Items tagged with Treatment
TMC207 (post with image)
TMC207 (also known as bedaquiline, R207910 or the ‘J’ compound) is an experimental anti-TB drug. Discovered by Johnson & Johnson, TMC207 is the first compound in a new class of potent anti-TB drugs, the first new class in 60 years. Studies have shown that it is effective against both drug-resistant and susceptible TB. A recently completed phase II trial found that it reduces the time it takes for sputum to become negative in patients, meaning that it has the potential to shorten the duration of TB treatment. Clinical phase II trials are currently being carried out to evaluate the effectiveness of TMC207 for TB treatment. How it works ------------ TMC207 is categorized as a diarylquinoline. This is an entirely new class of TB drug that works by inhibiting an enzyme that is vital for the production of energy, or ATP, in TB bacteria. This enzyme is called ATPase. TMC207 binds to ATPase and prevents it from supplying energy for the bacterial cell, which kills the bacterium. Pre-clinical trials ------------------- Researchers at Johnson & Johnson published their first report on TMC207 in 2005. They found that TMC207 was effective against both drug-sensitive (i.e. non-resistant) and drug-resistant TB bacteria in vitro. In mice, the drug was found to exceed the effectiveness of isoniazid and rifampicin when taken alone. When substituted for first-line drugs in the standard treatment programme, the activity of each new combination with TMC207 was improved.[^Andries] A study published in 2006 examined TMC207 as a treatment for MDR TB using the mouse model. Mice were treated with various combinations of TMC207 with the standard regimen of second-line drugs (amikacin, pyrazinamide, moxifloxacin, and ethionamide). Combinations that included TMC207 were found to be more effective against MDR TB than the current regimen in nearly every case.[^Lounis] A study in 2008 examined the activity of TMC207 against TB bacteria in mice lungs. Most notably, the study found that using a triple combination of TMC207 with rifapentine and pyrazinamide achieved outstanding bactericidal activity, with lung culture negativity in 9 of 10 mice.[^Veziris] These early studies revealed some potentially important attributes of TMC207. Firstly, the mouse model suggested a synergistic interaction between TMC207 and pyrazinamide, meaning that these drugs may be more powerful when given in combination than either drug alone. More studies are needed to investigate this. Secondly, the drug showed activity against both drug-resistant and non drug-susceptible strains of TB, meaning that it could work as a treatment for MDR / XDR TB. Additionally, in-vitro studies of TMC207 showed that the drug is a potent sterilizing agent, meaning that it is able to effectively eliminate TB bacteria. If the behavior of TB bacteria has this same property in-vivo (in human patients), then TMC207 could shorten the duration of TB treatment. This would be a much-needed change to what is currently a very lengthy and cumbersome treatment programme. The sterilizing ability of TMC207 also might make it a powerful drug in the struggle to eradicate TB.[^Matteelli] Phase I trials -------------- A phase I trial, the first stage of testing in human patients, was completed in South Africa. Results were published in 2008. The study examined the Early Bactericidal Activity (EBA), meaning its activity against TB early on, in 75 different TB-infected patients who had not had prior TB treatment. Of these patients, 31% were HIV positive. For seven days, these patients took either 600mg rifampicin, 300mg isoniazid, or a particular dose of TMC207. Researchers found that the bactericidal activity (i.e. ability to eliminate TB bacteria) of TMC207 at a dose of 7400 mg daily was similar to that of the other two first-line drugs, rifampicin and isoniazid. They found that TMC207 took slightly longer to start eliminating TB bacteria, with bactericidal effects beginning on day 4. In addition, the drug was well tolerated in patients, with no serious side effects.[^Rustomjee] Another phase I trial is currently being carried out at University Hospitals (UH) Case Medical Center in the U.S. This trial will give TMC207 to 32 healthy individuals to test for the drug’s safety and tolerability. The study will also examine whether TMC207 has any drug interactions with other TB medications, such as rifabutin and rifampicin.[^TB Online] Researchers believe that there may be a drug-drug interaction between TMC207 and rifampicin, which is of major concern given that rifampicin is a first-line TB drug. An enzyme (called CYP3A4) that metabolizes - and thereby activates - TMC207 is inhibited by rifampicin. This means that when both drugs are used together, rifampicin may prevent TMC207 from working properly. A study among 16 volunteers indicates that rifampicin might indeed make TMC207 less powerful.[^Lounis] More studies are needed to investigate this interaction. Phase II trials --------------- In a phase II trial, experimental drugs are given to a larger group of patients than in phase I. A phase II trial for TMC207 is currently being carried out in South Africa. The study is coordinated by teams of researchers at the Univ. of Stellenbosch, Univ. of Witwatersrand, Aurum Health, Medical Research Council, and Tibotec. This trial has two stages. The first stage has already been completed, and results were published in 2009. The purpose was to determine whether TMC207 was effective in reducing the time it took for patients to convert to sputum-negative. A group of 47 patients, all of whom were HIV negative and had been newly diagnosed with MDR TB, were randomly assigned to two groups. The first group received TMC207 at a dose of 400 mg daily for 2 weeks, followed by 200 mg three times a week for 6 weeks. The second group received the standard five-drug, second-line regimen for treating MDR TB, and a placebo was used instead of TMC207. Researchers found that TMC207 reduced the time it took for sputum to convert to negative in patients. At the end of the trial, 9% of patients who took the placebo were sputum-negative, as compared to 48% of those who received TMC27. TMC207 eliminated TB bacteria more quickly, and it was shown to be safe and well tolerated in patients. The only side effect that was significantly more common in the group that took TMC207 was nausea (26% vs. 4%). Researchers concluded that “the clinical activity of TMC207 validates ATPsynthase as a viable target for the treatment of tuberculosis.”