Infusion-related Adverse Effects Research Articles

Drug induced reversible cardiomyopathy reported for liposomal amphotericine B: a rare documented adverse event

Liposomal amphotericin B (LAmB), lipid formulation of amphotericin B (AmB) is used in the treatment of fungal infections, including invasive disease and cryptococcal meningitis and is associated with fewer nephrotoxic and infusion-related adverse effects than conventional amphotericin B. Cardiac toxicity due to LAmB is a rarely reported adverse event in literature. Here we report a case of 53 years female known case of vitiligo, Diabetes mellitus Type 2 diagnosed as case of sinonasal mucormycosis and started on inj LAmB, developed chest pain on day 4 of inj LAmB. ECG and 2D ECHO showed VPBs and ventricular ectopics that were transient and completely recovered on reducing the dose of LAmB. As LV function has recovered on reducing Liposomal AMB, and patient was not on any other cardiotoxic drugs. It was concluded that the patient developed Transient Cardiomyopathy also known as Takotsubo Cardiomyopathy likely due to Liposomal AMB that improved on reducing dose of the drug LAmB. Although very rare but reversible cardiomyopathy also known as Takotsubo Cardiomyopathy due to LAmB is a documented adverse effect. Therefore, ECG monitoring or cardiac monitoring (2D ECHO) should be done when patient is started on LAmB and if at any point cardiotoxicity is suspected then drug should be stopped or reduced in dose immediately. These adverse effects are reversible which recovere on stopping or reducing the dose of LAmB.

#657 Obinutuzumab is effective for the treatment of frequently-relapsing/steroid-dependent minimal change disease in adults

Abstract Background and Aims Higher relapse rates and steroid dependency are challenges in the treatment of minimal change disease (MCD). The aim of this study was to evaluate the efficacy and safety of obinutuzumab, a humanised type II anti-CD20 monoclonal antibody, in adults with frequently relapsing (FR) or steroid-dependent (SD) minimal change disease (MCD). Method Patients with FR/SD MCD receiving obinutuzumab at our center between September 2022 and February 2023 were enrolled. Complete remission was defined as the reduction of proteinuria to 0.3g/d. The time to remission, the relapse rate, and adverse events were evaluated. Results Six patients with FR/SD MCD were included in the present study. The median age of the patients was 30.44 years (range 18.80-72.09 years) and 3 of them were male. Prior to treatment with obinutuzumab, five patients remained in nephrotic syndrome and one patient was in partial remission after previous treatment. One or two doses of 1g obinutuzumab were given. All six patients achieved a complete remission. Five patients with nephrotic syndrome achieved complete recovery within a range of 14 to 57 days. The patient, who initially achieved partial remission, reached complete remission within 27 days after receiving the first obinutuzumab dose. The average follow-up duration was 12.53 ± 1.97 months, during which there was no observed relapse. Furthermore, None of the patients experienced infusion-related adverse effects, serious infectious complications or neutropenia following treatment with obinutuzumab. Conclusion Obinutuzumab is an effective and safe treatment option for adult patients with FR/SD minimal change disease. Further randomized trials are needed to confirm these findings.

Breakthrough Mucormycosis In Two Cases Of Hematological Malignancies Successfully Treated With Amphotericin B Colloidal Dispersion

