Something Old, Something New: Ion Channel Blockers as Potential Anti-Tuberculosis Agents

Tuberculosis (TB) remains a challenging global health concern and claims more than a million lives every year. We lack an effective vaccine and understanding of what constitutes protective immunity against TB to inform rational vaccine design. Moreover, treatment of TB requires prolonged use of multi-drug regimens and is complicated by problems of compliance and drug resistance. While most Mycobacterium tuberculosis (Mtb) bacilli are quickly killed by the drugs, the prolonged course of treatment is required to clear persistent drug-tolerant subpopulations. Mtb’s differential sensitivity to drugs is, at least in part, determined by the interaction between the bacilli and different host macrophage populations. Therefore, to design better treatment regimens for TB, we need to understand and modulate the heterogeneity and divergent responses that Mtb bacilli exhibit within macrophages. However, developing drugs de-novo is a long and expensive process. An alternative approach to expedite the development of new TB treatments is to repurpose existing drugs that were developed for other therapeutic purposes if they also possess anti-tuberculosis activity. There is growing interest in the use of immune modulators to supplement current anti-TB drugs by enhancing the host’s antimycobacterial responses. Ion channel blocking agents are among the most promising of the host-directed therapeutics. Some ion channel blockers also interfere with the activity of mycobacterial efflux pumps. In this review, we discuss some of the ion channel blockers that have shown promise as potential anti-TB agents.

Ion Channels as Therapeutic Targets for Viral Infections: Further Discoveries and Future Perspectives

Ion channels play key roles in almost all facets of cellular physiology and have emerged as key host cell factors for a multitude of viral infections. A catalogue of ion channel-blocking drugs have been shown to possess antiviral activity, some of which are in widespread human usage for ion channel-related diseases, highlighting new potential for drug repurposing. The emergence of ion channel–virus interactions has also revealed the intriguing possibility that channelopathies may explain some commonly observed virus induced pathologies. This field is rapidly evolving and an up-to-date summary of new discoveries can inform future perspectives. We herein discuss the role of ion channels during viral lifecycles, describe the recently identified ion channel drugs that can inhibit viral infections, and highlight the potential contribution of ion channels to virus-mediated disease.

Tamoxifen reduces inflammatory infiltration of neutrophils in the airways

ABSTRACTTamoxifen is a drug of choice for treatment of breast cancer but it has also been reported to bear anti-inflammatory activity. Previously, we have observed that tamoxifen treatment successfully reduced inflammation in horses affected by equine asthma syndrome. More notorious, tamoxifen was effective at reducing the infiltration of neutrophils in the inflamed airways by a mechanism that increases efferocytosis, allowing the resolution of inflammation. Due to the emerging increase in patients with chronic inflammatory lung diseases, there is an urgent need for therapies that help reduce airway inflammation. Thus we tested the effect of tamoxifen on airway neutrophil infiltration by using three different mouse models for acute and chronic inflammation of the lung. We found that the drug was able to produce a significant reduction in neutrophils in all scenarios. Ussing chamber experiments demonstrated that tamoxifen has no effect on fluid secretion and absorption, discarding a possible reduction in mucociliary clearance due to the known ion-channel blocking effects of tamoxifen. Since this drug has been largely used in human medicine, tamoxifen might be a “low hanging fruit” for a novel anti-inflammatory therapy for airway diseases characterized by neutrophilic inflammation.

Cardiac toxicity predictions: Safety pharmacologists correlate with the CiPA model

There has been a lot of interest and publicity regarding the use of a complex biophysical model within drug development for predicting the TdeP risk of new compounds. Throughout the development of the complex model numerous groups have shown that a simple linear mechanistic model explains the predictive behaviour of complex mechanistic models. That is the input-output relationship is almost linear even when complex kinetic assays are used. We hypothesized that given this linear relationship that scientist would be able to predict the outcome of the biophysical model. The objective of this pilot study was to assess the feasibility of such an analysis but also assess the initial degree of correlation. A set of 15 compounds with diverse ion-channel blocking against 4 ion-channel currents, IKr, ICaL, INa and INaL, was generated. Safety pharmacologists across numerous companies were approached and asked to categorize the TdeP risk of these compounds using only the % block depicted via a bar chart into one of 3 categories: Risk, No-risk or Unsure. 12 scientists participated in the study, of which 11 correlated strongly with the model (11 person ROC AUC range: 0.86-1, 7 scientists had a value >0.9). The combined prediction of all scientists also correlated strongly with the model. These results highlight that the linear input-output relationship can indeed be predicted by the scientist. A future study exploring the degree of correlation with a wider group of scientists and wider set of compounds would be required to get a more precise estimate of the correlation. We hope this initial exploratory study will encourage the community to pursue this idea.

Lignocaine’s substantial role in COVID-19 management: potential remedial and therapeutic implications

Background: The outbreak caused by SARS CoV-2 of the recent coronavirus disease-2019 (COVID-19) has been marked as a public health concern with a significant mortality at the global level. Lignocaine a common anesthetic agent being used for pain free surgeries for over a long period of time has expressed extensive characteristic of being an anti-inflammatory, antibacterial, direct spasmolytic, ion channel blocking and repolarization agent. We did a literature review Methodology: Currently compiled over-view has for the first time evaluated the probable curative and therapeutic role of nebulized lignocaine drug against SARS CoV-2 by utilization of PubMed, MEDLINE, NHS Evidence and Web of Science databases. Results: With evidence of nebulized lignocaine being used successfully in respiratory illness before and the established role of low concentration lignocaine as ion channel repolarization agent, we try to interpret and deduce the possible implication of nebulized lignocaine as possible therapeutic agent and a potential cure against SARS-CoV-2 caused respiratory illness by acting as an anti-inflammatory agent during SARS-CoV-2 caused acute lung injury and also possibly as an antiviral drug. Conclusion: By the virtue of possessing anti-inflammatory effect and potential antiviral effects, nebulized lignocaine can be a breakthrough in the management of the current COVID-19 pandemic. Citation: Malik NA, Lignocaine’s substantial role in COVID-19 management: potential remedial and therapeutic implications. Anaesth. pain & intensive care 2019;23(1):84-91 Received: 29 March 2020; Reviewed & Accepted: 5 April 2020;

Variation of the Spiking Dynamics of a Hodgkin-Huxley Neuron with an Electrical Autaptic Connection Under Ion Channel Blocking

In this paper, we investigate how the blockage of potassium and sodium ion channels embedded in membranes affects the spiking dynamics of a Hodgkin-Huxley neuron model owing autaptic connection. We consider an electrical autapse expressed by its coupling strength and delay time. It is found that the spiking behavior of the neuron becomes more ordered with the increment of autaptic conductance regardless of the ion channel block level. Furthermore, it is obtained that the blockage of potassium and sodium ion channels influences differently to the spiking regularity of the neuron. Potassium ion channel blockage promotes regularity, whereas sodium ion channel blockage destroys.