Izoniazid patrí k antituberkulotikám prvej línie. Uplatnenie nachádza v liečbe aktívnej aj latentnej tuberkulózy. Je súčasťou kombinovaných režimov, pri preventívnej liečbe tuberkulózy sa však podáva aj v monoterapii. Napriek tomu, že k zvýšeniu sérovej aktivity aminotransferáz dochádza počas terapie izoniazidom relatívne často, rozvoj symptomatickej hepatitídy je podľa odbornej literatúry zriedkavý. V prezentovanej kazuistike opisujeme prípad pacientky, u ktorej sa v priebehu preventívnej liečby latentnej tuberkulózy rozvinulo izoniazidom navodené poškodenie pečene klinicky sprevádzané rozvojom ikteru. V článku tiež sumarizujeme aktuálne poznatky týkajúce sa rizikových faktorov, patogenézy a incidencie hepatotoxicity popísanej počas užívania tohto antituberkulotika. Zároveň ilustrujeme proces diagnostiky liekmi indukovaného poškodenia pečene v podmienkach klinickej praxe s využitím aktualizovaného stratifikačného skórovacieho systému RUCAM.
Isoniazid belongs to the first line antituberculosis drugs and can be used for the treatment of both active and latent tuberculosis infections. It is a part of combined regimens, for the preventive treatment of tuberculosis isoniazid can be used in monotherapy as well. Even though elevations in serum aminotransferases levels during isoniazid therapy are seen frequently, the development of symptomatic hepatitis is rare, according to specialised literature. This article describes a case of a patient who developed drug-induced liver injury accompanied by jaundice during the isoniazid preventive treatment of tuberculosis. It also provides a summary of the currently known risk factors, pathogenesis, and incidence of hepatotoxicity observed throughout therapy with this antituberculosis drug. We also illustrate the process of diagnosing drug--induced liver injury in clinical practice settings with the utilisation of the updated RUCAM score.
- MeSH
- antituberkulotika škodlivé účinky terapeutické užití MeSH
- diferenciální diagnóza MeSH
- isoniazid * škodlivé účinky terapeutické užití MeSH
- latentní tuberkulóza farmakoterapie prevence a kontrola MeSH
- lékové postižení jater * diagnostické zobrazování etiologie farmakoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nežádoucí účinky léčiv MeSH
- žloutenka diagnóza etiologie terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Tuberculosis is the number one killer of infectious diseases caused by a single microbe, namely Mycobacterium tuberculosis (Mtb). The success rate of curing this infection is decreasing due to emerging antimicrobial resistance. Therefore, novel treatments are urgently needed. As an attempt to develop new antituberculars effective against both drugs-sensitive and drug-resistant Mtb, we report the synthesis of a novel series inspired by combining fragments from the first-line agents isoniazid and pyrazinamide (series I) and isoniazid with the second-line agent 4-aminosalicylic acid (series II). We identified compound 10c from series II with selective, potent in vitro antimycobacterial activity against both drug-sensitive and drug-resistant Mtb H37Rv strains with no in vitro or in vivo cytotoxicity. In the murine model of tuberculosis, compound 10c caused a statistically significant decrease in colony-forming units (CFU) in spleen. Despite having a 4-aminosalicylic acid fragment in its structure, biochemical studies showed that compound 10c does not directly affect the folate pathway but rather methionine metabolism. In silico simulations indicated the possibility of binding to mycobacterial methionine-tRNA synthetase. Metabolic study in human liver microsomes revealed that compound 10c does not have any known toxic metabolites and has a half-life of 630 min, overcoming the main drawbacks of isoniazid (toxic metabolites) and 4-aminosalicylic acid (short half-life).
