PEGylated carboxyhemoglobin bovine (SANGUINATE): results of a phase I clinical trial.

PEGylated carboxyhemoglobin bovine (SANGUINATE) is a dual action carbon monoxide releasing (CO)/oxygen (O2 ) transfer agent for the treatment of hypoxia. Its components inhibit vasoconstriction, decrease extravasation, limit reactive oxygen species production, enhance blood rheology, and deliver oxygen to the tissues. Animal models of cerebral ischemia, peripheral ischemia, and myocardial ischemia demonstrated SANGUINATE's efficacy in reducing myocardial infarct size, limiting necrosis from cerebral ischemia, and promoting more rapid recovery from hind limb ischemia. In a Phase I trial, three cohorts of eight healthy volunteers received single ascending doses of 80, 120, or 160 mg/kg of SANGUINATE. Two volunteers within each cohort served as a saline control. There were no serious adverse events. Serum haptoglobin decreased, but did not appear to be dose related. The T1/2 was dose dependent and ranged from 7.9 to 13.8 h. In addition to the Phase I trial, SANGUINATE was used under an expanded access emergency Investigational New Drug. SANGUINATE was found to be safe and well tolerated in a Phase I clinical trial, and therefore it will advance into further clinical trials in patients.

[Management of acute carbon monoxide poisoning--Polish Medical Society, Section of Clinical Toxicology position statement]. / Postepowanie w ostrych zatruciach tlenkiem wegla--stanowisko Sekcji Toksykologii Klinicznej Polskiego Towarzystwa Lekarskiego.

Paper presents Polish Medical Society, Section of Clinical Toxicology position statement on the prehospital and hospital management of carbon monoxide poisoning.

Population pharmacokinetic analysis of carboxyhaemoglobin concentrations in adult cigarette smokers.

AIMS: To develop a population-based model to describe and predict the pharmacokinetics of carboxyhaemoglobin (COHb) in adult smokers. METHODS: Data from smokers of different conventional cigarettes (CC) in three open-label, randomized studies were analysed using NONMEM (version V, Level 1.1). COHb concentrations were determined at baseline for two cigarettes [Federal Trade Commission (FTC) tar 11 mg; CC1, or FTC tar 6 mg; CC2]. On day 1, subjects were randomized to continue smoking their original cigarettes, switch to a different cigarette (FTC tar 1 mg; CC3), or stop smoking. COHb concentrations were measured at baseline and on days 3 and 8 after randomization. Each cigarette was treated as a unit dose assuming a linear relationship between the number of cigarettes smoked and measured COHb percent saturation. Model building used standard methods. Model performance was evaluated using nonparametric bootstrapping and predictive checks. RESULTS: The data were described by a two-compartment model with zero-order input and first-order elimination with endogenous COHb. Model parameters included elimination rate constant (k(10)), central volume of distribution (Vc/F), rate constants between central and peripheral compartments (k(12) and k(21)), baseline COHb concentrations (c0), and relative fraction of carbon monoxide absorbed (F1). The median (range) COHb half-lives were 1.6 h (0.680-2.76) and 30.9 h (7.13-367) (alpha and beta phases, respectively). F1 increased with increasing cigarette tar content and age, whereas k(12) increased with ideal body weight. CONCLUSION: A robust model was developed to predict COHb concentrations in adult smokers and to determine optimum COHb sampling times in future studies.

Gene transfer of heme oxygenase-1 and carbon monoxide delivery inhibit chronic rejection.

The hallmark of chronic rejection is the occlusion of the artery lumen by intima hyperplasia as a consequence of leukocyte infiltration and vascular smooth muscle cell (VSMC) migration and proliferation. Heme oxygenase-1 (HO-1) is a tissue protective molecule which degrades heme into carbon monoxide (CO), free iron and biliverdin. We analyzed the effects of HO-1 gene transfer into the vessel wall using an adenoviral vector (AdHO-1) and of CO delivery in a model of chronic allogeneic aorta rejection in rats. Carbon monoxide treatment was achieved by a new pharmacological approach in transplantation using methylene chloride (MC), which releases CO after degradation. AdHO-1-mediated gene transfer into aorta endothelial cells (ECs) or CO delivery resulted in a significant reduction in intimal thickness compared to untreated or noncoding adenovirus-treated controls. Aortas transduced with AdHO-1 or treated with CO showed a reduction in the number of leukocytes as well as in the expression of adhesion molecules, costimulatory molecules and cytokines, with the gene transfer treatment displaying a more pronounced effect than the CO treatment. Conversely, CO inhibited VSMC accumulation in the intima more efficiently than AdHO-1 treatment. Gene transfer of HO-1 and pharmacological manipulation of CO are novel approaches to the analysis and treatment of chronic rejection.

