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PDF file - 126K, Activity of tBregs is efficiently blocked by CpG-ODN

PDF file - 119K, Targeted tBreg inactivation with BLC-arp/CpG-ODN

PDF file - 172K, tBregs express low levels of 4-1BBL

PDF file - 96K, In vivo inactivation of tBregs with BLC-arp/CpG-ODN induces antitumor T cell responses

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PDF file - 206K, Regulatory activity is mostly retained in human tBregs expressing low levels of CD20

PDF file - 1209K, tBregs express low levels of CD20

This article demonstrates how time-dependent, interacting, and repeating risk factors can be used to create more accurate predictive medicine. In particular, we show how emergence of anemia can be predicted from medical history within electronic health records. We used the Veterans Affairs Informatics and Computing Infrastructure database to examine a retrospective cohort of 9,738,838 veterans over an 11-year period. Using International Clinical Diagnoses Version 9 codes organized into 25 major diagnostic categories, we measured progression of disease by examining changes in risk over time, interactions in risk of combination of diseases, and elevated risk associated with repeated hospitalization for the same diagnostic category. The maximum risk associated with each diagnostic category was used to predict anemia. The accuracy of the model was assessed using a validation cohort. Age and several diagnostic categories significantly contributed to the prediction of anemia. The largest contributors were health status ([Formula: see text] = -1075, t = -92, p 0.000), diseases of the endocrine ([Formula: see text] = -1046, t = -87, p 0.000), hepatobiliary ([Formula: see text] = -1043, t = -72, p 0.000), kidney ([Formula: see text] = -1125, t = -111, p 0.000), and respiratory systems ([Formula: see text] = -1151, t = -89, p 0.000). The AUC for the additive model was 0.751 (confidence interval 74.95%-75.26%). The magnitude of AUC suggests that the model may assist clinicians in determining which patients are likely to develop anemia. The procedures used for examining changes in risk factors over time may also be helpful in other predictive medicine projects.

Many common drugs induce megaloblastic anemia by interfering with folate or vitamin B12 absorption, altering B12 metabolism, or blocking pathways in which these vitamins play a role. Supplements to overcome these effects or discontinuation of the drug may be necessary.

The possible therapeutic benefits of B-cell depletion in combating tumoral immune escape have been debated. In support of this concept, metastasis of highly aggressive 4T1 breast cancer cells in mice can be abrogated by inactivation of tumor-evoked regulatory B cells (tBreg). Here, we report the unexpected finding that B-cell depletion by CD20 antibody will greatly enhance cancer progression and metastasis. Both murine and human tBregs express low levels of CD20 and, as such, anti-CD20 mostly enriches for these cells. In the 4T1 model of murine breast cancer, this effect of enriching for tBregs suggests that B-cell depletion by anti-CD20 may not be beneficial at all in some cancers. In contrast, we show that in vivo–targeted stimulation of B cells with CXCL13-coupled CpG oligonucleotides (CpG-ODN) can block cancer metastasis by inhibiting CD20Low tBregs. Mechanistic investigations suggested that CpG-ODN upregulates low surface levels of 4-1BBL on tBregs to elicit granzyme B–expressing cytolytic CD8+ T cells, offering some explanative power for the effect. These findings underscore the immunotherapeutic importance of tBreg inactivation as a strategy to enhance cancer therapy by targeting both the regulatory and activating arms of the immune system in vivo. Cancer Res; 73(7); 2127–38. ©2013 AACR.

Aging strongly promotes inflammation responses, which may predispose individuals after cancer therapies to lethal system toxicities and pathology that can be partially prevented by TNF blockade., Cancer commonly occurs in the elderly and immunotherapy (IT) is being increasingly applied to this population. However, the majority of preclinical mouse tumor models assessing potential efficacy and toxicities of therapeutics use young mice. We assessed the impact of age on responses to systemic immune stimulation. In contrast to young mice, systemic cancer IT regimens or LPS given to aged mice resulted in rapid and lethal toxicities affecting multiple organs correlating with heightened proinflammatory cytokines systemically and within the parenchymal tissues. This inflammatory response and increased morbidity with age was independent of T cells or NK cells. However, prior in vivo depletion of macrophages in aged mice resulted in lesser cytokine levels, increased survival, and decreased liver histopathology. Furthermore, macrophages from aged mice and normal human elderly volunteers displayed heightened TNF and IL-6 production upon in vitro stimulation. Treatment of both TNF knockout mice and in vivo TNF blockade in aged mice resulted in significant increases in survival and lessened pathology. Importantly, TNF blockade in tumor-bearing, aged mice receiving IT displayed significant anti-tumor effects. These data demonstrate the critical role of macrophages in the age-associated hyper-inflammatory cytokine responses to systemic immunostimulation and underscore the importance of performing preclinical assessments in aged mice.

