Papers by Friedericke Kazo
Journal of Clinical Toxicology, 2014
Conditions in patients with hemoglobinopathies are far more complex and variable than in healthy ... more Conditions in patients with hemoglobinopathies are far more complex and variable than in healthy humans due to the cascade of injury from hypoxia. Resulting complications can lead to tissue death, organ dysfunction and even death. Multi-faceted treatment is needed to address the array of complications. SANGUINATE™ (PEGylated, bovine carboxyhemoglobin) has multiple mechanisms of action that may prove effective. It acts both as a carbon monoxidereleasing molecule and as an oxygen transfer agent and is designed to safely perfuse the microvasculature to oxygenate tissue. Designing toxicology studies must not only deal with ensuring the safety of its mechanisms but deal with the potential safety issues of using bovine hemoglobin for both acute and chronic administration. Similar products have previously been shown to have effects on inflammation, vasoactivity, cardiac toxicity and nephrotoxicity as well as pro-coagulant activity. Therefore, studies were designed to thoroughly address the potential of these effects in conjunction with the traditional toxicology and safety pharmacology studies. These toxicology and safety studies were designed to address the FDA’s particular concerns of this novel drug candidate. There were several unique features to this preclinical program including a renal functional study, immunohistochemical and special staining of tissues, measurement of hemoglobin in the urine, measurement of troponin in the serum, inclusion of high dose/high volume groups, and analysis of interference for clinical pathology parameters. To address toxicity and safety concerns of its use as a single or repeating dose therapeutic, SANGUINATE was tested in pivotal studies using three species in repeating doses. There were no adverse effects identified for any doses and therefore, a no observed adverse effect level (NOAEL) was not determined even at dosage levels of 1200 mg/kg (monkey), 1600 mg/kg (pig) and 2400 mg/kg (rat). The completion of these studies permitted SANGUINATE to move into clinical trials.
Artificial Organs, Aug 1, 2014
Artificial oxygen (O 2) carriers were reported to be protective in ischemia/reperfusion (I/R) in ... more Artificial oxygen (O 2) carriers were reported to be protective in ischemia/reperfusion (I/R) in various organs including the heart. In the current study, 20 rats underwent ligation (MI) of the left anterior descending artery, were treated with 10 mL/kg of PEGylated carboxyhemoglobin bovine (SANGUINATE ® , S+, n=10) or saline (S-, n=10) 10 min after MI and daily thereafter for three days, and were followed by weekly echocardiography for four weeks, when they Accepted Article This article is protected by copyright. All rights reserved. had left ventricular pressure volume relationship (PVR) analyses followed by necropsy. Echocardiography showed an increase in end-systolic dimension rather than end-diastolic dimension, preserved fractional shortening (36 vs 26%, p<0.01), and milder mitral regurgitation (MR) in S+ compared with S-rats. PVR revealed a milder increase in end-systolic volume, larger stroke volume (101 vs 74 L, p<0.005) and cardiac output (33.4 vs 23.8 mL/min, p=0.004) in S+ rats in actual determination and under a wide range of standardized loading conditions four weeks after MI. Excised heart showed significantly limited area of MI (8.9 vs 13.3%, P=0.028). The results suggest that SANGUINATE ® in short-term repeated doses may accelerate weight recovery, preserving the myocardium, mitral competence, and cardiac function after MI. The mechanism of action and optimal treatment for MI remain to be studied.
Blood, Dec 7, 2017
Artificial oxygen (O 2) carriers were reported to be protective in ischemia/reperfusion (I/R) in ... more Artificial oxygen (O 2) carriers were reported to be protective in ischemia/reperfusion (I/R) in various organs including the heart. In the current study, 20 rats underwent ligation (MI) of the left anterior descending artery, were treated with 10 mL/kg of PEGylated carboxyhemoglobin bovine (SANGUINATE ® , S+, n=10) or saline (S-, n=10) 10 min after MI and daily thereafter for three days, and were followed by weekly echocardiography for four weeks, when they Accepted Article This article is protected by copyright. All rights reserved. had left ventricular pressure volume relationship (PVR) analyses followed by necropsy. Echocardiography showed an increase in end-systolic dimension rather than end-diastolic dimension, preserved fractional shortening (36 vs 26%, p<0.01), and milder mitral regurgitation (MR) in S+ compared with S-rats. PVR revealed a milder increase in end-systolic volume, larger stroke volume (101 vs 74 L, p<0.005) and cardiac output (33.4 vs 23.8 mL/min, p=0.004) in S+ rats in actual determination and under a wide range of standardized loading conditions four weeks after MI. Excised heart showed significantly limited area of MI (8.9 vs 13.3%, P=0.028). The results suggest that SANGUINATE ® in short-term repeated doses may accelerate weight recovery, preserving the myocardium, mitral competence, and cardiac function after MI. The mechanism of action and optimal treatment for MI remain to be studied.
