Liver stem cells: a two compartment system

STUDY OBJECTIVE: To develop management guidelines for the treatment of anaphylactoid reactions to intravenous N-acetylcysteine (NAC) and to assess the safety of restarting the infusion after a reaction. METHODS: In phased 1, we used a 6-year retrospective case series of hospitalized patients and a review of the literature to develop the management guidelines for anaphylactoid reactions to intravenous NAC. In phase 2, these guidelines were evaluated prospectively in our poison-control center. RESULTS: In phase 1, the charts of 11 patients with anaphylactoid reactions (9 cutaneous and 2 systemic) were reviewed. In most cases, no treatment or treatment with diphenhydramine alone or with salbutamol was sufficient to continue or restart NAC infusion safely. On the basis of our findings in those patients and on published experience, we concluded that anaphylactoid reactions to intravenous NAC are dose-related and the antihistamines are useful in controlling and in preventing recurrence of anaphylactoid symptoms. We developed the following guidelines: flushing requires no treatment, urticaria should be treated with diphenhydramine, and NAC infusion should be continued in both cases. Angioedema and respiratory symptoms each require the administration of diphenhydramine and symptomatic therapy. In these cases, NAC infusion should be stopped but, when necessary, can be started 1 hour after the administration of diphenhydramine in the absence of symptoms. In phase 2, 50 patients (31 cutaneous and 19 systemic reactions) were treated prospectively with the use of these guidelines. Recurrence of symptoms occurred in only one case involving a deviation from the guidelines. The NAC infusion was restarted immediately after the administration of diphenhydramine in a patient who sustained a systemic reaction. CONCLUSION: Non-life-threatening anaphylactoid reactions to intravenous NAC are treated easily and the infusion may be continued or restarted safely after the administration of diphenhydramine.     

Comparison of environmental quality in the districts of the Czech Republic with mortality pattern and selected health parameters

BACKGROUND: Cancer patients treated with the anticancer drug, paclitaxel (Taxol) often experience mild to severe hypersensitivity reactions. It is not known how these reactions are induced and whether the inducer is paclitaxel or its vehicle (i.e., Cremophor EL in 50% ethanol). Molecules present in Cremophor EL are similar in structure to certain nonionic block copolymers that activate complement proteins (i.e., proteins involved in various immune processes). To explore the role of complement in the observed hypersensitivity reactions, we studied the effects of paclitaxel and Cremophor EL plus ethanol on human complement in vitro. METHODS: Serum specimens from healthy individuals and cancer patients were incubated with paclitaxel or with relevant control compounds (Cremophor EL with ethanol, ethanol only, docetaxel, and cyclosporine), and markers of complement activation (SC5b-9 and Bb) were measured by enzyme-linked immunosorbent assay. Similar incubations were performed in the presence of inhibitors of complement activation (i.e., EGTA/Mg2+ and soluble complement receptor type 1 [sCR1]). RESULTS: Paclitaxel in Cremophor EL plus ethanol caused increased formation of SC5b-9 in serum specimens from 10 of 10 healthy control subjects and from five of 10 cancer patients. Experiments with one or more individual sera indicated the above effect was due to Cremophor EL plus ethanol, that increased formation of Bb also occurred, that the drug-induced rise in SC5b-9 was inhibited by sCR1, and that EGTA/Mg2+ partially inhibited SC5b-9 formation and stimulated Bb formation. IMPLICATION: The role of complement activation in hypersensitivity reactions associated with administration of paclitaxel in Cremophor EL plus ethanol should be studied in vivo.     

Pharmacologic intolerance reaction after intravenous injection of pethidine

We report on anaphylactoid reactions (urticae at the injection site and along the injection vein) after intravenous injections of pethidine in two patients. Skin tests with pethidine were negative, but intravenous challenge showed urticae. These results indicate that the reactions were due to a non-immunological mechanism resembling pharmacological intolerance. Retrospective analysis revealed a 5.6% incidence of pharmacological intolerance reactions to intravenous pethidine in 519 patients.     

