Structure-activity relationships of alkyl- and alkoxy-substituted 1,4-dihydroquinoxaline-2,3-diones: potent and systemically active antagonists for the glycine site of the NMDA receptor

We report on a series of alkyl- and alkoxy-substituted 1,4-dihydroquinoxaline-2,3-diones (QXs), prepared as a continuation of our structure-activity relationship (SAR) study of QXs as antagonists for the glycine site of the N-methyl-D-aspartate (NMDA) receptor. The in vitro potency of these antagonists was determined by displacement of the glycine site radioligand [3H]-5,7-dichlorokynurenic acid ([3H]DCKA) in rat brain cortical membranes. In general, methyl is a good replacement for chloro or bromo in the 6-position, and alkoxy-substituted QXs have lower potencies than alkyl- or halogen-substituted QXs. Ethyl-substituted QXs are generally less potent than methyl-substituted QXs, especially in the 6-position of 5,6,7-trisubstituted QXs. Fusion of a ring system at the 6,7-positions results in QXs with low potency. Several methyl-substituted QXs are potent glycine site antagonists that have surprisingly high in vivo activity in the maximal electroshock (MES) test in mice. Among these, 7-chloro-6-methyl-5-nitro QX (14g) (IC50 = 5 nM) and 7-bromo-6-methyl-5-nitro QX (14f) (IC50 = 9 nM) are comparable in potency to 6,7-dichloro-5-nitro QX (2) (ACEA 1021) as glycine site antagonists. QX 14g has an ED50 value of 1.2 mg/kg iv in the mouse MES assay. Interestingly, alkyl QXs with log P values of 0.5 or less tend to be more bioavailable than QXs with higher log P values. QX 14g has 440-fold selectivity for NMDA vs alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as determined electrophysiologically under steady-state conditions in oocytes expressing rat cerebral cortex poly(A)+ RNA. Overall, 14g was found to have the best combination of in vitro and in vivo potency of all the compounds tested in this and previous studies on the QX series.     

Wisconsin Cytology Proficiency Testing Program. Results of voluntary testing in 1994

OBJECTIVE: The Wisconsin Cytology Proficiency Testing Program (WCPTP) was developed cooperatively by the Wisconsin State Laboratory of Hygiene, the Wisconsin Society of Pathologists and the Wisconsin Society of Cytology to enable pathologists and cytotechnologists in Wisconsin to meet Clinical Laboratory Improvement Act of 1988 (CLIA '88) requirements for proficiency testing (PT). STUDY DESIGN: A joint steering committee designed the WCPTP to comply with all CLIA '88 regulations. The WCPTP application to the Health Care Financing Administration received tentative approval in May 1994. In 1994, mock PT was conducted at meetings of both state societies, and voluntary, on-site PT was conducted at 19 laboratories. RESULTS: Each of the 119 participants (49 pathologists, 70 cytotechnologists) was tested with sets of 10 glass slides, each representing one of four specified categories: A, unsatisfactory; B, normal/benign; C, low grade squamous intraepithelial lesion; and D, high grade squamous intraepithelial lesion and cancer. The failure rate for pathologists was 22.5% (11/49) and for cytotechnologists, 1.4% (1/70). The CLIA '88 scoring system for pathologists is more stringent. If cytotechnologists were scored as pathologists, 10% (7/70) would have failed. Using the cytotechnologist grid, 14.5% (7/49) of the pathologists would have failed. CONCLUSION: This voluntary program provided some preliminary insights into the issues related to PT evaluation of personnel competence and diagnostic criteria.     

Phase II trial of 9-aminocamptothecin administered as a 72-hour continuous infusion in metastatic colorectal carcinoma

PURPOSE: The camptothecin derivative irinotecan has demonstrated clinical activity in metastatic colorectal carcinoma in both chemotherapy-naive and fluorouracil-refractory patients. 9-Aminocamptothecin (9-AC; NSC 603071), another camptothecin derivative, was selected for clinical development based on preclinical activity, including cures in human tumor xenografts resistant to standard anticancer agents. We report a phase II trial of 9-AC in patients with previously untreated metastatic colorectal carcinoma. PATIENTS AND METHODS: Colorectal cancer patients with measurable disease, a performance status of 0 to 2 (Zubrod), and no prior chemotherapy for metastatic disease received 9-AC. A cycle of therapy was 35 microg/m2/h for 72 consecutive hours (840 microg/m2/d for 3 days) and rest on days 4 to 14; a course of therapy was defined as two cycles (28 days). Patients were assessed for response after two courses. RESULTS: Seventeen patients with metastatic colorectal cancer were entered onto this trial. No complete or partial responses were noted. Treatment was well tolerated; toxic effects consisted mainly of neutropenia, nausea, vomiting, stomatitis, fatigue, and anemia. Grade 3 to 4 toxicity was limited to neutropenia (grade 3 in four patients and grade 4 in six), anemia (grade 3 in two patients), and vomiting (grade 3 in two patients). No grade 3 or 4 diarrhea occurred. Only two patients had their 9-AC dose reduced to 30 microg/m2/h. The median nadir absolute granulocyte count (AGC) was 1,500/microL. The median number of courses given was two and the median time to disease progression was 8 weeks. CONCLUSION: At the dose and schedule used in this trial, 9-AC lacked antitumor activity in metastatic colorectal cancer. 9-AC infusion schedules of longer duration are currently being investigated in this disease.     