Background: Patients with hematologic malignancies have poor immunity, and they are more vulnerable to fungal invasion because of disease characteristics and clinical treatment such as chemotherapy. Mucor infections in hematologic malignancies are rare, but once occurred usually lead to high mortality. In this study, we report two cases of hematologic malignancies complicated with breakthrough mucormycosis (BT-MCR), which were treated with amphotericin B colloidal dispersion (ABCD) combined with or without other antifungal agents. Case Presentation: Case 1 shows a patient with natural killer cell leukemia, type 2 diabetes, and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This patient was admitted to the First Affiliated Hospital of Soochow University because of fever with cough and expectoration for a week. Next-generation sequencing (NGS) of alveolar lavage fluid revealed that the patient was infected with Rhizomucor pusillus and Enterococcus faecalis. This patient was infected with fungi although he had taken voriconazole for prevention. Considering the renal toxicity of amphotericin B deoxycholate, the patient received ABCD via intravenous drip combined with posaconazole via oral administration for Rhizomucor pusillus infection and meropenem via intravenous drip for Enterococcus faecalis infection during 45 days of treatment. The patient was free of complaints in the next 2-month follow-up. Case 2 represents a patient with acute myeloid leukemia. During induction chemotherapy, the patient presented with weakness of the left limbs, and head MRI showed multiple cerebral infarctions (MCI). In addition, he had high fever with right-face swelling and pain, and the NGS of blood revealed that he had Mucor circinelloides and Stenotrophomonas maltophilia infection. ABCD and ceftazidime/avibactam were administered to the patients via intravenous drip. The patient also achieved complete remission after later consolidation chemotherapy and successfully underwent allo-HSCT. Conclusion: ABCD shows great efficiency with or without other antifungal agents in treating hematological malignancies complicated with BT-MCR. Despite its infusion-related adverse effects and nephrotoxicity, ABCD shows great application potential for patients with hematologic malignancies, who are often more susceptible to fatal BT-MCR. Furthermore, more valid data should be collected on the combination therapy (ABCD and posaconazole).

Amphotericin B in Pediatrics: Analysis by Age Stratification Suggests a Greater Chance of Adverse Events from 13 Months of Age Onwards.

Amphotericin B deoxycholate (AMB-D) remains an antifungal agent with great therapeutic value in pediatric patients. The currrent consensus is that its use in neonates is safer than in older children. However, childhood presents different periods of development that deserve to be evaluated more precisely. Our goal was to assess the usage profile of AMB-D in stratified pediatric age groups, adapted according to the National Institute of Child Health and Human Development classification. This retrospective cross-sectional observational study was conducted at a Brazilian tertiary children's hospitalbetween January 2014 and December 2019. Data of patients who received at least two doses of intravenous AMB-D while hospitalized were extracted from electronic health files. Information on patient demographics, underlying diseases and comorbidities, laboratory examinations, fungal infection diagnosis, and AMB-D use were gathered following specific criteria.Nonparametric tests were applied, such as the chi-square test to compare proportions and Fisher's exact test to assess the association between categorical variables or contingency tables. One hundred and twenty-seven (127) medical records were stratified as preterm neonatal (birth <37 weeks postmenstrual age), term neonatal (birth-27 days), infants (28 days-12 months), toddlers (13 months-2 years), early childhood (3-5 years), middle childhood (6-11 years), and early adolescence (12-18 years). The criteria for the indication of AMB-D followed empirical use as the main indication (n = 74; 58.26%), proven and probable fungal infection (n = 39; 30.71%), and medical suspicion (n = 14; 11.02%). Candida spp. was the main etiologic agent isolated in cultures, with the highest frequency of C. albicans (n = 18; 40%), followed by Candida parapsilosis (n = 14; 31.11%), and Candida tropicalis (n = 6; 13.33%). Very few acute infusion-related adverse effects were observed during the administration of AMB-D in pediatric patients. We found an unfavorable impact of AMB-D use in patients from 13 months of age onwards suggesting this group as a turning point for a greater chance of adverse events, and not soon after the neonatal period. Clinical or observational studies based on age stratification are essential to accurately elucidate whether potentially toxic drugs can be used safely in the pediatric population. Our search for a turning point was shown to contribute to the accuracy of the study, as it provided data on the impact of D-AMB in specific pediatric age groups.

Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial

ObjectiveTo assess whether reshaping of the immune balance by infusion of autologous natural regulatory T cells (nTregs) in patients after kidney transplantation is safe, feasible, and enables the tapering of...

