ABSTRACT
PURPOSE: Ruxolitinib improves splenomegaly and disease-related symptoms in most patients with myelofibrosis (MF), and it has been associated with a survival benefit in higher-risk patients with splenomegaly. Spleen volume reduction has been associated with a survival benefit in ruxolitinib-treated patients; however, its use as a surrogate is limited. We hypothesized that an anti-inflammatory response to ruxolitinib would correlate with improved patient outcomes. METHODS: We interrogated serum albumin, an acute phase reactant and marker of nutritional status in 590 patients with MF and analyzed differential trajectories of albumin on the basis of ruxolitinib treatment. Additionally, we assessed the prognostic role of baseline albumin and change in albumin. RESULTS: We found that serum albumin levels tend to decrease in patients with MF; however, this tendency is abrogated by ruxolitinib treatment. To that end, baseline serum albumin level correlates with overall survival (OS) in patients with MF, independent of the variables that comprise the dynamic international prognostic scoring system; however, this correlation is limited to ruxolitinib-naïve patients. In ruxolitinib-treated patients, the change in serum albumin after ruxolitinib treatment, rather than the baseline value, is associated with improved OS, a finding not seen in ruxolitinib-naïve patients. CONCLUSION: These findings suggest that serum albumin, a ubiquitously available laboratory value, has specific relevance in patients with MF and reflects therapeutic response to ruxolitinib.
Subject(s)
Nitriles , Primary Myelofibrosis , Pyrazoles , Pyrimidines , Splenomegaly , Humans , Splenomegaly/complications , Splenomegaly/drug therapy , Primary Myelofibrosis/drug therapy , Primary Myelofibrosis/complications , Primary Myelofibrosis/diagnosis , Treatment Outcome , Serum Albumin/therapeutic useABSTRACT
ABSTRACT: Combat casualty care can be complicated by transport times exceeding the "golden hour," with intervention and resuscitation limited to what the medic can carry. Pharmaceutical albumin comes highly saturated with nonesterified fatty acids (NEFAs). We recently showed that treatment with 25% bovine serum albumin (BSA) loaded with oleic acid, but not NEFA-free BSA, improved survival for hours after severe hemorrhage and often eliminated the need for resuscitation in rats. However, it was unknown whether pharmaceutical albumin, derived from human sources and loaded with caprylic acid (CA), would have the same benefits. We compared adjunct treatment with oleic acid-saturated BSA, CA-saturated BSA, pharmaceutical human serum albumin, or a no-albumin control in a similar rat hemorrhagic shock model to determine whether the three NEFA-albumin groups provided the same benefits relative to control. We found almost no significant differences among the NEFA-albumin groups in any measure. Mortality in controls was too low to allow for detection of improvement in survival, but NEFA-albumin groups had significantly improved hemodynamics, lactate clearance, and greatly reduced fluid requirements compared with controls. Contrary to expectations of "dehydration," 25% albumins shifted little additional fluid into the vasculature. Rather, they restored protein to the autotransfusion fluid. Nonesterified fatty acids-albumin did not worsen lung permeability, but we observed a loss of circulating protein suggesting it may have increased overall vascular permeability. Our findings suggest that, though imperfect, 25% human serum albumin could be a solution for resuscitation in austere conditions requiring prolonged field care.
Subject(s)
Hemodynamics , Resuscitation , Serum Albumin , Shock, Hemorrhagic , Animals , Rats , Resuscitation/methods , Humans , Hemodynamics/drug effects , Shock, Hemorrhagic/therapy , Shock, Hemorrhagic/drug therapy , Male , Serum Albumin/therapeutic use , Rats, Sprague-Dawley , Disease Models, Animal , Wounds and Injuries/therapy , Wounds and Injuries/drug therapy , Serum Albumin, Human , Serum Albumin, Bovine , Oleic Acid , Fatty Acids, Nonesterified/blood , Caprylates/pharmacology , Emergency Medical Services , Hemorrhage/drug therapy , Hemorrhage/therapyABSTRACT
RATIONALE & OBJECTIVE: Rituximab is the first-choice therapy for patients with primary membranous nephropathy (MN) and nephrotic syndrome. However, approximately 30% of patients are treatment-resistant or become treatment-intolerant with hypersensitivity reactions upon repeated drug exposures. We aimed to assess whether ofatumumab, a fully human second-generation anti-CD20 antibody, could be a valuable alternative to rituximab in this population. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 7 rituximab-intolerant and 10 rituximab-resistant patients with MN who consented to receive ofatumumab (50-300mg, single intravenous infusion) and were followed at the nephrology unit of Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII (Bergamo, Italy) between September 2015 and January 2019. FINDINGS: Over a median (IQR) follow-up of 5.0 (3.0-9.8) months, all 7 rituximab-intolerant and 3 of the 10 rituximab-resistant patients exhibited complete (proteinuria<0.3g/d) or partial (proteinuria<3.5g/d with≥50% reduction vs baseline) remission of nephrotic syndrome. Circulating B cells were similarly depleted in all patients by 1 week, and serum anti-phospholipase A2 receptor antibody concentrations decreased to<2.7 relative units/mL in 3 of 4 rituximab-intolerant and 4 of 8 rituximab-resistant patients with phospholipase A2 receptor-related disease. Ofatumumab significantly reduced 24-hour urinary protein and immunoglobulin G excretion and increased serum albumin and immunoglobulin G levels. These effects were greater in rituximab-intolerant than in rituximab-resistant patients. Measured glomerular filtration rate significantly increased by an average of 13.4% at 24 months compared with baseline (P=0.036) among all patients in the series. There were 14 nonserious infusion-related adverse events in 9 patients that recovered with temporary infusion interruption. LIMITATIONS: Retrospective design, limited number of patients. CONCLUSIONS: Ofatumumab may represent an effective and safe treatment for rituximab-intolerant cases of MN. Larger prospective studies will be needed to validate these preliminary findings and explore the effectiveness of other second-generation anti-CD20 antibodies in this clinical setting. PLAIN-LANGUAGE SUMMARY: Primary membranous nephropathy (MN) is one of the most frequent causes of nephrotic syndrome (NS) in adults. In this case series, we explored the efficacy of ofatumumab, a fully human second-generation anti-CD20 antibody, in 17 patients with MN and NS who were intolerant or unresponsive to rituximab. All 7 rituximab-intolerant patients exhibited complete or partial clinical remission, compared with only 3 of the 10 rituximab-resistant patients. Autoantibody levels decreased in all patients with phospholipase A2 receptor-related disease. Ofatumumab achieved a significant reduction in urinary protein and immunoglobulin G excretion while increasing serum albumin and immunoglobulin G levels. Ofatumumab may be a promising option for patients with MN who are rituximab-intolerant. Further investigations are warranted to validate these preliminary findings.