A role for adenosine in immunosenescence was investigated in T cells from older (≥65 yr) and younger (24–45 yr) healthy humans. Adenosine concentrations in cultures of activated T cells were significantly higher (P

Inflammation is a double-edged sword that can promote or suppress cancer progression. In this study, we report that thymic stromal lymphopoietin (TSLP), an IL-7–like type 1 inflammatory cytokine that is often associated with the induction of Th2-type allergic responses in the lungs, is also expressed in human and murine cancers. Our studies with murine cancer cells indicate that TSLP plays an essential role in cancer escape, as its inactivation in cancer cells alone was sufficient to almost completely abrogate cancer progression and lung metastasis. The cancer-promoting activity of TSLP primarily required signaling through the TSLP receptor on CD4+ T cells, promoting Th2-skewed immune responses and production of immunosuppressive factors such as IL-10 and IL-13. Expression of TSLP therefore may be a useful prognostic marker, and its targeting could have therapeutic potential.

Chronic diseases often determine pathologic phenotypes similar to those traditionally attributed to aging, such as accelerated decline of muscle mass and increments of basic metabolic rate, suggesting that the true nature of aging is progressively increasing entropy in the face of failing homeostatic mechanisms. Aging in different animal species and in humans suggest that increasing entropy causes major problems in four domains; body composition, energetic imbalance between availability and demand, homeostatic dysregulation, and neurodegeneration. In humans, loss of integrity and function in these domains causes manifestations similar to frailty, especially if the damage is severe and/or involves multiple domains, and has catastrophic consequences, such as physical and cognitive disability. Characterizing these phenotypes, and understanding the mechanisms by which they emerge with increasing entropy is a necessary step to find interventions that can prevent, delay or moderate the effects of aging. Pharmacological and non-pharmacological interventions that may effectively modulate the aging phenotypes are actively studied and will certainly be ready in the near future. Until then, creating a “senior friendly society”, that allows maximal independence but also promotes an active and healthy lifestyle may be the most cost-effective intervention to improve the quality of life in the population.

Background Systemic amyloidosis complicated by heart failure is associated with high cardiovascular morbidity and mortality. Heart transplantation for patients with systemic amyloidosis is controversial due to recurrence of disease in the transplanted organ or progression of disease in other organs. Methods All patients with systemic amyloidosis and heart failure referred for heart transplant evaluation from 1997 to 2004 were included in this retrospective cohort analysis. An interdisciplinary protocol for cardiac transplantation using extended-donor criteria organs, followed in 6 months by either high-dose chemotherapy and stem cell transplantation for patients with primary (AL) or by orthotopic liver transplantation for familial (ATTR) amyloidosis, was developed. Survival of the transplanted amyloid cohort was compared to survival of those amyloid patients not transplanted and to patients transplanted for other indications. Results A total of 25 patients with systemic amyloidosis and heart failure were included in the study; 12 patients received heart transplants. Amyloid heart transplant recipients were more likely female (58% vs. 8%, P=0.02) and had lower serum creatinine (1.3+/-0.5 vs. 2.0+/-0.7 mg/dL, P=0.01) than nontransplanted amyloid patients. Survival at 1-year after heart transplant evaluation was higher among transplanted patients (75% vs. 23%) compared to patients not transplanted (P=0.001). Short-term survival posttransplant did not differ between transplanted amyloid patients and contemporaneous standard and extended-donor criteria heart transplant patients (P=0.65). Conclusions Cardiac transplantation for amyloid patients with extended-donor criteria organs followed by either stem cell or liver transplantation is associated with improved survival compared to patients not transplanted. Short- to intermediate-term survival is similar to patients receiving heart transplantation for other indications. This clinical management strategy provides cardiac amyloid patients a novel therapeutic option.

