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What is this plain language summary about? This plain language summary describes the results of a study looking at the effects of a medicine called ARRY-371797 (also known as PF-07265803) in people with dilated cardiomyopathy (DCM for short) caused by a faulty LMNA gene. This condition is called LMNA-related DCM. DCM happens when the heart becomes bigger and weaker than normal, impacting functional capacity and leading to symptoms of heart failure. This means the heart is not able to pump blood around the body as easily, and people are unable to do as much in their daily lives (like getting dressed and going shopping). People may inherit a faulty LMNA gene from one of their parents, or a faulty LMNA gene may develop when mistakes happen during cell growth and replication. ARRY-371797 targets a specific mechanism in the body that can lead to heart problems in people with a faulty LMNA gene. As ARRY-371797 is not currently approved for use outside of clinical trials, it doesn't currently have an easily recognizable trade name. What were the results? 12 American people (average age 50 years) with LMNA-related DCM took part in the study and received 400 mg or 100 mg of ARRY-371797 twice daily for 48 weeks. People knew which dose of ARRY-371797 they were taking. People were checked after 4, 12, 24, 36 and 48 weeks of taking ARRY-371797 to see how far they could walk in the 6-minute walk test (6MWT for short). The level of NT-proBNP in their blood was also measured. NT-proBNP is a biomarker used to measure the severity of heart failure. A biomarker is something found in the body that can be measured to indicate the extent of a disease. - After taking ARRY-371797 for 12 weeks, people were able to walk further in the 6MWT and had lower levels of NT-proBNP in their blood. This suggests improvement in functional capacity (exercise tolerance) and heart function. Researchers also asked people about their quality of life using the Kansas City Cardiomyopathy Questionnaire (KCCQ for short), and looked for any side effects. - Researchers saw some improvement in KCCQ scores. - Researchers saw no major side effects that they considered to be related to ARRY-371797 treatment. A side effect is something that people feel was caused by a medicine or treatment. Overall, this study showed that people with LMNA-related DCM who took ARRY-371797 had improved functional capacity (exercise tolerance), improved heart function, and improved quality of life. Phase 2 study ( NCT02057341 ) Phase 2 long-term extension study ( NCT02351856 ) Phase 3 REALM-DCM study ( NCT03439514 )

Dilated cardiomyopathy associated with lamin A/C (LMNA) gene variants (LMNA-related dilated cardiomyopathy [DCM]) is a life-threatening condition with a high unmet need, accounting for approximately 6% of idiopathic DCM cases. Currently, no disease-specific treatments target the underlying disease mechanism. ARRY-371797 (PF-07265803), a potent, selective, oral, small-molecule inhibitor of the p38α mitogen-activated protein kinase pathway, improved 6-minute walk test (6MWT) distance in 12 patients with symptomatic LMNA-related DCM in a 48-week, open-label, phase 2 study. This long-term extension study examined the safety and efficacy of ARRY-371797 in patients from the phase 2 study. 6MWT, N-terminal pro-B-type natriuretic peptide concentration, and 12-item Kansas City Cardiomyopathy Questionnaire score were assessed at weeks 48, 72, 96, 120, and 144 from phase 2 study baseline. Eight patients enrolled (mean [SD] age, 51 [10] years, 4 male). Mean 6MWT increased by30 m (10%) from phase 2 study baseline up to week 120. The decrease in N-terminal pro-B-type natriuretic peptide observed in the phase 2 study was maintained throughout the present study. Twelve-item Kansas City Cardiomyopathy Questionnaire Physical Limitation increased from baseline at all visits except week 96 (range: -0.8 [week 96] to 13.8 [week 120]); results for other domains were variable. Treatment was generally well tolerated; 2 patients discontinued because of causes not considered treatment-related. There were no deaths. ARRY-371797 was generally well tolerated over median (range) 155.7 (61 to 327)-week exposure; evidence suggested preserved exercise capacity over the study period. The ongoing, pivotal, phase 3, randomized, placebo-controlled study REALM-DCM investigates the efficacy and safety of ARRY-371797 (PF-07265803) in LMNA-related DCM. (ClinicalTrials.gov Identifier: NCT02351856).

