Frank C. Sciavolino

Back to Nature: The Alternative Paradigm for Drug Development

Nature has traditionally been a fruitful harbinger of new medicines. However, despite the history of past successes, interest in natural products as a source of new drugs has withered over the past two decades. The trend in drug research has been towards combinatorial chemistry and high throughput screens, relying on receptor mechanisms to identify leads for further development. Following passage of Dietary Supplement Health and Education Act (DSHEA) legislation in 1994 and the resurgence of interest in herbals and the dietary supplements market, natural products are again attracting attention as a potential source of new medicines. These developments are triggering powerful changes on how botanical mixtures are developed and regulated.

Chapter 10. Antibiotics

Publisher Summary This chapter discusses the development and clinical studies of antibiotics. The commercial 6-APA processes, chemical relationships between penicillins and cephalosporins, mechanism of action, bacterial resistance, and immunological properties of penicillins are examined. The physicochemical properties and biological activities of clinically significant 6-lactam antibiotics are reviewed. Comparative in vitro evaluations of tobramycin continue to indicate it is two to four times more active than gentamicin against clinical isolates of Pseudomonas aeruginosa . Gentamicin proved four times as potent as tobramycin against isolates of Serratia marcescens and both antibiotics demonstrated comparable-activity against the majority of other gram negative pathogens. Enzymatic inactivation of gentamicin by cell-free extracts from clinical isolates of Ps. aeruginosa and R-factor carrying Klebsiella pneumoniae was described. The mechanism of this pseudomonas resistance to gentamicin was established by showing that acetylation occurs on the amino group of the 2-deoxystreptamine ring. All gentamicin C components and sisomicin were reported to be excellent substrates for the inactivating enzyme gentamicin acetyltransferase, whereas tobramycin and kanamycin B proved to be poor substrates.

Chapter 11. Antibiotics

Publisher Summary This chapter discusses the clinical applications and side effects of antibiotics. The structure and preliminary pharmacological evaluation of pseudomonas-active aminoglycoside antibiotic nebramycin factor 6 were reported. Factor 6 inhibited all Gram-negative species of bacteria studied at 2 mcg/ml or less and was reported to be more active than gentamicin against 48 Pseudomonas aeruginosa strains. Peak serum levels of 2.8 mcg/ml were observed within 1 hour following administration of 75 mg of factor 6 intramuscularly. Antibiotic 6640 (sisomicin) was announced as a new aminoglycoside structurally related to gentamicin C 1A ; it had approximately 5 times the therapeutic activity of gentamicin in mice and twice the acute toxicity. Results of a worldwide evaluation of the toxicity and clinical effectiveness of rifampicin are also reported. Clinical and bacteriological cures generally fulfilled the expectations based on in vitro studies. Original pathogens were eliminated in 70–93% of infections due to staphylococci, pneumococci, and gonococci, and in 45–58% of cases due to streptococci and Gram-negative bacteria. Rifampicin is recommended as a primary treatment for tuberculosis. More than 82% of recent cases and more than 54% of chronic patients showed improvement on rifampicin therapy.