- MeSH
- antituberkulotika chemie MeSH
- isoniazid farmakologie MeSH
- kyselina aminosalicylová * farmakologie MeSH
- lidé MeSH
- methionin MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium tuberculosis * MeSH
- myši MeSH
- tuberkulóza * farmakoterapie mikrobiologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The elimination of most drugs based on liver/renal excretion; making liver and kidneys the commonest target organ for exposure to toxic materials. Long-term use of drugs surpassed the effect and aggravate the toxicity. Tuberculosis (TB) is chronic disease with long-term therapy and the deleterious impact of antitubelculosis is certain. Various pharmacokinetic manoveuors were proposed to avoid the potential harmful effect of TB therapy. The present study aimed at mitigating the destructive effects of TB therapy using propolis. To do so, rats were exposed to isoniazid or rifampicin or a combination of them in groups of 8 rats each for a period of 8-weeks these groups were matched with similar group with a propolis ad-on therapy. These results were compared to propolis-free negative control group and positive propolis-treated group. The histological and laboratory findings confirmed that isoniazid or rifampicin or a combination of them jeopardized hepatorenal function and induced deleterious damage. However, isoniazid has shown more intensive deleterious effect compared to rifampicin. Nonetheless, propolis restore the quasi-equilibrium status for kidney and liver via restoring its normal architecture and functionality. To sum up, the potential defect of anti-TB was restored via using propolis as add-on therapy, we do advise using propolis as an adjuvant TB therapy in critically-ill and clinical cases required long-term TB therapy.
- MeSH
- antituberkulotika antagonisté a inhibitory škodlivé účinky MeSH
- biochemická analýza krve metody přístrojové vybavení MeSH
- biomedicínský výzkum MeSH
- histologické techniky MeSH
- isoniazid antagonisté a inhibitory škodlivé účinky MeSH
- krysa rodu rattus * MeSH
- mikroskopie MeSH
- modely u zvířat MeSH
- nemoci jater prevence a kontrola MeSH
- nemoci ledvin prevence a kontrola MeSH
- nežádoucí účinky léčiv farmakoterapie terapie MeSH
- propolis * farmakologie MeSH
- rifampin antagonisté a inhibitory škodlivé účinky MeSH
- Check Tag
- krysa rodu rattus * MeSH
- Geografické názvy
- Irák MeSH
A series of eleven benzylated intermediates and eleven target compounds derived from salicylanilide were tested against Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 as reference strains and against three clinical isolates of methicillin-resistant S. aureus (MRSA) and three isolates of vancomycin-resistant E. faecalis. In addition, the compounds were evaluated against Mycobacterium tuberculosis H37Ra and M. smegmatis ATCC 700084. The in vitro cytotoxicity of the compounds was assessed using the human monocytic leukemia cell line THP-1. The lipophilicity of the prepared compounds was experimentally determined and correlated with biological activity. The benzylated intermediates were found to be completely biologically inactive. Of the final eleven compounds, according to the number of amide groups in the molecule, eight are diamides, and three are triamides that were inactive. 5-Chloro-2-hydroxy-N-[(2S)- 4-(methylsulfanyl)-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino}butan-2-yl]benzamide (3e) and 5-chloro-2-hydroxy-N-[(2S)-(4-methyl-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino)pentan-2-yl)benzamide (3f) showed the broadest spectrum of activity against all tested species/isolates comparable to the used standards (ampicillin and isoniazid). Six diamides showed high antistaphylococcal activity with MICs ranging from 0.070 to 8.95 μM. Three diamides showed anti-enterococcal activity with MICs ranging from 4.66 to 35.8 μM, and the activities of 3f and 3e against M. tuberculosis and M. smegmatis were MICs of 18.7 and 35.8 μM, respectively. All the active compounds were microbicidal. It was observed that the connecting linker between the chlorsalicylic and 4-CF3-anilide cores must be substituted with a bulky and/or lipophilic chain such as isopropyl, isobutyl, or thiabutyl chain. Anticancer activity on THP-1 cells IC50 ranged from 1.4 to >10 μM and increased with increasing lipophilicity.