What is this plain language summary about? This summary explains the results of a long-term extension study on the effects of a specific medicine. A long-term extension study allows people who have already completed a research study to continue taking treatment. Researchers can then look at how a treatment works over a long period of time. This extension study looked at the effects of a medicine called ARRY-371797 (also known as PF-07265803) in people with dilated cardiomyopathy (DCM for short) caused by a faulty lamin A/C gene (also known as the LMNA gene). This condition is called LMNA-related DCM. In people with LMNA-related DCM, the heart muscle becomes thinner and weaker than normal. This can lead to heart failure, where the heart is unable to pump enough blood around the body. The extension study allowed people who had completed an earlier 48-week study to continue taking ARRY-371797 for another 96 weeks (around 22 months). What were the results of the extension study? 8 people joined the extension study and continued with the dose of ARRY-371797 that they had taken in the first study. This means that people could have taken ARRY-371797 continuously for up to 144 weeks (around 2 years and 9 months). Using the 6-minute walk test (6MWT for short), researchers regularly checked people taking ARRY-371797 to see how far they could walk. Throughout the extension study, people were able to walk further than they could before they started taking ARRY-371797. This suggests that people could maintain the improvements in their ability to do daily activities with long-term ARRY-371797 treatment. Researchers also looked at how severe people's heart failure was by using a test that measures levels of a biomarker called NT-proBNP. A biomarker is something found in the body that can be measured to indicate the extent of a disease. Throughout this study, the levels of NT-proBNP in people's blood was lower than before they started taking ARRY-371797. This suggests that they maintained stable heart function. Using the Kansas City Cardiomyopathy Questionnaire (KCCQ for short), researchers asked people about their quality of life, and if they experienced any side effects. A side effect is something that people feel while taking a treatment. Researchers evaluate if a side effect is related to the treatment or not. Some improvement in KCCQ response during the study was seen, although results were varied. There were no serious side effects that were considered related to treatment with ARRY-371797. What do the results of the extension study mean? Researchers found that the improvements in functional capacity and heart function seen with ARRY-371797 treatment in the original study were maintained with long-term treatment. Larger studies are needed to determine if ARRY-371797 could be an effective treatment for people with LMNA-related DCM. One such study (called REALM-DCM) was started in 2018 but ended early, as it was unlikely to show a clear treatment benefit of ARRY-371797. Phase 2 long-term extension study ( NCT02351856 ) Phase 2 study ( NCT02057341 ) Phase 3 REALM-DCM study ( NCT03439514 )

Supplementary Data, Yeh, et al. from Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor

Purpose: The Ras-Raf-mitogen-activated protein kinase kinase (MEK) pathway is overactive in many human cancers and is thus a target for novel therapeutics. We have developed a highly potent and selective inhibitor of MEK1/2. The purpose of these studies has been to show the biological efficacy of ARRY-142886 (AZD6244) in enzymatic, cellular, and animal models.Experimental Design: The ability of ARRY-142886 to inhibit purified MEK1 as well as other kinases was evaluated. Its effects on extracellular signal-regulated kinase (ERK) phosphorylation and proliferation in several cell lines were also determined. Finally, the inhibitor was tested in HT-29 (colorectal) and BxPC3 (pancreatic) xenograft tumor models.Results: The IC50 of ARRY-142886 was determined to be 14 nmol/L against purified MEK1. This activity is not competitive with ATP, which is consistent with the high specificity of compound for MEK1/2. Basal and epidermal growth factor–induced ERK1/2 phosphorylation was inhibited in several cell lines as well as 12-O-tetradecanoylphorbol-13-acetate–induced ERK1/2 phosphorylation in isolated peripheral blood mononuclear cells. Treatment with ARRY-142886 resulted in the growth inhibition of several cell lines containing B-Raf and Ras mutations but had no effect on a normal fibroblast cell line. When dosed orally, ARRY-142886 was capable of inhibiting both ERK1/2 phosphorylation and growth of HT-29 xenograft tumors in nude mice. Tumor regressions were also seen in a BxPC3 xenograft model. In addition, tumors remained responsive to growth inhibition after a 7-day dosing holiday.Conclusions: ARRY-142886 is a potent and selective MEK1/2 inhibitor that is highly active in both in vitro and in vivo tumor models. This compound is currently being investigated in clinical studies.

