Lead development

V. Heubner and A. Ueberschaer, in Proceedings 6th International Conference Eead Lead Development Association, London, 1974, p. 59. 

Reviews on the occurrence, biochemical basis, and treatment of lead toxicity in children (11) and workers (3,12,13) have been pubhshed. Approximately 17% of all preschool children in the United States have blood lead levels >10 //g/dL. In inner city, low income minority children the prevalence of blood lead levels >10 //g/dL is 68%. It has been estimated that over two million American workers are at risk of exposure to lead as a result of their work. PubHc health surveillance data document that each year thousands of American workers occupationally exposed to lead develop signs and symptoms indicative of... 

W. Hofmann, EeadandEeadAlloys, English translation by Lead Development Association, Springer-Vedag, Berlin, Germany, 1970, pp. 349—356. U.S. Pat. 3,801,310 (Apr. 2, 1974), S. Nijhawan (to Varta Aktiegelsellschaft). 

R. D. Prengaman, Adpanced Eead Alloysfor Maintenance-Free Batteries, Lead Development Association, London, UK, 1980. 

Cattle feeding on herbage containing 25-50 mg/kg (ppm wt) lead develop excitable jerking of muscles, frothing at the mouth, grinding of teeth, and paralysis of the larynx muscles a "roaring" noise is caused by the paralysis of the muscles in the throat and neck. 

Prengaman, R. E., Structure Control of Non-Antimonial Lead Alloys via Alloy Additions, Heat Treatment and Cold Working, Pb80, Ed. Proc. 7lh Ini. Lead Conf., Madrid, Lead Development Association, London (1983)... 

Heubner, U. and Reinert, M., Effect of Small Silver Contents on the Characteristics of Lead and its Alloys , Pb80, Seventh International Lead Conference, Lead Development Association, London... 

Hill, R. H., Frost, P. C. and Smith, R. Corrosion of Aluminium in Contact with Lead in Atmospheric Environments , in Pb80, Ed. Proc. 7th Ini. Lead, Con/., Lead Development Association, London 194-203 (1983)... 

Hofmann, W. Lead and Lead Alloys Properlies and Technology, Springer-Verlag, English Trans, by Lead Development Association, London 302 (1970)... 

Mackay, C. A, and Barry, B. T, K., Terne plate — Prodwtion, Properties and Applications, Proceedings Fifth Intemotionai Conference on Lead, Lead-Development Assn, pp. 169-173... 

For information on lead and its uses, contact Lead Development Association International at httpy/www.ldaint.org. 

In general, the attempt to retest every compound that passes a statistically defined threshold of activity for each assay and to implement a concomitant assay interference test has been rewarded by recovery of a full spectrum of biological activities and diverse chemotypes in the confirmed hit set. In many cases, the compounds that the medicinal chemists ultimately judge to be the best starting points for lead development exhibited only modest activity (e.g., IC50 values of 0.5-5 pM) in HTS. 

Genomics to Lead Development Candidate (Preclinical Lead Profile, PLP)... 

In summary, in silico approaches to aid in removing D DI should be actively applied in early lead development. The application of these models in early drug discovery will reduce the frequency and cost of drug candidates that require clinical DDI studies. In the future, it is possible that a great majority of CYP-based DDI issues will be removed during lead development. 

In addition to the assessment of reversible inhibition, the role played by mechanism-based inhibitors (irreversible inhibitors) provides a focus during lead development, as it can result in a more profound and prolonged effect than that suggested by the therapeutic dose or exposure. Mechanism-based inhibition (MBI) occurs as a result of the CYP generating reactive intermediates that bind to the enzyme causing irreversible loss of activity. Oxidative metabolism via that CYP is only restored upon re-synthesis of that enzyme. Three mechanisms have been reported showing how intermediate species act as mechanism-based inhibitors ... 

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