- MeSH
- ampicilin MeSH
- anilidy MeSH
- antibakteriální látky farmakologie MeSH
- benzamidy MeSH
- isoniazid MeSH
- lidé MeSH
- methicilin rezistentní Staphylococcus aureus * MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium tuberculosis * MeSH
- peptidomimetika * MeSH
- salicylanilidy farmakologie MeSH
- vankomycin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The emergence and spread of resistant tuberculosis (TB) pose a threat to public health, so it is necessary to diagnose the drug-resistant forms in a clinically short time frame and closely monitor their transmission. In this study, we carried out a first whole genome sequencing (WGS)-based analysis of multidrug resistant (MDR) M. tuberculosis strains to explore the phylogenetic lineages diversity, drug resistance mechanisms, and ongoing transmission chains within the country. In total, 65 isolates phenotypically resistant to at least rifampicin and isoniazid collected in the Czech Republic in 2005-2020 were enrolled for further analysis. The agreement of the results obtained by WGS with phenotypic drug susceptibility testing (pDST) in the determination of resistance to isoniazid, rifampicin, pyrazinamide, streptomycin, second-line injectables and fluoroquinolones was more than 80%. Phylogenetic analysis of WGS data revealed that the majority of MDR M. tuberculosis isolates were the Beijing lineage 2.2.1 (n = 46/65; 70.8%), while the remaining strains belonged to Euro-American lineage. Cluster analysis with a predefined cut-off distance of less than 12 single nucleotide polymorphisms between isolates showed 19 isolates in 6 clusters (clustering rate 29.2%), located mainly in the region of the capital city of Prague. This study highlights the utility of WGS as a high-resolution approach in the diagnosis, characterization of resistance patterns, and molecular-epidemiological analysis of resistant TB in the country.
- MeSH
- antituberkulotika farmakologie terapeutické užití MeSH
- fylogeneze MeSH
- genotyp MeSH
- isoniazid MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- mnohočetná bakteriální léková rezistence genetika MeSH
- multirezistentní tuberkulóza * diagnóza farmakoterapie epidemiologie MeSH
- mutace MeSH
- Mycobacterium tuberculosis * MeSH
- rifampin MeSH
- sekvenování celého genomu metody MeSH
- tuberkulóza * farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
BACKGROUND: There is an urgent need for new antitubercular compounds. Modification of antimycobacterial isonicotinohydrazide at hydrazide N2 provided antimycobacterial active compounds. OBJECTIVE: Combining this scaffold with various aliphatic amines that are also frequently present in antitubercular compounds, we have designed, synthesized, and evaluated twenty-three N- (cyclo)alkyl-2-(2-isonicotinoylhydrazineylidene)propanamides and their analogues as potential antimycobacterial compounds. By increasing lipophilicity, we intended to facilitate the penetration of mycobacteria's highly impermeable cell wall. METHODS: The target amides were prepared via condensation of isoniazid and pyruvic acid, followed by carbodiimide-mediated coupling with yields from 35 to 98 %. The compounds were screened against Mycobacterium tuberculosis H37Rv and two nontuberculous mycobacteria (M. avium, M. kansasii). RESULTS: All the derivatives exhibited low minimum inhibitory concentrations (MIC) from ≤0.125 and 2 μM against M. tuberculosis and nontuberculous mycobacteria, respectively. The most active molecules were substituted by a longer n-alkyl from C8 to C14. Importantly, the compounds showed comparable or even several-fold lower MIC than parent isonicotinohydrazide. Based on in silico predictions, a vast majority of the derivatives share suitable physicochemical properties and structural features for drug-likeness. CONCLUSION: Presented amides are promising antimycobacterial agents.