Differentiation and activation of CD4 memory T cells (Tmem cells) require energy from different sources, but little is known about energy sources for maintenance and surveillance activities of unactivated Tmem cells. Mitochondrial fatty acid oxidation (FAO) in human unactivated CD4 Tmem cells was significantly enhanced by inhibition of glycolysis, with respective means of 1.7- and 4.5-fold for subjects 65 yr, and by stimulation of AMP-activated protein kinase, with respective means of 1.3- and 5.2-fold. However, CCL19 and sphingosine 1-phosphate (S1P), which control homeostatic lymphoid trafficking of unactivated Tmem cells, altered FAO and glycolysis only minimally or not at all. Inhibition of CD4 Tmem-cell basal FAO, but not basal glycolysis, significantly suppressed CCL19- and S1P-mediated adherence to collagen by >50 and 20%, respectively, and chemotaxis by >20 and 50%. Apoptosis of unactivated Tmem cells induced by IL-2 deprivation or CCL19 was increased significantly by >150 and 70%, respectively, with inhibition of FAO and by >110 and 30% with inhibition of glycolysis. Anti-TCR antibody activation of Tmem cells increased their chemotaxis to CCL5, which was dependent predominantly on glycolysis rather than FAO. The sources supplying energy for diverse functions of unactivated Tmem cells differ from that required for function after immune activation.—Taub, D. D., Hesdorffer, C. S., Ferrucci, L., Madara, K., Schwartz, J. B., Goetzl, E. J. Distinct energy requirements for human memory CD4 T-cell homeostatic functions.

The red cell distribution width (RDW) is a component of the automated complete blood count (CBC) that quantifies heterogeneity in the size of circulating erythrocytes. Higher RDW values reflect greater variation in red blood cell (RBC) volumes and are associated with increased risk for cardiovascular disease (CVD) events. The mechanisms underlying this association are unclear, but RBC deformability might play a role. CBCs were assessed in 293 adults who were clinically examined. RBC deformability (expressed as the elongation index) was measured using a micro fluidic slit-flow ektacytometer. Multivariate regression analysis identified a clear threshold effect whereby RDW values above 14.0% were significantly associated with decreased RBC deformability (β = −0.24; p = 0.003). This association was stronger after excluding anemic participants (β = −0.40; p = 0.008). Greater variation in RBC volumes (increased RDW) is associated with decreased RBC deformability, which can impair blood flow through the microcirculation. The resultant hypoxia may help to explain the previously reported increased risk for CVD events associated with elevated RDW.

Summary Suppressed T cell functions in human immunodeficiency virus (HIV) infection were identified and corrected by lenalidomide in middle-aged HIV-infected patients. Chemotaxis of T cells from HIV-infected men (n = 6, mean 43 years) to sphingosine 1-phosphate (S1P) and CCL21 was significantly lower than that of HIV-negative men (n = 6, mean 41 years), and was enhanced significantly up to control levels by 100 and 1000 nM lenalidomide. Generation of interleukin (IL)-2, but not interferon (IFN)-γ, by T cells of middle-aged HIV-infected men was significantly lower than that for controls and was increased significantly by 10–1000 nM lenalidomide up to a maximum of more than 300%. CD4 and CD8 T cells isolated from healthy middle-aged men and reconstituted in vitro at a low CD4 : CD8 ratio typical of HIV infection had depressed chemotaxis to S1P, but not CCL21, and generation of IL-2, but not IFN-γ. Significant enhancement of chemotaxis to S1P and CCL21was induced by 100–1000 nM lenalidomide only for normal T cells at a low CD4 : CD8 ratio. T cells from HIV-negative middle-aged CD4 T lymphocytopenic patients (n = 3), with a CD4 : CD8 ratio as low as that of HIV-infected patients, had similarly diminished chemotaxis to S1P and CCL21, and depressed generation of IL-2, but not IFN-γ. Lenalidomide at 30–1000 nM significantly enhanced chemotaxis to S1P and IL-2 generation for T cells from HIV-negative CD4 T lymphocytopenic patients as from HIV-infected patients, with less effect on CCL21-elicited chemotaxis and none for IFN-γ generation. Defects in functions of T cells from middle-aged HIV-infected men are partially attributable to CD4 T lymphocytopenia and are corrected by lenalidomide.

