Effect of Metformin on Plasma Exposure of Rifampicin, Isoniazid, and Pyrazinamide in Patients on Treatment for Pulmonary Tuberculosis.

BACKGROUND: To evaluate the effect of metformin on the plasma levels of rifampicin, isoniazid, and pyrazinamide in patients with drug-sensitive pulmonary tuberculosis being treated with first-line antituberculosis treatment (ATT) and to assess the influence of gene polymorphisms on the metabolic pathway of metformin and plasma levels of antitubercular drugs. METHODS: Nondiabetic adults aged 18-60 years with pulmonary tuberculosis were randomized to either the standard ATT (ATT group) or ATT plus metformin (METRIF group) groups in a phase IIB clinical trial. An intensive pharmacokinetic study with blood collection at 0 hour (predosing), followed by 1, 2, 4, 6, 8, and 12 hours after dosing was conducted during the first month of treatment in a subset of 60 study participants after a minimum of 14 doses. Plasma concentrations of rifampicin, isoniazid, pyrazinamide, and metformin were measured by high-performance liquid chromatography using validated methods, and pharmacokinetic parameters and OCT1 and MATE1 gene polymorphisms were compared between the groups. RESULTS: Significant increases in the clearance of rifampicin, isoniazid, and pyrazinamide were observed in patients in the METRIF group (n = 29) compared with those in the ATT group (n = 31). The AA genotypes of the single-nucleotide polymorphism of rs2289669 (MATE1) in the METRIF group showed a significantly decreased area under the concentration-time curve to the last observation point and increased clearance of rifampicin. CONCLUSIONS: Metformin altered rifampicin and isoniazid plasma concentrations in patients receiving antituberculosis treatment for pulmonary tuberculosis with little effect on sputum conversion at the end of treatment. Studies with larger sample sizes are needed to understand host drug-drug interactions.

Healthcare Policies to Eliminate Neglected Tropical Diseases (NTDs) in India: A Roadmap.

The need for systemic healthcare policies to systematically eliminate NTDs globally and in India has been stressed for more than two decades. Yet, the present policies and the research on them do not meet the need. We present an ontological framework, a research roadmap, and a policy brief to address the gap. The ontology clearly, concisely, and comprehensively represents the combinations of diseases, the objectives regarding the diseases, the entities to address them, the outcomes sought, and the potential policy instruments to invoke. The paper explicates the state of the-policies and state of the research on policies to eliminate NTDs in India. It highlights the significant gaps in the diseases covered, balance in the objectives, comprehensiveness of policies, portfolio of outcomes, and involvement of entities. Last, it presents a set of systemic policies congruent with the ontology to systematically address the gaps. The recommendations are aligned with the present research, policies, practices, and recommendations in India and of the WHO, UN agencies, and other similar bodies. The approach can be generalized to provide roadmaps for other countries facing a similar challenge and for other diseases of similar complexity. The roadmaps, with continuous feedback and learning, can help navigate the challenge efficiently and effectively.

Yes, we have the power to end TB!

Robust efforts are essential to sustain and increase the advancements made in battling TB, as well as to tackle persistent issues that have caused the fight against the disease to be uneven. The End TB Strategy proposes that new technologies are to be developed by 2025 to encourage a quick growth in TB occurrence diminishment. This calls for a cross-sectoral focus on creating and distributing suitable medical and programmatic modernizations in a fair manner. However, many difficulties and differences still exist in the realms of research and development regarding vaccines, drugs, technical advances, and services related to TB. Therefore, priority needs to be given to overcoming these difficulties and discrepancies for a better future. On World TB Day 2023, SEAR Union, TB Alliance, the National Institute of Advanced Studies (NIAS) and Open Source Pharma Foundation (OSPF) gathered to discuss an important topic under the heading: "YES, WE HAVE THE POWER TO END TB!" With a commitment to putting the patient first and increasing their collective efforts, the organizations recognized that it is possible to make this goal a reality. The organizations involved in the discussion have declared their commitment to engaging in collaborative efforts to end TB globally. They advocate for strengthening access to TB services, controlling and preventing TB, improving surveillance and drug resistance management, and investing in research and development. Furthermore, they recognize the importance of reducing stigma and integrating patient voices in this endeavour. This Round Table serves as a framework to build on and ensure that the goal of ending TB is achievable.

GATA and Nkx factors synergistically regulate tissue-specific gene expression and development in vivo.

In vitro studies have suggested that members of the GATA and Nkx transcription factor families physically interact, and synergistically activate pulmonary epithelial- and cardiac-gene promoters. However, the relevance of this synergy has not been demonstrated in vivo. We show that Gata6-Titf1 (Gata6-Nkx2.1) double heterozygous (G6-Nkx DH) embryos and mice have severe defects in pulmonary epithelial differentiation and distal airway development, as well as reduced phospholipid production. The defects in G6-Nkx DH embryos and mice are similar to those observed in human neonates with respiratory distress syndromes, including bronchopulmonary dysplasia, and differential gene expression analysis reveals essential developmental pathways requiring synergistic regulation by both Gata6 and Titf1 (Nkx2.1). These studies indicate that Gata6 and Nkx2.1 act in a synergistic manner to direct pulmonary epithelial differentiation and development in vivo, providing direct evidence that interactions between these two transcription factor families are crucial for the development of the tissues in which they are co-expressed.

Hop functions downstream of Nkx2.1 and GATA6 to mediate HDAC-dependent negative regulation of pulmonary gene expression.

Hop is an unusual homeodomain protein that was first identified in the developing heart where it functions downstream of Nkx2.5 to modulate cardiac gene expression. Hop functions through interactions with histone deacetylase (HDAC) 2 to mediate repression of cardiac-specific genes, and recent studies show that HDAC activity and HDAC2 expression are decreased in people with chronic obstructive pulmonary disease. Here, we show that Hop is expressed in airway epithelium coincident with HDAC2, and expression is induced by the combination of dexamethasone and cAMP in parallel with induction of surfactant protein gene expression. Hop functions in the developing pulmonary airway, acting downstream of Nkx2.1 and GATA6, to negatively regulate surfactant protein expression. Loss of Hop expression in vivo results in defective type 2 pneumocyte development with increased surfactant production and disrupted alveolar formation. Thus Hop represents a novel regulator of pulmonary maturation that is induced by glucocorticoids to mediate functionally important HDAC-dependent negative feedback regulation.

LMCD1/Dyxin is a novel transcriptional cofactor that restricts GATA6 function by inhibiting DNA binding.

The activity of GATA factors is regulated, in part, at the level of protein-protein interactions. LIM domain proteins, first defined by the zinc finger motifs found in the Lin11, Isl-1, and Mec-3 proteins, act as coactivators of GATA function in both hematopoietic and cardiovascular tissues. We have identified a novel GATA-LIM interaction between GATA6 and LMCD1/dyxin. The LIM domains and cysteine-rich domains in LMCD1/dyxin and the carboxy-terminal zinc finger of GATA6 mediate this interaction. Expression of LMCD1/dyxin is remarkably similar to that of GATA6, with high-level expression observed in distal airway epithelium of the lung, vascular smooth muscle, and myocardium. In contrast to other GATA-LIM protein interactions, LMCD1/dyxin represses GATA6 activation of both lung and cardiac tissue-specific promoters. Electrophoretic mobility shift and chromatin immunoprecipitation assays show that LMCD1/dyxin represses GATA6 function by inhibiting GATA6 DNA binding. These data reveal an interaction between GATA6 and LMCD1/dyxin and demonstrate a novel mechanism through which LIM proteins can assert their role as transcriptional cofactors of GATA proteins.