[^Diacon] The second stage of this two-part trial will be a multinational study of patients in South Africa, Peru, Latvia, India, Brazil, Thailand, The Philippines and Russia. Because the first part of the study showed that TMC207 is highly effective against TB, the study’s second stage will be open label and non-randomised. Future developments ------------------- Johnson & Johnson’s research subsidiary, Tibotec, is managing the clinical development of TMC207 to determine whether the drug can be used in the treatment of MDR / XDR TB. Tibotec will elaborate a program whereby developing countries can gain access to TMC207. In addition, Tibotec has given the TB Alliance a royalty-free license to develop TMC207 for drug-sensitive TB. Current and future clinical trials of TMC207 will examine the potential use of TMC207 in the treatment of children with MDR TB; for the treatment of latent TB infection; for use in combination with antiretrovirals; and as a shortened treatment regimen for drug-sensitive TB.[^Matteelli] Advocacy Issues --------------- - More clinical information is needed on the use of TMC207 in TB patients with HIV co-infection. - Organizations in South Africa have called for TMC207 to be made immediately available for compassionate use. They recommend that clinicians in South Africa apply to the Medicines Control Council (MCC) for Section 21 authorizations to use bedaquiline. These authorizations are already being used to procure access to PAS, a less effective and harder to tolerate medication than TMC207.[^TAC] [^Andries]: K Andries et al. A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis. Science. 2005 Jan 14; 307(5707): 223-7 [^Lounis]: N Lounis et al. Combinations of R207910 with Drugs Used To Treat Multidrug-Resistant Tuberculosis Have the Potential to Shorten Treatment Duration. Antimicrobial Agents and Chemotherapy. 2006 Nov; 50(11): 3543-3547. [^Veziris]: N Veziris et al. A Once-Weekly R207910-Containing Regimen Exceeds Activity of the Standard Daily Regimen in Murine Tuberculosis. Am J Respir Crit Care Med. 2009 Jan 1; 179(1): 75-9 [^Matteelli]: A Matteelli et al. TMC207: the First Compound of a New Class of Potent Anti-Tuberculosis Drugs. Future Microbiol. 2010 June; 5(6): 849-858. [^Rustomjee]: R Rustomjee et al. Early Bactericidal Activity and Pharmokinetics Of the Diarylquinoline TMC207 in Treatment of Pulmonary Tuberculosis. Antimicrob Agents Chemother. 2008 Aug; 52(8): 2831-5. [^TB Online]: The Medical News. [TMC207 represents first new class of anti-TB drugs in the past 60 years](http://www.tbonline.info/posts/2011/8/1/uh-case-medical-center-commence-phase-1-clinical-t/ "UH Med Centre"). [^Lounis]: N Lounis. Impact of the interaction of R207910 with rifampin on the treatment of tuberculosis studied in the mouse model. Antimicrob Agents Chemother. 2008 Oct; 52(10):3568-72 [^Diacon]: AH Diacon et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med. 2009 Jun 4;360(23):2397-405 [^Matteelli]: A Matteelli et al. TMC207: the First Compound of a New Class of Potent Anti-Tuberculosis Drugs. Future Microbiol. 2010 June; 5(6): 849-858 [^TAC]: [Mobilize Against TB](http://www.tbonline.info/posts/2011/8/30/addressing-tb-crisis-south-africa/ "TAC").
OPC-67683 (post with image)
OPC-67683 (also known as delamanid) is an experimental drug that has shown potent activity against drug-resistant and drug-susceptible TB. Along with another experimental medication called PA-824, OPC-67683 belongs to a class of drugs called nitroimidazoles. Interest in nitroimidazoles arose because of research into another antibiotic called [metronidazole](http://www.medicinenet.com/metronidazole/article.htm "Metronidazole"). The Japanese company Otsuka Pharmaceutical has been investigating this class of compounds for more than a decade. Early clinical trials demonstrated OPC-67683 to be a potent bactericidal and sterilizing drug. It is currently undergoing phase II trials to determine its role in TB treatment. How it works ------------ OPC-67683 kills TB-causing bacteria by disrupting the cell wall. It does so by preventing the synthesis of a molecule called mycolic acid, an essential mycobacteria cell wall component. Isoniazid also works by preventing the synthesis of mycolic acid. The difference between OPC-67683 and isoniazid lies in the type of mycolic acid molecule that each drug inhibits. OPC-67683 inhibits the synthesis of methoxy- and keto-mycolic acid but not a-mycolic acid. Isoniazid acts on all subclasses of mycolic acid.[^Tomioka] Pre-clinical trials ------------------- A study in 2006 conducted by Otsuka Pharmaceutical showed that OPC-67683 has potent activity against drug-resistant and drug-susceptible TB _in vitro_ and in mice. For the in vitro component, researchers tested the drug’s ability to inhibit bacterial growth in dishes of both drug-susceptible and MDR TB bacteria. Using the mouse model, researchers administered OPC-67683 to TB-infected mice, some of which were immunocompromised. The results from the in vitro and mouse models demonstrated that OPC-67683 was more potent at a smaller concentration than other first-line TB drugs. The in vitro experiment showed it to be effective against drug-susceptible and MDR TB bacteria at a low concentration of 0.006-0.024 µ/ml. Whereas no TB bacteria colonies were found after 4 months of treatment with the OPC-67683-containing regimen, colonies were still detected after 6 months of treatment with the standard intensive phase regimen. The mouse model showed OPC-67683 to be effective at low doses in vivo. It reduced the number of bacteria in the lungs of normal and immunocompromised mice at lower concentrations than the standard first-line drugs. The combination of OPC-67683 (2.5 mg/kg) with rifampicin (5 mg/kg) and pyrazinamide (100 mg/kg) eradicated TB bacteria more quickly - by at least 2 months - than the current intensive phase regimen of rifampicin (5mg/kg), isoniazid (10mg/kg), ethambutol (100 mg/kg), and pyrazinamide (100mg/kg). These early results, if reproducible in human patients, suggest that OPC-67683 could potentially shorten TB treatment time. [^Matsumoto] Another study in 2007 investigated the in vitro sterilizing activity of OPC-67683, i.e. its ability to completely eliminate an infection, against drug-susceptible bacteria. Researchers found that, at the highest dose levels tested (1.0 µg/ml), OPC-67683 was superior to isoniazid and equal to rifampicin.