All currently available general anesthetic agents possess potentially lethal side effects requiring their administration by highly trained clinicians. Among these agents is etomidate, a highly potent imidazole-based intravenous sedative-hypnotic that deleteriously suppresses the synthesis of adrenocortical steroids in a manner that is both potent and persistent. We developed two distinct strategies to design etomidate analogs that retain etomidate\'s potent hypnotic activity, but produce less adrenocortical suppression than etomidate. One strategy seeks to reduce binding to 11β-hydroxylase, a critical enzyme in the steroid biosynthetic pathway, which is potently inhibited by etomidate. The other strategy seeks to reduce the duration of adrenocortical suppression after etomidate administration by modifying the drug\'s structure to render it susceptible to rapid metabolism by esterases. In this chapter, we describe the methods used to evaluate the hypnotic and adrenocortical inhibitory potencies of two lead compounds designed using the aforementioned strategies. Our purpose is to provide a case study for the development of novel analogs of existing drugs with reduced side effects.

The objective was to better understand how a series compliance alters contraction kinetics and power output of muscle to enhance the work done on a load. A mathematical model was created in which a gravitational point load was connected via a linear spring to a muscle (based on the contractile properties of the sartorius of leopard frogs, Rana pipiens). The model explored the effects of load mass, tendon compliance, and delay between onset of contraction and release of the load (catch) on lift height and power output as measures of performance. Series compliance resulted in increased lift height over a relatively narrow range of compliances, and the effect was quite modest without an imposed catch mechanism unless the load was unrealistically small. Peak power of the muscle-tendon complex could be augmented up to four times that produced with a muscle alone, however, lift height was not predicted by peak power. Rather, lift height was improved as a result of the compliance synchronizing the time courses of muscle force and shortening velocity, in particular by stabilizing shortening velocity such that muscle power was sustained rather than rising and immediately falling. With a catch mechanism, enhanced performance resulted largely from energy storage in the compliance during the period of catch, rather than increased time for muscle activation before movement commenced. However, series compliance introduced a trade-off between work done before versus after release of the catch. Thus, the ability of tendons to enhance locomotor performance (i.e. increase the work done by muscle) appears dependent not only on their established role in storing energy and increasing power, but also on their ability to modulate the kinetics of muscle contraction such that power is sustained over more of the contraction, and maximizing the balance of work done before versus after release of a catch.

The lifespan of herbivorous Rana pipiens larvae is ∼3 months, while that of carnivorous Ceratophrys ornata larvae is only about 2 weeks. During metamorphic climax, the larval gut shortens dramatically, especially in R. pipiens, and its luminal epithelium is replaced by adult-type epithelium. To determine when programmed cell death occurs during the metamorphic restructuring of the gut, we prepared cross-sections of the stomach, small intestine, and large intestine from representative larval stages and from juvenile frogs of both species. The sections were incubated with monoclonal antibody against active caspase-3, one of the key enzymes in the apoptotic cascade. We observed apoptosis in some luminal epithelial cells in each of the three regions of the larval gastrointestinal tract of both species. However, apoptotic cells appeared earlier in larval stages of R. pipiens than C. ornata and few were seen in juvenile frogs of either species. The results demonstrate the occurrence of apoptosis in the metamorphic remodeling of the gut of both R. pipiens larvae and C. ornata larvae.

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Distortion product otoacoustic emissions (DPOAEs) are weak sounds emitted from the ear when it is stimulated with two tones. They are a manifestation of the nonlinear mechanics of the inner ear. As such, they provide a noninvasive tool for the study of the inner ear mechanics involved in the transduction of sound into nerve fiber activity. Based on the DPOAE phase behavior as a function of frequency, it is currently believed that mammalian DPOAEs are the combination of two components, each generated by a different mechanism located at a different location in the cochlea. In frogs, instead of a cochlea, two separate hearing papillae are present. Of these, the basilar papilla (BP) is a relatively simple structure that essentially functions as a single auditory filter. A two-mechanism model of DPOAE generation is not expected to apply to the BP. In contrast, the other hearing organ, the amphibian papilla (AP), exhibits a tonotopic organization. In the past it has been suggested that this papilla supports a traveling wave in its tectorial membrane. Therefore, a two-mechanism model of DPOAE generation may be applicable for DPOAEs from the AP. In the present study we report on the amplitude and phase of DPOAEs in the frog ear in a detailed f1, f2 area study. The result is markedly different from that in the mammalian cochlea. It indicates that DPOAEs generated by neither papilla agree with the two-mechanism traveling wave model. This confirms our expectation for the BP and does not support the hypothesized presence of a mechanical traveling wave in the AP.

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