Administration Of Human Serum Albumin Research Articles

Successful Use of Mycophenolate Mofetil as Adjunct to Prednisolone for Treatment of Acute Kidney Injury Secondary to Human Serum Albumin Administration in a Dog.

The use of human serum albumin (HSA) is described in dogs receiving critical care. However, despite the high degree of homology, anaphylactic and delayed hypersensitivity reactions are reported. Delayed type III hypersensitivity reactions can lead to glomerulonephritis and acute kidney injury (AKI). Undiluted 20% HSA was administered to a 4.8 yr old intact male Labrador Retriever with severe hypoalbuminemia, following surgical management of septic peritonitis of gastrointestinal origin. Nineteen days after HSA administration, the dog developed peracute high magnitude renal proteinuria and AKI. Rapid immunosuppression, using a combination of prednisolone and mycophenolate mofetil, resulted in full resolution of AKI, hypoalbuminemia, and proteinuria. Addition of mycophenolate mofetil may have resulted in the first documented case of full renal recovery from hypersensitivity-induced AKI caused by HSA administration.

Appropriate Human Serum Albumin Fluid Therapy and the Alleviation of COVID-19 Vulnerabilities: An Explanation of the HSA Lymphatic Nutrient Pump

COVID-19 and long COVID-19 vulnerabilities may be caused indirectly by albumin binding deficiency (ABD), which can be corrected by the correct administration of human serum albumin (HSA). The liver is the primary site of nutrient regulation and fluid volume maintenance; control of both is by changes to albumin concentration. In healthy subjects, the HSA lymphatic nutrient pump (HSALNP) ensures continual pumping of nutrients from the liver and that nutrients are appropriately distributed to organs. Nutrients are delivered to cells according to the availability of binding to HSA. The HSALNP, therefore, maintains the correct nutrient and colloidal pressure balance in all tissues independently. In unhealthy tissues, following COVID-19 infection, the passage of HSA/nutrients through the interstitial spaces and lymph will be impeded. Fluid therapy into the periphery leads to the dilution of essential nutrients attached to the protein carriers such as albumin. The levels of albumin being charged by the liver with nutrients is critical in maintaining immune stability by maintaining nutrient support and colloidal pressure of the cellular structures. The site of HSA binding by the liver is of great importance, and direct infusion of albumin into the hepatic portal vein is the most appropriate method of maintaining colloid pressure and cellular nutrient levels.

Expert consensus on the use of human serum albumin in critically ill patients.

Expert consensus on the use of human serum albumin in critically ill patients.

Albumin internalizes and inhibits endosomal TLR signaling in leukocytes from patients with decompensated cirrhosis.

Human serum albumin (HSA) is an emerging treatment for preventing excessive systemic inflammation and organ failure(s) in patients with acutely decompensated (AD) cirrhosis. Here, we investigated the molecular mechanisms underlying the immunomodulatory properties of HSA. Administration of HSA to patients with AD cirrhosis with elevated circulating bacterial DNA rich in unmethylated cytosine-phosphate-guanine dideoxynucleotide motifs (CpG-DNA) was associated with reduced plasma cytokine concentrations. In isolated leukocytes, HSA abolished CpG-DNA-induced cytokine expression and release independently of its oncotic and scavenging properties. Similar anti-inflammatory effects were observed with recombinant human albumin. HSA exerted widespread changes on the immune cell transcriptome, specifically in genes related to cytokines and type I interferon responses. Our data revealed that HSA was taken up by leukocytes and internalized in vesicles positively stained with early endosome antigen 1 and colocalized with CpG-DNA in endosomes, where the latter binds to Toll-like receptor 9 (TLR9), its cognate receptor. Furthermore, HSA also inhibited polyinosinic:polycytidylic acid- and lipopolysaccharide-induced interferon regulatory factor 3 phosphorylation and TIR domain-containing adapter-inducing interferon-β-mediated responses, which are exclusive of endosomal TLR3 and TLR4 signaling, respectively. The immunomodulatory actions of HSA did not compromise leukocyte defensive mechanisms such as phagocytosis, efferocytosis, and intracellular reactive oxygen species production. The in vitro immunomodulatory effects of HSA were confirmed in vivo in analbuminemic humanized neonatal Fc receptor transgenic mice. These findings indicate that HSA internalizes in immune cells and modulates their responses through interaction with endosomal TLR signaling, thus providing a mechanism for the benefits of HSA infusions in patients with cirrhosis.