Background: Lamin A/C gene ( LMNA )-related dilated cardiomyopathy is a serious and life-threatening condition with a high unmet medical need. This phase 2 study assessed the effects of the oral selective p38 mitogen-activated protein kinase inhibitor ARRY-371797 on functional capacity and cardiac function in patients with LMNA -related dilated cardiomyopathy. Methods: Patients with LMNA -related dilated cardiomyopathy in New York Heart Association class II–IIIA, on background heart failure treatment, received ARRY-371797 100 or 400 mg twice daily for 48 weeks. The primary end point was change from baseline in the 6-minute walk test distance at 12 weeks. Secondary end points included changes over time in 6-minute walk test distance, NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration, left ventricular ejection fraction, and quality-of-life scores on the Kansas City Cardiomyopathy Questionnaire. Data from the 2 dose groups were combined. Results: Twelve patients were enrolled; median (minimum, maximum) 6-minute walk test distance at baseline was 314 (246, 412) m. At week 12, the mean (80% CI) increase from baseline in 6-minute walk test distance was 69 (39, 100) m (median, 47 m). Median NT-proBNP concentration declined from 1409 pg/mL at baseline to 848 pg/mL at week 12. Mean left ventricular ejection fraction was stable at week 12. There was a trend toward improvement in Kansas City Cardiomyopathy Questionnaire Overall and Clinical Summary scores at week 12. No clinically significant drug-related safety concerns were identified. Conclusions: ARRY-371797 was well tolerated and resulted in potential increases in functional capacity and lower concentrations of cardiac biomarker NT-proBNP in patients with LMNA -related dilated cardiomyopathy. Registration: URL: https://clinicaltrials.gov ; Unique identifier: NCT02057341.

Objective To compare Prostate Health Index (PHI) and prostate‐specific antigen (PSA) density as secondary tests after multiparametric magnetic resonance imaging (mpMRI) in improving the detection accuracy of Gleason grade group (GG) 2‐5 prostate cancer (PCa) and in decreasing unnecessary biopsies in a multiethnic biopsy‐naïve population. Methods From February 2017 to February 2020, we recruited consecutive biopsy‐naïve men in participating urology clinics for elevated PSA levels. They all had a PHI score, mpMRI, and prostate biopsy. Experienced genitourinary radiologists read all mpMRI studies based on PIRADS version 2.0. Logistic regression models were used to generate receiver operating characteristic curves. Models were tested for effect modification between Race (Black vs White) and both PHI and PSA density, and Race and PIRADS to determine if race impacted their prediction accuracy. Sensitivity, specificity, and predictive values of PHI and PSA density thresholds were calculated by PIRADS scores. The primary outcome was GG2‐5 PCa, that is, Gleason score ≥3 + 4. Results The study included 143 men, of which 65 (45.5%) were self‐reported Black. Median age was 62.0 years and 55 men (38.4%) had GG2‐5 PCa. Overall, 18.1% had PIRADS 1‐2, 32.9% had PIRADS 3, and 49.0% had PIRADS 4‐5. For the binary logistic regressions, the interactions between PIRADS and Race (P = .08), Log (PHI) and Race (P = .17), and Log (PSA density) and Race (P = .42) were not statistically significant. Within PIRADS 3 lesions, a PHI ≥49 prevented unnecessary biopsies in 55% of men and missed no GG2‐5 PCa, yielding a negative predictive value of 100%. There was no reliable PHI or PSA density threshold to avoid PCa biopsies in PIRADS 1‐2 or 4‐5. Conclusions PHI and PSA density can be used after mpMRI to improve the detection of GG2‐5 PCa in a biopsy‐naïve cohort. PHI may be superior to PSA density in PIRADS 3 lesions by avoiding 55% of unnecessary biopsies. Using both PHI and PSA density in series may further increase specificity and lead to fewer unnecessary biopsies, but further larger studies are warranted to determine the optimal threshold of each biomarker.

Lamin A/C gene (Patients withTwelve patients were enrolled; median (minimum, maximum) 6-minute walk test distance at baseline was 314 (246, 412) m. At week 12, the mean (80% CI) increase from baseline in 6-minute walk test distance was 69 (39, 100) m (median, 47 m). Median NT-proBNP concentration declined from 1409 pg/mL at baseline to 848 pg/mL at week 12. Mean left ventricular ejection fraction was stable at week 12. There was a trend toward improvement in Kansas City Cardiomyopathy Questionnaire Overall and Clinical Summary scores at week 12. No clinically significant drug-related safety concerns were identified.ARRY-371797 was well tolerated and resulted in increases in functional capacity and lower concentrations of cardiac biomarker NT-proBNP in patients withURL: https://clinicaltrials.gov; Unique identifier: NCT02057341.

