ugt1a1, Gpx), MSCA (Ugt1a1, Meh), ChSCA (Ugt1a1, Ugt1a9), and OSCA (Ugt1a6, Ugt1a9, GstM). When given i.p., the most pervasive transcript changes were parallel increases in Nqo and Tr transcripts which occurred with BSCA, PhSCA, MSCA, and OSCA. PhSCA also increased GstP, and PhOHSCA increased Ugt1a1 and Ugt1a6 levels. Unique among the compounds, PhSCA reduced the transcript levels of GstA, and the 1.6 kb transcript of Gpx although only when given i.p. Neither l -selenocystine nor SCA affected the level of any transcript and no compound altered the amount of Ugt2b5 mRNA. Despite chemical similarity and common ability to potentially serve as a source of l -selenocysteine, each selenazolidine compound appeared to elicit a unique pattern of mRNA responses and by either route of administration, there was no correlation between the magnitude of response of any gene and the calculated C log P values of the organoselenium compounds.

Prodrugs of L-selenocysteine have potential utility in cancer chemoprevention. This study reports the efficacy of three selenazolidine-4(R)-carboxylic acids, (2-unsubstituted, 2-oxo, and 2-methyl derivatives; SCA, OSCA, and MSCA, respectively) against tobacco-related lung tumorigenesis in a mouse model. Seven days after initiation of an AIN-76A diet supplemented with sodium selenite (5 ppm Se), L-selenomethionine (3.75 ppm Se), Se-methyl-L-selenocysteine (3 ppm Se), L-selenocystine (15 ppm Se), SCA (15 ppm Se), OSCA (15 ppm Se), or MSCA (15 ppm Se), mice received 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; 10 μmol, i.p.). After an additional 16 weeks on the diets, two compounds, OSCA and selenocystine, significantly reduced lung adenoma multiplicity from 7.2 tumors per mouse in the NNK group to 4.5 and 4.6 tumors per mouse, respectively. Neither selenium concentration nor glutathione peroxidase activity in either RBCs or liver served as surrogate indicators of tumor reduction. Hepatic selenium levels were significantly elevated by all selenium-containing compounds except Se-methyl-L-selenocysteine and SCA; RBC selenium levels by all except sodium selenite and MSCA. With the exception of L-selenomethionine, RBC glutathione peroxidase activity was increased along with the elevated selenium levels. Hepatic glutathione peroxidase activity was elevated by all Se-compounds except SCA. The two compounds showing significant tumor reduction (OSCA and selenocystine) were the only two compounds that showed ubiquity of changes, elevating both selenium levels and GPx activity in both liver and RBC. © 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:396-405, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20105

Tea (Camellia sinensis) contains numerous polyphenolic flavonoid-derived compounds known as catechins, which have shown interesting protective activity against cancer and cardiovascular disease. Numerous products based on tea are commercially available, many of which claim to contain specific amounts of the bioactive catechins. The catechin content of seven commercial green tea products (encapsulated extracts or tea bags) was quantified by HPLC and, where possible, compared to that claimed on the label. Wide variability was observed in the catechin content between green tea products, even those that appear outwardly similar to consumers. Measured catechin content ranged from 9% to 48% of label claims; all values were significantly lower than those claims (P0.05). These results continue to demonstrate the problems that exist with quality control in the dietary supplement and herbal medicine industry and, there, for consumers of nutraceuticals.

We are carrying out studies aimed at reducing the mutagenic effects of high-LET 56Fe ions and 12C ions (56Fe ions, 143 keV/microm; 12C ions, 100 keV/microm) with certain drugs, including RibCys [2-(R,S)-D-ribo-(1',2',3',4'-tetrahydroxybutyl)-thiazolidine-4(R)-carboxylic acid]. RibCys, formed by condensation of L-cysteine with D-ribose, is designed so that the sulfhydryl amino acid L-cysteine is released intracellularly through nonenzymatic ring opening and hydrolysis leading to increased levels of glutathione (GSH). RibCys (4 or 10 mM), which was present during irradiation and for a few hours after, significantly decreased the yield of CD59- mutants induced by radiation in AL human-hamster hybrid cells. RibCys did not affect the clonogenic survival of irradiated cells, nor was it mutagenic itself. These results, together with the minimal side effects reported in mice and pigs, indicate that RibCys may be useful, perhaps even when used prophylactically, in reducing the mutation load created by high-LET radiation in astronauts or other exposed individuals.