[^Saliu] These pre-clinical studies revealed some potentially important attributes of OPC-67683. Firstly, the drug was found to have no cross-resistance with any other first-line TB drug. In addition, OPC-67683 is likely safe and effective when used in combination with antiretrovirals. Researchers found that OPC-67683 had no effects on a specific class of liver enzymes (called cytochrome P450 enzymes) that metabolize antiretrovirals. In addition, these liver enzymes did not affect the activity of OPC-67683. This indicates OPC-67683 is unlikely to cause problems or lose its effectiveness when given with drugs that are metabolized by this enzyme. These studies also found that the killing of TB bacteria by OPC-67683 is concentration-dependent. Unlike other first-line medications like isoniazid and rifampicin, which are effective against TB bacteria regardless of the drug concentration, OPC-67683 is only bactericidal at a minimum threshold concentration. Researchers postulated that this may be because, at low concentrations, OPC-67683 is metabolized by TB bacteria to an intermediate compound with slightly different chemical properties. According to the authors of the 2007 study, this chemical transformation could account for the observation that, in some TB bacterial cultures, OPC-67683 at low concentrations lost its effectiveness against the bacteria after 4-5 days. Interestingly, these studies also found that OPC-67683 is highly effective against intracellular bacteria, i.e. bacteria hidden within human cells, and therefore could be used to fight latent TB. TB is remarkably difficult to kill because bacteria are able to hide in different parts of the body, including white blood cells called macrophages. TB bacteria hiding in cells are in a latent state. While researchers are currently investigating exactly where and how bacteria hide in the body, they do know that OPC-67683 is effective against intracellular bacteria. The 2006 study determined that the in vitro intracellular activity of OPC-67683 was better than that of isoniazid and PA-824 and, at a concentration of 0.1 μg/ml, as good as that of rifampicin at a concentration of 3 μg/ml. This intracellular activity is believed by researchers to be an indication that OPC-67683 could be used as a treatment for latent TB.[^Matsumoto] OPC-67683 has another potentially useful property: it is effective against both aerobic and anaerobic bacteria. When TB bacteria are in an aerobic state, they require oxygen for survival and are active and self-replicating. In an anaerobic state, TB bacteria do not use oxygen and are often found hiding inside cells. Experts believe that this anaerobic state is similar to the state of TB bacteria that survive TB treatment with first-line drugs. First-line medications rifampicin and isoniazid are active against aerobic but not anaerobic bacteria, while metronidazole is active only against anaerobic bacteria. Researchers have postulated that, because OPC-67683 is active against bacteria in both states, it could be used to treat both active and latent TB, and to shorten the duration of the standard treatment programme. [^Anderson] Phase I trials -------------- Phase I and Early Bacterial Activity (EBA) studies of OPC-67683 have been completed. Studies of the drug in doses of up to 400mg showed that it was tolerated well by healthy volunteers, and no serious side effects were reported.[^Shi] A phase I trial was undertaken by researchers at the University of Stellenbosch in South Africa to examine the EBA of OPC-67683. Results were published in July 2011. In this study, 48 patients infected with drug-susceptible pulmonary TB were randomly assigned to receive OPC-67683 at a dose of 100, 200, 300 or 400 mg daily for 14 days. Sputum was collected from these patients and analyzed to determine OPC-67683’s EBA, i.e. its bactericidal effects early on in treatment. Researchers found that the average EBA of all dosages of OPC-67683 was significant from day 2 onward, meaning that it didn’t begin eliminating TB bacteria prior to the second day of treatment. The EBA of OPC-67683 did not differ significantly between dosages, although patients who received a dose of either 200 or 300 mg experienced a slightly greater decline in the number of TB bacilli in their sputum than those who received 100 mg or 400 mg of the drug. The effectiveness of the medication appeared to plateau at 300 mg, which researchers believed was due to limited absorption in doses exceeding 300 mg. Overall, the medication was tolerated well in patients, with no serious side effects.[^Diacon] Phase II trials --------------- Phase II clinical trials are currently being planned and undertaken to test the safety and efficacy of OPC-67683 in patients. A phase II study was conducted by Otsuka Pharmaceutical to evaluate the effectiveness of OPC-67683 in the treatment of MDR TB. It was completed in October 2010 but results have not yet been published. In this study, researchers randomly assigned a group of 481 patients infected with MDR TB to one of three groups. Group 1 received an Optimized Background Regimen (OBR, which refers to the standard treatment programme) for MDR TB in addition to 100 mg of OPC-67683 twice daily. Group 2 received the OBR plus 200 mg of OPC-67683 twice daily. Group 3 received the OBR in addition to a placebo. The study lasted for 56 days. Researchers are examining the results to determine how effective OPC-67683 was at inducing patients to convert to sputum-negative during the 56 days of treatment, and whether the medication caused any adverse side effects.