PURPOSE The Genomic Prostate Score (GPS), performed on biopsy tissue, predicts adverse outcome in prostate cancer (PCa) and has shown promise for improving patient selection for active surveillance (AS). However, its impact on treatment choice in high-risk populations of African Americans is largely unknown and, in general, the effect of the GPS on this difficult decision has not been evaluated in randomized trials. METHODS Two hundred men with National Comprehensive Cancer Network very low to low-intermediate PCa from three Chicago hospitals (70% Black, 16% college graduates) were randomly assigned at diagnosis to standard counseling with or without a 12-gene GPS assay. The primary end point was treatment choice at a second postdiagnosis visit. The proportion of patients choosing AS was compared, and multivariable modeling was used to estimate the effects of various factors on AS acceptance. RESULTS AS acceptance was high overall, although marginally lower in the intervention group (77% v 88%; P = .067), and lower still when men with inadequate specimens were excluded ( P = .029). Men with lower health literacy who received a GPS were seven-fold less likely to choose AS compared with controls, whereas no difference was seen in men with higher health literacy ( Pinteraction = .022). Among men with low-intermediate risk, 69% had GPS values consistent with unfavorable intermediate or high-risk cancer. AS choice was also independently associated with a family history of PCa and having health insurance. CONCLUSION In contrast to other studies, the net effect of the GPS was to move patients away from AS, primarily among men with low health literacy. These findings have implications for our understanding of how prognostic molecular assays that generate probabilities of poor outcome can affect treatment decisions in diverse clinical populations.

Introduction: Dilated cardiomyopathy due to LMNA gene mutations ( LMNA -DCM) accounts for ~6% of DCM cases and is a life-threatening condition with a high unmet need. No disease-specific treatment targeting the underlying mechanism of disease is currently available. ARRY-371797 (PF-0765803), a potent, selective, oral, small-molecule inhibitor of the p38α MAPK pathway, improved exercise capacity (6MWT) in symptomatic LMNA -DCM patients (n=12) in a 48-week, open-label, Phase 2 study. Methods: This was an open-label rollover study of the long-term safety and efficacy of ARRY-371797 in symptomatic LMNA -DCM patients previously participating in the Phase 2 parent study, with eligible patients continuing on the same dose. Safety and efficacy assessments (6MWT, NT-proBNP, and KCCQ) were performed at Weeks 48, 72, 96, 120, and 144 from treatment initiation in the parent study. Results: Eight patients were enrolled (mean [SD] age, 51 [10] years; 4 males). There was a >30 m mean improvement and >10% mean increase in 6MWT distance from parent study baseline up to Week 120 ( Table ), with 3 patients (37.5%) having ≥10% improvement from baseline to Week 144. The decrease in mean NT-proBNP concentration in the parent study was maintained ( Table ). KCCQ Physical Limitation score increased at all visits except Week 48. Changes in KCCQ Clinical Summary and Overall Summary scores were variable. Treatment was generally well tolerated: 3 patients discontinued due to causes not considered treatment-related (UTI and nausea, CRT-D, and LVAD implantation); 2 experienced Grade 1 adverse events considered treatment-related. There were no deaths. Conclusions: ARRY-371797 was generally well tolerated, with evidence suggesting preserved exercise capacity over >2 years’ follow-up. Efficacy and safety of ARRY-371797 is being investigated in the REALM-DCM trial, an ongoing, pivotal, Phase 3, randomized, placebo-controlled study in LMNA -DCM.

Aims Given the clinical impact of LMNA cardiomyopathies, understanding lamin function will fulfill a clinical need and will lead to advancement in the treatment of heart failure. A multidisciplinary approach combining cell biology, atomic force microscopy (AFM), and molecular modeling was used to analyse the biomechanical properties of human lamin A/C gene (LMNA) mutations (E161K, D192G, N195K) using an in vitro neonatal rat ventricular myocyte model. Methods and results The severity of biomechanical defects due to the three LMNA mutations correlated with the severity of the clinical phenotype. AFM and molecular modeling identified distinctive biomechanical and structural changes, with increasing severity from E161K to N195K and D192G, respectively. Additionally, the biomechanical defects were rescued with a p38 MAPK inhibitor. Conclusions AFM and molecular modeling were able to quantify distinct biomechanical and structural defects in LMNA mutations E161K, D192G, and N195K and correlate the defects with clinical phenotypic severity. Improvements in cellular biomechanical phenotype was demonstrated and may represent a mechanism of action for p38 MAPK inhibition therapy that is now being used in human clinical trials to treat laminopathies.