A method for the separation and quantitation of several important biological thiolamines is described. The procedure employs a C18 reversed-phase HPLC system to separate the dinitrophenyl derivatives of reduced and oxidized glutathione and cysteine and relies on an internal standard, Nϵ-methyllysine, to minimize experimental error. The method was validated in three matrices (water, HepG2 cell lysates, and mouse liver homogenates) using several criteria. The detector response was linear for the dinitrophenyl derivatives of glutathione, glutathione disulfide, cysteine, and cystine in the concentrations ranging from 10 to 50 nmol/ml. Inter- and intra-day variation, percent recovery in the biological matrices, and limits of detection and quantitation were determined. For the most accurate determination, it is essential that standard curves be produced daily and in the same matrix as that being analyzed.

Transport by ATP-dependent efflux pumps such as P glycoprotein (Pgp) and multidrug resistance associated protein (MRP), encoded by multidrug resistant (MDR) associated genes, is an increasingly recognized mechanism by which cells maintain substrate homeostasis and evade drug therapy. Pgp and MRP are members of the so-called ATP binding cassette (ABC) transporters superfamily, which are associated with many biological processes in both prokaryotes and eukaryotes, as well as clinical problems. The observation of upregulated sequences that are homologous to the Mycobacterium smegmatis phage resistance (mpr) gene and putative ABC transporters subunits in fetal Down syndrome (DS) using the gene hunting technique, subtractive hybridization formed the Rationale for this study. The expression of Pgp and MRP1 is therefore investigated in different brain regions of controls and adult DS patients with western blot technique. No apparent changes were observed between controls and DS in levels of Pgp in all brain regions examined. By contrast, MRP1 detection using the rat monoclonal antibody (MRPrl) produced a significant elevation in DS temporal cortex (P < 0.01) and parietal cortex (P < 0.05). Although MRP1 detected with the mouse monoclonal antibody (MRPm6) tended to increase in most of the regions of DS brain, it failed to reach significance level. Age or postmortem interval did not correlate with protein levels in both controls as well as DS. Taken together, the current data provide evidence for the presence of MDR related pumps in different regions of the human brain. In addition, overexpression of MRP1 in DS brain may have some relevance to the disorder either by deranging substrate homeostasis or limiting drug access.

Ribose cysteine (RibCys) is a cysteine prodrug that increases both hepatic and renal glutathione with documented antagonism of acetaminophen (APAP)-induced hepatotoxicity. To determine if RibCys could also protect against APAP-induced kidney damage, mice were injected with APAP (600 mg/kg) or APAP and RibCys (1.0 g/kg) (APAP/RIB) followed by additional RibCys injections 1 and 2 hours later. Mice were euthanatized 10-12 hours after APAP administration, and liver and kidney toxicity were assessed by plasma sorbitol dehydrogenase (SDH) activity and blood urea nitrogen (BUN), respectively, and by histopathology. APAP treatment resulted in elevation of SDH activity and BUN to 2,490 U/ml and 47 mg/dl, respectively. By contrast, SDH and BUN values for APAP/RIB-treated mice were not different from controls, 0 U/ml and 31 mg/dl, respectively. Histopathologic examination revealed moderate to severe hepatic centrilobular necrosis in 9/11 and renal proximal tubular necrosis in 10/11 APAP-treated mice. However, no evidence of hepatic or renal toxicity was noted in any of the 12 APAP/RIB-treated mice. Utilizing the same treatment regimen, APAP covalent binding to hepatic and renal cytosolic proteins was assessed 4 hours after APAP challenge. RibCys cotreatment decreased covalent binding to the 58-kDa acetaminophen-binding protein in both liver and kidney. RibCys decreased both toxicity and covalent binding after APAP administration, and in addition to protecting the liver, this cysteine prodrug can also effectively protect the kidney from APAP-induced injury.