Infusiontherapy with colloidal volumesubstitutes (author''s transl)

All colloidal plasma substitutes carry the risk of anaphylactoid complications with a general incidence of 0.03%. This incidence seems low; however severe complications may occur after infusion of colloids, including also human albumin solutions. In spite of the risk of anaphylactoid reactions, however, colloids should not be ommited from volume replacement therapy. When choosing a colloid for volume replacement the solution-specific risk of anaphylactoid complications has to be taken into consideration. From an increasing number of recent case reports the impression of a rising rate of complications has emerged; this impression was not substantiated by a prospective controlled trial performed in 1975. Since dextran in addition to its safe volume effect possesses well documented antithrombotic properties, it cannot be replaced by any other colloid without the addition of another thromboprophylactic agent.     

Update in ophthalmology (Prague, 10-13 March 1997)

The use of tissue plasminogen activator (t-PA) in the management of acute myocardial infarction, as effective thrombolytic agent, is well established. Thrombolytic therapy, limiting the extent of myocardial necrosis, reduces the infarct-related morbidity and mortality and improves the prognosis in patients with acute myocardial infarction. Thrombolytic agents present various side effects. Allergic reactions may occur with both streptokinase (ST) (or with anistreplase, the equimolecular mixture of streptokinase and human plasminogen); and t-PA. The incidence of allergic reactions associated with the use of t-PA is much lower if compared with other thrombolytic agents. Since t-PA is structurally identical to endogenous t-PA, its administration should not cause anaphylactic reactions. The purpose of this case presentation is to describe the occurrence of an anaphylactoid reaction during infusion of t-PA in a 63 year-old man, admitted to the Cardiac Care Unit (C.C.U.) with diagnosis of acute myocardial infarction.     

Paclitaxel-induced acute bilateral pneumonitis

OBJECTIVE: To report three cases of paclitaxel-induced acute bilateral pneumonitis, as well as to ascertain its incidence and outcome. CASE SUMMARIES: A total of 239 patients with a variety of underlying malignancies received 528 courses of paclitaxel-containing chemotherapy. Paclitaxel 200 mg/m2 was infused over 3 hours with standard premedication. Three patients developed bilateral interstitial infiltrates either during or within 6 hours of the administration of paclitaxel. Symptoms included a nonproductive cough, dyspnea, and sudden arterial oxygen desaturation. Response to parenteral corticosteroids was dramatic and reversed the process in all 3 patients. DISCUSSION: Paclitaxel-induced acute bilateral pneumonitis appears to be a rare adverse reaction. It may either be a direct toxic effect of the chemotherapeutic agent or an adverse effect of its Cremophor EL diluent. Although the exact pathophysiology is unclear, a variety of immune and nonimmune mechanisms have been postulated, including hypersensitivity reactions, release of cytokines from macrophages, and the possible role of prior thoracic irradiation. CONCLUSIONS: Acute bilateral pneumonitis occurs in less than 1% of individuals receiving 3-hour infusions of paclitaxel, and responds dramatically to parenteral corticosteroid therapy.     

Counterflow centrifugal elutriation as a method of T cell depletion may cause loss of immature CD34+ cells

BACKGROUND: Several clinical studies have shown that polychemotherapy with the taxanes paclitaxel or docetaxel preceded or followed by cisplatin is associated with important schedule-dependent differences in toxicities, such as leukocytopenia. In general, the pharmacokinetics of both drugs during the combined treatment are unaltered, suggesting that a pharmacodynamic interaction might have occurred. MATERIALS AND METHODS: In order to gain insight into this pharmacologic interaction, we performed in vitro drug accumulation studies using peripheral blood leukocytes and a panel of tumor and non-malignant cell lines with paclitaxel and docetaxel, as well as with their respective formulation vehicles Cremophor EL and Tween 80. RESULTS: Our results show a significant reduction in the intracellular cisplatin concentration in leukocytes of up to 42% in the presence of Cremophor EL and Tween 80 as compared to the control. This pharmacodynamic interaction of these surfactants with cisplatin seems to be specific for haematopoietic cells, and does not occur in solid tumor cells. CONCLUSION: The present data suggest that the pharmaceutical vehicles Cremophor EL and Tween 80 might contribute to the reduced cisplatin-associated myelotoxicity observed in the clinical combination chemotherapy studies with paclitaxel and docetaxel.     