Correction of Iron Deficiency with Intravenous Iron Replacement Immediately after Left Ventricular Assist Device Implant

Iron deficiency anemia (IDA) persists after left ventricular assist device (LVAD) placement and is associated with increased hospitalizations and mortality. Correction of IDA with IV iron replacement in patients with heart failure improves quality of life (QoL), functional capacity, and reduces hospitalizations. Minimal data for IV iron replacement in patients with LVAD exists. We sought to assess the safety and efficacy of protocolized iron deficiency diagnosis and IV iron replacement in newly implanted LVAD recipients. A prospective, observational study of all patients undergoing LVAD implant from 1/1/2019-9/30/2019 was conducted. Iron studies were obtained in all patients prior to index discharge; iron deficiency was defined as ferritin <100 ng/mL or ferritin 100-299 ng/mL with transferrin saturation (TSat) <20%. Patients with IDA received ferric gluconate (FG) 250 mg IV q12h to correction of iron deficit as calculated by the Ganzoni formula. Iron studies were repeated in 4-8 weeks in the ambulatory setting. Functional capacity and QoL were evaluated by the change in 6-minute walk test (6MWT) and Minnesota Living with Heart Failure Questionnaire (MLHFQ) pre-implant, compared to the 3 month follow up clinic visit, respectively. Of the 16 patients who received an LVAD in the study period, 12 (75%) were found to have IDA and received IV FG. Patients were 62±10 years old, 81% were male, and 50% were Caucasian. No infusion-related adverse effects occurred. At a median follow-up of 9.9 weeks, 87.5% were no longer iron deficient. Hemoglobin (HgB), hematocrit (HCT) and Tsat increased significantly; there was no difference in ferritin levels. For the 8 patients with a 3 month post-implant clinic visit, a significant increase in MLHFQ, but not 6MWT, was observed. IV FG infusions immediately after LVAD are well-tolerated and associated with increased HgB/HCT and correction of IDA. Future studies are needed to confirm improvement in clinical outcomes.

Effect of Rituximab on Expanded Disability Status Scale and Relapse Rate in Multiple Sclerosis Patients.

The aim of this study was to investigate the efficacy of rituximab, a monoclonal antibody that depletes circulating CD20+ B lymphocytes, in relapsing remitting multiple sclerosis (RRMS) patients with inadequate response to disease-modifying therapies. This single group quasi-experimental study recruited RRMS patients who were referred to Sina Farshchian Hospital, Hamadan, Iran, from March 2018 until August 2019. After getting informed consent from the patients, demographic data and duration of disease were recorded. Patients received 500 to 1000mg of intravenous rituximab every 6months until 18months. Relapse rate per year and expanded disability status scale (EDSS) were obtained at baseline and throughout the post treatment follow-up. A total of 70 RRMS patients with the mean age 40.25 ± 8.17 were studied. At baseline, the mean of EDSS and relapse rate was 5.3 ± 1.08 and 0.95 ± 0.64, respectively. After 18months treatment with rituximab, the relapse rates were significantly reduced (p < 0.000), but the mean EDSS almost remained unchanged (5.7 ± 1.4). Infusion-related adverse effects occurred in 60% of patients in first infusion, and most of them were mild. This study has indicated that rituximab can markedly reduce relapse rates in RRMS patients. The effect of rituximab on EDSS appears to be inappreciable. Also according to our results, administration of rituximab is safe and well tolerated.

Abatacept Decreases the Rate of Acute and Chronic Gvhd in Children with Sickle Cell Disease Undergoing Matched Sibling Transplants

