Three-dimensional quantitative structure-permeability relationship analysis for a series of inhibitors of rhinovirus replication.

Multiple three-dimensional quantitative structure-activity relationship (3D-QSAR) approaches were applied to predicting passive Caco-2 permeability for a series of 28 inhibitors of rhinovirus replication. Catalyst, genetic function approximation (GFA) with MS-WHIM descriptors, CoMFA, and VolSurf were all used for generating 3D-quantitative structure permeability relationships utilizing a training set of 19 molecules. Each of these approaches was then compared using a test set of nine molecules not present in the training set. Statistical parameters for the test set predictions (r(2) and leave-one-out q(2)) were used to compare the models. It was found that the Catalyst pharmacophore model was the most predictive (test set of predicted versus observed permeability, r(2) = 0.94). This model consisted of a hydrogen bond acceptor, hydrogen bond donor, and ring aromatic feature with a training set correlation of r(2) = 0.83. The CoMFA model consisted of three components with an r(2) value of 0.96 and produced good predictions for the test set (r(2) = 0.84). VolSurf resulted in an r(2) value of 0.76 and good predictions for the test set (r(2) = 0.83). Test set predictions with GFA/WHIM descriptors (r(2) = 0.46) were inferior when compared with the Catalyst, CoMFA, and VolSurf model predictions in this evaluation. In summary it would appear that the 3D techniques have considerable value in predicting passive permeability for a congeneric series of molecules, representing a valuable asset for drug discovery.

Natural products as insecticides: the biology, biochemistry and quantitative structure-activity relationships of spinosyns and spinosoids.

The spinosyns, a novel family of insecticidal macrocyclic lactones, are active on a wide variety of insect pests, especially lepidopterans and dipterans. The biological activity of a mixture (spinosad; Tracer, Spin-Tor, Success) of the two most abundant spinosyns (spinosyns A and D) against pest insects is on a par with that of many pyrethroid insecticides. The spinosyns also exhibit a very favorable environmental and toxicological profile, and possess a mode of action that appears unique, with studies to date suggesting that both nicotinic and gamma-aminobutryic acid receptor functions are altered in a novel manner. Compared to pyrethroids such as cypermethrin, spinosyn A is slow to penetrate into insect larvae such as tobacco budworm larvae (Heliothis virescens); however, once inside the insect, spinosyn A is not readily metabolized. To date, more than 20 spinosyns and more than 800 spinosoids (semi-synthetic analogs) have been isolated or synthesized, respectively. Artificial neural network-based quantitative structure activity relationship (QSAR) studies for the spinosyns suggested that modification of the 2',3',4'-tri-O-methylrhamnosyl moiety could improve activity and several spinosoids incorporating these modifications exhibited markedly improved lepidopteran activity compared to spinosad. Multiple linear regression-based QSAR studies also suggest that whole molecule properties such as CLogP and MOPAC dipole moment can explain much of the biological activity observed for the spinosyns and closely related spinosoids.

Obstructing giant colonic diverticulum.

We report the second case of an obstructing true colonic diverticulum. Of the 103 cases of giant sigmoid diverticulum found in the literature, 13% have been reported as true giant sigmoid diverticulum, ie, containing all layers of the colonic wall. Our 75-year-old patient had clinical symptoms for only 6 months, and endoscopy revealed an almost totally obstructing mass 20 cm from the anus. Surgical resection of the sigmoid colon with a primary anastomosis resolved all of the patient's obstructive symptoms. A flap-valve mechanism was the cause of this true giant colonic diverticulum. Microscopic examination of the diverticulum wall revealed all normal layers of colon wall.

Interaction of cyclohexanediones with acetyl coenzyme-A carboxylase and an artificial target-site antibody mimic: a comparative molecular field analysis.

Similarities and differences between steric and electrostatic potentials of a monoclonal-antibody-based surrogate of a herbicide target-site and its in vitro enzyme target were investigated using three-dimensional quantitative structure-activity relationship comparative molecular field analysis (3D-QSAR CoMFA). Two separate, five-component, partial least squares CoMFA models were developed to compare the interaction of cyclohexanedione herbicides with their target site, acetyl coenzyme-A carboxylase (ACCase; EC 6.4.1.2) and a cyclohexanedione pharmacophore-specific monoclonal antibody (mAb A). On the basis of CoMFA models, similarities in steric and electrostatic requirements around position 2 of the binding site for the oxime functional group of the cyclohexanedione molecule appear to be crucial for interaction of the herbicide with both ACCase and mAb A. These similarities explain the observed quantitative relationship between binding of cyclohexandedione herbicides to ACCase mAb A. Furthermore, these results support the production and use of mAb-based surrogates of pesticide targets as screening tools in pesticide discovery programs.

Geriatric acute perforated appendicitis: atypical symptoms lead to a difficult diagnosis.

A geriatric man was admitted to the hospital with left-sided chest pain and subsequently had a full cardiac evaluation by a cardiologist. The workup revealed no cardiac abnormalities, and the patient was discharged on the second hospital day. He returned within 48 hours for recurrence of the left-sided chest pain and the interval development of epigastric and left upper quadrant abdominal pain. He was admitted to the hospital for evaluation and serial examinations. Mild diffuse abdominal tenderness developed overnight, and computed tomography of the abdomen revealed a perforated appendix with suppuration. An appendectomy was done immediately. The diagnosis of appendicitis in the geriatric patient is occasionally difficult because of atypical and sometimes misleading physical findings.

Macrophage and polymorphonuclear leukocyte function in patients with Alzheimer disease.

Monocyte derived macrophages and polymorphonuclear leukocytes (PMNs) isolated from the peripheral blood of thirteen patients with Alzheimer disease were studied for their cytotoxic effects on a sensitive allogenic tumor target. PMN cells from 11 of the 13 patients with Alzheimer disease were able to kill the tumor cells. In addition, the macrophages from 12 of the 13 Alzheimer disease patients were cytotoxic towards the tumor targets. Four of these patients possessed a plasma inhibitory factor which was capable of suppressing macrophage mediated cytotoxicity. When the lymphocytes from these patients were studied for their ability to be stimulated with the specific antigen, streptokinase, to produce macrophage activating factor (MAF), only 5 of the 13 patients studied possessed lymphocytes which were capable of producing MAF. Thus, the only immunological defect in Alzheimer disease patients which was observed in this study was in the ability of the lymphocytes to synthesize MAF.

Necrotic arachnidism.

Ten bites by Loxosceles reclusa, the North American brown recluse spider, are reported from South Carolina. Envenomation by the brown recluse spider is becoming a public health problem in the United States. The spider reportedly now is found from coast to coast in the southern half of the country and its range is probably increasing. The spider bite varies in intensity, causing reactions ranging from an area of severe necrosis to a mild cutaneous reaction. Treatment is unsatisfactory, and no antivenom is currently available. Even though a specific test is available for loxoscelism, diagnosis remains difficult.