Metastatic renal adenocarcinoma in a mule

We previously developed a homoharringtonine resistant C-1300 neuroblastoma cell line with cross-resistance to adriamycin and increased levels of p-glycoprotein, and showed that drug resistance could be reversed in this cell line by cyclosporin A. The present study shows that cremophor EL, a parenteral vehicle for cyclosporin A, can also completely reverse this multidrug resistance in a clonogenic assay system. Cremophor EL incubated with resistant cells for up to six days did not reduce levels of p-glycoprotein. Intracellular homoharringtonine analysis using HPLC revealed increased drug accumulation in resistant cells treated with cremophor EL. The increased drug level was not due to blocking of drug efflux commonly seen in other multidrug resistant models. The data suggest that resistance modulation with cyclosporin A should be interpreted with caution when cremophor EL is a solvent. Our work suggests cremophor EL, a relatively nontoxic lipophylic solvent, may have a direct effect on membrane permeability, although other mechanisms cannot be ruled out.     

Toxicity management in patients receiving low-dose aldesleukin therapy

OBJECTIVE: To review the pathophysiology and subsequent treatment options for low-dose aldesleukin-induced toxicity when administered via intravenous bolus infusion, continuous intravenous infusion, or subcutaneous injection. BACKGROUND: The adverse events associated with high-dose aldesleukin therapy (600,000 IU per kg i.v. every 8 h for a maximum of 14 doses) are well documented in the literature; however, the adverse event profile of lower doses and alternative administration routes are less well described. An understanding of the adverse event profile associated with these alternative regimens can enhance management of toxicity. DATA SOURCES: English-language clinical studies, abstracts, and review articles pertaining to low-dose intravenous, continuous intravenous infusion, or subcutaneous injection of aldesleukin, as well as aldesleukin-induced adverse events. STUDY SELECTION AND DATA EXTRACTION: Relevant studies were selected that assist with understanding the pathophysiology, clinical management, diagnosis, and management of aldesleukin-induced adverse events. CONCLUSIONS: Aldesleukin therapy initiates a cytokine-mediated proinflammatory process resulting in a toxicity profile that is different from traditional nonbiologic chemotherapeutic agents. The frequency and severity of adverse events associated with aldesleukin administration are dependent upon dose, route, and administration schedule. In addition, most adverse reactions are self-limiting. Alleviation of aldesleukin-induced adverse effects can usually be achieved on an outpatient basis with agents such as antiemetics, antipyretics, and topical creams or lotions, as well as nonmedication interventions. Aggressive and proactive management of aldesleukin associated toxicities can help facilitate completion of therapy.     

Linkage map integration

Cyclosporin A (CsA) has been shown to be useful in the prophylaxis of acute graft-versus-host-disease (GVHD). However, this immunosuppressive agent produces multiple side-effects including nephrotoxicity, hypertension, hypertricosis, gum hyperplasia, infections, and neurotoxicity. We report a retrospective analysis of neurotoxicity in 625 recipients transplanted for thalassemia and given CsA as part of GVHD prophylaxis. Neurotoxicity consisted in mental status changes, tremor, headache (grade 1), visual disturbance and cortical blindness (grade 2) and seizures and coma (grade 3). The overall toxicity was 28.8% and the incidence of convulsions was 10.1%. Neurological findings were reversible after temporary reduction or discontinuation of CsA. Class 3 patients, when prepared with protocol 6 (Bu 14 + Cy 200 and CsA for GVHD) or when they developed acute GVHD, had the highest risk of convulsions. Age, sex, different conditioning regimens, different anticonvulsive prophylaxis, liver damage due to iron-overload and/or to chronic inflammation did not influence the occurrence of CsA-related CNS toxicity. The occurrence of acute GVHD with concomitant use of high-dose corticosteroids is the single significant predisposing factor in the occurrence of convulsions. Grades 1 and 2 of neurotoxicity occurred earlier and were not influenced even by acute GVHD.     

Anaphylactic reaction to N-acetylcysteine after poisoning with paracetamol

Paracetamol is among the most common substances consumed in self-poisoning attempts. The recommended treatment is intravenous N-acetylcysteine. Adverse reactions to this treatment are relatively common, but are rarely serious. The article reports and discusses a patient who had an anaphylactoid reaction to N-acetylcysteine after an overdose of paracetamol. This reaction was most probably an acute toxic effect of N-acetylcysteine, and not a result of an immunologic hypersensitivity reaction. Reducing the infusion rate of the initial loading dose might reduce the risk of adverse reactions. Recent guidelines recommend giving the loading dose over 60 minutes, instead of 15 minutes.     