The presence of S-sulfonated transthyretin in commercial human serum albumin solutions: Potential contribution to neuropathy

BackgroundCommercial solutions of human serum albumin (HSA) are administered to critically ill patients for the treatment of shock, restoration of blood volume, and the acute management of burns. Previously, conflicting results on the effects of HSA administration have been reported varying from a favorable increase in total plasma antioxidant capacity to a higher mortality rate in traumatic brain injury (TBI) patients. These results could be partially explained due to the known heterogeneity of HSA solutions. We report the discovery of S-sulfonated human transthyretin (hTTR) in HSA solutions. MethodsProteomics was performed on commercially available solutions of 5% HSA by LC-MS analysis. The MS charge envelope for hTTR was deconvolved to the uncharged native hTTR parent mass (13,762 Da). The parent mass was then integrated, and relative proportions of the 2 major species of hTTR, native and S-sulfonated hTTR (13,842 Da), were calculated. ResultsThe majority of hTTR found in 5% commercial HSA solutions is in the S-sulfonated form regardless of the age of the HSA solution. S-sulfonation of hTTR at the free cysteine residue in position 10 appears to be the result of a mixed disulfide exchange possibly with S-cysteinylated hTTR or S-cysteinylated HSA. hTTR is a tetramer composed of four identical monomers each containing a reduced cysteine residue in position 10. S-sulfonation of hTTR at this cysteine residue can destabilize the hTTR tetramer, an important step in the formation of TTR-related amyloid fibrils. ConclusionsAdministration of a commercial HSA solution that already contains S-sulfonated hTTR could potentially contribute to the development of amyloid-related/polyneuropathy in the critically ill.

Repeated Oral Administration of Human Serum Albumin Protects from the Cerebral Ischemia in Rat Brain Following MCAO.

Albumin is known to have neuroprotective effects. The protein has a long half-life circulation, and its effects can therefore persist for a long time to aid in the recovery of brain ischemia. In the present study, we investigated the neuroprotective effects of human serum albumin (HSA) on brain hemodynamics. Albumin is administrated using repeated oral gavage to the rodents. Sprague-Dawley rats underwent middle cerebral artery occlusion procedures and served as a stroke model. Afterwards, 25% human serum albumin (1.25 g/kg) or saline (5 ml/kg) was orally administrated for 2 weeks in alternating days. After 2 weeks, the rodents were assessed for levels of brain ischemia. Our testing battery consists of behavioral tests and in vivo optical imaging sessions. Modified neurological severity scores (mNSS) were obtained to assess the levels of ischemia and the effects of HSA oral administration. We found that the experimental group demonstrated larger hemodynamic responses following sensory stimulation than controls that were administered with saline. HSA administration resulted in more significant changes in cerebral blood volume following direct cortical electric stimulation. In addition, the mNSS of the treatment group was lower than the control group. In particular, brain tissue staining revealed that the infarct size was also much smaller with HSA administration. This study provides support for the efficacy of HSA, and that long-term oral administration of HSA may induce neuroprotective effects against brain ischemia.

SAT-052 - Human Serum Albumin administration prevents cell death-derived extracellular nucleosomes and core-histones-driven inflammasome activation and portal hypertension in Acute on Chronic Liver Failure

SAT-052 - Human Serum Albumin administration prevents cell death-derived extracellular nucleosomes and core-histones-driven inflammasome activation and portal hypertension in Acute on Chronic Liver Failure

Albumin administration prevents neurological damage and death in a mouse model of severe neonatal hyperbilirubinemia.

