# Intravenous ivermectin for sepsis

> **NIH NIH R41** · PURINE PHARMACEUTICALS, INC. · 2021 · $193,829

## Abstract

SUMMARY
 Sepsis is caused by severe infection, which results in systemic disease. Sepsis remains the leading
cause of morbidity and mortality in critically ill patients. One reason for this high morbidity and mortality is that
the treatment of sepsis relies only on supportive therapy including antibiotics and fluids and there are no FDA-
approved specific drugs to treat sepsis. Current concepts suggest that organ failure and mortality in sepsis are
caused by inappropriate regulation of the immune system. This manifests as an inability to control bacterial
growth and dissemination, and increased inflammation, processes that are interrelated and are due, in a large
part, to macrophage dysfunction. ATP is a danger-associated molecular pattern, which is released from the
intracellular into the extracellular space during infection, inflammation, and hypoxia, which are all present
during sepsis. Detection of the released ATP by P2 purinergic receptors on the surface of immune cells,
including macrophages, alerts the immune system to danger and initiates and orchestrates host immunity and
inflammation. P2 receptors fall into two classes, the ionotropic P2X (P2X1-7) receptors, and the metabotropic
P2Y (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14) receptors. ATP activation of P2X7
receptors has been implicated in killing of obligate intracellular bacteria, such as M. tuberculosis in
macrophages, but the role of P2 receptors in killing sepsis-causing extracellular bacteria is unknown. Our
preliminary data demonstrated that ATP increases the killing of sepsis-causing extracellular bacteria, such as
E. coli or S. aureus; however, this killing effect is not mediated by P2X7 receptors but instead it is mediated by
P2X4 receptors. Using intraperitoneally administered ivermectin, a positive allosteric modulator of P2X4
receptors, we demonstrated that P2X4 receptor activation protected mice against bacterial dissemination,
inflammation, and mortality during abdominal, polymicrobial sepsis in mice. Here we will test the hypothesis
that intravenously injected ivermection protects mice against sepsis-induced bacterial dissemination,
inflammation, organ injury, and mortality. To address this hypothesis, we propose two Specific Aims. In
Specific Aim 1, we will test the efficacy of ivermectin in preventing mortality in polymicrobial sepsis induced by
cecal ligation and puncture in mice. In Specific Aim 2, we will delineate the effect of ivermectin on bacterial
growth, inflammation and organ injury in sepsis. We expect that ivermectin will reduce bacterial growth,
inflammation, organ damage, and mortality in septic mice. The long-term goal of this study is to develop
ivermectin as a safe and effective treatment option for the management of patients with sepsis.

## Key facts

- **NIH application ID:** 10136360
- **Project number:** 1R41AI156935-01
- **Recipient organization:** PURINE PHARMACEUTICALS, INC.
- **Principal Investigator:** George HASKO
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $193,829
- **Award type:** 1
- **Project period:** 2021-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136360

## Citation

> US National Institutes of Health, RePORTER application 10136360, Intravenous ivermectin for sepsis (1R41AI156935-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10136360. Licensed CC0.

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