Cytotoxic effects of quinoxaline derivatives on human cancer cell lines

The cytotoxicities of 6,7-modified-5,8-quinoxalinedione derivatives and heterocyclic quinoxaline derivatives containing nitrogen, sulfur, and oxygen on human lung adenocarcinoma cell (PC 14), human gastric adenocarcinoma cell (MKN 45), and human colon adenocarcinoma cell (colon 205) were examined in vitro using MTT assay. Pyrido[1,2-a]imidazo[4,5-g]quinoxaline-6,11-dione (10) was markedly cytotoxic against MKN 45 compared with adriamycin and cis-platin used as anticancer drugs. The IC50 value of compound 10 was 0.073 microM while those of adriamycin and cis-platin were 0.12 microM and 2.67 microM, respectively.     

Ingestion of chromium(VI) in drinking water by human volunteers: absorption, distribution, and excretion of single and repeated doses

This study examines the magnitude of hexavalent chromium [Cr(VI)] absorption, distribution, and excretion following oral exposure to 5 and 10 mg Cr(VI)/L in drinking water administered as a single bolus dose (0.5 L swallowed in 2 min) or for 3 d at a dosage of 1 L/d (3 doses of 0.33 L each day, at 6-h intervals). Adult male volunteers ingested deionized water containing various concentrations of potassium chromate, and samples of urine, plasma, and red blood cells (RBCs) were collected and analyzed for total chromium throughout the studies. In the bolus dose studies, a fairly consistent pattern of urinary chromium excretion was observed, with an average half life of about 39 h. However, 4-d total urinary chromium excretion and peak concentrations in urine and blood varied considerably among the 5 volunteers. Studies of repeated exposure to smaller volumes ingested at a more gradual rate (i.e., 0.33 L over 5-15 min) showed similar urinary chromium excretion patterns but generally lower chromium uptake/excretion. Given that sustained elevations in RBC chromium levels provide a specific indication of chromium absorption in the hexavalent state, these data suggest that virtually all (> 99.7%) of the ingested Cr(VI) at 5 and 10 mg Cr(VI)/L was reduced to Cr(III) before entering the blood-stream. The interindividual differences in total chromium uptake and excretion are plausibly explained by ingestion of appreciable doses on an empty stomach, which likely results in the formation of well-absorbed Cr(III) organic complexes in gastrointestinal tissues and possibly the blood. The lack of any clinical indications of toxicity in the volunteers and the patterns of blood uptake and urinary excretion of chromium are consistent with a predominant uptake of Cr(III) organic complexes [derived from Cr(VI)] that are excreted more slowly than inorganic forms of Cr(III). Therefore, it appears that the endogenous reducing agents within the upper gastrointestinal tract and the blood provide sufficient reducing potential to prevent any substantial systemic uptake of Cr(VI) following drinking-water exposures at 5-10 mg Cr(VI)/L. Based on these data, the chemical environment in the gastrointestinal tract and the blood is effective even under relative fasting conditions in reducing Cr(VI) to one or more forms of Cr(III).     

Resident attrition from family practice residencies: United States versus international medical graduates

BACKGROUND: Attrition of residents from family practice residency programs may cause significant problems for faculty, residents, and patients. The objective of this study was to determine international medical graduates' attrition rate from family practice residencies, compared with US medical school graduates. METHODS: Surveys were sent to all family practice residency program directors asking them to calculate their attrition rate for a 10-year period. RESULTS: The overall response rate was 56.6%, but interpretable responses were received from 45% of all civilian, continental US family practice residencies. Responding programs did not differ from all family practice programs with respect to program overall. Of those residents leaving, 63% did so to enter other specialties. The attrition rate was 18.5% for international graduates, compared with 7.8% for US graduates (P < .0001). International graduates enrolled outside of the National Resident Matching Program (NRMP) were most likely to leave programs before completion. CONCLUSIONS: Attrition rates from family practice residency programs are higher for international medical graduates than for US graduates. International graduates enrolled outside of the NRMP were most likely to leave a program.     

New insights on P2X purinoceptors

Significant advances in understanding of P2X purinoceptor pharmacology have been made in the last few years. The limitations of nucleotide agonists as drug tools have now been amply demonstrated. Fortunately, inhibitors of the degrading ecto-ATPase enzymes are becoming available and it has become apparent that the complete removal of all divalent cations can be used experimentally in some systems to prevent nucleotide breakdown. Despite these issues, convincing evidence for P2X receptor heterogeneity, from data with agonists, has recently been reported. A number of new antagonists at P2X purinoceptors have also recently been described which to some degree appear to be more specific and useful than earlier antagonists like suramin. It is now apparent that suramin is a poor antagonist of ATP in many tissues because it potently inhibits ATPase activity at similar concentrations to those at which it blocks the P2X purinoceptor. Advances in the use of radiolabelled nucleotides as radioligands for binding studies has allowed the demonstration of P2X purinoceptors in a variety of tissues throughout the body including the brain. These studies have also provided evidence for receptor heterogeneity. Excitingly, two P2X purinoceptor genes have been cloned but operational studies suggest that more than two types exist. The cloning studies have also demonstrated a unique structure for the P2X purinoceptor which differentiates it from all other ligand-gated ion channel receptors. Further studies on P2X purinoceptor operation and structure are needed to help resolve controversies alluded to regarding the characterization and classification of nucleotide receptors. Hopefully such studies will also lead to a better understanding of the physiological and pathological importance of ATP and its activation of P2X purinoceptors. This will require the identification of better drug tools, in particular antagonists which may also provide the basis for novel therapeutic agents.