Gentamicin is an aminoglycoside antibiotic that possesses bactericidal activity against many gram-positive and gram-negative organisms. Clinically, it is used most often to treat life-threatening infections due to Pseudomonas, Proteus, and the Klebsiella-Enterobacter group. A relationship between gentamicin serum concentrations and clinical response has been demonstrated. Toxicities, notably ototoxicity and nephrotoxicity, are also associated with serum concentrations. Gentamicin is given intermittently either intramuscularly or intravenously resulting in peak and trough concentrations. The therapeutic range is defined as peak concentrations between 4-15mg/L (depending in part on the site of infection and the susceptibility of the infecting organism), and trough concentrations less than 2mg/L (to minimize toxicity). Gentamicin distributes into a space similar to the extracellular fluid volume (ECFV). Pathophysiologic changes which alter the extracellular fluid compartment also alter gentamicin volume of distribution (Vd). One intrinsic factor known to alter gentamicin Vd is obesity. Leanness is also thought to alter gentamicin Vd but its effect has not been quantitated. The objectives of this study were to: 1) accurately describe a Vd in "normal" patients, that is, those with no factors known to alter gentamicin volume of distribution; 2) determine if there is a continuous linear relationship between gentamicin volume of distribution (L/kg) and percent body fat; 3) determine if that relationship is associated with changes in ECFV; and 4) develop a formula for predicting Vd in a similar patient population. Twenty patients with no extrinsic factors known to alter gentamicin Vd participated in the study. Five blood samples were drawn around one steady state dose of gentamicin. A one-compartment model was used to calculate Vd. Tritiated water and anthropometric measurements were conducted simultaneously to provide estimates of body composition. Together these values were used to examine the relationship between gentamicin Vd and body composition. We have described a Vd for gentamicin that is larger but no less variable than is currently used to determine initial dosage regimens. This volume may be larger either due to the selection of patients or method of serum gentamicin analysis. This larger volume should be used to calculate empiric dosage regimens for similarly selected patients to decrease the risk of treatment failure. We were not able to describe a linear relationship between percent body fat and gentamicin volume of distribution. We have postulated several reasons as to why this relationship could not be detected; 1) the sample size may not have been large enough, 2) the relationship is not important in patients who are not at extremes of weight, or 3) the variations caused by changes in body composition were not as significant as other factors that may cause fluid alterations in hospitalized patients. There was a strong correlation between gentamicin Vd and total body water noted. Having eliminated all patients in whom the relationship between total body water and ECFV could not be assumed to be normal and constant, we have indirectly demonstrated a strong relationship between ECFV and gentamicin Vd. This relationship still leaves variability in gentamicin's distribution characteristics to be explained. The predictive formula is based on measurements of height, weight, and a larger Vd [L/kg(ideal body weight)] than has previously been used. The predictive formula recommended for clinical use in adults is Vd=0.30L/kg (Dosing Weight). Dosing weight equals ideal body weight (IBW) when actual body weight (ABW) is ≤ IBW, or 0.4(ABW-IBW)+IBW, when ABW is > IBW. The consequences of estimating a larger Vd are that patients empirically would receive larger doses than are currently being administered, thus more patients should obtain therapeutic serum concentrations within the first 24 hours of therapy. This information will be useful in our attempts to optimize gentamicin therapy. / Pharmaceutical Sciences, Faculty of / Graduate

Two fundamental problems of celestial mechanics are considered: the stellar or planetary three-body problem and a related form of the restricted four-body problem. Although a number of constraints are imposed, no assumptions are made which could invalidate the final solution. A consistent and rational approach to the analysis of four-body systems has not previously been developed, and an attempt is made here to describe problem evolution in a systematic manner. In the particular three-body problem under consideration two masses, forming a close binary system, orbit a comparatively distant mass. A new literal, periodic solution of this problem is found in terms of a small parameter e, which is related to the distance separating the binary system and the remaining mass, using the two variable expansion procedure. The solution is accurate within a constant error O(e¹¹) and uniformly valid as e tends to zero for time intervals 0(e¹⁴). Two specific examples are chosen to verify the literal solution, one of which relates to the sun-earth-moon configuration of the solar system. The second example applies to a problem of stellar motion where the three masses are in the ratio 20 : 1 : 1. In both cases a comparison of the analytical solution with an equivalent numerically-generated orbit shows .close agreement, with an error below 5 percent for the sun-earth-moon configuration and less than 3 percent for the stellar system. The four-body problem is derived from the three-body case by introducing a particle of negligible mass into the close binary system. Unique uniformly valid solutions are found for motion near both equilateral triangle points of the binary system in terms of the small parameter e, where the primaries move in accordance with the uniformly-valid three-body solution. Accuracy, in this case, is Q maintained within a constant error 0(e⁸), and the solutions are uniformly valid as e tends to zero for time intervals 0(e¹¹). Orbital position errors near L₄ and L₅ of the earth-moon system are found to be less than 5 percent when numerically-generated periodic solutions are used as a standard of comparison. The approach described here should, in general, be useful in the analysis of non-integrable dynamic systems, particularly when it is feasible to decompose the problem into a number of subsidiary cases. / Applied Science, Faculty of / Electrical and Computer Engineering, Department of / Graduate

Since no lean body mass (LBM) index was available for women, the purpose of the present study was to use the formula of Behnke et al. in the calculation of an LBM Index for women.

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