Alterations in pharmacokinetics of carboxyhemoglobin produced by oxygen under pressure.

The pharmacokinetic effect of elevated oxygen partial pressures in the elimination of carboxyhemoglobin (COHb) by O2 administration was studied in an inflatable hyperbaric chamber. A double crossover prospective analysis between the modified Gamow bag and non-rebreather (NRB) mask O2 was conducted among 12 healthy, adult volunteers who smoked five cigarettes sequentially within a 60-min period. COHb levels were measured using co-oximetry before and after smoking. Subjects inspired hyperbaric oxygen (HBO2) and normobaric oxygen (NBO2) in separate trials for 40 min. Mean COHb levels (1.16 +/- 0.28 g/dl) post-smoking were representative of low-level poisoning. NBO2 consisted of a NRB mask at a rate of 15 liter/min outside the Gamow bag. HBO2 was delivered inside the Gamow bag with a demand valve regulator mask at a Po2 of 1.58 atm abs. A significant increase in the half-life (t 1/2) of COHb was observed for each subject in the Gamow bag (P < 0.05; repeated measures analysis of variance). Average t 1/2 for COHb was 26.3 +/- 3.7 min (n = 12) and 71.3 +/- 9.9 min (n = 12) while breathing HBO2 and NBO2, respectively. Pharmacokinetic modeling was performed using PCNONLIN software for each subject. Both zero and first order elimination kinetics were tested and the model of best fit determined using the Akaike Information Criterion for each subject. A significant shift in COHb elimination from a zero to first order mechanism with elevation in O2 partial pressure was observed (P = 0.002; McNemar's test). HBO2 provides a pharmacokinetic advantage over NRB mask O2 in eliminating mild carboxyhemoglobinemia.

Elimination of CO from the body: an experimental study on the rabbit.

Rabbits were exposed to gases containing CO with concentrations ranging from 2.0 to 2.9% for 40 sec, 1 min, or 5 min, and the time course of the change in the arterial blood COHb concentration was followed from immediately after the end of exposure up to 180 min. All rabbits survived. Hypercapnia was not observed. The COHb concentration at the end of the 5-min exposure ranged from 68.8-82.0%. The pattern of the elimination of CO was not linear; the decreasing rate of COHb concentration became slower with the lapse of time. The COHb concentration plotted against the post-exposure time on a semi-logarithmic graph showed three phases. In the first 10 min, the rate of decrease was the fastest. The second phase was followed by the third phase at about 90 min after exposure. In the shorter exposure groups too, the initial phase was observed. The initial phase was considered to be a stage in which CO was distributed throughout the body. The appearance of the third phase is probably explained by the contribution of CO produced endogeneously. The existing equations for predicting COHb concentrations failed to explain the initial and third phases.

Alterations of pulmonary gas exchange after superimposed carbon monoxide poisoning in acute lung injury.