[^Otsuka] Another phase II study led by Otsuka Pharmaceutical is active but not yet recruiting participants. This study aims to assess the safety and efficacy of OPC-67683 in patients with MDR TB. OPC-67683 will be given to patients at a total dose of 500-800 mg per day. Researchers will evaluate the medication’s safety and side effects in patients during a period of nine months, and the rate of sputum culture conversion over a period of 24 weeks. The study is expected to be completed by December 2011.[^Otsuka2] Future developments ------------------- Otsuka is currently planning a phase III clinical trial that is expected to be completed in 2015. This will be a multicenter, randomized, placebo-controlled trial conducted globally at approximately 15 different sites qualified to treat MDR TB. There will be two parallel groups of patients in this study. In the first group, MDR TB infected patients will receive either the standard MDR treatment programme (OBR) plus a placebo, or the OBR plus 100 mg of OPC-67683 twice daily for 2 months followed by 200 mg once daily for 4 months. For the second group, researchers will examine the safety and efficacy of OPC-67683 in a group of HIV positive patients taking antiretrovirals.[^Otsuka3] Although early studies demonstrated OPC-67683 to be a potentially effective treatment for both drug-resistant and drug-susceptible TB, Otsuka Pharmaceutical has chosen to direct its initial focus on testing the drug as a treatment for MDR TB. Given that the current success rate for treating MDR TB is only about 70%, the drug will likely be licensed more quickly as a treatment for MDR TB. Otsuka has committed to conducting clinical trials for OPC-67683 once the drug has been licensed for drug-resistant TB.[^Boogaard] Advocacy Issues --------------- - More clinical information is needed to determine the effectiveness of OPC-67683 as a treatment for MDR and XDR TB in addition to drug-tolerant and latent TB. Its optimal formulation has yet to be established. - It is recommended that more resources be committed to clinical trials on TB medications. Research is hampered by issues such as a dearth of investigators experienced in conducting TB trials that adhere to international standards for clinical research, and by a lack of such internationally accepted standards. Larry Geiter from Otsuka Pharmaceutical acknowledged that investigators have yet to agree even on research methods within TB trials, such as a standard way to cultivate TB bacteria in the laboratory. There is also a lack of formal guidelines for benchmarks to be fulfilled by researchers seeking to secure drug licenses. For example, the U.S. FDA has yet to publish formal guidelines on TB drug licensing, guidelines that are well established for other diseases like hypertension.[^Anderson] - If phase II data shows OPC-67683 is likely effective, it should be offered on a compassionate care basis to people with MDR and XDR TB in conjunction with TMC207 and standard MDR TB treatment. [^Tomioka]: H. Tomioka et al. Antituberculous Drug Development and Novel Drug Targets: Present Status of the Development of New Antimycobacterial Agents. Expert Rev Resp Med. 2008; 2(4): 455-471 [^Matsumoto]: M Matsumoto et al. OPC-67683, a Nitro-dihydro-imidazooxazole Derivative with Promising Action Against tuberculosis In Vitro and in Mice. PLoS Med. 2006 Nov; 3(11): 466 [^Saliu]: OY Saliu et al. Bactericidal Activity of OPC-67683 Against Drug-Tolerant Mycobacterium tuberculosis. J Antimicrob Chemother. 2007 Nov; 60(5): 994-8 [^Matsumoto]: M Matsumoto et al. OPC-67683, a Nitro-dihydro-imidazooxazole Derivative with Promising Action Against tuberculosis In Vitro and in Mice. PLoS Med. 2006 Nov; 3(11): 466 [^Anderson]: Anderson, Tatum. Working for the ‘Dark Side’ Against TB. TropIKA.net. 29 Jan 2009. [^Shi]: R Shi et al. Development of New Anti-tuberculosis Drug Candidates. Tohoku J. Exp. Med. 2010; 22(1): 97-106 [^Diacon]: AH Diacon et al. Early Bactericidal Activity of Delamanid (OPC-67683) in Smear-Positive Pulmonary tuberculosis Patients. Int J Tuberc Lung Dis. 2011 Jul; 15(7): 949-954 [^Otsuka]: Otsuka Pharmaceutical. A Placebo-controlled, Phase 2 Trial to Evaluate OPC 67683 in Patients With Pulmonary Sputum Culture-positive, Multidrug-resistant Tuberculosis (TB). Clinical Trials.gov: A Service of the U.S. National Institutes of Health. 31 Aug 2011. [^Otsuka2]: Safety and Pharmacokinetics (PK) in Multidrug-Resistant (MDR) Refractive Tuberculosis. Clinical Trials.gov: A Service of the U.S. National Institutes of Health. 22 Jun 2011. [^Otsuka3]: Otsuka Pharmaceutical. Safety and Efficacy Trial of Delamanid for 6 Months in Patients With Multidrug Resistant Tuberculosis. 26 Aug 2011. [^Boogaard]: J van den Boogaard et al. New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development. Antimicrobial Agents and Chemotherapy. 2009 Mar; 53(3): 849-862 [^Anderson]: Anderson, Tatum. Working for the ‘Dark Side’ Against TB. TropIKA.net. 29 Jan 2009
PA-824 (post with image)
PA-824 is an experimental drug that is undergoing testing as a potential treatment for TB. Like OPC-67683, PA-824 is a nitroimidazole that has demonstrated bactericidal and sterilizing activity against drug-resistant and non drug-resistant TB. PA-824 has also shown activity against both active and latent TB. In a 2002 agreement with the former biotechnology company Chiron, the TB Alliance was granted exclusive rights to develop the drug as a treatment for TB. The TB Alliance is currently carrying out phase II clinical testing on PA-824. How it works ------------ PA-824 is a nitroimidazole. It is a prodrug, which means it needs to be activated before it becomes effective against TB bacteria. PA-824 is activated by either a bacterial enzyme or a cofactor, which is a compound that binds to a protein. This activation is the reason why PA-824 does not attack human cells. Human cells lack the bacterial enzyme and cofactor needed to convert PA-824 into its active form. PA-824 kills bacteria by inhibiting the synthesis of certain proteins and cell wall lipids (i.e. fat molecules) that are needed by bacteria for survival. Researchers believe that PA-824 acts this way against