Stanley D. Allen

Interrelationship of velocity and chest compression in blunt thoracic impact to swine

As part of a continuing study of thoracic injury resulting from blunt frontal loading, the interrelationship of velocity and chest compression was investigated in a series of animal experiments. Anesthetized male swine were suspended in their natural posture and subjected to midsternal, ventrodorsad impact. Twelve animals were struck at a velocity of 14.5 plus or minus 0.9 m/s and experienced a controlled thoracic compression of either 15,19,or 24%. Six others were impacted at 9.7 plus or minus 1.3 m/s with a greater mean compression of 27%. For the 14.5 m/s exposures the severity of trauma increased with increasing compression, ranging from minor to fatal. Injuries included skeletal fractures, pulmonary contusions, and cardiovascular ruptures leading to tamponade and hemothorax. Serious cardiac arrhythmias also occurred, including one case of lethal ventricular fibrillation. The 9.7 m/s exposures produced mainly pulmonary contusion, ranging in severity from moderate to critical. Cardiac arrhythmias occurred but were typically minor. In contrast to the lower compression impacts at 14.5 m/s, there were no rib fractures or cardiovascular ruptures. In general, peak sternal acceleration and applied force correlated with impact velocity but not with normalized compression; and spinal acceleration did not correlate with any parameter. Overall, the high velocity exposures, produced higher mechanical responses, more severe gross trauma and more serious cardiac arrhythmias despite lower compression levels. The results of this study while reconfirming normalized compression as one correlate of injury, emphasize the importance of loading velocity in determining the overall severity of blunt thoracic impact.

Selection of orally active antifungal agents from 3,5-substituted isoxazolidine derivatives based on acute efficacy-safety profiles.

Routine in vitro screening of a new synthetic series of 3,5-substituted 2-methylisoxazolidines revealed that three imidazole analogs (PR 967-248, PR 967-234, and PR 969-566) and, to a lesser extent, a triazole analog (PR 988-399) exerted rather potent antifungal activity against three systemic and four dermatophytic classes of fungi. When tested in vivo for ability to eradicate Candida vaginitis in the rat, the triazole derivative, PR 988-399, was effective after oral administration. In this in vivo test for efficacy, PR 967-234 and PR 969-566 reduced but did not eradicate the infection, while PR 967-248 was inactive. PR 988-399 was, moreover, 4- to 13-fold less potent than the three imidazoles in inhibiting testosterone synthesis in isolated rat Leydig cells. After oral or intravenous administration, PR 988-399 and PR 969-566 elicited the fewest cardiovascular and behavioural side effects in conscious dogs. The rat safety study consisted of oral dosing followed by evaluation of the exploratory motor activity of the naive animals in a novel environment. Motor activity was suppressed least by PR 988-399 and most by PR 969-566. In a battery of mouse behavioural-neuromuscular-drug interaction tests, PR 988-399 and PR 969-566 produced the fewest central-behavioural-neuromuscular signs. These efficacy-safety evaluations were performed with ketoconazole as a positive reference standard. The sequence of drug testing with respect to efficacy-safety considerations appears to be a suitable approach for early detection of orally active antifungal agents such as PR 988-399 for more advanced development.

A Novel Bovine Rotavirus Electropherotype from Outbreaks of Neonatal Diarrhea in Utah Beef Herds

Thirty-six showed a very strong (+ + + +) reaction, 8 a mod-erately strong (+ + +) reaction, 3 a weak (+ +) reaction, and14 a very weak (+) reaction. Of the animals where age wasreported, 24% of the positive tests were in calves less than6 days of age, 46% were in calves between 6 and 10 days ofage, and 32% were in calves older than 10 days. Polyacryl-amide gel electrophoresis (PAGE) was performed on all 142fecal samples using established techniques.

Studies on antifungal agents 30. Novel substituted 3-(2-furanyl)-3- (1H-imidazol-1-ylmethyl)-2-methyl-5-phenyl(or phenyloxymethy)-isoxazolidines

The synthesis of a novel class of antifungal agents, the 3-(2-furanyl)-3-(1H-imidazol-1-ylmethyl)-2-methyl-5-phenyl(or phenyloxymethyl)isoxazolidines (10–15) is described. When tested in vitro, derivatives 10–15 exerted a potent antifungal activity against dermatophytes, but were less effective against fungi causing systemic infections. However, analogues 10 and 12 showed minimum inhibitory concentration (MIC) values of 2.0 μg/ml against Aspergillus fumigatus.

Studies on Antifungal Agents

The influence of the C-5-aromatic substitution on the in vitro antifungal activity of novel ci5–3,5-substituted isoxazolidine derivatives was investigated. Compounds having a C-5-(substituted phenoxy)

Studies on antifungal agents. 27. Novel 5-{[(substituted phenyl)thio]-methyl}isoxazolidines

Abstract The synthesis and antifungal activity of a series of novel 5-(substituted phenyl)thio]methylisoxazolidine derivatives are discussed. The title compounds were prepared by 1,3-dipolar cycloaddition reaction of α-substituted ketonitrones with allyl phenyl sulfides to provide diastereometric mixtures of the corresponding cis/trans -analogues. When tested in solid agar cultures, the title derivatives exerted moderate to potent in vitro antifungal activity against a number of dermatophytes and fungi causing systemic infections. The minimum inhibitory concentration (MIC) values ranged between

In vitro antifungal activity of novel substituted 3,5-diphenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine derivatives.

To further investigate the role of the C-5 substituent on the isoxazolidine ring on antifungal activity, a number of novel substituted 3,5-diphenyl-3-( lH-imidazol1 -ylmethyl)-2-methylisoxazoiidine derivatives (1) were prepared and assayed in vitro using broth and agar cultures. The synthesis of the title compounds involved a 1,3-dipolar cycloaddition reaction of substituted phenyl1H-imidazol1-ylmethyl nitrones with appropriate styrene precursors. The resulting cis/trans mixtures of the corresponding isoxazolidines were separated by flash chromatography on silica gel (TABLE 1):

Comparisons of ketoconazole, PR 969-566, PR 967-234, and PR 967-248 as antifungals in vitro and in the rat model of candidal vaginitis based on efficacy/safety profiles.

Critical factors in the rational development of new antifungal drugs are standardized, quantitative, and coordinated approaches involving chemical discovery, preclinical evaluations, and comparisons of novel antifungal candidates with positive reference compounds. The reference compound ketoconazole has been found to be effective clinically against vaginal candidiasis as well as in the rat model of candidal vaginitis. A new chemical series of isoxazolidine compounds was targeted for preclinical evaluations involving 1) in vitro testing; 2 ) in vivo analysis in the rat model of candidal vaginitis; and 3 ) safety considerations involving hormonal, central nervous system (CNS), and cardiovascular (CV) effects. The following antifungal candidates were first compared to ketoconazole for in vitro activity: 1) PR 969-566 or cis-3-(4-chlorophenyl) 3 [ ( 1Himidazol1 yl) methyl] 2 -methyl 5 { [ ( 4 methylphenyl) thiolmethyl) isoxazolidine; 2) PR 967-234 or cis-3,5-bis(4-chlorophenyl)-3-[ ( ltl-imidazoll-yl)methyl]-2-methylisoxazolidine; and 3) PR 967-248 or cis-5-[ (4-chlorophenoxy ) methy1]-3-(4-~hlorophenyl)-3-[( lH-imidazol1 -yl)methyl]-2-methylisoxazolidine. In the in vitro evaluations, minimum inhibitory concentration (MIC) values were used for comparing antifungal activity of all four compounds against two strains of Candida