Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-14
2001-07-31
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06268393
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a method and composition for treating and/or preventing mycobacterium infections in patients.
BACKGROUND OF INVENTION
Infectious diseases remain the largest cause of death in the world today, greater than cardiovascular disease or cancer.
1
Among infectious diseases, tuberculosis (TB) is the leading cause of death.
2
The emergence of multidrug-resistant (MDR) strains and the global human immunodeficiency virus (HIV) pandemic amplify the incidence of TB.
Tuberculosis mainly affects the lungs but can also involve other organs. TB strikes people of all ages but is more common among the elderly. The disease can also afflict animals, especially livestock such as cattle, hogs, and poultry. Rod-shaped bacteria, tubercle bacilli discovered by the German physician Robert Koch in 1882, cause the disease. Tubercle bacilli belong to a genus of bacteria called Mycobacterium. This disease once ranked among the most common causes of death in the world. Today, improved methods of prevention, detection, diagnosis, and treatment have greatly reduced both the number of people who contract the disease and the number of people who die from it. However, in the last decade, the outbreaks of MDR tuberculosis (MDRTB) and TB amplified by the global HIV pandemic make TB an urgent global issue.
One-third of the world's population is infected with
Mycobacterium tuberculosis
(Mtb),
3
a facultative intracellular bacillus. After infection with Mtb, the lifetime risk of developing TB is approximately 10%, while 90% of infected persons have latent infection with viable bacilli. This 10% rate of TB accounts for the 8 million persons reported annually with active TB, and the resultant 3 million deaths. Moreover, TB is a serious problem faced by hemodialysis patients,
4
and TB is the No. 1 killer of women of childbearing age around the world with 1.2 million women dying of the disease in 1997 according to reports by the World Health Organization.
11a
a. Tuberculosis and AIDS
TB infection is a serious problem for acquired immunodeficiency syndrome (AIDS) patients. HIV-infected individuals are particularly susceptible to infection with Mtb and the development of TB. Compared to an individual who is not infected with HIV, an individual infected with HIV has a 10 times greater risk of developing TB. In an individual infected with HWV, the presence of other infections, including TB, may allow HIV to multiply more quickly. This may result in more rapid progression of HIV infection and AIDS.5 As HIV infection progresses, CD4+ lymphocytes decline in number and function. The immune system is less able to prevent the growth and local spread of Mtb. Even in HIV-infected patients, pulmonary TB (PTB) is still the most common form of TB. The presentation depends on the degree of immunosuppression.
As in adults, the natural history of TB in a child infected with HIV depends on the stage of HIV disease. Early in HIV infection, when immunity is strong, the signs of TB are similar to those in a child without HIV infection. As HIV infection progresses and immunity declines, dissemination of TB becomes more commnon. Tuberculous meningitis, miliary tuberculosis, and widespread tuberculous lymphadenopathy occur.
HIV-positive patients and staff in health units face daily exposure to TB. The risk of exposure is greatest in adult medical wards and TB wards where there are many PTB cases. From 1990-1992, the Centers for Disease Control and prevention (CDC) investigated outbreaks of multidrug-resistant tuberculosis (MDRTB) in several hospitals and a state correctional system. Almost 300 cases of MDRTB were identified in these outbreaks; most patients were HIV-seropositive. The mortality rate was 80%-90% and the median interval from diagnosis of tuberculosis to death ranged from 4-16 weeks.
6
In 1995, about one third of the 17 million HIVnfected people worldwide were also co-infected with Mtb.
5
(TB is the leading cause of death in AIDS patients).
b. Treatment of TB
Isoniazid (isonicotinic acid hydrazide) (INH) was first reported to be effective against Mtb and
M. bovis
in 1952.
7-9
Isoniazid, now still a front-line therapy against TB, has been shown to be an effective prophylactic antitubercular
10
, and modern short-course chemotherapy is initiated with three drugs: isoniazid, rifampin and pyrazinamide (PZA), often with the inclusion of a fourth drug, usually ethambutol. Recently, rifapentine, a derivative of rifamycin, was approved by the FDA for the treatment of tuberculosis.
11b
The American Thoracic Society and the CDC in the United States now recommend a treatment regimen of isoniazid, rifampin, and pyrazinamide for 2 months, followed by isoniazid and rifampin for an additional 4 months, as the standard 6-month regime. Isoniazid, cheap and safe, has a wide therapeutic margin and high early bactericidal activity so that it kills rapidly growing bacilli in lesions, but is inefficient in ultimately sterilizing these lesions. Rifampin and PZA are crucial in achieving sterilization by killing persisting semi-dormant bacilli, and are thus responsible for shortening the duration of treatment from the earlier norm of 12-18 months to the current standard of 6 months.
12
However, many people fail to complete the lengthy therapy, treatment failures are high, and MDR is increasing. A 4-year study, led by the World Health Organization, shows that of people who had been treated for TB for less than a month, 36 percent harbored microbes that resisted at least one of the four main anti-tuberculosis drugs. Moreover, 10% of infected people who had never been treated for the disease carried a strain of Mtb that resisted at least one drug.
13
d. Mechanism of Drug Action
Isoniazid is a prodrug that requires activation by the mycobacterial catalase-peroxidase enzyme (KatG) to an active form that then exerts a lethal effect on an intracellular target or targets.
14-16
The lethal effect lies in the biosynthetic pathway for mycolic acids,
14, 17-19
alpha-branched and beta-hydroxylated fatty acids found in the envelope of mycobacteria.
Rifamycins (e.g. rifampin, rifabutin and rifapentine) are potent inhibitors of prokaryotic DNA-dependent RNA polymerase,
20
with little activity against the equivalent mammalian enzymes. This group of antimicrobial agents are compounds composed of aromatic rings linked by an aliphatic bridge. Most likely, the lipophilic properties of the molecule are important for the binding of the drug to the polymerase and aid in the penetration of the drug across the mycobacterial cell wall.
Pyrazinamide (PZA) is a synthetic derivative (pyrazine analog) of nicotinamide and in combination with isoniazid is rapidly bactericidal for replicating forms of Mtb, with an average MIC of 20 &mgr;g/mL. The activity of PZA depends on the presence of a bacterial amidase which converts PZA to pyrazinoid acid (PZOA), the active antibacterial molecule.
21
Amidase activity is present in PZA-sensitive but not in PZA-resistant species such as
M. bovis,
opportunistic mycobacteria and Mtb resistant to PZA as a result of drug therapy. The gene (pncA) encoding the PZA (and nicotinamide) amidase which is responsible for processing PZA into its bactericidal form has been identified, and the mutations in pncA that confer PZA resistance to tubercle bacilli have been recently reported.
22
Ethambutol is active against Mtb, with MICs in the range of 1 to 5 &mgr;g/mL. The drug has much more variable activity against the other species of slowly growing mycobacteria and is significantly less active against rapidly growing mycobacteria. On the whole, ethambutol is inactive against other microorganisms. The mechanisms of action of ethambutol have focused on two targets: polyamine function and metabolism and cell wall synthesis. Ethambutol inhibits the transfer of mycolic acid into the cell wall and stimulates trehalose dimycolate synthesis.
23
e. Multidrug Resistance
The importance of KatG mutations in isoniazid resistance is well established, although the extent to which such mutations ac
Flavin Michael T.
Lin Yuh Meei
Xu Ze-Qi
McDonnell & Boehnen Hulbert & Berghoff
Sarawak MediChem Pharmaceuticals
Spivack Phyllis G.
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