replicating, aerobic (i.e. requiring oxygen) bacteria only. PA-824 is also active against latent TB bacteria. In a latent state, bacteria are anaerobic and either non-replicating or replicating very slowly. In 2008 researchers from the National Institute of Allergy and Infectious Diseases (NIAID) found that PA-824 kills latent bacteria by releasing a gas called nitric oxide (NO), which poisons the bacteria. NO gas is produced naturally by specific immune cells after they engulf TB bacteria; this is one way the body fights TB infection. But this immune response is sometimes not sufficient to eliminate an infection. PA-824 mimics the body's natural immune response, but it is more specific and only releases the gas upon entering the TB bacteria. While PA-824 was originally designed to act against active, aerobic bacteria, this NO mechanism explains how PA-824 is also active against latent, anaerobic bacteria. TB bacteria in their latent state are surrounded by immune cells in structures called granulomas. Oxygen levels are low inside granulomas, so these structures are said to have an anaerobic environment. Researchers determined that NO gas is released in greater quantities in an anaerobic environment. Understanding how PA-824 acts against latent bacteria may help investigators design other TB drugs that use this same mechanism in low-oxygen conditions.[^Mohit] Pre-clinical studies -------------------- Pre-clinical studies demonstrated that PA-824 has potent bactericidal and sterilizing effects against drug-resistant and drug-susceptible TB. The drug’s Minimum Inhibitory Concentration (MIC, or the lowest concentration at which it is effective against bacteria) was found to be between 0.015 and 0.25 µ/ml for drug-sensitive strains and between 0.03 and 0.53 µ/ml for drug-resistant strains. A study in 2005 using the mouse model found that when PA-824 was used alone, it exhibited bactericidal activity during the intensive phase of therapy that was similar to an equivalent dose of isoniazid in humans. When combined with isoniazid, PA-824 prevented the selection of isoniazid-resistant mutants. Researchers were surprised to find that PA-824 also demonstrated potent activity during the continuation phase of therapy, during which it eliminated bacteria that had survived the initial two-month intensive phase.[^Sandeep] This is likely because the bacteria that outlast the intensive phase treatment inhabit an anaerobic environment that facilitates bactericidal action by PA-824.[^Lenaerts] Other studies using the mouse model demonstrated that PA-824, when administered by itself, had bactericidal activity slightly greater than rifampicin (20mg/kg), and comparable to moxifloxacin (100 mg/kg) and isoniazid (25 mg/kg). PA-824 administered alone also showed comparable activity to combination therapy with rifampin and isoniazid in mice and in vitro.[^Lenaerts2] Early studies incorporated PA-824 into standard combination therapies of first-line drugs to investigate its interaction with these drugs and its potential to shorten the current six-month treatment programme. Researchers found some evidence that PA-824 could potentially lead to a shorter regimen. A 2006 study replaced isoniazid with PA-824 in the first-line combination of isoniazid, rifampin, and pyrazinamide. Researchers found that this substitution led to a more rapid conversion to sputum-negative, and had more potent sterilizing effects – as demonstrated by significantly lower bacterial counts after two months of treatment. However, there was no difference in the proportion of mice that relapsed following treatment. Researchers were "unable to establish a clear role for PA-824 in a treatment-shortening regimen." [^Nuermberger] A 2008 study reported that the novel combination of PA-824, moxifloxacin, and pyrazinamide cured mice more rapidly than the first-line regimen of rifampin, isoniazid, and pyrazinamide. PA-824, moxifloxacin, and pyrazinamide in a combination regimen had potent sterilizing activity that accelerated the rate of conversion to sputum-negative. This suggested that PA-824 may substitute well for rifampicin during intensive phase therapy. Researchers concluded that, if these results are applicable to humans, "regimens containing this combination may radically shorten the treatment of multidrug-resistant tuberculosis." [^Nuermberger2] Pre-clinical studies on PA-824 revealed some other notable characteristics of the drug. Researchers found that PA-824 has a narrow spectrum of action; while it kills TB bacteria, it does not act against other types of bacteria. This has important implications for TB treatment, because it means that TB bacteria will not be able to develop resistance to PA-824 as a result of the medication being used widely as a treatment for other bacterial infections. Additionally, PA-824 may be particularly effective against latent TB bacteria when used in combination with moxifloxacin, a 2005 study suggested. This study examined the activity of various drug combinations against latent TB. Researchers were surprised to find that the combination of PA-824 (100 mg/kg) with moxifloxacin (100 mg/kg) was at least as active as the current treatment of isoniazid therapy.[^Nuermberger3] Phase I trials -------------- In phase I trials of PA-824 in healthy volunteers, no serious side effects were reported. A 2009 trial evaluated the safety and efficacy of PA-824 in two escalating-dose clinical studies, one single-dose and one multiple-dose study. The drug was well-tolerated in 58 healthy individuals who were given PA-824 for a period of 7 days, and no adverse events occurred. Pharmacokinetic properties of the drug supported a regimen of one dose per day.