Subject(s)
Glomerulonephritis, Membranous , Nephrotic Syndrome , Adult , Humans , Rituximab/therapeutic use , Nephrotic Syndrome/drug therapy , Retrospective Studies , Prospective Studies , Antibodies, Monoclonal, Humanized/therapeutic use , Immunoglobulin G , Proteinuria/drug therapy , Serum Albumin/therapeutic use , Phospholipases/therapeutic use , Immunosuppressive Agents/therapeutic use , Receptors, Phospholipase A2ABSTRACT
ABSTRACT: Management of heart failure (HF) requires the use of loop diuretics to relieve congestion and improve symptoms. When loop diuretics alone fail to induce adequate diuresis, albumin has been proposed to enhance loop diuretic delivery and promote redistribution of fluid for excretion by the kidneys. Despite the theoretical benefits of albumin, studies suggesting its benefit in HF are scarce and the co-administration of loop diuretics and albumin remains controversial. This retrospective, observational study evaluated patients with HF 18 years or older who received concomitant intravenous loop diuretic and albumin administration. The primary objective was to evaluate the association of serum albumin level with urine output (UOP) in hospitalized patients with HF who received concomitant albumin and loop diuretic therapy. Secondary endpoints included total weight loss after 72 hours, and ICU and hospital lengths of stay. In total, 276 patients were included for analysis. There was no association between initial serum albumin level and 72-hour UOP (coefficient -623.1, 95% confidence interval -1558.6 to 312.4; P = 0.191) or weight difference at 72 hours (coefficient -1.0, 95% confidence interval -2.4 to 0.3; P = 0.131). Lower albumin levels were associated with longer ICU ( P = 0.034) and hospital ( P = 0.039) lengths of stay. Concomitant thiazide diuretic use and increasing loop diuretic doses were associated with increased 72-hour UOP. The results of our study suggests that providers should avoid using baseline albumin levels as guidance for albumin dosing in HF. Given the lack of comparator groups, larger randomized controlled trials should be done to provide a definitive role for albumin to enhance diuresis in patients with HF on intravenous loop diuretics.
Subject(s)
Heart Failure , Sodium Potassium Chloride Symporter Inhibitors , Humans , Sodium Potassium Chloride Symporter Inhibitors/adverse effects , Retrospective Studies , Heart Failure/diagnosis , Heart Failure/drug therapy , Administration, Intravenous , Serum Albumin/therapeutic use , Diuretics/adverse effectsABSTRACT
OBJECTIVE: To investigate the prognostic value of serum albumin (SA) levels before chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) after receiving chemotherapy. METHODS: This is a retrospective study, and 127 patients with DLBCL including 71 males (55.9%) and 56 females (44.1%) were included. Patients' gender, age, Ann Arbor staging, eastern cooperative oncology group (ECOG) score, treatment options, international prognostic index, response rate, overall survival (OS), and progression-free survival (PFS) were obtained for statistical analysis. RESULTS: Univariate analysis showed that SA≤34 g/L, Ann Arbor III-IV, B symptoms, ECOG≥2, and bone marrow involvement suggest a poor prognosis in patients with DLBCL. Patients with persistent SA>34 g/L had significantly longer OS than patients with persistent SA≤34 g/L (P=0.020). Multivariate analysis showed that SA≤34 g/L (HR=0.48, 95% CI=0.26-0.90, P=0.022) and R-CHOP-like treatment regimen (HR=0.43, 95% CI=0.24-0.76, P=0.004) are independent factors that could affect the prognosis of patients with DLBCL. CONCLUSION: SA can be used as an indicator of prognosis in patients with DLBCL before the first chemotherapy. DLBCL patients with SA≤34 g/L are associated with short OS and poor prognosis, which may potentially provide guidance for the clinician to pay more attention to this population before the first chemotherapy.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Male , Female , Humans , Prognosis , Retrospective Studies , Disease-Free Survival , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Serum Albumin/therapeutic useABSTRACT