Tuberculosis diagnosis and drug susceptibility testing (DST) are considered a priority for prompt initiation of effective therapy, increasing the chance of cure, decreasing the development of resistance, and reducing transmission. Aim: Our objective was to evaluate currently applied diagnostic tools for tuberculosis including microscopic examination, GeneXpert, culture, and microscopic observation drug susceptibility (MODS) assay, investigating MODS assay usage for second line DST against culture based methods. Material and Methods: In this study the 120 sputum samples collected from suspected cases were over one year duration from December 2018 to January 2020. The samples were subjected to ZN microscopic examination, GeneXpert, MODS assay, and culture for detection of mycobacteria. Moreover, resistance to 5 drugs: isoniazid, rifampicin, ofloxacin, levofloxacin, and amikacin were tested using MODS against the proportion method. Results: The sensitivity and specificity of the MODS assay were similar culture method with the advantage of obtaining the results in a median time of 10.7 days. Whereas the specificity of ZN and GeneXpert was high among untreated cases and decreased in subjects with a history of treatment. Monoresistance was the most common form of resistance detected among new cases followed by multidrug resistance, with a categorical agreement between the two methods above 90% for all tested drugs. Conclusions: MODS assay is an attractive option once standardized for second line susceptibility testing and GeneXpert assay is of high sensitivity for rapid detection of MTB and RIF resistance especially in treatment naive cases.
Tuberculosis is a dreaded disease, which causes innumerable death worldwide. The emergence of drug resistance strains makes the situation devastating. Therefore, for better management of public health, it is mandatory to search for new anti-mycobacterial agents. In this context, the current study investigated two edible marine algae, Ulva lactuca and Ulva intestinalis, for the probable source of new anti-mycobacterial agents. To test the anti-mycobacterial activity, alcoholic extracts of these two algae were spotted on the Mycobacterium smegmatis lawn. Upon incubation, clear zone was observed at the spots. It indicated that these two extracts have anti-mycobacterial activity. In addition, their anti-biofilm property was also tested. It was found that both the extracts inhibit the mycobacterial biofilm development as well as they can disperse the preformed mycobacterial biofilm. Since these two are capable of dispersing preformed mycobacterial biofilm, it is possible that in the presence of either of these two extracts, isoniazid and rifampicin can kill biofilm encapsulated mycobacterium in combinatorial therapy. Consistent with the hypothesis, rifampicin and isoniazid killed mycobacteria that were present in biofilm. Thus, these two extracts augment the activity of rifampicin and isoniazid upon biofilm dispersal. Moreover, treatment of different cell lines with these two extracts exhibited no or little cytotoxic effects. Thus, these two agents have the potential to be good therapeutic agents against mycobacterial diseases.
- MeSH
- antibakteriální látky izolace a purifikace farmakologie MeSH
- biofilmy účinky léků MeSH
- buněčné linie MeSH
- isoniazid farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- mořské řasy chemie MeSH
- Mycobacterium smegmatis účinky léků MeSH
- rifampin farmakologie MeSH
- rostlinné extrakty izolace a purifikace farmakologie MeSH
- synergismus léků MeSH
- Ulva chemie MeSH
- viabilita buněk MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- antituberkulotika * farmakologie terapeutické užití MeSH
- bakteriální proteiny * účinky léků MeSH
- ethambutol farmakologie terapeutické užití MeSH
- isoniazid farmakologie terapeutické užití terapeutické užití MeSH
- katalasa * účinky léků MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- multirezistentní tuberkulóza * genetika MeSH
- Mycobacterium tuberculosis * izolace a purifikace účinky léků MeSH
- rifampin farmakologie terapeutické užití MeSH
- streptomycin farmakologie terapeutické užití MeSH
- tuberkulóza * epidemiologie farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- antituberkulotika * MeSH
- ethambutol aplikace a dávkování terapeutické užití MeSH
- isoniazid aplikace a dávkování terapeutické užití MeSH
- lidé MeSH
- multirezistentní tuberkulóza MeSH
- pyrazinamid aplikace a dávkování terapeutické užití MeSH
- rifampin aplikace a dávkování terapeutické užití MeSH
- streptomycin aplikace a dávkování terapeutické užití MeSH
- tuberkulóza * farmakoterapie terapie MeSH
- Check Tag
- lidé MeSH
