Arrival of Imidazo[2,1-b]thiazole-5-carboxamides: Potent Anti-tuberculosis Agents That Target QcrB.

Increasing interest in the potent anti-tuberculosis activity and the novel target (QcrB) of imidazo[1,2-a]pyridine-3-carboxamides encouraged extended structure-activity relationship studies of additional scaffolds. This study reports on the in vitro profiling of the imidazo[2,1-b]thiazole-5-carboxamides as a new promising class of anti-tuberculosis compounds endowed with nanomolar potency against replicating and drug-resistant Mycobacterium tuberculosis (Mtb) as well as low toxicity to VERO cells. Compounds 6, 16, and 17 had MIC values <10 nM and toxicity >100 µM. On-target selectivity of this series was confirmed by cross-resistance of specific QcrB mutants as well as the hypersusceptibility of a mutant with a functional gene deletion of the alternative cytochrome bd oxidase. Additionally, to demonstrate selectivity, three analogues (6, 15, 17) were broadly screened against a diverse set of eight strains of bacteria, including both Gram-positive and Gram-negative as well as six disease-causing non-tuberculosis mycobacteria. Finally, compounds 16 and 17 were found to be active in macrophages infected with Mtb.

Putting Tuberculosis (TB) To Rest: Transformation of the Sleep Aid, Ambien, and "Anagrams" Generated Potent Antituberculosis Agents.

Zolpidem (Ambien, 1) is an imidazo[1,2-a]pyridine-3-acetamide and an approved drug for the treatment of insomnia. As medicinal chemists enamored by how structure imparts biological function, we found it to have strikingly similar structure to the antitubercular imidazo[1,2-a]pyridine-3-carboxyamides. Zolpidem was found to have antituberculosis activity (MIC of 10-50 µM) when screened against replicating Mycobacterium tuberculosis (Mtb) H37Rv. Manipulation of the Zolpidem structure, notably, to structural isomers ("anagrams"), attains remarkably improved potency (5, MIC of 0.004 µM) and impressive potency against clinically relevant drug-sensitive, multi- and extensively drug-resistant Mtb strains (MIC < 0.03 µM). Zolpidem anagrams and analogues were synthesized and evaluated for their antitubercular potency, toxicity, and spectrum of activity against nontubercular mycobacteria and Gram-positive and Gram-negative bacteria. These efforts toward the rational design of isomeric anagrams of a well-known sleep aid underscore the possibility that further optimization of the imidazo[1,2-a]pyridine core may well "put TB to rest".

Relative value units and cost analysis, Part 3 of 4.

In recent years, the interest in relative value unit (RVU) cost analysis has been on the rise. Why all the excitement? RVU cost analysis places the knowledge, and therefore the power, in the hands of the administrator to negotiate revenues, analyze expenditures, and control costs. Cost analysis at the per (relative)-unit level allows for procedure profitability (or loss) analysis, setting internal fee schedules based on costs, contract negotiation based on RVU cost and utilization, equitable provider compensation packages based on productivity and overhead coverage, and tracking ancillary and referral utilization risks. In short, RVU cost accounting uses the Resource-Based Relative Value Scale (RBRVS) instead of stopwatches and clipboards when measuring clinical costs and activity.

Relative value units and productivity: Part 2 of 4.

The initial article in this series (Volume 17, No. 5: 225-228) discussed relative value unit (RVU) basics and touched on some of the more practical applications of RVUs for managing a medical practice. This article addresses how RVUs differ from encounters and fees in terms of measuring provider productivity and resource consumption. RVUs empower practice administrators to objectively measure and quantify a medical practice's physician productivity and performance data versus traditional productivity measures such as office visits, net charges, net collections, etc. The Resource-Based Relative Value Scale (RBRVS) RVU work component is specifically designed to measure physician (and midlevel provider) effort and the degree of independent decision-making skill required for performing a procedure; therefore, productivity is directly linked to provider coding.

Relative value units: from A to Z (Part I of IV).

Relative value units (RVUs), originally developed as a physician payment mechanism, have expanded into a valuable practice management tool that allows common denominator analyses and per-unit comparisons for both clinical productivity and expense data. Use of RVUs in practice management falls into three broad categories: productivity, cost, and benchmarking. These will be covered in a series of four articles. RVU analysis can be readily applied to strategic planning, resource allocation, budgeting, provider compensation, cost-based fee schedules, payer analysis, contract review and maintenance, per-procedure profitability analysis, etc. Exactly what are RVUs? Where did they come from? How do they differ from encounters and fees in terms of measuring provider productivity? How can they be used to increase cost-effectiveness and maximize productivity within medical practices? This initial article discusses RVU basics and sets the groundwork for the series.