Background: We conducted this animal study to assess the efficacy of the novel hydrogel containing zinc oxide-loaded and minocycline serum albumin nanoparticals (Mino-ZnO@Alb NPs) on peri-implantitis in an experimental mouse model. Material and methods: Mino-ZnO@Alb NPs was prepared as previously reported. The peri-implantitis model was successfully established in rats, and the rats were divided into three groups randomly: Mino-ZnO@Alb NPs (Mino-ZnO) group, minocycline group, and untreated group. Four weeks later, clinical and radiographic assessments were performed to evaluate soft tissue inflammation and bone resorption level. Histologic analysis was performed to estimate the amount of remaining supporting bone tissue (SBT) around implants. ELISA tests were used to determine the concentration of inflammation factor interleukin-1-beta (IL-1β) and anti-inflammation factor tumor necrosis factor-alpha (TNF-α) around implants. Results: After one month, the Mino-ZnO group showed better results than the other two groups in regards to the results of bleeding on probing, probing pocket depth, bleeding index and gingival index. X-ray showed that SBT at mesial and distal sites around implants in the other two groups was significantly lower compared with that of Mino-ZnO group. The quantity of osteoclasts in peri-implant tissues of the Mino-ZnO group was less than that in the minocycline and untreated groups. IL-1β in the Mino-ZnO group was lower than that in the other two groups. TNF-α level was the opposite. Conclusions: Mino-ZnO@Alb NPs can effectively treat peri-implantitis and promote soft tissue healing, and may act as a promising product. (AU)
Subject(s)
Animals , Rats , Dental Implants , Peri-Implantitis/drug therapy , Zinc Oxide/therapeutic use , Hydrogels/therapeutic use , Serum Albumin/analysis , Serum Albumin/therapeutic use , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/therapeutic use , Minocycline/therapeutic useABSTRACT
BACKGOUND: Selinexor is an orally available selective inhibitor of exportin-1 that has offered a new treatment option in relapsed or refractory myeloma (RRMM) either in combination with dexamethasone (Sd) or with bortezomib and dexamethasone (SVd). PATIENTS-METHODS: We evaluated the efficacy and toxicity of selinexor combinations in the real world, post progression therapies and their outcomes. The analysis included 44 patients with RRMM treated with Sd (N = 21, 48%) or SVd (N = 23, 52%). RESULTS: On intent-to-treat, response rate (ORR) among all treated patients was 29.5% (13/44, of which CR: 2, VGPR: 3, PR:8); ORR was 35% for SVd and 24% for Sd. Median PFS was 3.0 months for all; 6.9 months for responders (≥PR),2.7 months for Sd and 3.4 months for SVd treated patients. In univariate analysis, serum albumin <3.5 g/dl and LDH >ULN were associated with worse PFS (P = .001 and P = .032, respectively).The OS of the whole cohort exceeded one year while serum albumin <3.5 gr/dl and LDH>ULN were associated with worse OS. After progression to Sd/SVd, 20 patients received further therapy; on ITT, the ORR was 40% (8/20) and the subsequent PFS was 3.4 months. The most common adverse events were fatigue, thrombocytopenia and nausea, while the most recorded grade 3 or 4 side effect was thrombocytopenia; 56% (25/44) of patients required dose reduction, however, this was not associated with inferior PFS. CONCLUSION: In conclusion, selinexor-based therapy provides an additional treatment option in the real word setting and with appropriate dosing and toxicity management a subset of patients may have significant benefit.
Subject(s)
Multiple Myeloma , Thrombocytopenia , Humans , Multiple Myeloma/drug therapy , Dexamethasone/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Serum Albumin/therapeutic use , Thrombocytopenia/chemically inducedABSTRACT
BACKGROUND: We conducted this animal study to assess the efficacy of the novel hydrogel containing zinc oxide-loaded and minocycline serum albumin nanoparticals (Mino-ZnO@Alb NPs) on peri-implantitis in an experimental mouse model. MATERIAL AND METHODS: Mino-ZnO@Alb NPs was prepared as previously reported. The peri-implantitis model was successfully established in rats, and the rats were divided into three groups randomly: Mino-ZnO@Alb NPs (Mino-ZnO) group, minocycline group, and untreated group. Four weeks later, clinical and radiographic assessments were performed to evaluate soft tissue inflammation and bone resorption level. Histologic analysis was performed to estimate the amount of remaining supporting bone tissue (SBT) around implants. ELISA tests were used to determine the concentration of inflammation factor interleukin-1-beta (IL-1ß) and anti-inflammation factor tumor necrosis factor-alpha (TNF-α) around implants. RESULTS: After one month, the Mino-ZnO group showed better results than the other two groups in regards to the results of bleeding on probing, probing pocket depth, bleeding index and gingival index. X-ray showed that SBT at mesial and distal sites around implants in the other two groups was significantly lower compared with that of Mino-ZnO group. The quantity of osteoclasts in peri-implant tissues of the Mino-ZnO group was less than that in the minocycline and untreated groups. IL-1ß in the Mino-ZnO group was lower than that in the other two groups. TNF-α level was the opposite. CONCLUSIONS: Mino-ZnO@Alb NPs can effectively treat peri-implantitis and promote soft tissue healing, and may act as a promising product.