Therapies to prevent severe neonatal unconjugated hyperbilirubinemia and kernicterus are phototherapy and, in unresponsive cases, exchange transfusion, which has significant morbidity and mortality risks. Neurotoxicity is caused by the fraction of unconjugated bilirubin not bound to albumin (free bilirubin, Bf). Human serum albumin (HSA) administration was suggested to increase plasma bilirubin-binding capacity. However, its clinical use is infrequent due to difficulties to address its potential preventive and curative benefits, and to the absence of reliable markers to monitor bilirubin neurotoxicity risk. We used a genetic mouse model of unconjugated hyperbilirubinemia showing severe neurological impairment and neonatal lethality. We treated mutant pups with repeated HSA administration since birth, without phototherapy application. Daily intraperitoneal HSA administration completely rescued neurological damage and lethality, depending on dosage and administration frequency. Albumin infusion increased plasma bilirubin-binding capacity, mobilizing bilirubin from tissues to plasma. This resulted in reduced plasma Bf, forebrain and cerebellum bilirubin levels. We showed that, in our experimental model, Bf is the best marker to determine the risk of developing neurological damage. These results support the potential use of albumin administration in severe acute hyperbilirubinemia conditions to prevent or treat bilirubin neurotoxicity in situations in which exchange transfusion may be required.

Can didactic continuing education improve clinical decision making and reduce cost of quality? Evidence from a case study.

Administration of human serum albumin (HSA) solutions for the resuscitation of critically ill patients remains controversial. The objective of this study was to assess the effect of continuing medical education (CME) on health care professionals' clinical decision making with regard to HSA administration and the costs of quality (COQ). A quasi-experimental study of time series association of CME intervention with COQ and use of HSA solution was conducted at the Surgery Department of the Hospital Valjevo, Serbia. The CME contained evidence-based criteria for HSA solution administration in surgical patients. The preintervention period was defined as January 2009 to May 2011. CME was provided in June 2011, with the postintervention period June 2011 to May 2012. Total mortality rate, the rate of nonsurgical mortality, the rate of surgical mortality, the rate of sepsis patient mortality, index of irrational use of HSA solutions, and number of hospital days per hospitalized patient were collected for each month as quality indicators. Statistical analysis was performed by multivariate autoregressive integrated moving average (MARIMA) modeling. The specification of the COQ was performed according to a traditional COQ model. The CME intervention resulted in an average monthly reduction of the hospital days per hospitalized patient, the rate of sepsis patient mortality, index of irrational use of HSA solutions, and COQ for $593,890.77 per year. Didactic CME presenting evidence-based criteria for HSA administration was associated with improvements in clinical decisions and COQ. In addition, this study demonstrates that models combining MARIMA and traditional COQ models can be useful in the evaluation of CME interventions aimed at reducing COQ.

Contribution of diuretic therapy with human serum albumin to the management of ascites in patients with advanced liver cirrhosis: A prospective cohort study.

The number of available studies on the role of human serum albumin (HSA) in the treatment of cirrhotic ascites is currently limited. In this study, we aimed to investigated the parameters associated with diuretic therapy with HSA in patients with advanced cirrhotic ascites. The patient inclusion criteria were cirrhotic ascites and a serum albumin (Alb) concentration of <3.5 g/dl. A total of 49 patients registered and 38 patients were ultimately included in this study. The enrolled patients were mainly treated with oral spironolactone and furosemide, which were not specified; the HSA amount was also not specified, although the administration period was set to a maximum of 7 days. Our results demonstrated that the administration of HSA significantly increased the serum levels of Alb [0.97 g/dl; two-sided 95% confidence interval (CI): 0.83-1.11 g/dl] and decreased body weight (-2.24 kg; 95% CI: -3.06 to -1.43 kg), hematocrit ratio (0.96; 95% CI: 0.94-0.98) and plasma renin concentration (day 4; geometric mean fold change, -0.1528; 95% CI: -0.2510 to -0.0545; log-transformed data) in patients with advanced cirrhotic ascites. The observed weight loss was found to be correlated with the total amount of HSA administered (P=0.0012), as indicated by the results of the multiple linear regression analysis. In conclusion, this study confirmed the efficacy of HSA in patients with advanced cirrhotic ascites.