Significant progress has been made in the treatment of breast cancer. However, treatment effect on survival in older patients, particularly the "oldest old" (85+ years), with breast cancer is not clear. Data from the Surveillance, Epidemiology, and End Results databases were used to determine relative survival of older patients with breast cancer for up to 9 years following diagnosis. We compared trends in survival and stage distribution in the years 1977-1986, 1987-1996, and 1997-2006 in patients from 65 to 74, 75 to 84, and 85+ years of age. Between 1977-1986 and 1997-2006, 1 year survival increased from 94.9 to 97.9 %, 93.6 to 96.7 %, and 88.5 to 93.5 % in the 65-74, 75-84, and 85+ age groups, respectively. Survival gains increased with each year in all three age groups with the largest improvement seen at 9 years of follow-up. Although the "oldest old" had the lowest survival rates, improvement in survival was greatest in this age group with greater than 20 % increase in survival at 9 years. There was an increased diagnosis of localized breast cancer and decrease in regional disease in all age groups over the three decades. In conclusion, relative survival for older patients has increased considerably in the interval between 1977 and 2006, with the largest improvement seen in those 85 years and older. These results likely indicate that the benefit from advances in therapy and supportive care also extends to older patients with breast cancer, including the 'oldest old', but the impact of early diagnosis on survival requires further clarification.

Purpose To characterize the number and functional status of CD4+CD25+ regulatory T cells (Tregs) in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC) treated with high-dose bolus interleukin-2 (IL-2). Patients and Methods Patients with MM or RCC treated with high-dose bolus IL-2 (600,000 IU/kg every 8 hours) at a single center provided pre- and post-treatment whole blood specimens. Peripheral blood mononuclear cells were isolated by Ficoll density gradient centrifugation, separated into cellular subsets, and analyzed by flow cytometry or used for in vitro proliferation assays. Results Between September 2003 and July 2005 57 patients were enrolled in the study with 48 patients available for analysis (45 MM, 12 RCC). Tregs were defined as CD4+CD25hi T cells, and this subset was significantly elevated in the cancer patients compared with normal donors (7.75% v 2.24%). The CD4+CD25hi T-cell pool in the patients constitutively expressed intracellular FoxP3, CTLA-4, and produced high amounts of IL-10. The Tregs were CCR7+ with 50% representing naïve and 50% central-memory T cells. The cells were functionally suppressive in mixed in vitro proliferation assays. Following IL-2 administration, the number and frequency of Tregs increased in patients with progressive disease but returned to normal levels in patients with objective clinical responses. Conclusion The number of Tregs, defined as CD4+CD25hi T cells is increased in patients with MM and RCC. High-dose IL-2 resulted in a significant decrease of Tregs in those patients achieving an objective clinical response to IL-2 therapy.

The use of immunotherapy (IT) in cancer has recently resulted in impressive responses. Yet, their usages, especially those involving cytokine therapies, have also resulted in the induction of severe systemic toxicities often not previously characterized in their preclinical animal studies. Our laboratory has demonstrated that treatment of EL4 lymphoma with a combination immunotherapy consisting of monoclonal agonistic antibody CD40 and IL-2 resulted in significant anti-tumor responses leading to overall increases in survival using young inbred mice (2-6 months of age). Yet, the majority of hematological cancers occur in aged individuals, with most diagnoses occurring past the age of 60. We now demonstrate that systemic immunotherapy administration in aged (>16 months of age), but not young, mice resulted in the induction of a rapid cytokine release syndrome, also known as “cytokine storm”, culminating in multi-organ damage (liver, lung, and gut) leading to rapid lethality by day 2 of treatment. Aging is accompanied by an overall redistribution of body mass, with a decrease in lean muscle mass and increase in adiposity. Similarly, we found that normal aging in inbred mice housed under specific pathogen free conditions was accompanied by increases in visceral fat that was similar to young obese (ob/ob or diet-induced obese [DIO]) mice. We therefore assessed the impact of aging and obesity on inflammatory responses to cancer immunotherapeutics. We determined the effects of increased body fat on systemic immunotherapy tolerance in aged mice compared to young obese mice. Both young ob/ob and DIO generated pro-inflammatory cytokine (ie TNFa and IL6) levels and organ pathologies comparable to aged WT mice following immunotherapy, culminating in rapid lethality after several days of therapy. We observed that young obese mice exhibited greater ratios of M1/M2 macrophages within the peritoneal and visceral adipose tissues and higher percentages of TNFa+ macrophages in comparison to young lean mice with immunotherapy. Administration of aCD40/IL-2 with macrophage depletion or TNF-blockade prevented the development of cytokine storms within young obese mice, providing protection from lethality, suggesting that the toxicity was macrophage mediated through increases in TNFa. Calorie-restricted aged mice contain less visceral fat and upon aCD40/IL-2 administration displayed reduced cytokine levels, protection from organ pathology, and protection from lethality. Our data demonstrates adiposity as a critical factor in the age-associated inflammatory pathologic responses to systemic anti-cancer immunotherapy and may have a significant impact when immunotherapy is used clinically within cancer therapy regimens. These data also underscore the critical importance of taking aging and body fat into consideration with preclinical assessments. Disclosures No relevant conflicts of interest to declare.