Subject(s)
Dental Implants , Peri-Implantitis , Zinc Oxide , Rats , Mice , Animals , Peri-Implantitis/drug therapy , Minocycline/therapeutic use , Zinc Oxide/therapeutic use , Hydrogels/therapeutic use , Serum Albumin/analysis , Serum Albumin/therapeutic use , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/therapeutic use , InflammationABSTRACT
BACKGROUND: Albumin infusion is the primary therapeutic strategy for septic patients with liver cirrhosis. Although recent studies have investigated the efficacy of albumin in the resuscitation stage of septic patients with liver cirrhosis, it remains unclear whether daily albumin administration can improve outcomes. Furthermore, the indications for initiating albumin therapy are not well defined. METHODS: Septic patients with liver cirrhosis were obtained from the Medical Information Mart for Intensive Care (MIMIC-IV 2.0) database. Marginal structural Cox models were employed to investigate the association between daily albumin infusion and 28-day mortality. We also aimed to explore under what circumstances enrolled patients could benefit most from albumin administration, based on the clinical parameters collected on the day of albumin infusion, including serum albumin concentration, serum lactate concentration, mean arterial pressure (MAP), and vasopressor dosage. RESULTS: A total of 2265 patients were included in the final analysis, of whom 1093 (48.3%) had received albumin treatment at least once. The overall 28-day mortality was 29.6%. After marginal structural modeling, daily albumin infusion was associated with a reduced risk of 28-day death (hazard ratio, 0.76; 95% CI 0.61-0.94). We found that patients benefit most from albumin infusion when initiated on the day of serum albumin concentration between 2.5 and 3.0 g/dL, serum lactate concentration greater than or equal to 2 mmol/L, MAP less than 60 mmHg, or vasopressor dosage between 0.2 and 0.3 mcg/kg/min (norepinephrine equivalent, NEE). CONCLUSIONS: Albumin infusion is associated with a reduction in mortality in septic patients with liver cirrhosis under specific circumstances. Serum albumin concentration, serum lactate, MAP, and vasopressor dosage were found to be modifiers of treatment effectiveness and should be considered when deciding to initial albumin infusion.
Subject(s)
Shock, Septic , Humans , Shock, Septic/drug therapy , Vasoconstrictor Agents/therapeutic use , Lactic Acid , Liver Cirrhosis/complications , Liver Cirrhosis/drug therapy , Serum Albumin/therapeutic useABSTRACT
PURPOSE: Oncogene-driven macropinocytosis fuels nutrient scavenging in some cancer types, yet whether this occurs in thyroid cancers with prominent MAPK-ERK and PI3K pathway mutations remains unclear. We hypothesized that understanding links between thyroid cancer signaling and macropinocytosis might uncover new therapeutic strategies. EXPERIMENTAL DESIGN: Macropinocytosis was assessed across cells derived from papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), non-malignant follicular thyroid, and aggressive anaplastic thyroid cancer (ATC), by imaging fluorescent dextran and serum albumin. The impacts of ectopic BRAFV600E and mutant RAS, genetic PTEN silencing, and inhibitors targeting RET, BRAF, and MEK kinases were quantified. BrafV600E p53-/- ATC tumors in immunocompetent mice were used to measure efficacy of an albumin-drug conjugate comprising microtubule-destabilizing monomethyl auristatin E (MMAE) linked to serum albumin via a cathepsin-cleavable peptide (Alb-vc-MMAE). RESULTS: FTC and ATC cells showed greater macropinocytosis than non-malignant and PTC cells. ATC tumors accumulated albumin at 8.8% injected dose per gram tissue. Alb-vc-MMAE, but not MMAE alone, reduced tumor size by >90% (P < 0.01). ATC macropinocytosis depended on MAPK/ERK activity and nutrient signaling, and increased by up to 230% with metformin, phenformin, or inhibition of IGF1Ri in monoculture but not in vivo. Macrophages also accumulated albumin and express the cognate IGF1R ligand, IGF1, which reduced ATC responsiveness to IGF1Ri. CONCLUSIONS: These findings identify regulated oncogene-driven macropinocytosis in thyroid cancers and demonstrate the potential of designing albumin-bound drugs to efficiently treat them.
Subject(s)
Thyroid Carcinoma, Anaplastic , Thyroid Neoplasms , Mice , Animals , Phosphatidylinositol 3-Kinases/genetics , Mutation , Proto-Oncogene Proteins B-raf , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/genetics , Thyroid Neoplasms/metabolism , Thyroid Carcinoma, Anaplastic/drug therapy , Thyroid Carcinoma, Anaplastic/genetics , Oncogenes , Thyroid Cancer, Papillary/genetics , Serum Albumin/genetics , Serum Albumin/therapeutic useABSTRACT
Serum albumin (SA), one of the most abundant proteins in blood plasma, plays essential roles in all living processes and has been used in various biomedical applications. Biomaterials fabricated from SAs (human SA, bovine SA, and ovalbumin) exhibit proper microstructure and hydrophilicity as well as remarkable biocompatibility; this makes them ideal for use in bone regeneration. This review provides a comprehensive overview of the structure, physicochemical properties, and biological features of SAs. SAs can be used to generate a wide array of biomaterials for bone repair because of their flexible structure and diverse functions, which enables us to control structure and morphology as well as modulate the biological responses with host tissue. This review summarizes the material categories, forms, and fabrication methods of SA in bone repair. Finally, concerns for future studies in biomedical fields with SA-derived biomaterials are discussed.