Review of the rational use and adverse reactions to human serum albumin in the People&amp;rsquo;s Republic of China

Human serum albumin (HSA) is an ideal natural colloid that has been widely used in clinical practice for supplemental albumin or as a plasma substitute during therapeutic plasma exchanges to redress hypoproteinemia. However, a paucity of well-designed clinical trials, a lack of a clear cut survival benefit, and frequent case reports of adverse drug reaction (ADR) make the use of HSA controversial. This study aims to review and to comment on the reported ADRs of HSA in the People’s Republic of China, so as to provide the basis for rational HSA use in clinical settings. Data on the ADR case reports from HSA administration between January 1990 and December 2012 available from the China National Knowledge Infrastructure (CNKI) database, Wanfang data (WF), and Chinese Biomedical Literature (CBM) were reviewed. The reasons for using HSA, the types of ADRs, the causality of ADRs and the rationality for HSA administration were extracted and analyzed. In total, 61 cases of ADR reports were identified of which the primary disease of patients using HSA was malignant tumor (34.42%). The primary ADR was anaphylaxis (59.02%). Of the 61 cases, 30 were caused by irrational use of HSA. The most common irrational use was off-label use (56.67%), followed by inappropriate infusion rate. Therefore, we conclude that to avoid the occurrence of ADRs, guidelines for using HSA are needed to guarantee its rational use and HSA should be used strictly according to these guidelines. In addition, medical staff, including clinical pharmacists and nurses, should pay more attention to the patients who inject HSA to ensure its safe use in the clinic.

Type III hypersensitivity reaction with immune complex deposition in 2 critically ill dogs administered human serum albumin

To describe 2 cases of vasculitis that were attributed to a type III hypersensitivity reaction in critically ill dogs occurring 8-16 days postadministration of human serum albumin (HSA). Skin biopsies were obtained from 3 different sites in 2 critically ill dogs that developed vasculitis 8-16 days following treatment with HSA. Histopathological findings from both dogs indicated epidermal pallor, widespread edema and hemorrhage, degenerative neutrophilic perivascular infiltrates, and multifocal areas of neutrophilic or leukocytoclastic vasculitis. Immunohistochemical staining using an anti-human serum albumin rabbit antibody suggested that the antigen-antibody complexes seen in the dermis were associated with the administration of HSA. In this case series, we documented a leukocytoclastic vasculitis and probable antigen-antibody complexes to human albumin in the dermis of 2 critically ill dogs after administration of HSA. Previously, type III hypersensitivity reactions had only been reported in healthy dogs that had received HSA. This report also describes the potential use of immunohistochemical staining to detect the HSA antigen in tissue sections through the use of specifically labeled antibodies.

Site-Specific Chemical Modification of Human Serum Albumin with Polyethylene Glycol Prolongs Half-life and Improves Intravascular Retention in Mice

Human serum albumin (HSA) is used as an important plasma volume expander in clinical practice. However, the infused HSA may extravasate into the interstitial space and induce peripheral edema in treating the critical illness related to marked increase in capillary permeability. Such poor intravascular retention also demands a frequent administration of HSA. We hypothesize that increasing the molecular weight of HSA by PEGylation may be a potential approach to decrease capillary permeability of HSA. In the present study, HSA was PEGylated in a site-specific manner and the PEGylated HSA carrying one chain of polyethylene glycol (PEG) (20 kDa) per HSA molecule was obtained. The purity, PEGylated site and secondary structure of the modified protein were characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), thiol group blockage method and circular dichroism (CD) measurement, respectively. In addition, the pharmacokinetics in normal mice was investigated, vascular permeability of the PEGylated HSA was evaluated in lipopolysaccharide (LPS)-induced lung injury mouse model and the pharmacodynamics was investigated in LPS-induced sepsis model with systemic capillary leakage. The results showed that the biological half-life of the modified HSA was approximately 2.3 times of that of the native HSA, PEG-HSA had a lower vascular permeability and better recovery in blood pressure and haemodilution was observed in rats treated with PEG-HSA. From the results it can be inferred that the chemically well-defined and molecularly homogeneous PEGylated HSA is superior to HSA in treating capillary permeability increase related illness because of its longer biological half-life and lower vascular permeability.