[^Ginsberg] Phase II trials --------------- The development of PA-824 experienced a setback when the U.S. Federal Drug Administration (FDA) put the medication on clinical hold following reports of PA-824 causing cataracts in monkeys. Phase I trials, however, found no evidence of this side-effect in human patients, most likely because the dose administered in animal studies far exceeded the comparable dose given to human patients. The FDA removed the clinical hold in July 2009. The following month, a phase II trial was initiated to examine the Early Bactericidal Activity (EBA) of PA-824. An EBA study investigates a drug's ability to quickly kill TB bacteria when administered alone. A randomized, controlled EBA study was conducted at two sites in South Africa and coordinated by Stellenbosch University, the University of Cape Town and the Global Alliance for TB Drug Development. TB-infected patients were separated into five different groups, with about 15 patients per group. Four groups received one of four oral doses of PA-824: 200, 600, 1,000, or 1,200mg per day for a period of 14 days. For the control group, 8 patients received the standard first-line TB treatment. Results were published in 2010. As researchers expected, PA-824 showed promising bactericidal activity. The results confirmed that PA-824 "could someday be incorporated into a regimen to treat drug-susceptible and drug-resistant TB more quickly and effectively." [^Diacon] However, investigators were surprised to find that each of the four PA-824 doses resulted in an essentially the same EBA, with a steady decrease in the number of TB bacteria in the sputum (~0.1 log drop in CFU per day for 14 days, as compared with 0.148 for the standard regimen). This means that maximum effectiveness was seen at the lowest dose tested: 200 mg. The lack of difference in bactericidal activity between 200 mg and 1200 mg contradicted pre-clinical studies in mice, where the activity of PA-824 was dose-dependent (i.e. increased with increasing doses). Researchers recommended more studies to test lower doses of the drug.[^Tyagi] A study published in 2011 conducted more experiments in mice and in vitro to examine the activity of lower doses of PA-824 against TB bacteria. Some of the bacterial cultures used were isolated from human patients. This study confirmed the earlier finding that 200 mg/day of PA-824 in humans is sufficient to achieve maximum bactericidal effects. The study showed that PA-824 could be active against TB bacteria in doses as low as 50 or 100 mg/day in humans. Based on pharmacokinetic results, researchers postulated that human patients require relatively lower doses of the drug than mice because PA-824 has a longer half-life in humans.[^Ahmad] Future developments ------------------- The TB Alliance is leading the development of PA-824 as a treatment for TB. A second EBA study was commenced in 2009 to explore the activity of PA-824 at lower doses (50 to 200 mg/day), but results have not yet been published. Another EBA study that will evaluate PA-824 as part of a novel three-drug combination is currently in its planning stages.[^Wingfield] Advocacy issues --------------- - The TB Alliance gained global exclusive rights to PA-824 and related compounds for the treatment of TB in an agreement with Chiron (now part of Novartis) in 2002. This agreement ensured that the technology would be made available royalty-free in endemic countries, and it was the first such arrangement between a private company and a nonprofit organization. - According to a TB Alliance statement, in 2007 the U.S. FDA approved a request for orphan drug designation for PA-824. The Orphan Drug Act is designed to reduce the costs of developing and registering drugs for some diseases and conditions that are rare in the U.S. The designation confers a number of benefits for the development of PA-824, including a waiver of the nearly $1 million fee usually paid on submission of a New Drug Application. The European Union has just approved similar Orphan Medical Product status for PA-824. The FDA also has granted PA-824 fast-track designation, which is designed to expedite the application and review process for products that have the potential to address a serious or life-threatening condition.[^TBAlliance] - Coordination between future research efforts to develop PA-824 and OPC-67683 is warranted due to the chemical similarities between these two nitroimidazole compounds. - It is taking an extraordinarily long time to push the drug through clinical trials. [^Mohit]: Joshi, Mohit. Experimental Drug Shows Promise Against Latent TB Bacteria. Top News Health. 28 Nov 2008. [^Sandeep]: T Sandeep. Bactericidal Activity of the Nitroimidazopyran PA-824 in a Murine Model of Tuberculosis. Antimicrob Agents Chemother. 2005 June; 49(6): 2289-2293 [^Lenaerts]: AJ Lenaerts et al. Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models. Antimicrob Agents Chemother. 2005 June; 49(6): 2294–2301 [^Lenaerts2]: AJ Lenaerts et al. Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models. Antimicrob Agents Chemother. 2005 June; 49(6): 2294–2301 [^Nuermberger]: E Nuermberger et al. Combination Chemotherapy with the Nitroimidazopyran PA-824 and First-Line Drugs in a Murine Model of Tuberculosis. Antimicrob Agents Chemother. 2006 Aug; 50(8): 2621-2625 [^Nuermberger2]: E Nuermberger et al. Powerful Bactericidal and Sterilizing Activity of a Regimen Containing PA-824, Moxifloxacin, and Pyrazinamide in a Murine Model of Tuberculosis. Antimicrob Agents Chemother. 2008 Apr; 52(4): 1522–1524 [^Nuermberger3]: E Nuermberger et al. Rifapentine, Moxifloxacin, or DNA Vaccine Improves Treatment of Latent Tuberculosis in a Mouse Model. Am. J. Respir. Crit. Care Med. 2005; 172: 1452-1456 [^Ginsberg]: AM Ginsberg et al. Safety, Tolerability, and Pharmacokinetics of PA-824 in Healthy Subjects. Antimicrob Agents Chemother. 2009 Sept; 53(9): 3720-3725 [^Tyagi]: S Tyagi et al. Bactericidal Activity of the Nitroimidazopyran PA-824 in a Murine Model of Tuberculosis. Antimicrob Agents Chemother. 2005 June; 49(6): 2289-2293 [^Diacon]: AH Diacon et al. Early Bactericidal Activity and Pharmacokinetics of PA-824 in Smear-Positive Tuberculosis Patients. Antimicrob Agents Chemother. 2010 Aug; 54(8): 3402-3407 [^Ahmad]: A Ahmad et al. PA-824 Exhibits Time-Dependent Activity in a Murine Model of Tuberculosis. Antimicrob Agents Chemother. 2011 Jan; 55(1): 239–245 [^Wingfield]: Wingfield, Claire. Tuberculosis Treatment Pipeline. I-Base, HIV Treatment Bulletin. July 2010. [^TBAlliance]: TB Alliance. TB Alliance Advances Two Drugs In Clinical Trials On Path To Faster, Better Tuberculosis Treatments. 11 August 2007.