Subject(s)
Biocompatible Materials , Serum Albumin , Animals , Cattle , Humans , Biocompatible Materials/pharmacology , Biocompatible Materials/therapeutic use , Serum Albumin/pharmacology , Serum Albumin/therapeutic use , Serum Albumin/chemistryABSTRACT
OBJECTIVE: To describe the clinical use of canine-specific albumin (CSA) in critically ill dogs, report adverse events, and evaluate measurable clinical effects of CSA administration. DESIGN: Retrospective case series from 2019 to 2020. SETTING: Large, urban, private-practice referral and emergency center. ANIMALS: Consecutive sample of 125 client-owned dogs administered CSA transfusions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The conditions most commonly associated with the use of CSA were surgical (32/125) and nonsurgical (20/125) gastrointestinal disease. Both serum albumin and total plasma protein concentrations were significantly increased posttransfusion (P < 0.001), and 16% albumin transfusions produced the greatest magnitude increase in serum albumin (P = 0.0015). Concurrent crystalloid administration did not affect change in albumin. While there was no significant improvement in blood pressure seen in those patients that received albumin, a significant improvement in shock index was identified (P = 0.02). Adverse events were uncommon; however, 8 critically ill dogs died during CSA administration. CONCLUSIONS: CSA appears to be a relatively safe alternative to synthetic colloids and complementary to crystalloids in critically ill patients. More concentrated solutions may be more effective in raising serum albumin concentration. Further investigation into the indications for and efficacy of CSA will continue to improve our knowledge of this blood product.
Subject(s)
Critical Illness , Serum Albumin , Dogs , Animals , Retrospective Studies , Serum Albumin/therapeutic use , Serum Albumin/metabolism , Crystalloid Solutions/therapeutic use , Colloids/therapeutic use , Fluid Therapy/veterinaryABSTRACT
The use of cisplatin is severely limited by the risk of developing cardiovascular complications. Sinapic acid may reduce cisplatin's side effects. The anti oxidant, anti-inflammatory, and peroxynitrite-scavenging properties of sinapic acid could provide protection against the cardiotoxicity caused by cisplatin. To induce toxicity in rats, cisplatin was administered for a period of 5 weeks. Animal electrocardiograms were obtained after cisplatin toxicity had taken effect. Blood samples and heart tissues were then harvested from the anesthetized animals. The ELISA technique was used to evaluate the level of proinflammatory cytokines and oxidative and nitrosative stress indicators in the heart tissue and serum. A real-time PCR was used to analyze GPX4 and NF-κB expression in the heart tissue. Hematoxylin-eosin and Masson's trichrome were also utilized. Electrocardiograms data showed an increase in QRS and QT intervals. Biochemically, cisplatin increased oxidative, nitrosative, and proinflammatory cytokine levels. Animals exposed to cisplatin had histopathological findings in the heart tissue, according to the results of histological assessment. Sinapic acid reduced TNF-alpha, interleukin-6, malondialdehyde, and ischemia-modified albumin. Sinapic acid also reduced oxidative and nitrosative stress. Furthermore, Sinapic acid restored lengthy QT and QRS. Cisplatin-treated rats had higher NF-κB activation than controls. This effect was successfully inhibited by sinapic acid. Histopathologically, tissues treated with sinapic acid were less damaged than tissues treated with cisplatin. In conclusion, our results suggest that sinapic acid exhibited a protective effect against the cardiotoxicity induced by cisplatin. These effects may be caused by the overexpression of GPX4 and the downregulation of NF-KB, as well as antioxidant and anti-inflammatory properties.
Subject(s)
Cisplatin , NF-kappa B , Animals , Rats , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antioxidants/metabolism , Biomarkers/metabolism , Cardiotoxicity/metabolism , Cisplatin/toxicity , Cytokines/metabolism , Inflammation/metabolism , NF-kappa B/metabolism , Oxidative Stress , Serum Albumin/metabolism , Serum Albumin/pharmacology , Serum Albumin/therapeutic useABSTRACT
Intravenous administration of crystalloid or colloid solutions is the most common intervention for correcting hypovolemia in intensive care unit patients. In critical illness, especially sepsis and severe trauma, vascular wall permeability increases, and trans-endothelial escape of serum albumin, the major oncotic plasma constituent, contributes to the development of hypoalbuminemia and edema formation. The volume effects of intravenous human albumin solution exceed those of crystalloid solutions. If hypoalbuminemia is an effect moderator, the crystalloid-to-albumin ratio of fluid resuscitation volumes is not well characterized. Randomized controlled trials have confirmed that intravenous administration of human albumin solutions for volume resuscitation results in a lower net fluid balance compared with crystalloids, and smaller infusion volumes may be sufficient for hemodynamic stabilization when human albumin solutions are used. This narrative review summarizes the current evidence and conclusions drawn regarding the role of hypoalbuminemia in volume resuscitation. In the 'Saline versus Albumin Fluid Evaluation' study using 4% human albumin solution or saline, the saline-to-albumin ratio of study fluids was significantly higher in patients with baseline serum albumin concentrations of 25 g/L or less as compared to patients with baseline serum albumin concentrations of more than 25 g/L. In patients receiving renal replacement therapy, intravenous administration of 20-25% human albumin solution reduces intradialytic hypotension and improves fluid removal better than saline if serum albumin levels are similarly reduced. These data suggest that hypoalbuminemia acts as an effect moderator in volume resuscitation and plasma expansion with albumin solution. The volume effectiveness of intravenous human albumin solution in resuscitation appears to be greater when the serum albumin levels are low. In clinical situations, serum albumin concentrations per se may inform when and how to include intravenous albumin in fluid resuscitation if large amounts of crystalloids are needed, which requires further studies.