Current perspectives on potential role of albumin in neuroprotection

Albumin is the most abundant plasma protein synthesised mainly in the liver. It is also a major component of extracellular fluids including cerebrospinal fluid, interstitial fluid and lymph. Albumin has several biochemical properties including regulation of colloid osmotic pressure of plasma, transportation of hormones, fatty acids, drugs and metabolites across plasma, regulation of microvascular permeability, antioxidant activity, anti-thrombotic activity and anti-inflammatory activity. This multifunctional protein has been implicated in many neurological diseases owing to its ability to regulate hemodynamic properties of the brain circulation as well as the direct neuroprotective actions on neuronal and glial cells. In this review, we summarise various neuroprotective actions of the albumin in the brain. In experimental ischemic stroke, exogenous human serum albumin administration has been found to be neuroprotective via reducing brain swelling, prevention of post-ischemic thrombosis, anti-oxidant activity, hemodilution and increasing the perfusion to the ischemic tissue. Also, human serum albumin administration is currently under clinical trials for treatment of cerebral ischemia. In the experimental models of Alzheimer's disease, albumin has been implicated in neuroprotection by inhibiting polymerisation and enhancing the clearance of amyloid β. The direct neuroprotective actions on neuronal and glial cells are mediated via endogenously produced albumin or cellular uptake of blood derived albumin. These neuroprotective effects of albumin are partly attributed to anti-oxidant property and modulation of intracellular signalling of neuronal or glial cells. The recent finding of de novo synthesis of albumin in microglial cells directs us to explore newer roles of this endogenously produced multifunctional protein in normal as well as pathological conditions of the brain.

Administration of 5% human serum albumin in critically ill small animal patients with hypoalbuminemia: 418 dogs and 170 cats (1994-2008)

To describe the administration of 5% human serum albumin (HSA) in 588 critically ill hypoalbuminemic dogs and cats, and report outcome to discharge, changes in albumin concentration, and adverse effects during hospitalization. Retrospective clinical study. Private emergency and general veterinary center. Client-owned dogs and cats. None. The medical records of 588 critically ill hypoalbuminemic animals (418 dogs and 170 cats) were reviewed. All animals had hypoalbuminemia (serum albumin<20 g/L [2.0 mg/dL]) at admission, received an infusion of 5% HSA, and received no other colloid infusion. The HSA solution was administered through a peripheral vein at 2 mL/kg/h for 10 h/d (total volume 20 mL/kg/d) until albumin reached 20 g/L. The number of days of HSA infusion (median and range) was 4 days (2-11 d) for dogs and 3 days (2-7 d) for cats. Three hundred and sixteen dogs (75.6%) survived to discharge; 56 of 418 (13.4%) died in hospital. One hundred and twenty-three cats (72.3%) survived to discharge; 21 of 170 (12.4%) died in hospital. Severe hypersensitivity reactions such as anaphylaxis, angioedema, and urticaria were not noted. Interruption of albumin infusion and specific treatment of reactions were not required in any animal. In this study, administration of 5% HSA appeared to be safe in a large group of critically ill, hypoalbuminemic dogs and cats. The results should be interpreted with caution due to the retrospective, descriptive nature of the study, the absence of control groups and the lack of follow-up data, as well as the potentially life-threatening complications of HSA administration.

Use of recombinant human serum albumin in pediatric patients with nephrotic syndrome

