Application of an Allosteric Ternary Complex Model to the Technique of Pharmacological Resultant Analysis

A simple ternary complex model of drug-receptor interaction has been used to extend the procedure of pharmacological resultant analysis, enabling the quantitation of interactions between allosteric modulators and orthosteric antagonists. Equations derived in the theoretical treatment were used to analyse functional data for the interaction between the allosteric modulator gallamine and the orthosteric antagonist scopolamine, with oxotremorine as the agonist, at rat tracheal muscarinic acetylcholine receptors. Quantitative estimates of the affinity of gallamine for the allosteric site (pK_Z = 4.7) and the extent of negative, heterotropic co-operativity between gallamine and scopolamine (α′ = 13.1) were obtained. Furthermore, an alternative direct, model-fitting approach, that does not rely on the determination of concentration ratios, was also developed, and yielded similar results. It is suggested that the approach presented in this paper is useful for quantifying interactions between orthosteric antagonists and allosteric modulators, particularly when the extent of co-operativity is low or the modulators possess multiple pharmacological properties, or both.     

Addiction versus stages of change models in predicting smoking cessation

Prospective data from the California Tobacco Surveys (n=2066) were used to perform a critical test of the Prochaska et al. (1991) stages of change model. When the stages of change model was used as a stand alone predictor, smokers in preparation at baseline were more likely to be in cessation at follow-up than smokers in pre-contemplation at baseline (OR adj="1.9)" When stage membership was combined with baseline measures of addiction including smoking behaviors and quitting history, it was not a significant predictor of future cessation. A prediction equation that combined daily vs. occasional smoking, cigarettes per day smoked, life-time quits of at least a year, and quits of more than 5 days in the previous year discriminated smokers in cessation at follow-up of 1 to 2 years better than did the stages of change model. The area under the ROC curve for the equation based on addiction measures was 69.3% vs. 55.1% for the stages of change. Cessation rates ranged from 7.7% to 35.7% for the four-category addiction equation compared with 15.1% to 24.9% for stages of change model.     

Subchronic and Chronic Inhalation Toxicity of Antimony Trioxide in the Rat

Fischer 344 rats were exposed by inhalation to Sb₂O₃ (antimonytrioxide) dust at exposure levels of 0, 0.25, 1.08, 4.92, and23.46 mg/m³ for 6 hr/day, 5 days/week for 13 weeks followedby a 27-week observation period. Subsequently, an inhalationon-cogenicity study was conducted at exposure levels of 0, 0.06,0.51, and 4.50 mg/m³ for 12 months followed by a 12-month observationperiod. The Sb₂O₃ in the subchronic study had a mass medianaerodynamic diameter (MMAD) of 3.05 ± 0.21 microns (mean± SD) with a geometric standard deviation (GSD) of 1.57± 0.06. In the chronic study, the MMAD was 3.76 ±0.84 and the GSD was 1.79 ± 0.32. Except for the eyes,no adverse clinical observations were attributed to Sb₂O₃ ineither study. In the subchronic study, corneal irregularitieswere seen after about 2 weeks of exposure and did not abateduring the observation period. In the chronic study, ophthalmoscopicevaluation at 24 months revealed a dose-related increase incataracts of 11, 24, 28, and 32% (both sexes combined) for eachgroup, respectively. Body weights were significantly lower (6%)than the control group's weights in the 23.46 mg/m³ males inthe subchronic study. These rats did not recover this weightduring the 27-week observation period. Body weights of the femalesin both studies and males in the chronic study were unaffected.There were no Sb₂O₃ effects on clinical chemistry or he-matologyin either study. Mean absolute and relative lung weights weresignificantly increased in the 4.92 and 23.46 mg/m³ groups inthe subchronic study. The 23.46 mg/m³ group's lung weights didnot recover to control levels during the 27-week observationperiod. Lung weights for rats in the chronic study were unaffected.Microscopic changes in the lungs in the subchronic and chronicstudy were limited to subacute-chronic interstitial inflammation,increased numbers of alveolar-in-traalveolar macrophages, foreignmaterial in the alveolar-in-traalveolar macrophages in the peribronchialand perivascular (chronic study only) lymphoid aggregates andin the peribronchial lymph nodes, granulomatous inflammation/granulomas,and fibrosis. In the chronic study, any observed neoplasms occurredwith comparable incidence among all groups and were within thehistorical range for controls. Clearance of Sb₂O₃ from the lungwas burden dependent and was reduced by 80/ in the 4.50 mg/m³group in the chronic study. The previously reported studies,which found Sb₂O₃ to be a carcinogen, were run at higher lungburdens. Under the exposure conditions of the current study,Sb₂O₃ was not a carcinogen.     