Differential scanning calorimetry was used to study the interactions of nuclei isolated from Chinese hamster V79 cells with the radioprotector WR-1065, other thiol compounds, and polyamines. Differential scanning calorimetry monitors denaturation of macromolecules and resolves the major nuclear components (e.g. constrained and relaxed DNA, nucleosome core, and nuclear matrix) of intact nuclei on the basis of thermal stability. WR-1065 treatment (0.5-10 mM) of isolated nuclei led to the irreversible denaturation of nuclear proteins, a fraction of which are nuclear matrix proteins. Denaturation of 50% of the total nonhistone nuclear protein content of isolated nuclei occurred after exposure to 4.7 mM WR-1065 for 20 min at 23 degrees C. In addition, a 22% increase in the insoluble protein content of nuclei isolated from V79 cells that had been treated with 4 mM WR-1065 for 30 min at 37 degrees C was observed, indicating that WR-1065-induced protein denaturation occurs not only in isolated nuclei but also in the nuclei of intact cells. From the extent of the increase in insoluble protein in the nucleus, protein denaturation by WR-1065 is expected to contribute to drug toxicity at concentrations greater than approximately 4 mM. WR-33278, the disulfide form of WR-1065, was approximately twice as effective as the free thiol at denaturing nuclear proteins. The proposed mechanism for nucleoprotein denaturation is through direct interactions with protein cysteine groups with the formation of destabilizing protein-WR-1065 disulfides. In comparison to its effect on nuclear proteins in isolated nuclei, WR-1065 had only a very small effect on non-nuclear proteins of whole cells, isolated nuclear matrix, or the thiol-rich Ca(2+)ATPase of sarcoplasmic reticulum, indicating that WR-1065 can effectively denature protein only inside an intact nucleus, probably due to the increased concentration of the positively charged drug in the vicinity of DNA.

The synthetic porphyrins, N -benzyl-5,10,15,20- tetrakis (4-carboxyphenyl)porphine ( N -bzHTCPP) and N -4-nitrobenzyl-5-(4-carboxyphenyl)-10,15,20- tris (4-sulfophenyl)porphine ( N -bzHCS 3 P), represent excellent radiocopper chelating agents that may find utility in antibody-mediated diagnosis and/or therapy. N -bzHCS 3 P was conjugated to an anti-renal cell carcinoma (RCC) antibody, A6H, and labeled with copper-67. 67 CuCS 3 P-A6H was studied for its biodistribution in human RCC xenograft-bearing nude mice, along with the radiolabeled free porphyrins. The porphyrins resulted in tumor:blood ratios in the range of 3 to 4 after 48 h. The radiolabeled antibody achieved a tumon:blood ratio of over 16 after 45 h, indicating accumulation at the desired site. However, unwanted localization also occurred in the liver and spleen, which will have to be rectified before realizing the full potential of this approach.

In 2006, dean William H. Campbell made the following observations: For academic programs to provide quality professional instruction, full-time faculty must be actively engaged in research in the pharmaceutical sciences...Faculty who cannot participate in expanding the body of knowledge required by practice and science cannot be expected to provide mastery level instruction to pharmacy students. Demonstration of active engagement in the pharmaceutical sciences must include extramural support, scholarly publication, scientific presentations, and supervision of graduate (masters, PhD, postdoctoral) students... (1) The authors agree with this assessment. Indeed, in crafting Standards 2007, (2) the Accreditation Council for Pharmacy Education (ACPE), through stakeholder feedback, listed "scholarship and research" as one of 12 areas that were emphasized in the revision process. There are different forms of scholarship, (3) with research (or the scholarship of discovery) being just one. In Standards 2007, the relevant section is Standard 25 (Faculty and Staff), guideline 8, which reads: Faculty should generate and disseminate knowledge through scholarship. Scholarship by faculty members, including the scholarship of teaching, must be evident and demonstrated by productive research and other scholarly activities, such as contributions to the scientific, professional, and educational literature; publication of books and review articles; and successes in securing extramural funding to support research and other scholarly activities. Although the standard may seem straightforward, it could be interpreted in different ways: from non-research forms of scholarship (eg, review papers); to alternate forms of scholarship not necessarily associated with publication, such as the scholarship of application (ie, clinical practice) or the scholarship of engagement (ie, public service); to the traditional currency of research in colleges and schools of pharmacy, with benchmarks such as competitive federal funding and subsequent peer-reviewed publications of original work in visible, high-impact journals. The authors do not wish to minimize the importance of scholarship, broadly defined (3); all forms of scholarly contribution within colleges and schools of pharmacy are clearly important. Nevertheless, what we are most concerned with, and is the subject of this statement, is the latter form of scholarship, defined by Boyer (3) as the scholarship of discovery. The report of the 2003-2004 American Association of Colleges of Pharmacy (AACP) Research and Graduate Affairs Committee (4) noted an increasing concern about the "potential diminution of the academy's collective scholarship, particularly in the area of the scholarship of discovery, because of the increasing numbers of new pharmacy programs at institutions with an unknown culture of scholarship." Eight years after that report, it is now possible to objectively describe the cohort of newer colleges with regard to their emphasis on research and to preliminarily discern if this committee's concerns were well founded. For the purposes of this paper, we compared the new colleges and schools of pharmacy (those that admitted students during or after the year 2000) and the older colleges from the AACP Web site (5) list of members with respect to their research focus. There are 45 colleges and schools of pharmacy that first admitted students during or after the year 2000 and 79 colleges in the pre-2000 group. Of the newer colleges and schools, 10 of the 45 have "research" as a stated part of their mission (though many more mention "scholarship"). Most are not associated with academic health centers, (6) which are great sources of interdisciplinary education and also provide access to patients for research, non-pharmacy collaborators, and a culture of translational research and discovery. …

