Microbiological Studies A definitive diagnosis of tuberculosis can only be made my culturing Mycobacterium tuberculosis organisms from a specimen taken from the patient (Most often sputum, but may also include pus, cerebero spinal fluid (CSF)), biopsied tissue, etc. Sputum smears and cultures should be done for acid-fast bacilli. The preferred method for the identification is fluorescence microscopy which is more sensitive than conventional Ziehl- Neelson staining denoted by Steingart et al. , 2006 6.
If sputum is not produced, specimens can be obtained by gastric washings, an laryngeal swab, bronchoscopy with broncho alveolar lavage or fine needle aspiration of a collection. A comparative study found that inducing three sputum samples is more sensitive than three gastric washings. Many types of culture media are available. Traditionally Lowenstein –Jensen (LJ), Kirchner or Middle Brook media (7H9, 7H10, 7H11 and 7H12) are used for cultivating of Mycobacterial species. A culture of the acid-fast bacilli distinguishes the various forms of Mycobacteria.
New automated systems that are faster include BACTEC 460 TB, BACTEC 9000 and the Mycobacterial growth Indicator tube (MGIT). The microscopic observation drug susceptibility assay (MODS) culture may be faster and more accurate method. Drugs Used In Tuberculosis in the current scenario Active tuberculosis will kill about two of every three people affected if left untreated. Treated tuberculosis if taken up early has a mortality rate of less than 5%. The standard short course treatment for tuberculosis comprises of Isoniazid, Rifampicin, Pyrazinamide and Ethambutol for two months, then Isoniazid and Rifampicin alone for a further four months.
For latent tuberculosis, the standard treatment is six to nine months of Isoniazid alone. Drug regimens are abbreviated in a standardized manner. a). Streptomycin is STM or S b) Isoniazid is INH or H c) Rifampicin is RMP or R d) Ethambutol is EMB or E e) Pyrazinamide is PZA or Z. a)According to WHO norms, there are six classes of second line drugs that are used for the treatment of tuberculosis. A drug may be classified as second line instead of first line for one of two possible reasons; it may be less effective than the first line drugs or it may produce toxic side –effects.
They are classified based on their chemical nucleus: Aminoglycosides – Amikacin and Kanamycin b)Polypeptides – Capreomycin c)Fluoroquinolones – Ciprofloxacin d)Thioamides – Ethionamide, Prothionamide and Cycloserine. e)Para-amino Salicylic acid. Tuberculosis has been treated by combination therapy over fifty years. Single drug treatment is ineffective and regimens that use only single drugs result in the rapid development of resistance and thus treatment results in failure. The rationale for using multiple drugs to treat tuberculosis is based on simple probability.
The frequency of spontaneous mutations that confer resistance to an individual drug is well known: 1 in 10 7 for Ethambutol (EMB); 1 in 108 for streptomycin (STM) and Isoniazid (INH); 1 in 10 10 for Rifampicin (RMP). A patient with extensive pulmonary tuberculosis has approximately 10 12 bacteria in his body and therefore will probably be harbouring approximately 10 5 Ethambutol resistant bacteria, 10 4 Streptomycin resistant bacteria, 104 Isoniazid resistant bacteria and 102 Rifampicin resistant bacteria respectively.
DOTS stands for ‘Directly Observed Therapy, Short – course’ and is a major plank in the WHO global tuberculosis eradication programme. The WHO advises that all tuberculosis patients should have atleast the first two months of their drug therapy should be observed with the aid of observer within that society. DOTS is used with intermittent dosing – Thrice weekly (Rifampicin, Isoniazid, Ethambutol and Pyrazinamide) or twice weekly. The relative incidence of major adverse effects has been carefully described . a)Isoniazid – Hepatitis, Neuropathy – 0. 49%. )Rifampicin – Skin rash, Thrombocytopenia and Hepatitis – 0. 43 % c)Pyrazinamide – Skin rash and Hepatitis – 1. 48 % d)Streptomycin – Vertigo – 0. 43 % Drug Resistant Tuberculosis (MDR and XDR – TB) Multi Drug Resistant Tuberculosis (MDR-TB) is defined as tuberculosis that is resistant at least to Isoniazid and Rifampicin isolates. In the year 2006 “Extensively- Drug Resistant Tuberculosis” (XDR-TB) has emerged and defined as multi drug resistant tuberculosis that is resistant to quinolones and also to any one of kanamycin, capreomycin or amikacin.
A 1997 survey of 35 countries found that 2% of the tuberculosis populations are infected by drug – resistant tuberculosis. The highest rates were in USSR, The Baltic states, Argentina, India and China. In 2006, MDR –TB in New York city has been increased to 20-30%. Annual risk of mortality rates increases by 10-15%. There is currently an epidemic of XDR-TB in South Africa. The outbreak was first reported as a cluster of 53 patients in a rural hospital in Kwazulu –Natal of whom 52 died . The treatment and prognosis of MDR-TB are much more akin to that of cancer than to that for infection.