Subject(s)
Hypoalbuminemia , Humans , Hypoalbuminemia/drug therapy , Isotonic Solutions , Crystalloid Solutions/therapeutic use , Infusions, Intravenous , Serum Albumin/therapeutic use , Serum Albumin, Human/therapeutic useABSTRACT
Objective: To explore the long-term efficacy of low-dose rituximab (RTX) treatment in patients with primary membranous nephropathy (PMN). Methods: Patients with biopsy-proven PMN who received low-dose RTX as initial or second-line regimen from August 2018 to May 2020 in the Department of Nephrology, Tianjin Medical University General Hospital were respectively enrolled. The clinical parameters of patients were urinary protein>3.5 g/24 h, serum albumin<30 g/L and estimated glomerular filtration rate (eGFR)>20 ml·min-1·(1.73 m2)-1. The treatment response of patients with PMN was observed during follow-up, and the remission rate of patients with urinary protein<8 g/24 h or ≥8 g/24 h, anti-PLA2R antibody<150 RU/ml or ≥150 RU/ml, eGFR≥ 60 ml·min-1·(1.73 m2)-1 or<60 ml·min-1·(1.73 m2)-1 were analyzed, respectively. Results: A total of 40 patients were enrolled, including 26 males and 14 females, aged (53±15) years. There were 14 patients received RTX as initial treatment and 26 patients as second-line therapy. The total median dose of RTX in the first course was 800 (425, 1 075) mg. The overall remission rate at the 1st, 3rd, 6th, 12th and 24th months were 12.5% (5/40), 17.5% (7/40), 47.5% (19/40), 57.5% (23/40), 60% (24/40), respectively. The median overall response time was 6.0 (3.0, 7.5) months. Two cases relapsed. Patients with remission (n=24) had a higher level of baseline eGFR [(93.9±28.0) vs (62.4±28.1) ml·min-1·(1.73 m2)-1, P=0.001), and a lower level of both urinary protein [5.9 (5.0, 6.5) vs 11.7 (8.6, 15.5) g/24 h, P<0.001] and anti-PLA2R antibody level [73 (29, 132) vs 453 (182, 950) RU/ml, P=0.004] than those without remission (n=16) 24 month after treatment. There was no statistically significant difference in the remission rate between initial and second-line treatment (P=0.101). Moreover, patients had a higher remission rate in urinary protein<8 g/24 h group (21/26 vs 3/14, P<0.001), anti-PLA2R antibody<150 RU/ml group (16/19 vs 5/16, P=0.002) and eGFR ≥ 60 ml·min-1·(1.73 m2)-1 group (22/29 vs 2/11, P=0.003). Conclusions: Low-dose RTX treatment in PMN is effective during long-term follow-up, and has a lower recurrence rate. The results also suggest that it is more suitable for patients with baseline urinary protein<8 g/24 h, anti-PLA2R antibody<150 RU/ml and eGFR≥ 60 ml·min-1·(1.73 m2)-1.
Subject(s)
Glomerulonephritis, Membranous , Female , Humans , Male , Autoantibodies , Glomerular Filtration Rate , Glomerulonephritis, Membranous/drug therapy , Glomerulonephritis, Membranous/metabolism , Immunosuppressive Agents/therapeutic use , Receptors, Phospholipase A2 , Rituximab/therapeutic use , Serum Albumin/therapeutic use , Adult , Middle Aged , AgedABSTRACT
BACKGROUND: The coexistence of Neuromyelitis Optica spectrum disorder (NMOSD) with other autoimmune diseases (AD-NMOSD) presents worse clinical outcomes and healthcare costs than NMOSD alone (NMOSD-only). NMOSD and other autoimmune diseases also have a higher prevalence and morbidity in Black. We aim to compare clinical features and treatment responses in NMOSD patients with and without overlapping autoimmunity in a predominantly Black cohort. We further identify predictors associated with each clinical subtype. METHODS: AD-NMOSD (n = 14) and NMOSD-only (n = 27) patients were identified retrospectively. Demographic, clinical, laboratory, imaging, and response to treatment data were examined. RESULTS: Our cohort was predominately Black (82.9%). The prevalence of grouped-comorbidities, history of infections, sensory symptoms, Expanded Disability Status Scale (EDSS) before treatment, double-stranded DNA, antinuclear, ribonucleoprotein, and antiphospholipid antibodies, spinal-cord edema, white matter occipital lesions, and the levels of C-reactive protein, urine protein/creatinine, white blood cell count in cerebrospinal fluid (CSF), were higher in AD-NMOSD patients (p < 0.05 and/or Cramer's V > 30, Cohen's d > 50), whereas the age of males, visual symptoms, serum albumin, platelet count, and optic nerve enhancement were lower. EDSS after treatment improved in both groups being more evident in NMOSD-only patients (p = 0.003, SE = 0.58 vs p = 0.075, SE = 0.51). Other variables had a close to moderate SE, and others did not differ between NMOSD subtypes. A higher frequency of grouped-comorbidities, lower serum albumin, and platelet count were independently associated with a higher risk for AD-NMOSD. CONCLUSIONS: Some clinical features between AD-NMOSD and NMOSD-only patients were similar, while others differed. Comorbidities, serum albumin, and platelet count may be independent predictors of AD-NMOSD.
