December 9, 2004 - Scientists at Johnson & Johnson Pharmaceutical Research and Development (J&JPRD) have identified a novel anti-tuberculosis (TB) compound that works better and faster than the current standard of care in mouse models of TB infection. Also, preliminary studies in healthy human volunteers show that the drug is safe. The findings are published in the December 9 issue of Science Express, the online version of the journal Science, and will be published in the January 14 print edition. The studies are reported by scientists at J&JPRD and colleagues at the Swedish Institute for Infectious Disease Control in Solna, Sweden, and Pitié-Salpêtrière School of Medicine in Paris, France.
The compound, called R207910, belongs to a new family of anti-TB agents called diarylquinolines (DARQ) and appears to have better, and more differentiated antibiotic properties than currently used drugs for TB, individually and in combination. R207910 was better at clearing infection from the lungs of mice than the triple cocktail regimen currently recommended by the World Health Organization (WHO). Also, cocktail regimens containing R207910 cleared infection in mice in half the time than the currently used regimen.
"The drug acts through a novel mechanism of action, and is therefore active against all multi-drug resistant (MDR) strains of TB tested so far," says Dr. Koen Andries, D.V.M., Ph.D., Distinguished Research Fellow, Antimicrobial Research at J&JPRD. "A combination including R207910 but excluding rifampin, one of the current TB drugs, looks especially promising. A combination excluding rifampin would be compatible with anti-HIV drugs, making it suitable for treating patients co-infected with HIV and TB."
The World Health Organization (WHO) has declared TB a global health crisis. TB now infects one-third of the world's population and causes close to nine million new cases of active TB and 2 million deaths each year. Unfortunately, many TB strains have become resistant to several antibiotics used today to treat the disease. More than 300,000 new cases of multi-drug-resistant TB per year are detected, mainly in Eastern Europe and Central Asia.
"For a long time, there has been a move to find a drug that is safe and effective and completely cures the patient in a shorter time," Andries says. "A new drug that could shorten or simplify effective treatment of TB would dramatically improve TB control programs."
No new anti-TB drugs have been brought into the clinic in the past 40 years, and although doctors have effective first-line TB drugs that work, there have been difficulties getting these medicines to the patients who need them as well as effectively treating patients with drug resistant disease.
One out of three people in the world are infected with latent TB. Even in the developed world, one out of twenty carry the TB bacillus. In some developing countries, one in two people are infected. A carrier of latent TB has a 10 percent life-long risk to develop TB. However, in HIV patients, that risk is 10 percent per year.
"That is the main reason why there is now such a resurgence of tuberculosis in countries that were previously hit by HIV," Andries says. "The HIV epidemic has worsened the TB epidemic substantially."
TB is currently treated with a cocktail of antibiotics, including rifampin, isoniazid, and pyrazinamide, which must be taken for six to nine months. The TB symptoms disappear after several weeks, and patients begin to feel healthy. However, to completely clear the infection, they must continue therapy at least four more months. This is often difficult, especially for people living in remote areas in developing countries, and discontinuing treatment prematurely increases the risk of developing resistant bacteria.
To ensure compliance, TB patients are monitored under the DOT (Directly Observed Treatment) program, with patients taking their cocktail of medicines each day under the supervision of a healthcare worker.
R207910 Study Findings
"Our findings suggest that at least in mice, R207910 seems to have the desired properties of simplifying and shortening the treatment duration, and perhaps, more," says Andries. In bacterial cell cultures, R207910 was effective against many different strains of mycobacteria, including strains that are resistant to other drugs. The drug is bactericidal, meaning that it kills the TB bacilli.
In mouse models, the studies showed that a cocktail regimen containing this compound reduced bacterial load after one month to the same level as the currently used regimen after two months of treatment, shortening normal treatment time by 50 percent. After two months treatment with the R207910 containing cocktail, no TB bacilli could be isolated from the lungs anymore, a finding that the French group that did those studies called "unprecedented".
The mouse studies also show that this new compound quickly enters the bloodstream and is actually concentrated in lung cells-which harbour the TB bacilli-killing the bacilli soon after they enter the body. Also, R207910 lingers in the body for days continuing to kill bacilli even when administered only once a week in mice.
R207910 is unique in the way it works. The compound attacks an enzyme called ATP synthase, the energy source for the bacterium. Given its new mechanism of action and apparent impact on drug resistant strains of TB, according to Andries, R207910 could lead to a shift in the current treatment paradigm for tuberculosis. "Preliminary data show R207910 has the desired properties we need and holds a great deal of promise," he said.
However, Koen added, considerable work needs to be done to fully determine this compound's clinical potential. Since the compound seems to be safe and well tolerated in Phase I studies with healthy human volunteers, R207910 will now be tested in humans with active pulmonary TB.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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