ITPP

ITPP (myo-inositol trispyrophosphate, also coded OXY111A) is a small synthetic molecule: a myo-inositol ring whose oxygens are closed into three cyclic pyrophosphate bridges. It is not a peptide and holds no amino acids. The family was described in a 2005 report: nine salts were prepared, all bound hemoglobin, all crossed the red cell membrane to some degree, and the oxygen dissociation curve shifted toward higher oxygen partial pressures (Fylaktakidou et al., 2005).

Entry into red cells runs through the band 3 anion transporter, which makes uptake selective for erythrocytes (Duarte et al., 2010).

Its formula, weight and CAS number match PubChem CID 10439981, the record for the free acid: a neutral molecule with six acidic P-OH groups, not a salt.

Published work falls into six areas, each named with its model. Nearly all is blood, cell or rodent data; the one early-phase human study is research history.

Hemoglobin allostery and oxygen release in red cells

ITPP lowers hemoglobin's affinity for oxygen, so red cells give up more at a given oxygen tension. In free hemoglobin and whole blood, the oxygen dissociation curve moved to higher oxygen partial pressures (Fylaktakidou et al., 2005). In human red cells, anion transport inhibitors blocked uptake, and intracellular levels peaked at 5.5 millimolar (Duarte et al., 2010). An independent group measured P50 by oxygen electrode after one hour at 37°C: it rose with ITPP concentration and with falling pH, with nothing measurable at pH 7.6, so the Bohr effect held (Evans et al., 2021).

Oxygen delivery and exercise capacity endpoints in mice

In normal mice, intraperitoneal ITPP at 0.5 to 3 g/kg raised P50, the oxygen tension at which hemoglobin is half saturated, by up to 31%, and maximal exercise capacity by 57 plus or minus 13%; in transgenic mice with severe heart failure from cardiac Gaq overexpression, by 63 plus or minus 7%.

Myocardial HIF-1 alpha messenger RNA fell, while myocyte contractility and arterial pressure did not change (Biolo et al., 2009). Several authors disclosed stock in the patent holder, NormOxys, and three were employed by it. Later papers carry their own declarations: the phase Ib report and a 2026 zebrafish report name NormOxys founders, and a 2019 rodent report lists two authors with a NormOxys affiliation.

Tumor hypoxia, vessel normalization and radiation in rodent models

In syngeneic mouse melanoma and breast carcinoma, ITPP raised tumor oxygen tension and blood flow, suppressed hypoxia-inducible factors and activated endothelial PTEN, normalizing vessels and reducing metastasis (Kieda et al., 2013). In two orthotopic mouse models of colorectal liver metastasis it blocked the hypoxic response, an effect lost in mice pretreated with a Hif activator, and FOLFOX plus ITPP extended survival by more than 140% over FOLFOX alone (Limani et al., 2016).

Radiation work is mixed. ITPP alone did not change tumor growth, but before a single large radiation fraction it reduced growth and raised gamma-H2AX foci, only in that order (Grgic et al., 2021). Across six rodent models it raised tumor oxygen tension, with reoxygenation lasting at least four days after 2 g/kg once daily for two days, yet with radiation it changed nothing in rhabdomyosarcomas and split outcomes in 9L gliomas (Tran et al., 2019).

Two reports are negative: in mice with intracranial GL261 glioblastoma, radiation extended survival, ITPP did not, and the combination looked blunted (Iyengar and Schwartz, 2017); in zebrafish pancreatic xenografts the authors found no major effect, attributing that to a model without a hypoxic microenvironment (Abou Khouzam et al., 2026).

Cardiac and pulmonary models in rats

The cardiovascular work centers on oxygen tension inside the right ventricle. Rats received monocrotaline to induce pulmonary hypertension, or saline, then ITPP or placebo for five weeks. ITPP lowered mortality and relieved intramyocardial right ventricular hypoxia, measured with a fluorescent probe, alongside better right ventricular function and lower wall stress, but did not change pulmonary vascular resistance or capillary density (Oknińska et al., 2024).

Human research history under the code OXY111A

Under the code OXY111A, the compound entered an open-label Ib/IIa program in people with non-resectable liver, pancreatic and biliary tumors (Limani et al., 2016). The phase Ib report covers 28 people given repeated eight-hour infusions over three weeks across eight escalating levels, then standard chemotherapy.

The authors recorded 32 compound-related toxicities, mostly hypercalcemia, reported as needing little or no intervention; the authors reported morphological disease stabilization in 52% of participants under ITPP alone, and after chemotherapy partial responses in 10% and stable disease in 60%, in an unrandomized escalation trial whose stated primary objectives were tolerability and the maximum tolerated level (Schneider et al., 2021).

Detection in doping control laboratories

ITPP is small, highly polar and poorly retained on reversed-phase columns, so chemists built dedicated assays. A validated hydrophilic interaction chromatography high-resolution mass spectrometry method confirms it in human urine, at reported limits of 15 ng/mL screening and 1 ng/mL confirmation (Görgens et al., 2014).