Abstract 5214 Background: Indolent lymphomas account for 35–40% of Non-Hodgkin's lymphomas (NHL). The treatment choices, and as a result, the overall outcome of these indolent lymphomas seem to be changing with the introduction of chemoimmunotherapy. However, the impact of these new treatment approaches on the survival in older patients has not been specifically studied. Methods: We used data from the Surveillance, Epidemiology and End Results database to determine survival for older patients diagnosed with indolent lymphomas. We compared trends in survival between 1977–86, 1987–96 and 1997–2006 in men and women, for three age groups 65–74, 75–84 and 85+ years. Survival rates were calculated up to 9 years post-diagnosis. Results: Between 1977 and 2006, survival rates increased for both men and women in all three age groups. The greatest improvement in survival was seen at 5 years. Between 1977–86 and 1997–2006, 5-year survival rates increased in men/women by 21%/22%, 23%/29% and 16%/24% in the 65–74, 75–84 and 85+ age groups respectively. Survival gains increased with each decade in all age groups for both sexes with the most marked improvements between 1987–1996 & 1997–2006. Women in the first two groups consistently demonstrated a better survival than men. The oldest old men (85+) had the lowest survival rate with the majority of the deaths occurring in the first year of diagnosis. Conclusions: Survival for older patients has increased considerably in the interval between 1977–2006 with the largest improvement seen in the 75–84 year old age group. Larger increases in the survival rates between 1987–1996 and 1997–2006 might be accounted for by the benefits of immunotherapy with the introduction of rituximab in 1998. The increased early deaths noted in men 85+, could be related to treatment toxicity. While earlier treatment is being advocated for patients diagnosed with indolent lymphoma, the data we present imply that more careful consideration should be given to the selection of patients above the age of 85 for such treatment. Male-female differences in survival are interesting and further study would seem important to elucidate the causes. Disclosures: No relevant conflicts of interest to declare.

Significant progress has been made in the treatment of breast cancer. However, treatment effect on survival in older patients, particularly the “oldest old” (85+ years), with breast cancer is not clear. Data from the Surveillance, Epidemiology, and End Results databases were used to determine relative survival of older patients with breast cancer for up to 9 years following diagnosis. We compared trends in survival and stage distribution in the years 1977–1986, 1987–1996, and 1997–2006 in patients from 65 to 74, 75 to 84, and 85+ years of age. Between 1977–1986 and 1997–2006, 1 year survival increased from 94.9 to 97.9 %, 93.6 to 96.7 %, and 88.5 to 93.5 % in the 65–74, 75–84, and 85+ age groups, respectively. Survival gains increased with each year in all three age groups with the largest improvement seen at 9 years of follow-up. Although the “oldest old” had the lowest survival rates, improvement in survival was greatest in this age group with greater than 20 % increase in survival at 9 years. There was an increased diagnosis of localized breast cancer and decrease in regional disease in all age groups over the three decades. In conclusion, relative survival for older patients has increased considerably in the interval between 1977 and 2006, with the largest improvement seen in those 85 years and older. These results likely indicate that the benefit from advances in therapy and supportive care also extends to older patients with breast cancer, including the ‘oldest old’, but the impact of early diagnosis on survival requires further clarification.