In these aspects, molecular manipulation is a productive source of new drugs. This research work pertains to the modification of Schiff bases on isoniazid to explore the new drugs with a desire to obtain highly potent, more specific and less toxic drugs. In the foregoing literature retrieval, it had been observed that the drug design can be performed by molecular manipulation and resulting in new productive drugs. The biological study of natural products with medicinally useful property and some of the chemical structure and its analogs had furnished to lead compounds, and its variation in the biological behavior.
The pre-existing tuberculosis had made a challenging effect of medicinal chemists resulting in the extreme drug resistance. The performance of molecular manipulation still existed in a major line approach for the discovery of new drug analogues. To synthesize a derivative, an intermediate step has to be performed and to proceed for the further molecular manipulation. Combination of two or more active moieties in to one is a common procedure of manipulation and this can be possibly result in augmenting the activity, removal of untoward side effects and particularly to prevent development of resistance by the infectious microorganisms.
Abundant literature support were available with regard to the study of Schiff bases as potent antibacterial, antifungal, antihypertensive, antiviral and anticancer perspectives. Schiff bases were the intermediate for the synthesis of azetidine -2 & 4- ones, thiazolidine -2 & 4- ones, triazoles & tetrazoles. It was interesting to observe that some analogues of Schiff bases were combined with other moieties like phenothiazines,hydrazines and some hydrazide derivatives of carboxylic acid resulting in a better performance in their respective biological activities.
Hence, it was our interest to associate the Schiff bases with the primary drug isoniazid. Since Isoniazid is a well known antitubercular drug. As a vast number of reports were been available regarding the antitubercular perspectives of the isoniazid, there is still lacuna existing in the study of Schiff bases in the multi drug and extremely drug resistant M. tb strains. This study will full fill the properties of Schiff bases relevant to the prevailing drug resistant tuberculosis. Biological activities of Schiff bases Schiff bases are of interest and its important moiety which is associated with biological activity.
Initially, most of the research program has been conducted to explore the antimicrobial perspectives of Schiff base derivatives. Based on the intermediate Schiff base various molecular manipulation were attempted to investigate and discover an effective antibacterials, antifungals & antiviral agents. In this preview of literature the various activities of Schiff bases pertaining to antibacterial perspectives has been studied. 1. Hearn et. al. , 2003 7 performed enzymatic acylation of the antitubercular isoniazid (INH) by N-acetyl transferases reduces therapeutic effectiveness of the drug.
Since it dealt with the major metabolic pathway for INH in human beings, many of these derivatives were prepared and screened against Mycobacterium tuberculosis in the mice. They conclude the structural cogners of metabolites of INH may serve as significant leads in antitubercular drug discovery and in the exploration of the mode of action of INH. 2. Tarek Aboul – fadi et. al. , 2003 8 had synthesized N- alkyl derivative of INH and the Pharmacokinetic studies were been carried out in the bovine and sensitive strains of Mycobacterium tuberculosis.
The pharmacokinetic study revealed that the rate and extent absorption of the tested derivatives. They show relative bioavailability of 183. 15 and 443. 25 respectively. 3. Sultana et. al. , 2007 9 studied the synthesis of hydrazones. The study afforded to the hitherto unreported 1-(4-chloro benzylidene) – hydrazinophthalazine, 1- nitrobenzylidene hydrazine phthalazine. , 3-(4-Chlorophenyl) –S-Triazolo (3,4-a) phthalazine. These structures were confirmed by spectroscopic techniques – IR, UV, H-NMR, EIMS, FD & HRMS. Anti hypertensive activity were been evaluated. 4.
Koussi and Abdel rahman. , 2006 10 illustrated certain novel Schiff bases of 4- methyl-1,2,4 –triazole -3-mercaptoacetic acid hydrazide were synthesized and their chemical identities were elucidated by elemental analyses. IR, H-NMR,13- C-NMR and mass spectral data. The percentage of the geometrical isomers was elucidated using the 1-H NMR. The synthesized compounds were selected for screening at the tuberculosis antimicrobial acquisition and co-ordination facility against Mycobacterium tuberculosis H37RV strain in which they showed moderate activity at a concentration of 625 mg/mL. . Jiang et. al. , 2003 11 studied the series of chemically modified aryl- aldehyde Schiff bases has been synthesized and tested for their antioxidant activity and radiation protection. It was observed that disulfide –containing aryl –aldehyde schiff base exhibited potent free radical scavenging, antioxidation and radioprotective activities. 6. Pandeya et. al. ,1999 12 synthesized antibacterial, antifungal and anti human immunodeficiency virus activities of Schiff and Mannich bases derived from isatin derivatives and N – (4-(4’ chlorophenyl) thiazolyl thiosemi carbazide.
