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The four parameters in aRT represent the forward transfer function in the lossy element 2, the re ection at the input to element 3, the reverse transmission in the lossy element, and the re ection at the output of element 1, respectively. Here 1 includes re ections due to module 1 directly as well as all previous modules. Likewise, 3 includes re ections from the rst and all subsequent modules within the load. All of these parameters can be small so the product aRT can be much less than one, in which case it can be ignored in Eq. (2.88). This condition can be true regardless of 1 and 3 (which are always less than 1) if there is enough

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Perceptual-motor skill learning in Gilles de la Tourette syndrome: Evidence for multiple procedural learning and memory systems Neuropsychologia, 43, 1456 1465 Marsh, R, Alexander, G M, Packard, M G, Zhu, H, Wingard, J C, Quackenbush, G, et al (2004) Habit learning in Tourette syndrome: A translational neuroscience approach to a developmental psychopathology Archives of General Psychiatry, 61, 1259 1268..

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Compounds with this function readily undergo intraconversion between two forms called tautomers. One of those has two carbonyls; the alternative isomer formed by a simple shift of a double bond places the acidic proton on oxygen and is called the enol isomer. A similar functional group will be seen later in a several much more recent drugs. Phenylbutazone is oxidized in the liver to the corresponding hydroxylated derivative. That product, oxyphenbutazone,7 is a drug in its own right in synthetic form. The several other close analogs that have been assigned nonproprietary names are of minor importance as they offer no advantages over the original drug. Phenylbutazone itself nds considerable use in veterinary medicine, particularly in treating arthritis in horses. Its use is racehorses is, however, grounds for disquali cation. Good anti-in ammatory activity is retained when an extra carbon is inserted between the benzene ring and the carboxylic acid. This changes the side chain to an acetic acid. The sizeable number of structurally quite diverse compounds in this class that have been assigned nonproprietary names re ects the fact that the seemingly small change provided a rich source for novel compounds. It also illustrated the relatively loose structural constraints on NSAID activity. The anti-in ammatory drug diclofenac,8 on which a benzene ring bears the acetic acid side chain, is better known as the widely used Voltarenw (Fig. 4). The extra benzene ring, which is connected by a nitrogen bridge in diclofenac, can alternatively be attached via an oxygen bridge as in fenclofenac.9 Although this related drug showed reasonable

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both these renin inhibitors share features reminiscent of small peptides such as the recurrence of amide functions (C5 5ONH) along the backbone. As noted in 2, some of the work that led to the development of small-molecule renin directly aided development of a new class of drugs for treating HIV/AIDS patients. Yet another example of the discovery of a new class of drugs that emerged from the search for new ways in which to treat high blood pressure had its origin in the treatment of asthma, a seemingly quite unrelated disease. It has been known for the better part of a century that the natural product purine base, theophylline, relaxes the constricted bronchioles during asthmatic attacks. The discovery of the role of the phosphodiesterase enzyme (PDE) by Sutherland in the early 1960s helped explain how this drug worked.53 He and his colleagues had found that a large number of physiological responses were controlled at the cellular level by molecules based on the purine adenosine. The process, simpli ed, involves the reversible conversion of the esteri ed form adenosine phosphate (AMP) to cyclized AMP (cAMP). This process, they found is mediated by PDE. Cleavage of the phosphate ester in cAMP by PDE reverses the signal and results in relaxation of involuntary muscle. The development of more delicate assays led to the nding that PDE, like many other messenger molecules, exists as many subtypes. There are recognized at present at least eleven PDEs, each with its own specialized target. It should not come as a surprise that this class of enzymes came under scrutiny as a source of

focus on relaxation training/stress management skills and may include behavioral interventions shown to be effective with children with Tourette syndrome, such as self-monitoring and habit reversal. Continued neurologic follow-up with Dr. Elliott is recommended.