<h3>Introduction</h3> We wanted to study the role of abatacept on the incidence of graft versus host disease (GVHD) in patients with sickle cell disease (SCD) undergoing allogeneic hematopoietic stem cell transplant (HSCT). <h3>Methods</h3> We conducted a retrospective chart review of patients who received an allogeneic HSCT for SCD at Cincinnati Children's Hospital Medical Center and compared various transplant characteristics between patients with and without abatacept for acute GVHD prophylaxis. <h3>Results</h3> Sixteen patients were transplanted for SCD at our center. Nine patients received a calcineurin inhibitor, methotrexate and abatacept at 10 mg/kg intravenously on days -1, +5, +14 and +28 while 7 patients received a calcineurin inhibitor with methotrexate and methylprednisolone for acute GVHD prophylaxis (table 1). No abatacept infusion related adverse effects were observed. Neutrophil engraftment was comparable at a median of 12.5 days (range 11-21) in patients without abatacept versus 13 days (range 12-16 days) in the abatacept cohort. Incidence of grade 2-4 GVHD was 0/9 in the abatacept cohort versus 3/7 patients in the no-abatacept cohort. Two of the 3 acute GVHD patients in the no-abatacept cohort had visceral involvement. One patient in the abatacept cohort had mild chronic GVHD compared to 3 patients in the no-abatacept cohort with mild (n=1) and moderate (n=2) chronic GVHD. Six patients in the no-abatacept cohort had viral reactivation compared to 8/9 patients in the abatacept cohort. No patient in either cohort had viral disease. One patient in the abatacept cohort had secondary graft loss and was transplanted again with the same donor and conditioning regimen successfully. There was no graft loss in patients who did not receive abatacept. The disease-free survival was 100% in both groups at last follow up of 1925 days (range 837-8164 days) in the no-abatacept group and 770 days (range 112-1634 days) after HSCT in the abatacept cohort. <h3>Conclusions</h3> Abatacept is well tolerated and decreases the incidence of acute and chronic GVHD in children with SCD undergoing fully matched sibling transplants. Larger studies are needed to definitively determine the impact of abatacept in GVHD prophylaxis in the matched sibling donor setting.

Peripheral venous route for administration of ammonul infusion for treatment of acute hyperammonemia. An experience from a tertiary center in Saudi Arabia.

Objectives:To determine the local effects of peripheral Ammonul infusion on the skin and the subcutaneous tissues.Methods:This retrospective study was conducted at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. All children <16 years of age admitted between December 2015 and October 2018 with hyperammonemia and received Ammonul infusion for treatment were recruited.Results:Twenty-one patients received the Ammonul infusion. They were admitted 58 times with acute hyperammonemia during the study period, with an average of 2.8 admissions per patient. The mean age of the included patients was 49.5 months. The most frequent underlying diagnoses were propionic acidemia (n=9), urea cycle disorders (n=5), and intrinsic liver disease (n=3). All participants received Ammonul through peripheral lines except 3 who received it through central lines. No extravasation, burns, or other local side effects were observed in this cohort.Conclusion:This data indicate that the use of Ammonul through a peripheral venous route appears to be safe and not associated with infusion-related local adverse effects.

Cardiac side effect of rituximab

Rituximab is an anti-CD20 monoclonal antibody frequently used for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, and anti-neutrophilic cytoplasmic antibody-associated vasculitis. In addition, rituximab has recently been increasingly used as an off-label treatment in a number of inflammatory and systemic autoimmune diseases. Its side effect profile includes infusion-related reactions and adverse cardiac effects such as arrhythmia and angina, particularly in patients with prior history of cardiovascular diseases. However, its detailed cardiotoxicity profile, effects on cardiac function, and its management are not well described in the literature. As the utility of rituximab expands, primary physicians, intensivist, dermatologist who use drug should be made of these serious cardiovascular adverse effect.

Complement proteins bind to nanoparticle protein corona and undergo dynamic exchange in vivo

When nanoparticles are intravenously injected into the body, complement proteins deposit on the surface of nanoparticles in a process called opsonization. These proteins prime the particle for removal by immune cells and may contribute toward infusion-related adverse effects such as allergic responses. The ways complement proteins assemble on nanoparticles have remained unclear. Here, we show that dextran-coated superparamagnetic iron oxide core-shell nanoworms incubated in human serum and plasma are rapidly opsonized with the third complement component (C3) via the alternative pathway. Serum and plasma proteins bound to the nanoworms are mostly intercalated into the nanoworm shell. We show that C3 covalently binds to these absorbed proteins rather than the dextran shell and the protein-bound C3 undergoes dynamic exchange in vitro. Surface-bound proteins accelerate the assembly of the complement components of the alternative pathway on the nanoworm surface. When nanoworms pre-coated with human plasma were injected into mice, C3 and other adsorbed proteins undergo rapid loss. Our results provide important insight into dynamics of protein adsorption and complement opsonization of nanomedicines.