Inhibition of murine renal carcinoma pulmonary metastases by systemic administration of interferon gamma: mechanism of action and potential for combination with interleukin 4

We have previously demonstrated that IFN-gamma causes cell growth inhibition and up-regulation of MHC antigens in human renal cell carcinoma cell lines. In this study, we have investigated the therapeutic potential of IFN-gamma for the treatment of 5-day established pulmonary metastases induced by i.v. injection of Renca cells, a murine renal adenocarcinoma. We found that systemic injections of IFN-gamma significantly reduced the number of lung metastases in a dose-dependent manner and increased mouse survival. Histological evaluation of IFN-gamma-treated lungs showed residual small tumor nodules containing extensive necrosis and mononuclear infiltrates. Immunohistochemistry studies on lung sections showed macrophage infiltration into tumor nodules, and in vivo depletion of macrophages partially inhibited IFN-gamma antitumor effect, suggesting a role for the macrophages in tumor destruction. Lymphocyte depletion of either natural killer (NK) cells or CD4+ or CD8+ T-cell subsets or both T-cell subsets did not affect the IFN-gamma effect, whereas depletion of both NK and T cells decreased the antitumor activity of IFN-gamma. These data indicate that neither T cells nor NK cells are essential for this activity but that either lymphocyte population can contribute to the IFN-gamma effect. An optimal dose of IFN-gamma inhibited by 60% the growth of Renca cells treated for 3 days in vitro, but this effect was transient and less pronounced in a long-term colony assay, suggesting that IFN-gamma direct growth inhibition may play a role but may not be sufficient to mediate its antitumor effect in vivo. In vitro, IFN-gamma caused up-regulation of class I MHC antigens and induction of class II antigen expression in Renca cells, an effect that may enhance Renca immunogenicity but may be relevant only when a T-cell response is elicited. A sequential administration of IFN-gamma followed by interleukin 4 was therapeutically better than IFN-gamma alone for the treatment of advanced pulmonary metastases, probably due to different antitumor mechanisms induced by these two cytokines.     

Classifying rehabilitation inpatients by expected functional gain

OBJECTIVES: To create a more suitable payment system for medical rehabilitation, the authors developed a companion classification system to the original functional independence measure-function-related groups (FIM-FRGs), which classify patients having similar lengths of stay in a rehabilitation hospital or inpatient unit. The companion system presented here groups patients according to their gains in functional status during the rehabilitation stay. METHODS: Data from 84,492 patients discharged from 252 rehabilitation facilities in 1992 were provided by the Uniform Data System for Medical Rehabilitation. Classification rules were formed using clinical judgment and a recursive partitioning algorithm. The gain-FRGs system used four predictor variables: (1) diagnosis leading to disability, admission scores on the (2) motor and (3) cognitive subscales of the FIM, and (4) patient age. RESULTS: The gain-FRGs system contained 74 patient groups and explained 21% of the variation in functional gain for patients in a different set of records withheld for validation. CONCLUSIONS: The gain-FRGs system should be considered for prospective payment systems because it gives the provider an incentive to improve patient outcomes, which is missing in a payment system based on FIM-FRGs alone.     

ALATOP-RIA in the screening of atopy in a non Caucasian population

ALATOP is an "in vitro" radioimmunoassay screening test for atopy, previously validated in a caucasian population. The aim of the study was to assess the usefulness of a screening test of atopy in a non caucasian population. We select a non caucasian population (n = 208), from hospital immunoallergy consultations, Cape Verde Republic (Africa). It was determined the sensitivity, specificity and predictive values comparing with skin prick tests (SPT) results for the 208 patients, and with clinical data (Clin) in 115 patients. It was also determined the levels of total IgE, done by IRMA. RESULTS: Using different corrections factors, 0.85 gives the best results: ALATOP/SPT-Sensitivity-88.5% +/- 4.34; Specificity-73.8% +/- 8.41; Positive predictive value-66.9%; Negative predictive value-91.4%; Efficiency of the test-79.3%. ALATOP/CLIN-Sensitivity-95.2% +/- 3.89; Specificity-71.2% +/- 12.07; Positive predictive value-65.6%; Negative predictive value-96.2%; Efficiency of the test-80.0%. The mean values of total IgE were-406 IU/ml. CONCLUSIONS: The mean value of total IgE was significantly increased even in the ALATOP-/SPT-not saw in caucasian populations. The use of a different correction factor (0.85) for ALATOP, optimize the test, showing a good negative predictive value, but raises the question of adapted compositions of screening tests for different populations.