Modelling the interaction of small organic molecules with biomacromolecules. III. Interaction of benzoates with anti-p-(p'-azophenylazo)benzoate antibody

A novel approach for modelling the biological activity of organic molecules, which requires simultaneous consideration of the influence of all factors (topological, steric, hydrophobic, and electronic) that determine the bioactivity, is used to study the interaction of a series of benzoates with anti-p-(p'-azophenylazo)benzoate antibody. The results obtained suggest that this biological interaction proceeds by a two-step stereospecific mechanism. The first step requires a geometrical correspondence between the benzoates and the cavity in the biomacromolecule, which enables the pharmacophore to come into close contact with the receptor. The second step is the orbitally controlled electronic interaction between the active parts of the benzoates and the antibody. The electronic interaction results from pi-charge transfer from the pharmacophore to the biomacromolecule and from the formation of pi-complexes. A proposed mathematical model for this biological interaction exhibits some statistical advantages over existing models.     

Bioavailability of mefenamic acid: influence of food and water intake

The influence of food and water intake on mefenamic acid (N-2,3-xylylanthranilic acid) bioavailability from commercial capsules of high bioavailability was studied in four healthy male volunteers. The drug was administered as a single oral dose of 250 mg, under fasting or nonfasting conditions, and a 4 X 4 Latin-square design was used. Eight blood samples were collected over a 24-h period following drug administration, and the drug plasma concentrations were determined by HPLC. The bioavailability of mefenamic acid from capsules was markedly influenced in the fasting subjects by the water but not by the food intake. A good correlation was found between the bioavailability and amount of water ingested with the drug in the fasting subjects. The area under the plasma concentration-time curve (AUC0-infinity) of mefenamic acid was highest when the capsule was taken with 50 mL of water or immediately after a meal. Increasing the amount of water from 50 to 500 mL in the fasting subjects caused a significant reduction in AUC0-infinity.     

Association between PCBs and lower embryonic weight in black-crowned night herons in San Francisco Bay

Reproductive problems, including congenital malformations, reduced hatching success, and decreased survival of hatchlings, have been observed in colonial-nesting water birds at the San Francisco Bay National Wildlife Refuge (SFBNWR). Twenty-four black-crowned night heron (Nycticorax nycticorax) eggs were collected from SFBNWR in 1983. Twelve of these were collected from separate nests when late-stage embryos were pipping, and an additional egg was randomly collected from each nest for organochlorine analysis. Overt anomalies and skeletal defects were not apparent. Embryonic weights (with partially absorbed yolk sacs removed) were 15% lower (p less than 0.05) in SFBNWR embryos compared to control embryos from the Patuxent Wildlife Research Center (PWRC). Crown-rump length and femur length were shorter for SFBNWR embryos. The geometric mean polychlorinated biphenyl (PCB) concentration in SFBNWR eggs was 4.1 ppm wet weight, with a range of 0.8-52.0 ppm. A negative correlation (r = -0.61; p less than 0.05) existed between embryonic weight and log-transformed PCB residues in whole eggs collected from the same nest at SFBNWR, suggesting a possible impact of PCBs on embryonic growth. A correlation with embryonic weight did not occur for DDE [1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene] residues. Liver microsomal aryl hydrocarbon hydroxylase activity was neither significantly elevated nor correlated with PCB, DDE, or PCB plus DDE log-transformed residues. It is unknown whether the apparent association between PCBs and lower weight is persistent through hatching.     

Phase II trial of 10 deaza-aminopterin in patients with bladder cancer

Summary Deaza-aminopterin is a folate analog which is transported more rapidly than methotrexate into cells and appears to be more active than methotrexate against human and animal tumor in vitro. Fifteen patients with advanced urothelial tract cancer were given deaza-aminopterin 30–37.5 mg/m² IV QW. In responding patients drug was given QOW after 4–6 consecutive doses. Doses were escalated or de-escalated by 7.5 mg/m² depending on toxicity. Twelve patients had received prior chemotherapy which included methotrexate in nine. Three patients achieved a partial remission lasting 1, 3, and 3 months respectively: all responders had previously failed methotrexate after an initial response to a methotrexate containing regimen. None of the six patients who were methotrexate naive responded to deaza-aminopterin; 3 subsequently received methotrexate without response. Mild mucositis was universal and in 5 was severe. Six patients had an increase in liver transaminases probably secondary to anti-folate hepatotoxicity. Other toxicities included diarrhea, nausea, skin rash and fever. Further studies are needed to define the precise efficacy of deaza-aminopterin in patients with urothelial tract cancers.     

Cor triatriatum associated with partial anomalous pulmonary venous connection to the coronary sinus: Echocardiographic and angiocardiographic features

Summary An infant girl is described who had cor triatriatum and partial anomalous pulmonary venous connection of the left pulmonary veins to the coronary sinus, the first report of this combination of lesions. The infant also had a Dandy-Walker malformation and multiple facial and intrathoracic hemangiomas. The cardiac diagnosis was made by two-dimensional echocardiography. Cardiac catheterization and angiography confirmed the findings and also demonstrated a persistent left superior vena cava draining to the coronary sinus. The infant underwent successful surgical repair. Partial anomalous pulmonary venous connection and left superior vena cava not infrequently are associated with cor triatriatum. Although two-dimensional echocardiography is sensitive for the detection of cor triatriatum, preoperative cardiac catheterization is necessary to identify unequivocally systemic and pulmonary venous connections.     

Practical value of a new serum digitoxin assay

The purpose of this study was to evaluate a new fluorescence polarization immunoassay, TDx, for digitoxin by comparing the results of this assay with those of a radioimmunoassay (RIA). Thirty-three serum samples were obtained from 15 patients during, and for 4 weeks after, a 4-week course of digitoxin therapy. Each sample was separated by centrifugation, coded, and frozen until analysis. At the time of analysis, each sample was divided and analyzed simultaneously by TDx and RIA. Nine samples yielded results less than 2 ng/ml (limit of assay sensitivity) by one or both methods and were excluded from further data analysis. Linear regression analysis of the results of the remaining 24 paired samples (x = TDx, y = RIA) revealed a strong correlation coefficient of r2 = 0.95, slope = 0.95, and a y intercept of -0.99 (y = -0.99 + 0.95x). Additionally, the TDx results were lower than the RIA values in only five of 33 paired samples; and these occurred in four patients who had a significantly lower mean estimated creatinine clearance than that of the other 11 patients (39.0 +/- 9.1 ml/min/1.73 m2 vs. 63.3 +/- 11.8 ml/min/1.73 m2, p less than 0.01). The TDx system is a comparable alternative to the RIA method, but differences in specificity and sensitivity may exist and should be evaluated more thoroughly.