Blood, 2014
Background: Red blood cell (RBC) sickling is the hallmark phenotype of Sickle Cell Disease (SCD) ... more Background: Red blood cell (RBC) sickling is the hallmark phenotype of Sickle Cell Disease (SCD) resulting from an inherited hemoglobin (HbS) point mutation genotype. Sickling is a direct consequence of HbS polymerization that occurs as RBC encounter low oxygen environments. Sickled RBCs have increased rigidity restricting their passage through the microvasculature that can lead to a vaso-occlusive crisis (VOC). VOCs are painful, debilitating and can be associated with more severe co morbidities including acute chest syndrome, leg ulcers and stroke. Treatments for VOC are limited and include IV hydration and opioid for pain control. Extensive VOC events often require hospitalization, supplemental oxygen and transfusions. Improved therapies that can be administered early during VOC that directly target the causative RBC sickling events are warranted. PEGylated carboxyhemoglobin bovine (Sanguinate™ SG) is currently in clinical development being evaluated for the ability to treat the c...
Artificial Cells, Nanomedicine, and Biotechnology, 2019
Hypoxia drives sickle cell disease (SCD) by inducing sickle cell haemoglobin to polymerize and de... more Hypoxia drives sickle cell disease (SCD) by inducing sickle cell haemoglobin to polymerize and deform red blood cells (RBC) into the sickle shape. A novel carboxyhaemoglobin-based oxygen carrier (PEG-COHb; PP-007) promotes unsickling in vitro by relieving RBC hypoxia. An in vivo rat model of vaso-occlusive crisis (VOC) capable of accommodating a suite of physiological and microcirculatory measurements was used to compare treatment with PEG-COHb to a non-oxygen carrying control solution (lactated ringer's [LRS]). Male Sprague-Dawley rats were anesthetized and surgically prepared to monitor microvascular interstitial oxygenation (P ISF O 2), cardiovascular parameters and blood chemistry. Human homozygous SCD RBCs were isolated and exchange transfused into the rats until the distal microcirculation of the exteriorized spinotrapezius muscle was hypoxic and RBC aggregates were visualized. VOC was left untreated (Sham) or treated 15 min later with PEG-COHb or LRS and observed for up to 4 h. Treatment with PEG-COHb showed better improvement of P ISF O 2 , end-point lactate, mean arterial pressure and survival duration compared to Sham and LRS. Restoring P ISF O 2 was associated with relieving the RBC aggregates driving VOC, which then affected other study metrics. Compared to LRS, PEG-COHb's oxygen-carrying properties were key to improved outcomes.
Artificial Organs, 2014
Artificial oxygen (O 2) carriers were reported to be protective in ischemia/reperfusion (I/R) in ... more Artificial oxygen (O 2) carriers were reported to be protective in ischemia/reperfusion (I/R) in various organs including the heart. In the current study, 20 rats underwent ligation (MI) of the left anterior descending artery, were treated with 10 mL/kg of PEGylated carboxyhemoglobin bovine (SANGUINATE ® , S+, n=10) or saline (S-, n=10) 10 min after MI and daily thereafter for three days, and were followed by weekly echocardiography for four weeks, when they Accepted Article This article is protected by copyright. All rights reserved. had left ventricular pressure volume relationship (PVR) analyses followed by necropsy. Echocardiography showed an increase in end-systolic dimension rather than end-diastolic dimension, preserved fractional shortening (36 vs 26%, p<0.01), and milder mitral regurgitation (MR) in S+ compared with S-rats. PVR revealed a milder increase in end-systolic volume, larger stroke volume (101 vs 74 L, p<0.005) and cardiac output (33.4 vs 23.8 mL/min, p=0.004) in S+ rats in actual determination and under a wide range of standardized loading conditions four weeks after MI. Excised heart showed significantly limited area of MI (8.9 vs 13.3%, P=0.028). The results suggest that SANGUINATE ® in short-term repeated doses may accelerate weight recovery, preserving the myocardium, mitral competence, and cardiac function after MI. The mechanism of action and optimal treatment for MI remain to be studied.
Artificial Cells Nanomedicine and Biotechnology, Feb 10, 2019
Hypoxia drives sickle cell disease (SCD) by inducing sickle cell haemoglobin to polymerize and de... more Hypoxia drives sickle cell disease (SCD) by inducing sickle cell haemoglobin to polymerize and deform red blood cells (RBC) into the sickle shape. A novel carboxyhaemoglobin-based oxygen carrier (PEG-COHb; PP-007) promotes unsickling in vitro by relieving RBC hypoxia. An in vivo rat model of vaso-occlusive crisis (VOC) capable of accommodating a suite of physiological and microcirculatory measurements was used to compare treatment with PEG-COHb to a non-oxygen carrying control solution (lactated ringer's [LRS]). Male Sprague-Dawley rats were anesthetized and surgically prepared to monitor microvascular interstitial oxygenation (P ISF O 2), cardiovascular parameters and blood chemistry. Human homozygous SCD RBCs were isolated and exchange transfused into the rats until the distal microcirculation of the exteriorized spinotrapezius muscle was hypoxic and RBC aggregates were visualized. VOC was left untreated (Sham) or treated 15 min later with PEG-COHb or LRS and observed for up to 4 h. Treatment with PEG-COHb showed better improvement of P ISF O 2 , end-point lactate, mean arterial pressure and survival duration compared to Sham and LRS. Restoring P ISF O 2 was associated with relieving the RBC aggregates driving VOC, which then affected other study metrics. Compared to LRS, PEG-COHb's oxygen-carrying properties were key to improved outcomes.
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Papers by Friedericke Kazo