Sirs, We have read with great interest the article of Dharmaraj et al. [1]. In a clinical setting, some patients with nephrotic syndrome (NS) who are unresponsive to diuretic therapy alone develop severe edema, pleural effusion and ascites. In this context, the administration of human serum albumin in combination with the infusion of loop diuretics is the treatment of choice, although this treatment regimen remains controversial. Since plasma-derived human serum albumin (pHSA) is manufactured from human blood, the supply is limited and the risk of infection by unknown viruses or prions cannot be completely excluded [2]. Recombinant human serum albumin (rHSA) has recently been developed from Pichia pastoris without the use of any animal-derived materials [3], and the clinical use of 25% rHSA for patients suffering from significant albumin loss due to burns, NS and liver cirrhosis, among other conditions, has been approved by the Ministry of Health and Welfare in Japan. Although rHSA has been successfully applied without significant serious adverse effects in the treatment of adult patients with hemorrhagic shock, NS, burns, acute abdominal complaints and liver cirrhosis, poorrisk patients before surgery and post-open heart surgery patients [3–5], little information is currently available on the use of rHSA for the treatment of pediatric patients with NS. Here, we report our preliminary experience of using of rHSA in pediatric patients with NS. Seven patients with NS [four patients with minimal change NS (MCNS), two with focal segmental glomerulosclerosis (FSGS) and one with Henoch–Schonlein purpura nephritis (HSPN)] were initially examined in our study. We started rHSA treatment after receiving both the approval of the ethics committee of our institution and written informed consent from each of the patients and their parents. Specific immunoglobulin (Ig)E antibody titers against Pichia yeast components were measured before the start of rHSA administration. If the serum IgE antibody was positive for Pichia yeast, rHSA administration was prohibited. Of the seven patients initially included in the study, one patient with MCNS who showed weak positivity for serum specific IgE antibody was excluded. The remaining six patients received rHSA treatment in combination with the infusion of loop diuretics for the treatment of refractory edema at Hirosaki University Hospital between September 2008 and January 2009. Among these six patients, one patient with FSGS received three separate rHSA treatments, with the treatment repeated every other month. Thus, a total of eight clinical observations were evaluated. Intravenous rHSA (25% rHSA; Medway, Bipha Co, Chitose, Japan) was administered at a dose of 0.3–0.5 g/kg, one to three times daily in combination with furosemide (1 mg/kg). One treatment course of rHSA was scheduled for at least three consecutive days of administration. Since this study was initially designed mainly to evaluate the safety of rHSA for the treatment of childhood NS, the treatment protocol was individualized according to each patient’s status. Allergic adverse drug reactions to rHSA were carefully monitored during the study period. After 1 month of treatment, a repeat measurement of serum specific IgE antibody against Pichia yeast components was performed, revealing that serum specific IgE antibody for Pichia had remained Pediatr Nephrol (2009) 24:2275–2276 DOI 10.1007/s00467-009-1221-y

Risk of immunologic reactions to human serum albumin solutions

MADAM We write to highlight the potential risk of immunologic reactions to human serum albumin (HSA) solutions. Recent advances in veterinary emergency and critical care and the greater availability of HSA solutions has led to increased use of these products in small animals. We feel that the potential for adverse reactions to HSA solutions is not widely recognised however. Recent research has identified a dichotomous response to the use of HSA solutions in critically ill versus healthy dogs. In critically ill dogs, HSA was reportedly associated with a low number of mild adverse effects although several serious adverse drug reactions were also potentially attributable to HSA administration (Mathews and Barry 2005, Trow and others 2008). In contrast, administration of HSA to healthy animals may be fatal (Francis and others 2007). A study by Martin and others (2008) suggested this may be due to different patterns of anti-HSA antibody production by these two populations. Importantly, of the 68 healthy dogs with no known prior HSA exposure sampled by Martin and others, 7 per cent had pre-existing anti-HSA antibodies. HSA is antigenic in both healthy and in critically ill dogs and repeat administration of HSA to previously exposed dogs can lead to severe anaphylactic reactions and should not be performed (Cohn and others 2007, Martin and others 2008). Based on these studies the potential risks of using HSA must be carefully considered before the product is administered. Published reports suggest that HSA solutions do increase serum albumin concentrations and colloid osmotic pressure although this may not be associated with a survival benefit. As such, we suggest that other colloids may offer safer alternatives for provision of oncotic support and HSA solutions should only be administered if other forms of treatment have failed. At present, no veterinary licensed preparations containing human serum albumin are available. Use of these products is therefore subject to the cascade as described by the Veterinary Medicines Regulations 2008 thus requiring veterinary surgeons to ensure clients are made aware of the risks of using such a product. At the Queen Mother Hospital for Animals, we record the use of HSA prominently within patients’ medical records. In addition, in our written communications to referring practitioners, we report the use of these solutions in order to prevent inadvertent repeat HSA administration. If the decision to administer HSA is made, we would strongly encourage readers to diligently and prominently record HSA use in the medical records of their patients. In addition, we also feel it is essential that this information be conveyed to any specialist referral centre to which the patient is transferred. Provision of this information may help prevent potentially fatal acute hypersensitivity reactions.