BACKGROUND: Smoke inhalation injury produces substantial morbidity and mortality caused both by immediate catastrophic pulmonary failure and by the subsequent development of pneumonia. Although carbon monoxide (CO) poisoning is present to a degree in nearly all instances of smoke inhalation, the importance of CO in the pathogenesis of smoke inhalation injury remains controversial because smoke contains numerous other potential pulmonary toxins such as aldehydes, chlorine gas, and hydrochloric acid. This study was performed to determine whether CO poisoning acts as a cofactor in the evolution of inhalation injury. METHODS: Four groups of anesthetized dogs received ventilation with 1% CO in room air alone, intratracheal instillation of 2.0 ml/kg 0.1 N hydrochloric acid (HCl) alone, or acid either immediately or 30 minutes before CO. Ventilation/perfusion relationships were measured for 4 hours thereafter with the multiple inert gas elimination technique. RESULTS: Acid instillation established 30 minutes before CO poisoning resulted in significantly decreased carboxyhemoglobin concentrations after ventilation with 1% CO in air for 10 minutes. However, CO elimination was markedly delayed in both acid-challenged groups ventilated with CO. Moreover, acid instillation immediately before CO poisoning significantly exacerbated the development of ventilation/perfusion inequality caused by the acid, because the development of shunt was accelerated. CONCLUSIONS: CO poisoning is an important cofactor in the development of inhalation injury by acceleration of the development of ventilation/perfusion inequality after inhalation.

Cyanide and methemoglobin kinetics in smoke inhalation victims treated with the cyanide antidote kit.

STUDY OBJECTIVE: To evaluate serial cyanide, methemoglobin, and carbon monoxide levels in smoke inhalation patients. SETTING: Regional poison center and regional toxicology treatment center. PARTICIPANTS: Seven critically ill smoke inhalation patients referred to the regional poison center. INTERVENTIONS: Peak level and half-life were determined by obtaining serial carboxyhemoglobin, cyanide, and methemoglobin levels. RESULTS: The mean observed half-life of cyanide was 3.0 +/- 0.6 hours. Methemoglobinemia was evaluated in four patients after sodium nitrite administration. The peak measured methemoglobin levels (mean, 10.5% +/- 2%; range, 7.9% to 13.4%) did not occur until a mean of 50 minutes (range, 35 to 70 minutes) following administration of sodium nitrite. The total oxygen-carrying capacity reduced by the combination of carboxyhemoglobin and methemoglobin was never more than 21% (range, 10% to 21%) in this series. CONCLUSION: The administration of sodium nitrite to smoke inhalation patients in the presence of concomitant carbon monoxide poisoning may be relatively safe.

[Monoxycarbogenic reaction of chloral: application to the obtention of carboxyhemoglobin and to its determination in blood]. / La réaction monoxycarbogénique du chloral: application à l'obtention de la carboxyhémoglobine et à son dosage dans le sang.

Carbon monoxide CO, generated from chloral (10(-2) M) in a dilution of hemochrome (pH 13), turns the solution of hemochrome into a solution of carboxyhemoglobin. The spectrum of this solution is identical to the one obtained after bubbling with CO. The reaction is fast and makes it possible to determine the percentage of carboxyhemoglobinemia in whole blood.

Importance of exposure to gaseous and particulate phase components of tobacco smoke in active and passive smokers.

The uptake of tobacco smoke constituents from gaseous and particulate phases of mainstream smoke (MS), inhaled by smokers, and of environmental tobacco smoke (ETS), breathed in by non-smokers, was investigated in two experimental studies. Tobacco smoke uptake was quantified by measuring carboxyhemoglobin (COHb), nicotine and cotinine in plasma and urine and the data obtained were correlated with urinary excretion of thioethers and of mutagenic activity. An increase in all biochemical parameters was observed in smokers inhaling the complete MS of 24 cigarettes during 8 h, whereas only an increase in COHb and, to a minor degree, in urinary thioethers was found after smoking the gas phase of MS under similar conditions. Exposure of non-smokers to the gaseous phase of ETS or to whole ETS at similar high concentrations for 8 h led to identical increases in COHb, plasma nicotine and cotinine as well as urinary excretion of nicotine and thioethers which were much lower than in smokers. Urinary mutagenicity was not found to be elevated under either ETS exposure condition. As shown by our results, the biomarkers most frequently used for uptake of tobacco smoke (nicotine and cotinine) indicate on the one hand the exposure to particulate phase constituents in smoking but on the other hand the exposure to gaseous phase constituents in passive smoking. Particle exposure during passive smoking seems to be low and a biomarker which indicates ETS particle exposure is as yet not available. These findings emphasize that risk extrapolations from active smoking to passive smoking which are based on cigarette equivalents or the use of one biomarker (e.g. cotinine) might be misleading.