Page 244

APPENDIX F

Approval Dates for Existing and Prospects for Development of New Antituberculosis Drugs and Vaccines


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TABLE F-1 Approval Dates for Antituberculosis Drugs and Vaccines

Drug

FDA Approval Date or Year of First USPHS Published Trial (*)

Isoniazid

1953*

Rifamycins

rifampin

1974*

rifabutin

12/23/1992

rifapentine

6/22/1998

Pyrazinamide

1959*

Ethambutol

1968*

Streptomycin

1947*

Para-aminosalicylic acid (PAS)

1950*

Ethionamide

1968*

Cycloserine

1968*

Capreomycin

1956*

Kanamycin

Discovered early 1950s; not studied in USPHS trial

Thiacetazone (not available in United States)

Fluoroquinolones

ciprofloxacin

12/26/1990

ofloxacin

12/28/1990

levofloxacin

12/20/1996

Amikacin

Before 1/01/1982



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Page 244 APPENDIX F Approval Dates for Existing and Prospects for Development of New Antituberculosis Drugs and Vaccines Please refer to the page image for an unflawed representation of this content. TABLE F-1 Approval Dates for Antituberculosis Drugs and Vaccines Drug FDA Approval Date or Year of First USPHS Published Trial (*) Isoniazid 1953* Rifamycins rifampin 1974* rifabutin 12/23/1992 rifapentine 6/22/1998 Pyrazinamide 1959* Ethambutol 1968* Streptomycin 1947* Para-aminosalicylic acid (PAS) 1950* Ethionamide 1968* Cycloserine 1968* Capreomycin 1956* Kanamycin Discovered early 1950s; not studied in USPHS trial Thiacetazone (not available in United States) — Fluoroquinolones ciprofloxacin 12/26/1990 ofloxacin 12/28/1990 levofloxacin 12/20/1996 Amikacin Before 1/01/1982

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Page 245 Please refer to the page image for an unflawed representation of this content. TABLE F-2 Pharmaceutical Companies: Current (1999) Prospects for Development of New Antituberculosis Drugs and Vaccines New Antimicrobials Available in: Company 2 Years 5 Years 8 Years Vaccines Abbott Laboratories 0 0 0 0 American Home Products (Lederle/Wyeth-Ayerst) 0 0 0 0 Astro-Zeneca Pharmaceuticals 0 0 0 0 Bristol-Myers Squibb 0 0 0 0 Dupont Pharmaceuticals 0 ?oxazolidinones ?oxazolidinones 0 Eli Lilly and Company 0 0 0 0 Glaxo-Wellcome 0 0 ? Working on vaccines DNA Whole attenuated live organism Therapeutic vaccine Hoechst Marion Roussel 0 0 0 0 Rifapentine approved by FDA in 1998 Janssen Pharmaceuticals 0 0 0 0 Merck and Company 0 0 0 Very exploratory; have rights to a DNA vaccine in the public domain. Would also be interested in a subunit vaccine

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Page 246 Novartis Pharmaceuticals 0 0 0 0 Ortho-McNeil Johnson & Johnson 0 Sending some candidate drugs out for in vitro testing; marketing experts not enthusiastic 0 Parke-Davis 0 0 0 0 Pfizer, Inc. 0 0 0 0 Pharmacia/Upjohn 0 ?oxazolidinones ?oxazolidinones 0 Rhone-Poulene Rorer 0 0 0 0 Roche Pharmaceuticals Had some preliminary work on IL-12 but gave up when in animals it increased CFU in lung Had some preliminary work on IL-12 but gave up when in animals it increased CFU in lung Had some preliminary work on IL-12 but gave up when in animals it increased CFU in lung Had some preliminary work on IL-12 but gave up when in up when in animals it increased CFU in lung Schering-Plough Corp. 0 0 0 0 G.D. Searle-Monsanto Co. 0 0 0 0 Smith Kline Beecham Pharmaceuticals 0 0 0 0 Warners Chilcott Laboratories 0 0 0 0 Warner Lambert Co. 0 0 0 0

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Page 247 Please refer to the page image for an unflawed representation of this content. TABLE F-3 Biotechnology Companies: Current (1999) Prospects for Development of New Antituberculosis Drugs and Vaccines New Antimicrobials Available in: Company 2 Years 5 Years 8 Years Vaccines Biogen 0 0 0 0 Corixa Corp. 0 0 0 Vaccines are their approach, not antimicrobials Collaborating with Smith Kline Beecham Working on vaccine for 3 years Have developed a vaccine utilizing 3–5 protein antigens made by incorporating genes for these proteins (a synthetic gene) with effective epitopes (multiple) in one recombinant protein Efficacy already shown in a rodent model Safety already shown in monkeys Clinical trials (Brazil and in another country) phase I/II in approximately 1 year Genetech 0 0 0 0 Genetics Institute IL-12 plus 3 drugs—study vs. TB in Gambia (currently under way) IL-12 plus 3 drugs—study vs. MA-I in patients with genetic defects in interferon receptor IL-12 plus 3 drugs—study in treatment of M. tuberculosis or MA-I in HIV-infected patients, an ACTG study ? ? ? Pathogenesis Corp. Rifamycin analog (Rifalizyl) with longer half-life cross- resistant with rifampin so not pursuing any longer PA 824 (a nitroimidizopyrene) under development—active as a drug vs. drug-resistant M. tuberculosis (acts by inhibiting glycolipid cell wall synthesis, but at a different step than is inhibited by ethambutol). Presented as a prodrug that is activated in host (as in the case of INH). 0 0 0

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Page 249 1) Activity: mole for mole as active as INH 2) Orally active 3) Bactericidal 4) Active vs. nongrowing organisms (e.g., M. tuberculosis cultured under anaerobic conditions) 5) Now in initial stages of testing Ribozyme Pharmaceuticals 0 0 0 0 Sequella Corp. Ethambutol analogs (3 candidates) Clinical testing probably Clinical testing probably Vaccine: Has license for new experimental vaccine (Nature 400[6741]:269; 1999) Shikemic acid pathway 0 0 (inhibitor) New diagnostic being studied: A patch test that may be positive in patients with active disease but not in individuals with prior infection