Rifapentine (post with image)
Rifapentine (also known as cyclopentyl rifampicin and Priftin) is a medication recommended by the World Health Organization as a first-line treatment for TB. It was first synthesized in 1965 by the Italian company that developed rifampicin and approved by the U.S. Food and Drug Administration (FDA) as a treatment for pulmonary TB in 1998. Rifapentine is a long-acting derivative of rifampicin, and therefore is similar in structure to rifampicin. The primary benefit of rifapentine is that it simplifies TB treatment; its long-acting nature means that the drug is taken only once or twice weekly by patients. In addition, clinical studies have also demonstrated that rifapentine could potentially shorten the current six-month treatment regimen for latent TB. Rifapentine is not available for commercial use in South Africa. **Rifapentine (RPT)** Dosage ------ _Adults_ - Initial intensive phase dose: 600 mg orally two times a week with at least 72 hours between doses for 2 months - Continuation phase dose: Following the 2 month intensive phase, 600 mg orally once a week for at least 4 months _Children_ 15 years or older: - Initial intensive phase dose: 600 mg orally two times a week with at least 72 hours between doses for 2 months - Continuation phase dose: Following the 2 month intensive phase, 600 mg orally once a week for at least 4 months 12 years to less than 15 years weighing less than 45 kg: - Initial intensive phase dose: 450 mg orally two times a week with at least 72 hours between doses for 2 months. - Continuation phase dose: 450 mg orally once a week for at least 4 months following the initial phase 12 years to less than 15 years weighing 45 kg or more: - Initial intensive phase dose: 600 mg orally two times a week with at least 72 hours between doses for 2 months - Continuation phase dose: 600 mg orally once a week for at least 4 months following the initial phase _Notes on dosing_ - To be eligible for rifapentine therapy, patients must be more than 12 years of age; have culture- positive, noncavitary pulmonary tuberculosis; be infected with TB strains that are susceptible to rifampicin, isoniazid, and pyrazinamide; and be HIV negatve. Only HIV-negative patients should receive rifapentine - During the intensive phase, rifapentine should be administered in combination with daily companion drugs (such as ethambutol, pyrazinamide, and streptomycin). - The continuous phase of treatment may consist of rifapentine with isoniazid or an appropriate anti-TB medication. - Patients with resistance to rifampicin should not be given rifapentine, due to cross resistance between these drugs. How it works ------------ Rifapentine is similar in structure to rifampicin and uses a similar mechanism against TB bacteria. It kills TB bacteria by inhibiting bacterial RNA polymerase, which is the enzyme responsible for transcribing DNA into RNA (RNA is subsequently used to make bacterial proteins). By disrupting the bacterial RNA polymerase only, rifapentine eliminates TB bacteria while leaving human RNA polymerase unaffected. Rifapentine has a long half-life in serum and is therefore administered less frequently. Its half-life is 5 times that of rifampicin. Side effects ------------ Mild side effects include red, orange, or brown discoloration of skin, tears, sweat, saliva, urine, or tools, which is a harmless but potentially alarming side effect if the patient is not forewarned; nausea and loss of appetite; stomach pain; mild skin rash or itching; headache; and joint pain. Less common side effects include vomiting; diarrhea; blood in stools; and, in rare cases, liver problems. Pricing ------- Rifapentine (Brand: Priftin) 150 mg, 100 tablets: $363.48 / R2988 Price per tablet: $3.63 / R30 (exchange rate 21/09/2011) (Rifapentine is not available in South Africa) Clinical trials and approval ---------------------------- Rifapentine is recommended by the WHO as a first-line drug for the treatment of TB. It demonstrates excellent activity against TB bacteria in vitro , animal studies, and clinical trials. Rifapentine is as effective as rifampicin at eliminating TB bacteria. Clinical trials have demonstrated rifapentine to be safe and effective for the treatment of TB. Several studies, however, have suggested that patients treated with rifapentine have a slightly higher risk of relapse following the completion of treatment. A 2002 study in the USA and Canada administered rifapentine to a group of HIV positive patients with non drug-resistant TB who had completed a 2 month intensive phase of treatment. These patients received either 600 mg rifapentine plus 900 mg isoniazid once a week or 600 mg rifampicin plus 900 mg isoniazid twice a week. Rifapentine was shown to be safe and effective in HIV negative patients, which was the basis for the current CDC recommendation for using rifapentine and isoniazid in selected patients during the continuation phase of therapy. However, rates of relapse among rifapentine-receiving patients were slightly higher; crude rates of failure/relapse were 46/502 (9.2%) in patients administered rifapentine-isoniazid, and 28/502 (5.6%) in those given rifampicin-isoniazid[^Benator] Early on, this study had included a group of HIV-positive patients. However, recruitment in the HIV-positive study arm was stopped in 1997 after 4 of 36 patients in the rifapentine-isoniazid group experienced relapse with acquired rifampicin-monoresistant TB. Researchers have subsequently advised against administering rifapentine to patients co-infected with HIV and TB.[^Munsiff] A study in 2007 used the mouse model to compare the effectiveness of rifapentine- and moxiflocacin-containing regiments with that of the standard daily short course regimen with rifampicin, isoniazid, and pyrazinamide. Researchers found that replacing rifampicin with rifapentine and isoniazid with moxifloxacin dramatically increased the activity of the standard daily regimen and led to negativity in mice after only 2 months. They concluded that their results warrant urgent clinical investigation, and suggested that rifapentine should no longer be viewed solely as a long-acting substitute for rifampicin. According to the study’s authors, “our results suggest that treatment regimens based on daily and thrice-weekly administration of rifapentine and moxifloxacin may permit shortening the current 6 month duration of treatment to 3 months or less."