Ribose-cysteine (RibCys) is a prodrug ofl-cysteine that stimulates glutathione biosynthesis. Increased glutathione levels have been shown to have a protective effect against radiation-induced injury and oxidative stress. Surface oximetry has previously been used successfully to predict anastomotic leakage. PURPOSE: The following study was done to evaluate the protective effect of RibCys and the predictive value of PtO2 determinations in a swine model. METHODS: Domestic swine were divided into three groups: Group A served as a nonradiated control; Group B received 6,000 to 6,500 rad to the rectosigmoid; and Group C received RibCys (1 g/kg) prior to receiving 6,000 to 6,500 rad. Radiated animals and controls underwent rectosigmoid resection after a three-week rest period. Intraoperative anastomotic PtO2 was checked with a modified Clark electrode. Anastomoses were evaluated radiographically at three and seven days; animals were sacrificed, and bursting strength was recorded at 10 days. RESULTS: Mean bursting pressures were 243.8±59.4, 199.5±37.8, and 209.5±54.9 mmHg (NS) for Groups A, B, and C, respectively. Anastomotic PtO2 ranged from 19 to 98 mmHg and could not be correlated with anastomotic leaks or bursting pressure. There were 11/15 radiation-related deaths and leaks (eight deaths and three leaks) in the radiated group and 4/12 radiation-related deaths and leaks (three deaths and one leak) in the group receiving radiation and RibCys (P < 0.04). CONCLUSIONS: 1) RibCys protected animals against radiation-related deaths and anastomotic leaks following high doses of pelvic irradiation; 2) anastomotic PtO2 levels did not correlate with anastomotic healing in this model.

2(RS)-D-ribo-(1',2',3',4'-Tetrahydroxybutyl)thiazolidine-4(R)-carb oxylic acid (Ribose-Cysteine, RibCys), a latent form of L-cysteine, releases the sulfhydryl amino acid in vivo by non-enzymatic ring opening and solvolysis. The liberated L-cysteine then stimulates hepatic glutathione biosynthesis. In the present studies, the efficacy of hepatoprotection by RibCys was evaluated to explore its potential utility as an acetaminophen (APAP) antidote. Protection was evaluated in the Swiss-Webster mouse model both by survival data as well as by quantitative histological criteria of hepatic damage. A dose-response study showed increased protection with increased intraperitoneal doses of RibCys ranging from 0.5 to 8.0 mmol/kg. RibCys administration 30 min. prior to and up to four hours after the APAP dose showed varying degrees of protection; however, the best protection was seen when RibCys was given shortly after APAP administration. A single RibCys dose given by the intraperitoneal or intravenous route gave better protection than when administered orally; however, RibCys given in three doses, one hour apart, regardless of the mode of administration, offered the best protection after an LD90 dose of APAP. Overall, RibCys continues to exhibit promising protective capabilities against APAP hepatotoxicity, which may be capitalized upon in clinical overdose situations.

RibCys, a thiazolidine prodrug of l -cysteine synthesized by the condensation of the sulfhydryl-containing amino acid with the aldose monosaccharide d -ribose, successfully elevated glutathione (GSH) levels in numerous organs of tumor-bearing CDF1 mice. GSH content was assayed 1, 2, 4, 8 and 16 h after RibCys administration (8 mmol kg , i.p.); various organs achieved maximal GSH content at different time points. GSH in the liver was elevated 1.5-fold compared to untreated controls at the 16-h time point. Kidney GSH also was maximal at 16 h and achieved 1.6-times control values. GSH in muscle achieved 2.5 times the levels in control animals, while the bladder was elevated 2.1-fold, and the heart 1.8-fold. Other tissues tested (spleen, pancreas, lung) showed a 1.1- to 1.2-fold increase in GSH content. GSH in implanted L1210 tumors was also elevated only 1.2-fold. These data suggest the possibility of protecting organs other than the liver from toxic insults that require the intervention of GSH for detoxication and may allow such protection without compromising the utility of chemotherapy.