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But these proposals fail to address the fundamental cyclical as well as contextual dynamics underlying drug development and use order ondansetron 4 mg with visa treatment plan. Furthermore, the parties overlook what seems to have become a rather important phenomenon in drug regulation in the post-thalidomide era: the so-called double bind trade-off phenomenon. Following the thalidomide drug disaster (1958-1962), and the subsequent introduction and enforcement of high drug testing and safety standards, drug regulatory agencies came under attack for delaying the introduction of useful medicines and weakening industrial competitiveness. At the same time they faced the political criticism for approving me-too drugs or drugs later shown to have, detrimental side effects. By describing the twisting career of triazolam (Halcion®) in the Netherlands we shall point out how this regulatory double bind between safety and innovation may interfere with the pace, direction and intensity of the Seige cycle. Moreover, the Halcion case helps to understand the importance of economic, political and cultural contexts in shaping drug life cycles by creating, reinforcing, legitimating or obstructing (inter-)national career paths. Triazolam (Halcion®) and the Dutch regulatory context Triazolam was frst synthesized and tested by the American drug company Upjohn in 1969. The new compound promised to be the lead compound of a new generation of safe and short- acting benzodiazepines (benzos). Since the introduction of Librium in 1960 the members of this chemical class led the top-selling drug list in Western countries. However, over time reports on adverse effects of these minor-tranquillizers accumulated: tolerance, dependence, drowsiness, reduced alertness and other reactions leading to traffc accidents. The historian Susan Speaker shows how the critique on the making and taking of benzos 4 T. Brynner, Dark remedy; The impact of thalidomide and its revival as a vital medicine. Daemmrich, A tale of two experts: Thalidomide and political engagement in the United States and West Germany. Nelemans, ‘Psychofarmaca in het verkeer’, Nederlands Tijdschrift voor Geneeskunde, 112 (1968): 1862-8; Geneesmiddelen en Verkeersongevallen’, Geneesmiddelenbulletin 1 (1967): 9-12; F. Nelemans, ‘Psychofarmaca in het verkeer’, Nederlands Tijdschrift voor Geneeskunde 112 (1968): 1862-8; D. By 1976 a number of clinical trials had been performed showing that the new drug was an effective and safe sleeping pill with a very short half-life that compared favourably with older benzodiazepine analogues.
Objective lens aberration–corrected transmission electron microscopes and condenser lens aberration–corrected scanning transmission electron microscopes in the bright-ﬁeld mode allow for sufﬁciently thin crystals the retrieval of Fourier coef- ﬁcients of the projected electrostatic potential down to the sub-A length scale and buy generic ondansetron 4mg on-line treatment kitty colds,˚ thus, represent a novel type of crystallographic instrument. The higher the directly interpretableb resolution in an aberration-corrected transmission electron microscope is, the lower will, in principle, be the lateral over- lap of the electrostatic potentials from adjacent atomic columns and the more zone axes will be revealed by crossed lattice fringes in structurealb images. Note that the relationship between directly interpretable image resolution and visibility of zone axes is strongly superlinear. This is, for example, demonstrated in Table 1 for a densely packed model crystal with a very small unit cell. This hypothetical material is very densely packed, as 8 atoms occupy one unit cell. It is assumed that both hypothetical atoms have similar atomic scattering factors. A com- plementary integrated diffraction spot–based technique that utilizes a large-angle defocused incident beam and a spherical aberration corrector (and which will be especially useful for beam-sensitive crystals) has recently been developed (95). For noncubic nanocrystals, these lat- tice constant changes may result in changes of the angles between net planes (and, therefore, affect the position of data points in lattice-fringe ﬁngerprint plots) on the order of a tenth of a degree to a few degrees for some combinations of reciprocal lattice vectors while other combinations may be negligibly affected. There are also “crystallographically challenged materials” and “intercalated mesoporous materials,” that is, tens of nanometer-sized entities with a well-deﬁned atomic structure over small length scales that can be described by a relatively large crystallographic unit cell with a low symmetry (99,100). Signiﬁcant structural dis- tortions that might be considered as classical defects or nanocrystal-speciﬁc defects to the average structure may be present to such an extent that it may make little sense to consider the disorder as a defect away from an ideal structure. In short, the deviations from the perfect atomic structure might be rather severe in these mate- rials but remnants of the crystallinity might still be present. For those structures that are really new to science, there will be no entries in the existing databases. Because crystallographically challenged materials do not possess a char- acteristic powder X-ray diffraction ﬁngerprint (Fig. Other structural ﬁnger- printing databases and/or crystallographic reference databases should, therefore, be erected and such structural nanocrystal ﬁngerprint information and/or whole nanocrystal structures should be collected for reference purposes. The emerging community of “nanocrystallographers” may decide to start an open-access database all by themselves because database development has traditionally been done by active research scientists.
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