Monitoring and Risk Assessment for New Anti-tuberculosis Drugs
Methodological and Information Support for Risk Analysis of the Production and Use of New Generation Anti-tuberculosis Drugs, on the Basis of Hydrazine and its Derivatives
Tech Area / Field
- ENV-EHS/Environmental Health and Safety/Environment
- ENV-MIN/Monitoring and Instrumentation/Environment
- ENV-MRA/Modelling and Risk Assessment/Environment
3 Approved without Funding
Lomonosov Academy of Fine Chemical Technologies, Russia, Moscow
- Kazan State Technological University, Russia, Tatarstan, Kazan\nInstitute of Phthsiopulmonology, Russia, St Petersburg\nSiberian Branch of RAS / Institute of Organic Chemistry, Russia, Irkutsk reg., Irkutsk
- US Environmental Protection Agency / National Exposure Research Laboratiry, USA, NV, Las-Vegas\nUniversité de Versalles Saint-Quentin-En-Yvelines, France, Versailles\nUniversity of Florida / Department of Chemistry / Florida Center for Heterocyclic Compouns, USA, FL, Gainesville\nUniversité Libre de Bruxelles, Belgium, Brussels
Project summaryThe objective of the present project is to develop the methodological and information support for risk analysis of new generation antituberculosis drugs (tuberculostatics), on the basis of chemical-pharmaceutical utilization of nonsymmetrical 1,1-dimethylhydrazine (NDMH) (and also its derivatives), component of a liquid rocket fuel - one of major objects of military-technical conversion of Russia.
In Russia the large reserves of nonsymmetrical 1,1-dimethylhydrazine being one of components of a liquid rocket fuel and, as are known, object of modern military-technical conversion of country are accumulated. In connection with actual fulfillment by Russia of the international obligations on a reduction of strategic offensive armaments the task of development of methods of controlled utilization of this high-toxic compound is extremely actual. One of the most perspective technical approaches of such version of utilization of NDMH is its use as a row material for synthesis of different tuberculostatics. However in conventional statement the problem of pharmacochemical detoxification of NDMH, rocket fuel component is ecologically and genetically noncorrect.
The realization of chemical-pharmaceutical version of utilization of NDMH in the present project supposes necessity of development of monitoring system for water and air working mediums, and also intermediates and products on the contents of NDMH and other chemical toxicants in production of new generation antituberculosis drugs, and of estimation on this basis of risk of use of proposed pharmaceuticals, what corresponds to the aims of ISTC (contributing to conversion processes, in particular, support of the "weapon" scientists and engineers at fulfillment by them of applied researches and mining of know-hows in the peace purposes in the field of environmental protection and health of the man).
The sharp necessity of development of new generation antituberculosis drugs is determined by those last years even more often the strains of tuberculosis (for example, № 3714) are discovered. These strains are steady against operating widely known drugs - Isoniazide, Streptomycin, Pyrazinamid etc. inhibiting the strain of human tuberculosis H37Rv. It is known that the synthesis of the main antituberculosis drugs is founded on a hydrazine and its derivatives. So, most widely applicable preparation- Isoniazide (Tubazide) is Hydrazide of isonicotinic acid. Other active preparation - Phthivazide represents isonicotinoyl-(3-methoxy-4-oxybenzal) hydrazon. The physiological activity of compounds of a hydrazine line is conventional high and prolongs to be investigated.
At the same time, the practice of an intrusion of new medicinal preparations (MP) up to clinical conditions supposes necessity of realization of a broad complex of researches of its metabolic transformations in organism of the man (patient) and their chemical simulation, detection potentially dangerous for health of the patient of products of a biotransformation of the main substance in a structure of MP. All this will allow to estimate the collateral effects from use of MP, to take into account the genetic features of the patient influencing on metabolic processes, to determine the groups of heightened risk at applying particular MP.
The relevant stage of researches of new tuberculostatics (substances for their synthesis one could be NDMH and (or) its derivatives), and also study of their action on the patients is the detection of storage lifes in natural conditions.
The results of the project will support further development of researches, spent earlier by the performers, with reference to new technologies of chemical processing NDMH up to medicinal preparations, will allow at stages of laboratory and industrial synthesis, preclinical trials of potential drugs to ensure the ecological and genetic safety of the corresponding productions and medicinal preparations.
The method of the genetically predetermined processes of a biotransformation NDMH in an organism of the man, offered in the project, will become the basis for a drastic decrease of risk of a defeat of working staff in production of the applicable antituberculosis drug, and also for monitoring of medicinal substance (usually transforming at an endogenic metabolism or at storage in NDMH and its derivatives) at its overdosages or for optimization of medicinal therapy in view of genetic features of an organism of the patient. In that context the project has not a precedent in the world.
