Potential tuberculostatic agent: Micelle-forming pyrazinamide prodrug

Pyrazinamide was condensed with the poly(ethylene glycol)-poly(aspartic acid) copolymer (PEG-PASP), a micelle-forming derivative was obtained that was characterized in terms of its critical micelle concentration (CMC) and micelle diameter. The CMC was found by observing the solubility of Sudan III in Poly(ethylene glycol)-poly(pyrazinamidomethyl aspartate) copolymer (PEG-PASP-PZA) solutions. The mean diameter of PEG-PASP-PZA micelles, obtained by analyzing the dynamic light-scattering data, was 78.2 nm. The PEG-PASP-PZA derivative, when assayed for anti-Mycobacterium activity, exhibited stronger activity than the simple drug.

Potential tuberculostatic agents: Micelle-forming copolymer poly(ethylene glycol)-poly(aspartic acid) prodrug with isoniazid

With the objective of obtaining slow-acting isoniazid derivatives, of potential use as chemoprophylactics or chemotherapeutics in tuberculosis, the micelle-forming copolymer of poly(ethylene glycol)-poly(aspartic acid) prodrug with isoniazid was synthesized. The derivative obtained was found to be active in Mycobacterium Il(tuberculosis culture, with a minimal inhibitory concentration (MIC) 5.6 times lower than that of the tuberculostatic drug.

Relevance of the deletion polymorphisms of the glutathione S-transferases GSTT1 and GSTM1 in pharmacology and toxicology

Although cytosolic glutathione S-transferase (GST) enzymes occupy a key position in biological detoxification processes, two of the most relevant human isoenzymes, GSTT1-1 and GSTM1-1, are genetically deleted (non-functional alleles GSTT1*0 and GSTM1*0) in a high percentage of the human population, with major ethnic differences. The structures of the GSTT and GSTM gene areas explain the underlying genetic processes. GSTT1-1 is highly conserved during evolution and plays a major role in phase-II biotransformation of a number of drugs and industrial chemicals, e.g. cytostatic drugs, hydrocarbons and halogenated hydrocarbons. GSTM1-1 is particularly relevant in the deactivation of carcinogenic intermediates of polycyclic aromatic hydrocarbons. Several lines of evidence suggest that hGSTT1-1 and/or hGSTM1-1 play a role in the deactivation of reactive oxygen species that are likely to be involved in cellular processes of inflammation, ageing and degenerative diseases. There is cumulating evidence that combinations of the GSTM1*0 state with other genetic traits affecting the metabolism of carcinogens (CYP1A1, GSTP1) may predispose the aero-digestive tract and lung, especially in smokers, to a higher risk of cancer. The GSTM1*0 status appears also associated with a modest increase in the risk of bladder cancer, consistent with a GSTM1 interaction with carcinogenic tobacco smoke constituents. Both human GST deletions, although largely counterbalanced by overlapping substrate affinities within the GST superfamily, have consequences when the organism comes into contact with distinct man-made chemicals. This appears relevant in industrial toxicology and in drug metabolism.

Situacao atual da quimioterapia contra a tuberculose

Actions to overcome a disease are dependant, essentially, on what is known about it. Procedures followed in the past were sometimes bizarre, but justified because of how little was known about the disease. The tuberculosis prechemotherapeutic age was somber due to the high levels of fatalities and morbidity. With the arrival of the chemotherapeutic treatment its prognosis has changed. Tuberculosis declined in the 50's and stabilized in the 80's. Nevertheless, it is back increasing alarming its numbers more than ever; probably because of some factors, among them, the public health system lack of attention and the government's policies, increasing in the migration to and from the endemic areas, development of drug multi-resistant cepa and also to the HIV infection. An universal antimycobacteria chemotherapy treatment is not accepted, maybe because of the number of drugs that are available. Modern chemotherapy, however, has an attack and a maintenance phases with the aim to eliminate the bacillus of fast and slow multiplication, respectively. The treatment period is long, when compared with other infectious diseases, that leads to the lack of compliance. In spite of the available resources in the fight against tuberculosis they seem insufficient to restrain the disease. This has forced the search for new chemotherapy alternatives to avoid strong come back of tuberculosis to the point of being called the 'white plague' well into the 21'st century.