Objective To determine whether inhibition of p38 mitogen-activated protein kinase (p38MAPK) reduces the pathogenicity of anti-neutrophil cytoplasmic autoantibodies (ANCAs) in vitro and in vivo.Methods The effects of the p38MAPK-specific inhibitor AR-447 were studied in vitro using neutrophil respiratory burst and degranulation assays, and in lipopolysaccharide (LPS)-stimulated human glomerular endothelial cells. In vivo, p38MAPK inhibition was investigated in a mouse anti-myeloperoxidase (MPO) IgG/LPS glomerulonephritis model. Mice were treated orally with AR-447 daily, starting before (pretreatment group) or 24 h after disease onset (treatment group), and killed after 1 or 7 day(s).Results In vitro, AR-447 diminished neutrophil respiratory burst and degranulation induced by patient-derived MPO-ANCA and proteinase 3 (Pr3)-ANCA. In glomerular endothelial cells, AR-447 reduced LPS-induced secretion of IL-6 and IL-8, but not of MCP-1. In mice, pretreatment with AR-447 reduced albuminuria 1 day after induction of glomerulonephritis. After 7 days, no effects on urinary abnormalities were observed upon AR-447 pretreatment or treatment. Also, glomerular neutrophil accumulation was not diminished. In contrast, glomerular macrophage accumulation and the formation of glomerular crescents was significantly reduced by AR-447 pretreatment (vehicle: 12.5 +/- 5.6% crescentic glomeruli; AR-447: 7.7 +/- 2.7%) and treatment (vehicle 14.6 +/- 1.8%; AR-447 6.0 +/- 3.4%) at 7 days.Conclusion This study shows that p38MAPK inhibition markedly reduces ANCA-induced neutrophil activation in vitro. In vivo, p38MAPK inhibition partly reduced crescent formation when the drug was administered prior to disease induction and after disease onset, suggesting that besides p38MAPK activity other signalling pathways contribute to the disease activity.

OBJECTIVE To evaluate the effects of short-term, high-volume hemofiltration (STHVH) on hemodynamic and metabolic status and 28-day survival in patients with refractory septic shock. DESIGN Prospective, interventional. SETTING Intensive care unit (ICU), tertiary institution. PATIENTS Twenty patients with intractable cardiocirculatory failure complicating septic shock, who had failed to respond to conventional therapy. INTERVENTIONS STHVH, followed by conventional continuous venovenous hemofiltration. STHVH consisted of a 4-hr period during which 35 L of ultrafiltrate is removed and neutral fluid balance is maintained. Subsequent conventional continuous venovenous hemofiltration continued for at least 4 days. MEASUREMENTS AND MAIN RESULTS Cardiac index, systemic vascular resistance, pulmonary vascular resistance, oxygen delivery, mixed venous oxygen saturation, arterial pH, and lactate were measured serially. Fluid and inotropic support were managed by protocol. Therapeutic endpoints were as follows during STHVH: a) by 2 hrs, a > or =50% increase in cardiac index; b) by 2 hrs, a > or =25% increase in mixed venous saturation; c) by 4 hrs, an increase in arterial pH to >7.3; d) by 4 hrs, a > or =50% reduction in epinephrine dose. Patients who attained all four goals (11 of 20) were considered hemodynamic "responders"; patients who did not (9 of 20) were considered hemodynamic "nonresponders." There were no differences in baseline hemodynamic, metabolic, and Acute Physiology and Chronic Health Evaluation and Simplified Acute Physiology Scores between responders and nonresponders. Survival to 28 days was better among responders (9 of 11 patients) than among nonresponders (0 of 9). Factors associated with survival were hemodynamic-metabolic response status, time interval from ICU admission to initiation of STHVH, and body weight. CONCLUSIONS These data suggest that STHVH may be of major therapeutic value in the treatment of intractable cardiocirculatory failure complicating septic shock. Early initiation of therapy and adequate dose may improve hemodynamic and metabolic responses and 28-day survival.