The indicated objective of the project will be reached with the help unified scientific - methodical collective of the highly professional researchers from four leading Russian organizations having positive experience within the framework of scientific-technological cooperation with ISTC in adjacent areas of chemical, ecological, analytical and pharmacological problems, and owning by methods of synthesis of medicinal matters (see, for example, Patent of RF № 1621449, 25.10.1993 on anti-tuberculosis drug "Perkhlozon", Patent of RF №839224 on an antiatherosclerotic drug "Parmidinum"), researches and monitoring both technological, air and water environments accompanying these matters (see, for example, Patent of RF.N 201 2869, 12.07.93), and processes of a biotransformation of definite xenobiotics in an organism of the man (factory staff, patient) (see also [1-3]).
The expected results of the project and their scientific novelty consists in the fact, that methods of synthesis of new compounds - potential tuberculostatics of a new generation on the basis of a hydrazine, NDMH and their derivatives, for the first time will be designed, the physicochemical and toxicological characteristics of the synthesized compounds will be determined, antituberculosis activity of drugs will be investigated. For the again synthesized compounds the monitoring system of high-toxic components of air, water and technological environments which are form during directional chemical-pharmaceutical utilization NDMH and its derivatives up to specialized matters of antituberculosis assigning will be created; the input data about metabolic transformations of new medicinal preparations in an organism of the man and at a model level essential for methodological and information support for risk analysis of their production and use will be obtained.
After realization of the considered project in a full volume its outcomes can and should be utilized at creation of hightechnological commercially significant production of new tuberculostatics, on the basis of a substance (raw) nonconventional and at the same time perspective for the world chemical pharmaceutics.
For the solution of a proposed systemic task the realization of scale researches and approbation of their result in preclinical and plant conditions on following directions are planned:
- development of methods of synthesis of new compounds - potential tuberculostatics of a new generation, on the basis of a hydrazine, NDMH and their derivatives: definition of the physicochemical and toxicological characteristics of the synthesized compounds: research of antituberculosis activity:
- system development of high-performance, express and cost-effective flow-injection determination of NDMH and other hazardous components of reaction mixtures, air and water emissions accompanying processes of controlled utilization of NDMH and its derivatives as raw for synthesis, of new chemical substances-matters of a medicinal means (MP);
- study of processes of transformation of medicinal matters at their storage, establishment of periods of validity (storage life) of the medicinal forms;
- research of processes of a biotransformation of new medicinal matters in an organism of the man; development of the personal schemes of dosage on the basis of pharmacogenetic structure (profile) of the patients;
- study of compatibility of medicinal matter and products of its transformation, screening of inductors of their excretion from an organism, for reduction of collateral effects of MP use;
- realization of preclinical tests of MP with the registration of the generically determined processes of their biotransformation.
The outcomes of activity can present significant interest for foreign collaborators, who have agreed to cooperate with the participants of the project and interested in rendering of the methodical recommendations in questions of study of state and environment safety, monitoring and instrumentation, risk assessment of drugs use, on the basis of NDMH and its derivatives.
In the present planned work the systemic (complex) approach at information support for risk analysis of the use of new generation antituberculosis drugs, on the basis of NDMH, at all stages of their functioning, for the first time will be utilized; i. e. in a chain: synthesis ® research and stability simulation ® monitoring in environment and in an organism of the man. The methodology of the project includes developed by the1-performers hightechnological physicochemical methods of control of a substance and products.
The quoted references:
1. Evgenyev M.I., Garmonov S.Yu., Evgenyeva I.I., Pogoreltsev V.I., Gorynova S.M. Reversed-phase liquid chromatographic determination of drugs in human urine as a test of the genetically predermined type of biotransformation by acetylation // Talanta. 1998. V.47, ©4, P.891-898.
2. M.I.Evgenyev, S.Yu. Garmonov, I.I.Evgenyeva, V.V.Ugrichich-Trebinskii. Selective Flow- Injection Determination of Hydrazine // J. Analyt. Chem. 1998. V.53, © 3. P. 240-245.
3. M.I.Evgenyev, S.Yu. Garmonov, I.I.Evgenyeva, S.M.Goryunova, LM.Schakirova, D.G.Pobedimsky. Derivatization reactions in flow analysis of hazardous aminocompounds. // Abstr. of XVIth Mendeleev Congr. Saint-Petersburg. 22-30 May. 1998. V.3. P.90.
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