Subject(s)
Autoimmune Diseases , Neuromyelitis Optica , Male , Humans , Neuromyelitis Optica/diagnostic imaging , Neuromyelitis Optica/epidemiology , Neuromyelitis Optica/drug therapy , Retrospective Studies , Autoimmune Diseases/epidemiology , Autoimmune Diseases/complications , Hospitals, Urban , Serum Albumin/metabolism , Serum Albumin/therapeutic use , Aquaporin 4 , AutoantibodiesABSTRACT
Immune checkpoint inhibitors (ICIs) for treatment of metastatic melanoma (MM) offer lasting overall survival (OS) benefit in a subset of patients. However, outcomes remain poor for non-responders. Clinical predictors of long-term survival remain elusive. We utilized the Alberta Immunotherapy Database to investigate the association of host and disease characteristics, and treatment factors with overall survival (OS) greater than 3 years. We identified patients treated between August 2013 and May 2020 with single-agent anti-PD1 or combination (anti-PD1 and anti-CTLA4) ICI regimens. A logistic regression model was used to assess for independent association between clinical factors captured and survival greater than 3 years. Statistically significant factors on univariable analysis were assessed using multivariable analysis. In total, 284 of 460 patients were identified to have short-term (<1 year) or long-term (>3 years) survival with 186 surviving <1 year and 98 surviving >3 years. The median age was 64 and 18.4% of patients were ECOG ≥ 2. On logistic regression, Breslow's Depth ≤ 4 mm, normal serum LDH, normal serum albumin and M-stage 1a/b were associated with OS > 3 years on univariable and multivariable analysis. ECOG < 2, dNLR ≤ 3, normal hemoglobin were only associated with survival on the univariable analysis but not in the multivariable analysis. The objective response rate in long-term survivors was 83.7% compared to 7.5% in the short-term survivors. Our study identifies four easily accessible predictors of long-term survival in a large real-world MM cohort treated with ICI.
Subject(s)
Antineoplastic Agents, Immunological , Melanoma , Neoplasms, Second Primary , Humans , Antineoplastic Agents, Immunological/therapeutic use , Hemoglobins/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Ipilimumab/therapeutic use , Melanoma/drug therapy , Melanoma/pathology , Serum Albumin/therapeutic useABSTRACT
Dear Editor, Scurvy is a nutritional disorder which can develop after prolonged (>1-3 months) severe vitamin C deficiency. Vitamin C is a cofactor in several enzyme reactions involved in collagen synthesis. The defect in collagen causes blood vessel fragility, poor wound healing, mucocutaneous bleedings, hair abnormalities, bone pains, and joint contractures due to periosteal and intraarticular bleeding (1,2). Risk factors for scurvy development are undernutrition, low socioeconomic status, older age, male sex, alcoholism, tobacco smoking, and severe psychiatric illnesses (1-3). The required daily intake for vitamin C is ~60 mg, and this amount of vitamin C can be found in only one medium-sized orange. For this reason, the disease is rarely encountered in developed countries and is often underrecognized by healthcare personnel. Herein, we present an illustrative case of scurvy in order to raise the awareness of this disorder. A 61-year-old Caucasian man was admitted to hospital due to fatigue, hypotension (80/50 mmHg), severe normocytic anemia (hemoglobin 76 g/L), kidney failure (estimated glomerular filtration rate of 6 mL/min/1.73m2) and mild elevation in C-reactive protein (30.9 mg/L). Prior medical history included radical cystoprostatectomy with an ileal conduit performed eight years ago due to a bladder tumor and moderate chronic kidney disease with recurrent urinary tract infections. The patient was also an alcoholic and tobacco smoker, with a very low-income and a poor diet. He did not use any medications. Heteroanamnestically, the current clinical state had developed slowly over several weeks. At admission, the patient was afebrile, lethargic, malnourished, and immobile due to generalized weakness, bone pains, and hip and knee contractures. He had generalized edema, mostly related to kidney failure, as well as severe hypoalbuminemia (serum albumin 19 g/L). There were multiple ecchymoses (Figure 1, a) and perifollicular bleedings (Figure 1, b) in the skin. The teeth were defective, and the patient's facial hair had a "corkscrew" appearance (Figure 1, c). The platelet count was normal, as was the serum fibrinogen level and the prothrombin- and activated partial thromboplastin times. Vancomycin-resistant Enterococcus faecium and multi-drug-resistant Acinetobacter baumanii were isolated from the urine. Therefore, hemodialysis, linezolid, and colistin were started. However, the patient continued to be lethargic, immobile, and with prominent skin bleeding. Medical workup excluded the possibility of an underlying malignancy or an autoimmune disorder. Finally, scurvy was suspected and 500 mg daily of oral vitamin C was introduced into therapy. In the following two weeks, the general condition of the patient significantly improved and he was