Objectives. The goals of this study were: a) to evaluate the efficacy of controlled, continuous arteriovenous hemofiltration in improving morbidity and mortality rates in an immature swine model of Staphylococcus aureus-induced septicemia; b) to determine if ultrafiltrate from septic animals contained mediators that produce pathophysiologic changes observed in untreated S. aureus septic pigs. Design. Prospective, randomized, controlled study with age-matched controls. Setting. U.S. Department of Agriculture-licensed biomedical research facility. Subjects. Sixty-five weaned Poland-China swine (4 to 6 wks of age; 5 to 10 kg). Interventions: Part 1. Animals received a lethal dose of live S. aureus (8 ± 109 colony-forming units/kg) over 1 hr. The three treatment groups included: hemofiltration group 1 (eight filtered, eight nonfiltered animals), plasma filtration fraction = 5.5%; hemofiltration group 2 (six filtered, six nonfiltered animals), filtration fraction = 16.6%; and hemofiltration group 3 (six filtered, six nonfiltered animals), filtration fraction = 33.4%. A control, nonseptic group of animals (n = 4) was filtered to obtain “clean” ultra-filtrate (hemofiltration group 4). Part 2: Sterile ultrafiltrate concentrate batches obtained from each group of filtered, septic animals were concentrated and infused into healthy, nonseptic pigs (reinfusion groups 1 through 3). Measurements and Main Results. Physiologic, biochemical, and hematologic variables were measured in all animals every 1 to 3 hrs. Overall length of survival was also recorded. In hemofiltration groups 1 through 3, filtered animals survived significantly longer than matched, nonfiltered (sham-filtered) animals. Increments in survival time increased directly with filtration fraction. Ultrafiltrate concentrate from septic pigs produced death (LD41) and disease similar to those rates observed in untreated S. aureus-septic pigs. Infusion of clean ultrafiltrate concentrate produced no response. Conclusions. Continuous arteriovenous hemofiltration significantly improved survival rates in swine with S. aureus-induced sepsis. Resultant ultrafiltrate concentrate contained mediators responsible for some pathophysiologic responses observed in this animal model. (Crit Care Med 1993; 21:914–924)

To evaluate the effect of hemofilter pore size on the efficacy of continuous arteriovenous hemofiltration (CAVH) in improving morbidity and mortality in an immature swine model of Staphylococcus aureus-induced septicemia.Prospective, randomized study with age-matched controls.Biomedical research facility.Fourteen 4 to 8-wk-old, weaned Poland-China swine, weighing 5 to 10 kg.Spontaneously breathing, ketamine-sedated swine (4 to 8 wks of age) were given an intravenous lethal dose of live S. aureus. Animals were then filtered with either a 50-kilodalton (kD) pore size filter (control) or a 100-kD pore size filter (experimental). No animals received antibiotics.Physiologic, biochemical, and hematologic parameters were measured in all animals every 1 to 3 hrs. Animals were monitored continuously and survival time (hr) was recorded (permanent survival = 168 hrs/7 days). Animals filtered with the 100-kD filter survived significantly longer than control animals (103 +/- 18 [SEM] vs. 56 +/- 9 hrs). The 100-kD-filtered group had one permanent survivor (168 hrs). Protein concentration of the ultrafiltrate obtained from the 100-kD-filtered animals was eight-fold higher than control ultrafiltrate. The protein removed did not contain a high percentage of albumin (as determined by autoanalyzer methods). No significant differences were seen in any of the other measured parameters.CAVH significantly improved survival in swine with S. aureus-induced sepsis. The superior performance of the 100-kD filter vs. the 50-kD filter suggests that higher molecular weight mediators that are not removed efficiently by the 50-kD filter may be responsible for the morbidity and mortality seen in this model of sepsis. These mediators may be removed in greater proportion by our customized (100-kD pore size) filter.

Cyanide-induced cytotoxicity is primarily a result of inhibition of O2 uptake by the terminal enzyme of the mitochondrial respiratory chain, cytochrome-c oxidase (cytochrome aa3). The oxidase in the brain is highly vulnerable to cyanide cytotoxicity, but few studies have evaluated the effects of cyanide on cerebral oxygen metabolism. In the present study, we measured oxidation-reduction responses of cerebrocortical cytochrome aa3 to cyanide and related changes in cerebral blood flow (CBF) and O2 metabolism (CMRO2). Accurate measurement of cytochrome aa3 redox state in vivo by reflectance spectrophotometry was accomplished by using fluorocarbon-circulated rats to eliminate spectral interference from hemoglobin. The data indicate that constant intravenous infusions of cyanide caused rapid, progressive reduction responses by cerebrocortical cytochrome aa3 concomitant with increases in CBF of up to 200%. However, CMRO2 was maintained near normal until cerebral O2 delivery began to fall. These cerebral oxidative responses to cyanide may be explained either by redistribution of intracellular O2 supply to mitochondria respiring in an O2-dependent manner or by branching effects within brain mitochondria in vivo.