Efficacy of Third Party BK Virus (BKV) Specific Cytotoxic T-Lymphocytes Generated By Ex Vivo Expansion for the Treatment of BKV Infection in Stem Cell Transplant Recipients, a Phase 2 Trial

Clinical manifestations of BKV hemorrhagic cystits (HC) following hematopoietic stem cell transplantation (HSCT) range from microscopic hematuria to bladder hemorrhage and renal failure. Pharmacologic treatments for HC have limited efficacy and significant adverse effects.Here, we report the preliminary analysis of adoptive immunotherapy with most closely HLA-matched third party BKV-specific CTL lines (BKV-CTLs) generated by ex vivo expansion.We generated a bank of BKV-specific CTLs from 17 virus-immune healthy donors (mean age, 55; range, 25 to 75 years). Mononuclear cells enriched from donor buffy coats were stimulated with BKV peptide mix from capsid proteins VP1, VP2, VP3, large T antigen (LT) and small T antigen (ST) in the presence of IL-2, IL-7 and IL-15 for 14 days. At the end of culture, the cells were harvested and cryopreserved until use.Patients with symptomatic BKV cystitis after HSCT for leukemia or lymphoma were eligible. Patients with acute GVHD grades II-IV, those receiving >0.5 mg/kg systemic steroids/day or on treatment with cidofovir or leflunomide were excluded. A search for the most closely HLA-matched donor was initiated through the MDACC cell therapy donor bank. BKV-specific T cells were infused intravenously directly after thawing. Patients could receive up to 2 infusions.BKV PCR and clinical symptoms were monitored every week for 28 days after infusion. Complete response was defined as complete resolution of symptoms and gross hematuria and partial response (PR) as decrease in grade of HC from 3 (urinary blood clots) or 4 (red cell transfusion requirement/renal impairment) to 2 (macroscopic hematuria) or 3 respectively. Patients with stable disease (SD) or progression had insufficient changes to qualify as PR or had an increase in symptoms or worsening hematuria, respectively.To date, 10 patients (2 HLA-matched related, 5 HLA-matched unrelated and 3 haploidentical HSCT recipients) have received BKV-CTLs for BK cystitis. The median number of BKV-specific CD3+IFN-gamma+ and CD3+IL-2+ T-cells infused was 10e3/kg and 4.8e3/kg, respectively. The ratio of BKV-specific CD4+/CD8+ T cells in the infused product was 7.8 (range 3.1-22.1). There were no infusion-related adverse effects. Based on end-organ response, BKV-CTLs controlled infection in 9/9 evaluable patients with BKV cystitis (4 CRs and 5 PRs)- one patient was not evaluable due to disease relapse, sepsis and anuria. All patients achieved a response by day 14 post-infusion. Two of 5 patients with PR received a second BK CTL infusion from a different donor. One had an initial PR to the first CTL infusion but symptoms progressed after 6 weeks. A second infusion resulted in a PR with reduction in BKV PCR and symptoms. The other patient achieved CR within 28 days of the second infusion. The time to second infusion was 6 and 3 weeks, respectively. The response in all patients was sustained.Following infusion, we detected high frequencies of polyfunctional BKV-specific CD4+ and CD8+ T-cells, capable of producing IL-2, IFN-gamma and TNF-alpha in response to ex vivo stimulation with BKV peptide pools (VP1, VP2, VP3, LT and ST). The response was mainly CD4+ T cell dominant, reflecting the composition of the infused BKV T cell line and consistent with previous reports of a predominantly CD4-mediated T cell response in BKV infection.De novo grade 2-4 acute graft versus host disease (aGVHD) occurred in 1/10 patients. The patient developed grade 2 duodenal GVHD 14 days following infusion. A second patient had recurrence of a prior skin GVHD and developed grade 2 aGVHD 9 days after infusion. Both were successfully treated with 1mg/kg/day systemic steroids.This analysis demonstrates the safety, feasibility and efficacy of administration of most closely HLA-matched BKV CTLs for the treatment of BKV cystitis in HSCT patients. The response rate of 100% in the first 10 patients treated with BKV CTLs is promising. DisclosuresCiurea:Cyto-Sen Therapeutics: Equity Ownership; Spectrum Pharmaceuticals: Other: Advisory Board.