discharged from the hospital in good condition - mobile and with complete resolution of skin lesions (Figure 1, d and e). Three months later, the patient was still under maintenance hemodialysis and had mild anemia (hemoglobin 123 g/L). Interestingly, scurvy was the first disease in the history of medicine for which a randomized trial found a cure (4). The differential diagnosis of scurvy includes skin infections, hematologic disorders, collagen vascular disorders, and anticoagulant/antiplatelet side-effects (1). Pathognomonic skin findings which may help raise suspicion of scurvy are perifollicular bleedings and "corkscrew" hair. Notably, laboratory testing for vitamin C concentration is not necessary to confirm scurvy as it tends to reflect recent dietary intake of vitamin C (2). Nevertheless, it may be useful to identify less typical cases (2). In our case, rapid clinical improvement with the resolution of skin lesions and joint contractures after the introduction of vitamin C confirmed the clinical diagnosis of scurvy. Additionally, vitamin C deficiency could be, at least partly (besides kidney failure and acute infection), responsible for severe anemia at disease presentation (5). This case serves to remind clinicians not to forget scurvy when treating patients at risk for vitamin C deficiency who present with fatigue, anemia, bone pains, and unexplained mucocutaneous bleedings. In suspected cases, vitamin C should be administered without hesitation.
Subject(s)
Anemia , Ascorbic Acid Deficiency , Contracture , Renal Insufficiency , Scurvy , Anemia/drug therapy , Anticoagulants/therapeutic use , Ascorbic Acid/therapeutic use , Ascorbic Acid Deficiency/complications , Ascorbic Acid Deficiency/diagnosis , Ascorbic Acid Deficiency/therapy , C-Reactive Protein/therapeutic use , Colistin/therapeutic use , Contracture/drug therapy , Fatigue , Fibrinogen/therapeutic use , Humans , Linezolid/therapeutic use , Male , Middle Aged , Prothrombin/therapeutic use , Renal Insufficiency/drug therapy , Scurvy/complications , Scurvy/diagnosis , Serum Albumin/therapeutic use , Thromboplastin/therapeutic use , Vancomycin/therapeutic use , VitaminsABSTRACT
BACKGROUND: Long-term prophylactic therapy is considered the standard of care for hemophilia A patients. This study models the long-term clinical and cost outcomes of two factor VIII (FVIII) products using a pharmacokinetic (PK) simulation model in a Chinese population. METHODS: Head-to-head PK profile data of BAY 81-8973 (KOVALTRY®) and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, ADVATE®) were applied to a two-state (alive and dead) Markov model to simulate blood FVIII concentrations at a steady state in prophylactically-treated patients with hemophilia A. Worsening of the Pettersson score was simulated and decline was associated with the probability of having orthopaedic surgery. The only difference between the compounds was FVIII concentration at a given time; each subject was treated with 25 IU/kg every 3 days. The model used a lifetime horizon, with cycle lengths of 1 year. RESULTS: Cumulative bleeding events, joint bleeding events, and major bleeding events were reduced by 19.3% for BAY 81-8973 compared to rAHF-PFM. Hospitalizations and hospitalization days were also reduced by 19.3% for BAY 81-8973 compared to rAHF-PFM. BAY 81-8973 resulted in both cost savings and a gain in quality adjusted life years (QALYs) compared to rAHF-PFM. CONCLUSION: Based on modeled head-to-head comparisons, differences in PK-properties between BAY 81-8973 and rAHF-PFM result in a reduced number of bleeding events, leading to reduced costs and increased quality of life for BAY 81-8973. These results should be used to inform clinical practice in China when caring for patients with severe hemophilia A.
Subject(s)
Factor VIII , Hemophilia A , Delivery of Health Care , Factor VIII/pharmacokinetics , Factor VIII/therapeutic use , Hemophilia A/complications , Hemophilia A/drug therapy , Hemorrhage/drug therapy , Hemorrhage/prevention & control , Humans , Quality of Life , Recombinant Proteins/adverse effects , Recombinant Proteins/pharmacokinetics , Serum Albumin/therapeutic useABSTRACT
The enhanced permeability and retention (EPR) effect has been the gold standard in developing drug delivery systems for passive tumor targeting. Although the importance of this concept remains unchanged, some controversies have arisen. In this review, various strategies for tumor targeting using macromolecules and nanoparticles based on the EPR effect are discussed from the viewpoint of pharmacokinetics. Overall, such strategies seek to retain therapeutic material in the blood circulation, which is a key factor for successful targeting. Strategies using macromolecules, including antibody-drug conjugates, serum albumin-based delivery systems, PEGylated recombinant proteins, and stealth liposomes as well as nanoparticle-based strategies such as those based on lipid nanoparticles, and polymeric micelles, have been discussed. The feasibility of small extracellular vesicles, a new class of nanosized delivery carriers, is also discussed.