{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T20:18:56Z","timestamp":1776025136620,"version":"3.50.1"},"reference-count":0,"publisher":"Bentham Science Publishers Ltd.","issue":"1","license":[{"start":{"date-parts":[[2008,12,29]],"date-time":"2008-12-29T00:00:00Z","timestamp":1230508800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/legalcode"}],"content-domain":{"domain":["benthamopenarchives.com","benthamopen.com"],"crossmark-restriction":true},"short-container-title":["TOIDJ"],"published-print":{"date-parts":[[2008,12,29]]},"abstract":"<jats:p>The pathology of tuberculosis in humans starts with an initial Ghon focus in the lungs followed by transmission\nof bacilli though the blood and lymph to other regions in the lungs and to other organs. While these bacilli usually lie latent\nwithout causing further disease, some 10% start foci of adult type disease usually starting in the sub-apical regions of\nthe lungs. Bacilli multiply, killing tissue by caseation and then forming colonies within the caseum. Cavities form connecting\nto the air in whose walls vigorous bacillary multiplication occurs. The history of the development of antituberculosis\nchemotherapy is described, starting with the use of multi-drug regimens to prevent the emergence of drug resistance\nand continuing with the shortening of the treatment period to 6 months by the incorporation in the regimens of rifampicin\nand pyrazinamide, which are the two drug responsible for bactericidal activity during treatment. Prospects for\nfurther shortening of treatment rest with the introduction of higher dosage with rifamycins and with new anti-tuberculosis\ndrugs. These new drugs include the 8methoxyfluoroquinolones moxifloxacin and gatifloxacin which inhibit topoisomerases\nand protein formation, the diarylquinoline TM-207 which inhibits the mycobacterial ATP synthase and thus\nenergy formation, the nitroimidazopyran PA-824 and the closely related OPC-676832 which are pro-drugs with uncertain\nmodes of action and the pyrrole SQ-109, a cell wall inhibitor. Anti-tuberculosis drugs have widely variable pharmacokinetic\ncharacteristics but as they work efficiently together, it is unnecessary to match these when giving drug combinations.\nThe effects of drug-drug interactions are usually small though the interactions with anti-retroviral drugs can pose problems.\nDose sizes have usually been chosen to minimize side effects while retaining activity and thus tend to have low\ntherapeutic margins, the exception being the margin of about 20 for isoniazid. The role of high plasma binding, important\nin limiting the efficacy of rifamycins, is uncertain for the newer drugs. Post antibiotic effects are vital to the prevention of\ndrug resistance and need exploration for new drugs. The main aims of current drug development are (1) to shorten treatment,\nand (2) to make it more convenient, by for instance using widely intermittent regimens. The current techniques for\nmeasuring efficacy during drug development start with in vitro models, including the Hu\/Coates models, which should\ncontain bacterial populations resembling the bacterial persisters in lesions that are responsible for the long duration of\ntreatment. The next stage is the mouse model of the chemotherapy of established tuberculosis, which has proved remarkably\nuseful in assessing the value of the different drugs. The main problem in clinical assessment arises from the use of relapse\nafter treatment as the main end-point, and the consequent need for very large numbers of patients required to provide\nmeasurable relapse rates in final phase III licensing studies. For this reason, surrogate studies are necessary in phase\nII which require much smaller numbers of patients. The first such investigations are phase IIA studies of early bactericidal\nactivity which establish whether the drug given alone has bactericidal activity on cavitary bacilli and which can estimate\nthe minimal effective dose of the drug, useful for decisions of dose size. The next step should be phase IIB studies which\nmeasure the rate of elimination of viable bacilli in sputum during the initial 8-weeks of treatment with various combinations\nof the new drug with established drugs. Measurement can be as (1) the proportion of patients with positive sputum at\nthe end of the 8-weeks period, the easiest method but the least sensitive, or (2) as the speed with which sputum cultures\nbecome negative in a survival analysis, or (3) as the mean regression in modeling of serial sputum collections colony\ncounts (SSCC). The relation between these surrogate estimates and the amoun of treatment shortening that can be obtained\nhas still to be worked out.<\/jats:p>","DOI":"10.2174\/1874279300802010059","type":"journal-article","created":{"date-parts":[[2009,1,5]],"date-time":"2009-01-05T17:41:47Z","timestamp":1231177307000},"page":"59-76","update-policy":"https:\/\/doi.org\/10.2174\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Assessment of the Efficacy of New Anti-Tuberculosis Drugs"],"prefix":"10.2174","volume":"2","author":[{"given":"Denis A.","family":"Mitchison","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geraint R.","family":"Davies","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"965","container-title":["The Open Infectious Diseases Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/benthamopenarchives.com\/contents\/pdf\/TOIDJ\/TOIDJ-2-59.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/benthamopenarchives.com\/contents\/fulltext-xml\/TOIDJ\/TOIDJ-2-59.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/benthamopenarchives.com\/contents\/pdf\/TOIDJ\/TOIDJ-2-59.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T05:23:23Z","timestamp":1735536203000},"score":1,"resource":{"primary":{"URL":"https:\/\/benthamopenarchives.com\/abstract.php?ArticleCode=TOIDJ-2-59"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,12,29]]},"references-count":0,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2008,12,29]]}},"alternative-id":["TOIDJ-2-59"],"URL":"https:\/\/doi.org\/10.2174\/1874279300802010059","relation":{},"ISSN":["1874-2793"],"issn-type":[{"value":"1874-2793","type":"print"}],"subject":[],"published":{"date-parts":[[2008,12,29]]},"assertion":[{"value":"Peer Reviewed","order":0,"name":"review_status","label":"Review Status","group":{"name":"peer_review_details","label":"Peer Review Details"}},{"value":"Single blind","order":1,"name":"review_process","label":"Review Process","group":{"name":"peer_review_details","label":"Peer Review Details"}},{"value":"Checked with iThenticate","order":0,"name":"screening_status","label":"Screening Status","group":{"name":"plagiarism_screening","label":"Plagiarism Screening"}},{"value":"2008-07-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-09-22","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-11-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-12-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}