The Clinical Effects of Targeting

Other data indicate that bronchodilator particles that are 5.6 pm are more efficacious than larger particles. Rees et al. (49) incorporated terbutaline crystals into standard MDIs and generated polydisperse aerosols characterized by three different MMADs 5.6, 9.1, and 13.6 pm. In 10 patients with asthma, they found that only the smallest aerosol (5.6 pm) significantly improved the FEVj, sG, and MEFjq. Since the two other aerosols had no significant bronchodilating ef- 

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The importance of the mass of aerosol that is deposited in the lung was also shown by Persson et al. (51), who modified the mouthpiece of terbutaline Turbuhalers so that they delivered either 90, 40, or 5 pg as 5-pm particles. When pulmonary function was measured before and after administration of these three aerosols in a group of patients with asthma, the FEV, was least improved when the low dose (i.e., 5 pg) was delivered. The two higher doses did not differ from each other. 

I/O ratios for the 1.5-pm aerosol ranged from 2.1 1 to 3.2 1. In contrast, the I/O ratio for the 3.3-pm aerosol ranged between 3.4 1 to 8.0 1. In 3 of 6 patients, Ruffin found that the cumulative dose-response curves and the ED q for the 3.3-pm aerosol were significantly shifted to the left of the 1.5-pm aerosol curves. EDjq is the effective dose that caused 50% of the maximum possible response. An example of this shift in the dose-response curve for one of the subjects is shown in Fig. 6. 

These patients also demonstrated large differences in their VO ratios for the two aerosols. The aerosol with the larger particles resulted in higher I/O 

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The central role that the PI3K/AKT pathway plays in cancer continues to fuel excitement in this arena as a potential target for cancer therapy. Progress with small molecule AKT inhibitors continues to be made, as judged by the compounds described in this review. However, the full scope of the clinical effectiveness of targeting this pathway has yet to be proven, as most of the reported small molecule AKT inhibitors are still in pre-clinical development, with only a few examples in early phase clinical trials. 

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