Investigation of antimicrobial activity of compounds was done by agar dilution method. 7. Jayasekar et. al. , 1997 13 synthesized the Schiff bases of mesalazine and studied the anti inflammatory activity. The inhibition shows about 50-60% of the potency of the drug. In the present study, we had investigated certain Schiff base derivatives modified from isoniazid and it has screened for Extreme drug-resistant and Multidrug resistant tuberculosis strain procured from the patients suffering from tuberculosis. Bibilography: 1. Rothschild, B. , Martin, L. , Bercovier, L. G. , Gal, B. G. , Blatt, G.
C. , Donoghue, H. , Spigelman, M and Brittain, D. Mycobacterium tuberculosis complex DNA from an extinct bison dated 17,000 years before the present. Clin. Infect. Dis. 30(3) : 305-311 ( 2001). 2. Pearce-Duvet, J. The origin of human pathogens evaluating the role of agriculture and domestic animals in the evolution of human disease. Biol. Rev. Camb. Philos. Soc. 31(3) : 369-382 (2006). 3. Koch, R. Die Aetiolgieder Tuberculosis. Berliner Klinsche Wochenschrift. 19 : 221-230 (1882). 4. Wells, A. Q. The Murine type of tubercle bacillus : Medical Research Council Special Report No. 259.
HMSO, London (1946). 5. Mark Spigelman, 2008. Excavated Jericho Bones may help Israeli- Plaestinian – German team to combat tuberculosis. News release, Feb 29, (2008): 1-5. 6. Steingart,K. , Henry,M. , Pasval,G. , Avery,T. O and Lyall, W. H. Fluorescence versus conventional sputum smear microscopy for tuberculosis : a systematic review. Lancet. Infect. Dis. 6 : 570-571 (2006). 7. Michael J Hearn, Michael H Cynamon. Design and synthesis of antituberculars: preparation and evaluation against Mycobacterium tuberculosis of an isoniazid Schiff base. Journal of Anti Microb. Chemotherapy. 53(2):185-191 (2004). . Tarek Aboul-Fadl, Faragany Abdel-Hamid Mohammed, Ehsan Abdel-Saboor Hassan. Synthesis, antitubercular activity and pharmacokinetic studies of some Schiff bases derived from 1-alkylisatin and isonicotinic acid hydrazide (INH). ARCHIVES OF PHARMACAL RESEARCH , 26(10):778-784 ( 2003 ). 9. Sultana-N; Sarfaraz-TB; Nelofar-A; Hussain-SA. Potential antibacterial agents: Part VI – Synthesis and structure elucidation of schiff bases derived from hydralazine. Pak-J-Sci-Ind-Resch (Pakistan-Journal-of-Scientific-and-Industrial-Research); 50(3); 169-172 (2007). 10. El-Koussi-NA; Abdel-Rahman-HM .
Novel 1,2,4-triazole-3-mercaptoacetic acid derivatives as potential antimycobacterial and antimicrobial agents. Bull-Pharm-Sci-Assiut-Univ (Bulletin-of-Pharmaceutical-Sciences); 29(Part 1); 127-136 (2006). 11. Jiang-JJ; Chang-TC; Hsu-WF; Hwang-JM; Hsu-LY. Synthesis and biological activity of sulfur-containing aryl-aldehyde Schiff bases. Chem-Pharm-Bull (Chemical-and-Pharmaceutical-Bulletin); 51(11); 1307-1310 (2003). 12. Pandeya-SN; Sriram-D; Nath-G; De-Clercq-E. Synthesis, antibacterial, antifungal and anti HIV activity of Schiff and Mannich bases of isatin with N-(6-chlorobenzothiazol-2-yl) thiosemicarbazide.
Indian-J-Pharm-Sci (Indian-Journal-of-Pharmaceutical-Sciences); 61(6); 358-361 (1999). 13. Jayasekhar-P; Rao-SB; Santhakumari-G. Synthesis and anti-inflammatory activity of Schiff bases of mesalazine. Indian-J-Pharm-Sci (Indian-Journal-of-Pharmaceutical-Sciences); 59(1); 8-12 (1997). 14. Mcomia ; Protective group in Organic chemistry. P-66. 15. Trivedi,P. , Undavia,N. K. ,Dave, A. M. , Bhatt,K. N and Desai ,N. C. Indian Journal of Chem . , Vol 32B(7) : 760-765 ( 1993). 16. Divakar, C. M and Nair, G. R. N. Antiulcer, antibacterial and spermicidal activities of Salanin. Indian Drugs. 38(2): 629-932 (2001).
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