Development of a 2,4-diaminothiazole series for the treatment of human African trypanosomiasis highlights the importance of static-cidal screening of analogues

While treatment options for human African trypanosomiasis (HAT) have improved significantly, there is still a need for new drugs with eradication now a realistic possibility. Here, we report the development of 2,4-diaminothiazoles that demonstrate significant potency against Trypanosoma brucei, the causative agent of HAT. Using phenotypic screening to guide structure-activity relationships, potent drug-like inhibitors were developed. Proof of concept was established in an animal model of the hemolymphatic stage of HAT. To treat the meningoencephalitic stage of infection, compounds were optimized for pharmacokinetic properties, including blood-brain barrier penetration. However, in vivo efficacy was not achieved, in part due to compounds evolving from a cytocidal to a cytostatic mechanism of action. Subsequent studies identified a nonessential kinase involved in the inositol biosynthesis pathway as the molecular target of these cytostatic compounds. These studies highlight the need for cytocidal drugs for the treatment of HAT and the importance of static-cidal screening of analogues

Mokoia Island, Rotorua DOC SCIENCE INTERNAL SERIES 25

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The Words-in-Noise (WIN) Test With Multitalker Babble and Speech-Spectrum Noise Maskers

The Words-in-Noise (WIN) test uses monosyllabic words in seven signal-to-noise ratios of multitalker babble (MTB) to evaluate the ability of individuals to understand speech in background noise. The purpose of this study was to evaluate the criterion validity of the WIN by comparing recognition performances under MTB and speech-spectrum noise (SSN) using listeners with normal hearing and listeners with hearing loss. The MTB and SSN had identical rms and similar spectra but different amplitude-modulation characteristics. The performances by the listeners with normal hearing, which were 2 dB better in MTB than in SSN, were about 10 dB better than the performances by the listeners with hearing loss, which were about 0.5 dB better in MTB with 56% of the listeners better in MTB and 40% better in SSN. The slopes of the functions for the normal-hearing listeners (8-9%/dB) were steeper than the functions for the listeners with hearing loss (5-6%/dB). The data indicate that the WIN has good criterion validity

Detection of simultaneous movement at two human arm joints

To detect joint movement, the brain relies on sensory signals from muscle spindles that sense the lengthening and shortening of the muscles. For single-joint muscles, the unique relationship between joint angle and muscle length makes this relatively straightforward. However, many muscles cross more than one joint, making their spindle signals potentially ambiguous, particularly when these joints move in opposite directions. We show here that simultaneous movement at adjacent joints sharing biarticular muscles affects the threshold for detecting movements at either joint whereas it has no effect for non-adjacent joints. The angular displacements required for 70% correct detection were determined in 12 subjects for movements imposed on the shoulder, elbow and wrist at angular velocities of 0.25–2 deg s(−1). When moved in isolation, detection thresholds at each joint were similar to those reported previously. When movements were imposed on the shoulder and wrist simultaneously, there were no changes in the thresholds for detecting movement at either joint. In contrast, when movements in opposite directions at velocities greater than 0.5 deg s(−1) were imposed on the elbow and wrist simultaneously, thresholds increased. At 2 deg s(−1), the displacement threshold was approximately doubled. Thresholds decreased when these adjacent joints moved in the same direction. When these joints moved in opposite directions, subjects more frequently perceived incorrect movements in the opposite direction to the actual. We conclude that the brain uses potentially ambiguous signals from biarticular muscles for kinaesthesia and that this limits acuity for detecting joint movement when adjacent joints are moved simultaneously