Breast cancer escape and metastasis is an active process that requires inflammation and participation of immune cells. We have previously reported that this is a primary tumor-controlled process which activates lungs to produce CCL17 and CCL22 to facilitate lung metastasis together with the recruitment of CCR4+ regulatory T cells (Tregs). To understand the mechanism of this process, we performed expression array analysis in both metastatic and non-metastatic cancer cells and found that metastatic cells produced thymic stromal lymphopoietin (TSLP), an IL-7-like type 1 inflammatory cytokine that is often associated with the induction of Th2-type allergic responses in the lungs. Moreover, TSLP was also abundantly expressed in variety of human solid tumors, including breast, lung, colon and ovarian cancers. To gain further insights into the role of TSLP in cancer progression, we have blocked TSLP expression in cancer cells and found that TSLP is required for efficient breast cancer escape and metastasis. Moreover, utilizing adoptive transfer studies in TSLPR deficient mice, we demonstrated that by targeting CD4+ T cells to induce Th2-type inflammatory responses, cancer-produced TSLP promoted cancer escape. Taken together, our data indicate that TSLP is an important factor that needs to be controlled to effectively combat with cancer escape.

Abstract 3412 Poster Board III-300 Introduction High-dose cyclophosphamide (HD CY) is a potent immunosuppressive agent that is used as conditioning for HSCT in most patients with both hematologic malignancies and autoimmune diseases. HD CY is highly toxic to lymphocytes, but spares hematopoietic stem cells because of their abundant levels of aldehyde dehydrogenase (the primary mechanism of CY inactivation). We and others have shown that HD CY without stem cell support can induce durable remissions in a variety of severe autoimmune diseases. Here, we report the long term follow-up of 124 patients with a variety of severe autoimmune diseases treated with HD CY. Methods From August 1996 through August 2008, 124 consecutive patients with severe, refractory autoimmune diseases (excluding acquired severe aplastic anemia) were treated with HD CY (50mg/kg/d) for 4 consecutive days without HSCT. Six days after the last dose of CY, all patients received granulocyte colony stimulating factor (5 μg/kg/day) until the neutrophil count exceeded 0.5 × 109/liter. Response was defined as a decrease in disease activity in conjunction with a decrease or elimination of immune modulating drugs. Relapse was defined as worsening disease activity and/or a requirement of an increase in dose or administration of a new immunosuppressive medication. Results The most common diseases treated with HD CY included lupus (n=42), multiple sclerosis (MS, n=32), myasthenia gravis (n=14) scleroderma (SSC, n=10), autoimmune hemolytic anemia (n=9) and pemphigus (n=9). The median follow up is 47 (range 1-127) months. All patients experienced rapid hematopoietic recovery: an absolute neutrophil count (ANC) > 500/μL was achieved at a median of 13 (range 8-22) days after the last dose CY and the median duration of an ANC < 500/μL was 9 (range 4-23) days. The median time to last platelet transfusion after completion of CY was 13 (range 0-33) days and the median time to last packed red blood cell transfusion was 12 (range 0-24) days. The median number of PRBC transfusions was 2 (range 0-27) and the median number of platelet transfusions was 2 (range 0-18.) The overall treatment related mortality was 0.8% with the lone death occurring in a non-neutropenic SSC patient on day 51 after HD CY. Median number of hospitalized days was 4 (range 0-55) days. The overall response rate was 94% with 42% of responders maintaining a durable response at the time of analysis. Durability of response seemed to vary according to the underlying disease and/or disease severity. The actuarial event-free survival (EFS) at 60 months is 10.6% for SLE, 31% for MS, 42.1% for MG, 50% for AIHA, 33% for pemphigus, and 25% for the other diseases. Interestingly, disease activity improved from pre-HD CY in virtually all patients even at the time of relapse, as many patients became responsive to immunosuppressive agents that were previously ineffective in controlling their disease. Discussion HD CY with or without HSCT has a potent disease modifying effect in wide variety of autoimmune disorders. These data suggest that eliminating HSCT after HD CY maintains both its efficacy and safety. The duration of cytopenias compares favorably with HSCT, especially when factoring in the mobilization phase of HSCT. Furthermore, eliminating mobilization and HSCT may have at least theoretical advantages in that the overall duration of the procedure is shortened, any toxicity associated with mobilization is avoided, and the potential of reinfusing autoreactive lymphocytes with the autograft is averted. Disclosures Jones: Accentia: Patents & Royalties. Brodsky:Accentia: Patents & Royalties.

Long-term (greater than 48 h) sodium nitroprusside (SNP) infusion significantly reduced cobalamin (vitamin B12) levels in 23 patients treated in a CCU after myocardial infarction. There was no evidence of vitamin B12 deficiency or SNP toxicity. Low vitamin B12 levels should not limit the use of SNP, because prolonged infusion of SNP at maximum doses of 2.5 micrograms/kg X min did not adversely affect hemodynamic stability.