Efficacy and Safety of Rituximab Therapy in Neuromyelitis Optica Spectrum Disorders

Neuromyelitis optica spectrum disorders (NMOSDs) are autoimmune astrocytopathies characterized by predominant involvement of the optic nerves and spinal cord. In most patients, an IgG autoantibody binding to astrocytic aquaporin 4, the principal water channel of the central nervous system, is detected. Rituximab, a chimeric monoclonal antibody specific for the CD20 B-lymphocyte surface antigen, has been increasingly adopted as a first-line off-label treatment for patients with NMOSDs. To perform a systematic review and a meta-analysis of the efficacy and safety of rituximab use in NMOSDs, considering the potential predictive factors related to patient response to rituximab in this disease. English-language studies published between January 1, 2000, and July 31, 2015, were searched in the MEDLINE, Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov databases. Patient characteristics, outcome measures, treatment regimens, and recorded adverse effects were extracted. Forty-six studies were included in the systematic review. Twenty-five studies that included 2 or more patients with NMOSDs treated with rituximab were included in the meta-analysis. Differences in the annualized relapse rate ratio and Expanded Disability Status Scale score before and after rituximab therapy were the main efficacy measures. Safety outcomes included the proportion of deaths, withdrawals because of toxic effects, and adverse effects. Among 46 studies involving 438 patients (381 female and 56 male [sex was not specified in 1 patient]; mean age at the outset of treatment, 32 years [age range, 2-77 years]), rituximab therapy resulted in a mean (SE) 0.79 (0.15) (95% CI, -1.08 to -0.49) reduction in the mean annualized relapse rate ratio and a mean (SE) 0.64 (0.27) (95% CI, -1.18 to -0.10) reduction in the mean Expanded Disability Status Scale score. A significant correlation was observed between disease duration and the Expanded Disability Status Scale score. Adverse effects were recorded in 114 of 438 (26%) patients treated with rituximab. Specifically, 45 patients (10.3%) experienced infusion-related adverse effects, 40 patients (9.1%) had an infection, 20 patients (4.6%) developed persistent leukopenia, 2 patients (0.5%) were diagnosed as having posterior reversible encephalopathy, and 7 patients (1.6%) died. This systematic review and meta-analysis provides evidence that rituximab therapy reduces the frequency of NMOSD relapses and neurological disability in patients with NMOSDs. However, the safety profile suggests caution in prescribing rituximab as a first-line therapy.

Vancomycin induced Red Man Syndrome

Vancomycin is a glycoprotein antibiotic that has been associated with an anaphylactoid reaction termed the Red-man syndrome. It usually consists of erythema, flushing and pruritis of the face and upper torso and occasionally progresses to include dyspnoea, chest pain and hypotension. Red man syndrome (RMS) is also known as red neck syndrome. Discontinuation of the vancomycin infusion and administration of diphenhydramine can abort most of the reactions. Slow intravenous administration of vancomycin should minimize the risk of infusion-related adverse effects. Antibiotics such as ciprofloxacin, amphotericin B, rifampcin and teicoplanin can potentially cause red man syndrome. The effects of red man syndrome can be relieved by antihistamines.

Rituximab treatment for autoimmune limbic encephalitis in an institutional cohort.

