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Clinical Pharmacology of the Anti-Tuberculosis Drugs
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Gerry Davies, Charles Peloquin
para-Aminosalicylic acid (PAS) is a poorly water-soluble weak acid (log P 0.83, pKa 2.19–3.68, MW 153.14). It is a synthetic structural analog of para-aminobenzoic acid. PAS is a prodrug activated by the hydropteroate and dihydrofolate synthases and inhibiting dihydrofolate reductase,167 though it has also been suggested that it may interfere with mycobacterial iron uptake.168 Wild-type MIC99s range from 0.12 to 4 μg/mL.169 Resistance is mediated by mutations in the thyA locus in about 30% of isolates and folC and ribD in vitro.5
Mycotic Keratitis
Published in Mahendra Rai, Marcelo Luís Occhiutto, Mycotic Keratitis, 2019
Mahendra Rai, Avinash P. Ingle, Indarchand Gupta, Pramod Ingle, Priti Paralikar, Marcelo Luís Occhiutto
The effective management of MK is a major concern. Moreover, the delay in diagnosis and unavailability of potential antifungal agents is mostly responsible for the poor outcome. However, in the last decade, considerable research efforts have been made by the scientific community towards the development of new techniques for rapid diagnosis of MK and efficient therapeutic and pharmacological treatments (Maharana et al. 2016). Despite the availability of some topical and systemic antifungal agents and adjuvant surgery like corneal transplantation, it is difficult to treat MK. Thomas and Kaliamurthy (2013) made the Cochrane Database systematic review of medical interventions for MK and analyzed nine randomized controlled trials which were performed on 568 MK patients, who were subjected to randomized treatments of different antifungal agents (i.e., 1% topical itraconazole versus 1% topical itraconazole and oral itraconazole, voriconazole 1% versus natamycin 5%). Further, from the various studies including this report, it was proposed that there is no antifungal drug, or combination of drugs very effective in the management of MK. Moreover, the new triazole, Posaconazole is recently used as active broad-spectrum antifungal agent against various causative agents of MK such as Candida species, Cryptococcus neoformans, Aspergillus species, Zygomycetes, and endemic fungi. Chemically it is a synthetic structural analogue of itraconazole. It helps in the management of MK by blocking of the fungal cell wall ergosterol synthesis (Torres et al. 2005, Prajna et al. 2010).
Mechanisms of Resistance to Antineoplastic Drugs
Published in Robert I. Glazer, Developments in Cancer Chemotherapy, 2019
Philip J. Vickers, Alan J. Townsend, Kenneth H. Cowan
In recent years, studies of the mechanisms of cellular resistance to antineoplastic drugs have yielded information which will dramatically alter our understanding of carcinogenesis and our approach to chemotherapy. First, these studies have helped to clarify the sites and mechanisms of action of drugs whose cytotoxic actions were previously only poorly understood. Such information is already helping in the rational design of chemotherapeutic regimens and structural analogs of dfugs in order to optimize clinical efficacy. Second, as our understanding of the mechanisms by which cells become resistant to drugs becomes clearer, it may be possible to design specific therapies to overcome or block particular mechanisms of resistance. Third, the characteristics of certain proteins now known to be crucial to certain mechanisms of resistance may be taken advantage of in order to specifically attack drug-resistant populations of cells (e.g., immunotoxins targeted to P-glycoprotein). Finally, while the striking analogies between MDR and chemical carcinogenesis raise questions regarding the suitability of standard chemotherapy regimens for the treatment of certain cancers, they also suggest novel approaches (e.g., inhibition of P-glycoprotein or specific GSTs) which may prove useful in the therapy of those cancers.
A review on the pharmacological properties, toxicological characteristics, pathogenic mechanism and analytical methods of aristolochic acids
Published in Toxin Reviews, 2021
Miaomiao Zhang, Haiyan Liu, Yamei Han, Ligai Bai, Hongyuan Yan
AAs are a kind of nitrophenanthrene carboxylic acids, mainly including AA-I, AA-II, AA-C, AA-D and so on (Figure 1) (Yuan et al. 2007). The carbon skeleton of AAs is same, except that the carboxyl group, the nitro group and the methoxy group are different in position and quantity. Among the AAs, the main toxic components are AA-I and AA-II, which are classified as class I (human) carcinogens by the International Agency for Research on Cancer (IARC) (Kathuria et al. 2015, Chan et al. 2016). They can cause UUC, tumors in multiple organs, testicular toxicity, gastric toxicity and ovarian toxicity and AAN. AA-I and AA-II are believed to be the causes of nephrotoxicity and carcinogenesis (Michl et al. 2016), and it is found that AA-I is more toxic than AA-II. Other structural analogs are either less toxic or nontoxic (Balachandran et al. 2005). These compounds are widely distributed in nature, especially in Chinese herbs of the Aristolochiaceae family of plants. There are more than 200 kinds of Chinese herbal medicines containing AAs, including: Caulis Aristolochia manshuriensis, Herba Aristolochiae, Radix Aristolochia fangchi, Asarum heterotropoides, Fructus Aristolochiae, Radix Aristolochiae, Aristolochia mollissima Hance, Aristolochia cinnabarina and so on.
Berberine and its structural analogs have differing effects on functional profiles of individual gut microbiomes
Published in Gut Microbes, 2020
Leyuan Li, Lu Chang, Xu Zhang, Zhibin Ning, Janice Mayne, Yang Ye, Alain Stintzi, Jia Liu, Daniel Figeys
Several studies have suggested that BBR’s structural analogs could have similar or improved functions.23 For example, studies have shown that BBR analogs also increase the activity of the low-density-lipoprotein receptor.24 Two BBR analogs were found to be good acetylcholinesterase inhibitors and more potent than BBR as radical scavengers.25 Three synthesized BBR derivatives were found to induce a stronger effect of cell cycle arrest and cell death through apoptosis.26 Moreover, a study reported the hypoglycemic activity of modified BBR.27 BBR is known to have mild antibacterial activity,28 and similar antibacterial activity of its analogs was reported.29 However, how the BBR analogs modulate the human gut microbiome is unexplored.
In silico insights into the identification of potential novel angiogenic inhibitors against human VEGFR-2: a new SAR-based hierarchical clustering approach
Published in Journal of Receptors and Signal Transduction, 2018
Kranthi Kumar Konidala, Uma Devi Bommu, Neeraja Pabbaraju
SBDD approaches were utilized as esteemed part of novel VEGFR-2 domain inhibitors invention through several computational systems biology tools. Initially, lead optimization approaches were established to develop a seed structure library of pyrrolopyrimidine (reference drug) associated structural analogs. Structural analogs were screened from the PubChem database with 90% of the Tanimoto coefficient structural similarity. Structural conflicts of predicted compounds were relaxed by energy minimization method with the CHARMM22 force field and topology parameters acquired from SwissParam tool, and optimized by using the OpenBable module in PyRx program. A total of one hundred forty-two lead scaffolds were optimally charged and aligned as a spreadsheet for docking. All leads were commonly consists of A, C, F, OA, N, and HD atoms as AutoDock elements with adaptable torsional degrees of freedom (Torsional-DOF) (Supplemental Table S1).