Crohn''s Disease of the Colon

Retroperitoneal lumbocrural abscess occurred in 12 patients of 231 with Crohn's colitis or ileocolitis. Although all patients with this complication fell within the group of 175 ileocolitis patients, at least four originated in fistulous tracts of the colon. Eleven of the 12 abscesses developed spontaneously as the first major complication of the disease. The prominent clinical features included pain radiating down the thigh, hip joint flexion, difficulty in walking, hydronephrosis and hydroureter. Internal and external fistulas were significantly more common in the abscess group of 12 patients than in the 219 patients without retroperitoneal abscess. Radiological evidence of granulomatous disease was found in all patients; fistulous tract formation was characteristic and the development of extraperitoneal gas bubbles, in four patients, pathognomonic of abscess with gast-forming organisms. In the presence of established retroperitoneal abscess, the surgical sequence suggested is drainage synchronous with, or followed by diversion and ultimately definitive resection. Resection with anastomosis should not be carried out in the presence of an acute inflammatory process with frank abscess or free pus communicating with the peritoneal cavity. The spontaneous development of retroperitoneal abscess is a serious development in the natural history of Crohn's (ileo) colitis. It frequently heralds the first of a series of operative procedures to deal with the abscess. It sequels are enterocutaneous fistulas and further extension of the disease process.     

The Influence of Race and Phenotype on the Erythrocyte D Antigen Studied by I131--labeled Anti--D

A method for the preparation of I¹³¹-labeled anti-D eluates (I^[unknown] anti-D)specific for the D antigen by adsorption and elution from intact D positivered cells is presented. A standard D antigen reference system for the quantitative comparison of the red cell D antigen from various donors was developedon the basis of kinetic studies of the effect of pH, temperature and antigenconcentration on the I^[unknown] anti-D reaction with the D antigen. The red cell Dantigen determinations of the blood from 33 Negro and 102 Caucasiandonors showed wide monomodal frequency distributions which indicate aheterogeneity of quantitative D antigen reactivity consistent with previousserologic and I¹³¹-labeled anti-D studies. The average red cell D antigenreactivity of the 20 probable D homozygote and 14 established D hemizygoteCaucasian donors was similar to the D antigen reactivity of the 102 randomCaucasian donors. The red cell D antigen reactivity was strongly depressedby the C antigen (or C gene) in Caucasian bloods and enhanced by the Eantigen (or E gene) in Negro bloods. The E antigen (or E gene) may alsohave enhanced the D antigen reactivity in red cells from Caucasian donors,but the difference in D zygosity provides an alternative explanation for theresults. The marked influence on red cell D antigen reactivity in the presenceof the C and E antigen may well have obscured any lesser influence of Dzygosity.

Accepted on December 6, 1962     

Crohn's Disease of the Colon

Using accepted diagnostic criteria we have selected, for study, 160 patients with Crohn's disease involving the colon. There is a remarkable discrepancy between the clinical diagnosis prior to or at the time of initial admission to this hospital and the diagnosis following definitive investigation and observation of the progression of disease.
The peak age incidence occurred in the second decode The colitis group showed a greater percentage of patients over 30 years of age. Although histopathology was not obtained in all patients, there appeared to be sparing of the ascending colon in a small percentage (9%) of patients with ileocolitis.
Comparison of the clinical features of granulomatous disease limited to the colon and granulomatous ileocolitis shows a significantly greater incidence of extraintestinal symptoms and overt bleeding in the former. Nausea, vomiting, subacute obstruction, abdominal mass and internal fistulas were substantially more common in ileocolitis but the difference was not statistically significant. In this series retroperitoneal abscess did not occur in patients with disease localized to the colon. In the 10 patients with ileocolitis who developed an abscess, however, the site of fistula was the colon in four patients. In one of these, the abscess was left-sided.