To determine efficacy and safety of rituximab treatment as a second-line immunotherapy treatment for autoimmune limbic encephalitis (ALE) and to determine factors associated with functional improvement and favorable outcome following rituximab treatment. We recruited 80 patients with ALE who were treated with rituximab as a second-line immunotherapy from the Korea Autoimmune Synaptic and Paraneoplastic Encephalitis Registry and reviewed 81 patients without rituximab as a control. We grouped patients according to the detection or type of antibodies; in addition, we evaluated clinical, laboratory, first-line immunotherapy, and rituximab treatment profiles and defined main outcomes as improvements on the modified Rankin Scale (mRS) score and a favorable mRS score (0-2) at the last follow-up. Functional improvement occurred more frequently in the rituximab group compared to the control group. In the rituximab group, 30 (37.5%) patients had synaptic autoantibodies, 15 (18.8%) in the paraneoplastic autoantibodies, and 35 (43.8%) were antibody-negative. The effect of rituximab was the same regardless of autoantibody status. Additional monthly rituximab therapy and partial response to first-line immunotherapies were associated with mRS score improvements, as well as favorable mRS scores. mRS scores of 4-6 as the worst neurologic status predicted an unfavorable mRS score. There were no reported serious infusion-related or infectious adverse effects of rituximab. Rituximab is effective and safe as a second-line immunotherapy for ALE, regardless of autoantibody status. Additional monthly rituximab therapy might potentiate the efficacy of rituximab. This study provides Class IV evidence that rituximab improves mRS scores for patients with autoimmune limbic encephalitis who fail first-line therapy.

Adverse Effects of IgG Therapy

IgG is widely used for patients with immune deficiencies and in a broad range of autoimmune and inflammatory disorders. Up to 40% of intravenous infusions of IgG may be associated with adverse effects (AEs), which are mostly uncomfortable or unpleasant but often are not serious. The most common infusion-related AE is headache. More serious reactions, including true anaphylaxis and anaphylactoid reactions, occur less frequently. Most reactions are related to the rate of infusion and can be prevented or treated just by slowing the infusion rate. Medications such as nonsteroidal anti-inflammatory drugs, antihistamines, or corticosteroids also may be helpful in preventing or treating these common AEs. IgA deficiency with the potential of IgG or IgE antibodies against IgA increases the risk of some AEs but should not be viewed as a contraindication if IgG therapy is needed. Potentially serious AEs include renal dysfunction and/or failure, thromboembolic events, and acute hemolysis. These events usually are multifactorial, related to combinations of constituents in the IgG product as well as risk factors for the recipient. Awareness of these factors should allow minimization of the risks and consequences of these AEs. Subcutaneous IgG is absorbed more slowly into the circulation and has a lower incidence of AEs, but awareness and diligence are necessary whenever IgG is administered.

Pharmacokinetics, tissue distribution and immunomodulatory effect of intralipid formulation of nystatin in mice

We developed a novel lipid formulation of nystatin suitable for parenteral administration, nystatin-intralipid (NYT-IL), with antifungal activity and reduced toxicity in mice. We investigated the pharmacokinetics, tissue distribution and immunomodulatory effect of NYT-IL in mice. Nystatin levels in serum and organs were determined using HPLC after NYT-IL or nystatin administration in mice. The levels of the pro-inflammatory cytokines tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) and the anti-inflammatory cytokine interleukin 10 (IL-10) produced by splenocytes from mice injected with NYT-IL or nystatin were evaluated by an ELISA assay. Injection of NYT-IL resulted in similar levels and similar kinetics of nystatin in serum, higher concentrations in the liver and lower concentrations in the kidneys, in comparison with nystatin injection. Injection of mice with NYT-IL yielded higher levels of IL-10 than that of nystatin, whereas the levels of TNF-α and IFN-γ induced by NYT-IL were lower than those elicited by nystatin. Since polyene treatment is associated with nephrotoxicity, lower levels of nystatin in the kidneys following NYT-IL injection suggest the possibility of reduced toxicity. As the acute infusion-related adverse effects associated with polyene treatment are considered to be induced by pro-inflammatory cytokines, a higher level of anti-inflammatory and lower levels of pro-inflammatory cytokines elicited by NYT-IL administration suggest the possibility of amelioration of such effects. In summary, the altered pharmacokinetics, tissue distribution and immune response due to the use of this intralipid formulation of nystatin merit further research towards the development of a therapeutic agent against invasive mycoses.

