A Phase I, Single-Center, Randomized, Single-Blind, Placebo-Controlled, Single-Dose, Dose-Escalation Study to Evaluate the Tolerability, Safety, and Pharmacokinetics of an Intravenous Infusion of INO-4885 Administered to Healthy Adult Male Volunteers – Part 3

Start Date17 Aug 2008

Sponsor / Collaborator

Inotek Pharmaceuticals Corp.

100 Clinical Results associated with INO-4885

100 Translational Medicine associated with INO-4885

100 Patents (Medical) associated with INO-4885

Literatures (Medical) associated with INO-4885

01 Dec 2019·Intensive Care Medicine Experimental

Peroxynitrite decomposition catalyst reduces vasopressin requirement in ovine MRSA sepsis

Article

Author: Herndon, David N ; Zeng, Yaping ; Niimi, Yosuke ; DeWitt, Douglas S ; Prough, Donald S ; Fukuda, Satoshi ; Enkhbaatar, Perenlei ; Lopez, Ernesto ; Fujiwara, Osamu

AbstractBackgroundSepsis is one of the most frequent causes of death in the intensive care unit. Host vascular hypo-responsiveness to vasopressors during septic shock is one of the challenging problems. This study tested the hypothesis that adjunct therapy with peroxynitrite decomposition catalyst (WW-85) would reduce arginine vasopressin (AVP) requirements during sepsis resuscitation, using ovine sepsis model.MethodsThirteen adult female Merino sheep, previously instrumented with multiple vascular catheters, were subjected to “two-hit” (cotton smoke inhalation and intrapulmonary instillation of live methicillin-resistantStaphylococcus aureus; 3.5 × 1011colony-forming units) injury. Post injury, animals were awakened and randomly allocated to the following groups: (1) AVP: injured, fluid resuscitated, and titrated with AVP,n = 6 or (2) WW-85 + AVP: injured, fluid resuscitated, treated with WW-85, and titrated with AVP,n = 7. One-hour post injury, a bolus intravenous injection of WW-85 (0.1 mg/kg) was followed by a 23-h continuous infusion (0.02 mg/kg/h). Titration of AVP started at a dose of 0.01 unit/min, when mean arterial pressure (MAP) decreased by 10 mmHg from baseline, despite aggressive fluid resuscitation, and the rate was further adjusted to maintain MAP. After the injury, all animals were placed on a mechanical ventilator and monitored in the conscious state for 24 h.ResultsThe injury induced severe hypotension refractory to aggressive fluid resuscitation. High doses of AVP were required to partially attenuate the sepsis-induced hypotension. However, the cumulative AVP requirement was significantly reduced by adjunct treatment with WW-85 at 17–24 h after the injury (p < 0.05). Total AVP dose and the highest AVP rate were significantly lower in the WW-85 + AVP group compared to the AVP group (p = 0.02 and 0.04, respectively). Treatment with WW-85 had no adverse effects. In addition, the in vitro effects of AVP on isolated artery diameter changes were abolished with peroxynitrite co-incubation.ConclusionsThe modulation of reactive nitrogen species, such as peroxynitrite, may be considered as a novel adjunct treatment option for septic shock associated with vascular hypo-responsiveness to vasopressors.

01 Mar 2013·Current Vascular PharmacologyQ4 · MEDICINE

Role of Peroxynitrite in the Cardiovascular Dysfunction of Septic Shock

Q4 · MEDICINE

Review

Author: Rosenblatt-Velin, Nathalie ; Liaudet, Lucas ; Pacher, Pal

The intense systemic inflammatory response characterizing septic shock is associated with an increased generation of free radicals by multiple cell types in cardiovascular and non cardiovascular tissues. The oxygen-centered radical superoxide anion (O2 .-) rapidly reacts with the nitrogen-centered radical nitric oxide (NO.) to form the potent oxidant species peroxynitrite. Peroxynitrite oxidizes multiple targets molecules, either directly or via the secondary generation of highly reactive radicals, resulting in significant alterations in lipids, proteins and nucleic acids, with significant cytotoxic consequences. The formation of peroxynitrite is a key pathophysiological mechanism contributing to the cardiovascular collapse of septic shock, promoting vascular contractile failure, endothelial and myocardial dysfunction, and is also implicated in the occurrence of multiple organ dysfunction in this setting. The recent development of various porphyrin-based pharmacological compounds accelerating the degradation of peroxynitrite has allowed to specifically address these pathophysiological roles of peroxynitrite in experimental septic shock. Such agents, including 5,10,15,20-tetrakis(4- sulfonatophenyl)porphyrinato iron III chloride (FeTTPs), manganese tetrakis(4-N-methylpyridyl)porphyrin (MnTMPyP), Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether)pyridyl porphyrin) (FP-15) and WW-85, have been shown to improve the cardiovascular and multiple organ failure in small and large animal models of septic shock. Therefore, these findings support the development of peroxynitrite decomposition catalysts as potentially useful novel therapeutic agents to restore cardiovascular function in sepsis.

01 Nov 2012·ShockQ2 · MEDICINE

Administration of a Peroxynitrite Decomposition Catalyst Into the Bronchial Artery Attenuates Pulmonary Dysfunction After Smoke Inhalation and Burn Injury in Sheep

Q2 · MEDICINE

Article

Author: Takashi Yamaki ; Perenlei Enkhbaatar ; Lillian D. Traber ; Daniel L. Traber ; Hiroyuki Sakurai ; Matthias Lange ; Hiroaki Nakazawa ; Motohiro Nozaki ; Atsumori Hamahata

Reactive nitrogen species such as peroxynitrite play a significant role in burn and smoke inhalation injury. The bronchial circulation increases more than 10-fold in response to this combination injury. We hypothesized that direct delivery of low-dose WW-85, a peroxynitrite decomposition catalyst, into the bronchial artery would attenuate burn- and smoke inhalation-induced acute lung injury. In adult female sheep (n = 17), the bronchial artery was cannulated in preparation surgery. After a 5- to 7-day recovery period, sheep were subjected to a burn (40% total body surface area, third degree) and inhalation injury (48 breaths of cotton smoke, <40°C). The animals were divided into three groups following the injury: (i) WW-85 group: 1 h after injury, WW-85 (0.002 mg/kg per hour) was continuously infused into the bronchial artery, n = 5; (ii) control group: 1 h after injury, an equivalent amount of saline was injected into the bronchial artery, n = 6; (iii) sham group: no injury, no treatment, same operation and anesthesia, n = 6. All animals were mechanically ventilated and fluid resuscitated equally. In the control group, the injury induced a severe deterioration of pulmonary oxygenation and shunting and an increase in pulmonary microvascular permeability toward sham. The injury was further associated with an increase in reactive nitrogen species in lung tissues of the control group. All these alterations were significantly attenuated in the WW-85 group. We demonstrated that a low dosage of WW-85 directly administered into the bronchial artery attenuated pulmonary dysfunction to the same extent as higher systemically administered doses in previous experiments. Our data strongly suggest that local airway production of peroxynitrite contributes to pulmonary dysfunction following smoke inhalation and burn injury.

100 Deals associated with INO-4885

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 1	US	Inotek Pharmaceuticals Corp.	-
Kidney Diseases	Phase 1	US	Inotek Pharmaceuticals Corp.	-
Radiation Injuries	Phase 1	US	Inotek Pharmaceuticals Corp.	-

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