An Albumin-Exendin-4 Conjugate Engages Central and Peripheral Circuits Regulating Murine Energy and Glucose Homeostasis

Glucagon-like peptide-1 (GLP-1) regulates glucose homeostasis through multiple mechanisms including direct actions on the endocrine pancreas and indirect activation of central nervous system circuits regulating gastric emptying, satiety, and body weight. Because native GLP-1 is rapidly degraded, there is considerable interest in development of more potent GLP-1 receptor (GLP-1R) agonists with sustained activity; however, the extent to which much larger GLP-1R agonists will mimic some or all of the actions of smaller peptides remains uncertain. We studied the actions of CJC-1134-PC, a recombinant human serum albumin-exendin-4 conjugated protein, at the GLP-1R using heterologous cells expressing the GLP-1R in vitro and both wild-type and Glp1r(-/-) mice in vivo. CJC-1134-PC activated GLP-1R-dependent signaling in baby hamster kidney-GLP-1R cells and acutely lowered blood glucose in wild-type but not in Glp1r(-/-) mice. Moreover, acute administration of CJC-1134-PC rapidly activated c-Fos expression in multiple regions of the central nervous system, acutely inhibited gastric emptying, and produced sustained inhibition of food intake in a GLP-1R-dependent manner. Furthermore, chronic daily treatment of high-fat diet-fed wild-type mice with CJC-1134-PC for 4 weeks led to improved glucose tolerance, increased levels of glucose-stimulated insulin, decreased HbA1c, and weight loss associated with decreased hepatic triglyceride content. These findings illustrate that a high-molecular-weight exendin-4-albumin conjugate retains the ability to mimic a full spectrum of GLP-1R-dependent actions, including activation of central nervous system circuits regulating gastric emptying, food intake, and body weight.

Anaphylactoid shock in a patient following 5% human serum albumin infusion during off-pump coronary artery bypass grafting

A 59-year-old diabetic male patient undergoing off-pump coronary artery bypass grafting developed anaphylactoid shock after 5% human serum albumin (HSA) infusion started. During the first anastomosis, blood loss was more than 600 ml, with slightly decreased blood pressure. Therefore, 5% HSA, 250 ml, was infused against hypovolemia. However, as his blood pressure was decreasing continuously during the second anastomosis, another 250 ml of 5% HSA was added. The blood pressure rapidly dropped to 50/30 mmHg after the second 5% HSA administration started. As i.v. phenylephrine and ephedrine were not effective, norepinephrine was infused. Then we found a high cardiac output (10 l x min(-1)) and peak airway pressure (32 cmH(2)O), with a decrease of oxygenation (P/F ratio, 82), and we suspected 5% HSA-caused anaphylactic shock. Therefore, aminophylline was infused to treat bronchoconstriction. These treatments were effective, and the operation was successfully completed. Postoperatively, we noticed that these reactions may have been anaphylaxis, because the patient had a higher serum tryptase level (16.2 ng x ml(-1)) than the reported nonanaphylaxis serum tryptase level (8.23 ng x ml(-1)). HSA is a relatively safe colloid for use as a volume expander, because it has been reported that the risk of anaphylactoid reactions with HSA was much less than that with gelatins and dextrans, and similar to that with starches. However, the present case suggests that severe allergic reactions should be kept in mind with the use of any colloids.

Response of healthy dogs to infusions of human serum albumin

To evaluate the clinical and immunologic response in healthy dogs to infusions of human serum albumin (HSA). 9 healthy purpose-bred mixed-breed dogs. Each dog was administered a 25% HSA solution once or twice. Various physical examination and laboratory variables were serially evaluated. Antibody against HSA was assayed before and after infusion by use of an ELISA. Intradermal testing was also conducted. A repeated-measures ANOVA or Friedman repeated-measures ANOVA on ranks was used to compare results for the variables. Adverse clinical reactions were observed after the first or second infusion in 3 dogs. Anaphylactoid reactions were observed in 1 of 9 dogs during the first infusion and in 2 of 2 dogs administered a second infusion. Two dogs developed severe edema and urticaria 6 or 7 days after an initial infusion. All dogs developed anti-HSA antibodies. Positive responses for ID tests were observed in 8 of 9 dogs. Short-term increases were detected in blood protein, total bilirubin, and calcium concentrations after HSA infusion. Serum cholesterol concentrations and platelet counts decreased after HSA infusion. Administration of HSA resulted in profound reactions in 2 of 9 dogs administered a single infusion and in 2 of 2 dogs administered a second infusion. This indicates that there is risk of life-threatening adverse reactions to HSA infusion in healthy dogs.