[^Rosenthal] Rifapentine has also showed considerable promise as an effective treatment for latent TB. A study in 2005 demonstrated that a three-month, once-weekly regimen of rifapentine combined with either isoniazid or moxifloxacin were as active as the current treatment of daily isoniazid for 6–9 months.[^Nuermberger] In addition, a 10 year trial concluded in 2011 and sponsored by the international Centers for Disease Control and Prevention (CDC) recently demonstrated that a once-weekly regimen of rifapentine and isoniazid for just 3 months is as effective as a standard self-administered 9-month daily regimen of isoniazid alone, and has a significantly higher completion rate. The study was one of the largest ever conducted on latent TB preventative therapy, and consisted of 8053 participants in South Africa who were randomized to receive either 3 months of once-weekly rifapentine 900 mg plus isoniazid 900 mg (administered with directly observed supervision), or the current standard treatment regimen (9 months of self-administered daily isoniazid 300 mg). Of the study volunteers, 7 cases of TB occurred in the group assigned rifapentine, while 15 occurred in the standard treatment group. The rate of permanent drug discontinuation due to adverse side effects was slightly higher with the rifapentine/isoniazid regimen (4.7% vs 3.6%). Despite this, the rate of participants who completed treatment was substantially higher with the rifapentine regimen than with the standard regimen (82% vs 69%). This demonstrates that reducing the required treatment regimen from 270 doses to just 12 doses through rifapentine therapy could potentially lead to better rates of completion and patient compliance. Due to these encouraging results, the CDC has launched an effort to develop new guidelines on the use of the treatment regimen. In addition, current clinical trials are investigating the tolerability of the rifapentine-containing regimen amongst children and HIV positive patients.[^March] Advocacy issues --------------- - More clinical information is needed on the effectiveness, safety, and tolerability of rifapentine-containing regimens as a treatment for both active and latent TB in children and patients co-infected with HIV and TB. - The long-acting nature of rifapentine therapy simplifies TB treatment and has been shown to potentially lead to increased patient compliance. - It is recommended that the price of rifapentine therapy be reduced to increase access. [^Benator]: D Benator et al. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet. 2002 Aug 17; 360(9332): 528-534 [^Munsiff]: SS Munsiff et al. Rifapentine for the Treatment of Pulmonary Tuberculosis. Clin Infect Dis. (2006) 43(11): 1468-1475 [^Rosenthal]: IM Rosenthal et al. Daily Dosing of Rifapentine Cures Tuberculosis in Three Months or Less in the Murine Model. PLoS Med. 2007 Dec; 4(12): e344 [^Nuermberger]: E Nuermberger et al. Rifapentine, Moxifloxacin, or DNA Vaccine Improves Treatment of Latent Tuberculosis in a Mouse Model. Am J Respir Crit Care Med. 2005 Dec 1; 172(11): 1452-1456 [^March]: March, David. Simpler Combination Therapy as Good as Old Regimen to Prevent Full-Blown TB in People with and Without HIV. Johns Hopkins Medicine. 7 July 2011.
How TB drugs work (post with slideshow)
Use this slideshow to see the different TB drugs and how they work.
DR-TB drugs under the microscope (document)
This joint publication by Médecins Sans Frontières and the International Union Against Tuberculosis and Lung Disease describes the problems with medicines used to treat drug-resistant TB. It makes recommendations to address these problems.
Treatment of Tuberculosis: Guidelines for National Programmes (document)
Treatment of tuberculosis: Guidelines for National Programmes follows new WHO procedures for guidelines development. Seven important recommendations have been identified and are being promoted in this new edition. New objectives include universal access to patient-centred treatment and protection of populations from TB/HIV and multidrug-resistant TB (MDR-TB). The recommendations are based on the quality of the evidence, patient values, and costs, as well judgements about trade-offs between benefits and harms.
South African National Tuberculosis Management Guidelines (document)
These guidelines advise how to address the challenges of: TB control and successful management of all clients presenting with TB, especially those co-infected with HIV as well as early detection of drug resistant TB. The strategies laid out build on achievements of the DOTS strategy, however call for additional strategies to better address constraints and challenges in TB control. Including such efforts as: strengthening health systems, alleviating poverty and advancing human rights. Specific local aspects include improving continuity of care,ensuring equitable access to services, and improving the care of those co-infected with TB and HIV.
Drug Resistant Tuberculosis Guidelines and Manual for Swaziland (document)
These guidelines and manual lay out Swaziland's 5 year plan to combat the escalating drug resistant TB problem by incorporating a short-term plan in to the National TB Control Programme. Highlighted activities include: increasing TB case detection and treatment success rates with expanded DOTS coverage at national and lower levels; reducing the combined TB patient default and transfer out rates, and strengthening basic TB care and ensuring prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission.
Guidelines for the Management of Adverse Drug Effects of Antimycobacterial Agents (document)
In these guidelines, common adverse drug effects (ADE) and drug interactions people commonly experience while taking TB medication is explained. Such ADE include: dermatalogic, gastrointestinal, Arthalgias (joint pain), Influenza Syndrome, and Neurotoxicity (Nervous System. It also goes over clinical presentations of reactions, causative agents, and management recommendations for each ADE.
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