Use of cryoprotectant-depleted allogeneic peripheral blood stem cells for transplantation

Transplantation with cryopreserved allogeneic peripheral blood stem cells (PBSCs) from related donors is widely conducted in Japan. To freeze PBSCs, a solution containing dimethyl sulfoxide (DMSO), which can have various adverse effects, is added. DMSO-depleted allogeneic PBSCs were transplanted into 21 patients. The cryoprotectant was manually removed from thawed PBSCs and the cells were mixed with a solution containing citrate dextrose as an anticoagulant and RPMI-1640 medium. DMSO-depleted PBSCs were immediately infused into patients subjected to conditioning. Infusion-related adverse effects were only observed in three patients. The median neutrophil recovery (⩾0·5×109/l) and platelet recovery (⩾20×109/l) were 13·0 and 14·0 days, respectively. Only one patient with mixed-lineage leukemia in non-complete remission did not show engraftment, likely due to a second transplantation and a two-antigen disparity in human leukocyte antigen system A. The results suggest the removal of DMSO from thawed PBSCs to be safe and useful for transplantation.

Comparative Efficacy of Amphotericin B Lipid Complex and Liposomal Amphotericin B for the Treatment of Invasive Fungal Infections in HSCT Recipients and other Immunocompromised Patient Populations with Hematologic Malignancies: A Critical Review

Amphotericin B is an important agent for the treatment of invasive fungal infections in immunocompromised patients because of its broad spectrum. However, its toxicities and the availability of alternative agents limit its application. Lipid-based formulations of amphotericin B, such as amphotericin B lipid complex (ABLC) and liposomal amphotericin B (L-AMB), are less nephrotoxic and as effective as conventional amphotericin B. However, because of their similarities, choosing between the two formulations remains a challenge. The majority of prospective and retrospective comparative studies have shown equivalence in terms of efficacy although some subset analyses favor ABLC over L-AMB. While both drugs penetrate well in the reticuloendothelial system, ABLC gets concentrated in the lungs to a much greater extent. This may have clinical implications because the lungs are the commonest site of invasive fungal infections. L-AMB is associated with less infusion-related adverse effects and less nephrotoxicity than ABLC. ABLC has been shown to be more cost-effective than L-AMB, although this is affected by variable institutional contracts and pricing. The choice between the two drugs should be based upon due consideration of all these factors.

Echinocandins: A ray of hope in antifungal drug therapy

Invasive fungal infections are on the rise. Amphotericin B and azole antifungals have been the mainstay of antifungal therapy so far. The high incidence of infusion related toxicity and nephrotoxicity with amphotericin B and the emergence of fluconazole resistant strains of Candida glabrata egged on the search for alternatives. Echinocandins are a new class of antifungal drugs that act by inhibition of β (1, 3)-D- glucan synthase, a key enzyme necessary for integrity of the fungal cell wall. Caspofungin was the first drug in this class to be approved. It is indicated for esophageal candidiasis, candidemia, invasive candidiasis, empirical therapy in febrile neutropenia and invasive aspergillosis. Response rates are comparable to those of amphotericin B and fluconazole. Micafungin is presently approved for esophageal candidiasis, for prophylaxis of candida infections in patients undergoing hematopoietic stem cell transplant (HSCT) and in disseminated candidiasis and candidemia. The currently approved indications for anidulafungin are esophageal candidiasis, candidemia and invasive candidiasis. The incidence of infusion related adverse effects and nephrotoxicity is much lower than with amphotericin B. The main adverse effect is hepatotoxicity and derangement of serum transaminases. Liver function may need to be monitored. They are, however, safer in renal impairment. Even though a better pharmacoeconomical choice than amphotericin B, the higher cost of these drugs in comparison to azole antifungals is likely to limit their use to azole resistant cases of candidial infections and as salvage therapy in invasive aspergillosis rather than as first line drugs.