Recombinant human interleukin-3 hastens trilineage hematopoietic recovery following high-dose (7 g/m2) cyclophosphamide cancer therapy

BACKGROUND: Interleukin-3, a recombinant cytokine with multilineage stimulatory effect on hematopoietic cells, was administered to 22 previously untreated breast cancer patients following high-dose therapy with cyclophosphamide (7 g/m2). PATIENTS AND METHODS: The growth factor, administered through continuous intravenous infusion at 1 (3 patients), 2.5 (3 patients), 5 (10 patients) and 10 micrograms/kg/day (6 patients), was well tolerated up to 5 micrograms/kg/day. RESULTS: Nausea, vomiting, fever and headache prevented administration of the intended dose to all 6 patients in the 10 micrograms/kg/day cohort. At the maximal tolerable dose (5 micrograms/kg/day) the growth factor significantly accelerated granulocyte, platelet and reticulocyte recovery as compared to matched historical controls who received high-dose cyclophosphamide without cytokine infusion. Moreover, no platelet transfusions and fewer erythrocyte transfusions were required in interleukin 3-treated patients. In contrast to GM-CSF and G-CSF, interleukin 3 showed no effect on the mobilization of hematopoietic progenitor cells in the peripheral blood. CONCLUSIONS: Interleukin-3 represents a well-tolerated cytokine, clinically useful for accelerating trilineage hematopoietic recovery following severely myelotoxic treatments such as high-dose cyclophosphamide.     

Phase I and pharmacologic study of weekly doxorubicin and 1 h infusional paclitaxel in patients with advanced breast cancer

Doxorubicin and paclitaxel both display strong antitumor activity in the treatment of breast cancer. The optimal schedule of this combination, however, remains undefined. In this phase I and pharmacologic study, we administered weekly 12 mg/m2 doxorubicin as a bolus infusion immediately followed by a 1 h 80 mg/m2 paclitaxel infusion to patients with metastatic breast cancer. A total of 119 weekly courses were delivered to seven patients. Grade IV neutropenia was observed in two patients at the first dose level, thus already defining the maximum tolerated dose. Pronounced non-hematologic toxicities were mild neuropathy (grade I: 39%) and stomatitis (grade I: 19%, grade II: 8%). No signs of cardiac toxicity were observed with this dose schedule. Three partial responses were achieved in this group of heavily pretreated patients. The pharmacokinetics of paclitaxel, doxorubicin and Cremophor EL with this schedule were analyzed. Overall, the schedule was well tolerated and combined with its preliminary response rate justifies further evaluation in phase II studies.     

Cyclosporin A and cyclosporin SDZ PSC 833 enhance anti-CD5 ricin A-chain immunotoxins in human leukemic T cells

Recent studies have shown that cyclosporin A (CsA) may affect ricin A-chain immunotoxin (RTA-IT) therapy. In this study, we evaluated the ability of CsA and its nonimmunosuppressive analog, SDZ PSC 833, to enhance anti-CD5 T101 RTA-ITs in vitro. Both 4 mumol/L CsA and 4 mumol/L SDZ PSC 833 significantly and specifically enhanced the cytotoxic activity of T101 RTA-IT on the human lymphoblastic T-cell line, CEM III (101-fold and 105-fold, respectively). Furthermore, these Cs also enhanced the cytotoxicity of the more potent T101 F(ab')2 RTA-IT (ninefold and eightfold, respectively). The effect of human plasma, originating from four patients enrolled in a phase I high-dose CsA regimen, was examined on T101 RTA-IT cytotoxicity on CEM III cells. In each case, with plasma CsA levels between 3,090 and 4,860 ng/mL (2.5 to 4 mumol/L), a significant increase in T101 RTA-IT-mediated cytotoxicity was observed ranging from 31% to 60%. Neither CsA nor SDZ PSC 833 affected the rate of RTA-IT binding, internalization, intracellular trafficking, or degradation. Analysis of internalized T101 RTA-IT molecules showed that these were essentially intact, which suggests that these enhancers may act only on a small population of RTA-ITs that escapes present investigational techniques. In conclusion, because the concentrations used are clinically achievable, Cs appear to be promising agents for in vivo enhancement of RTA-ITs.     

CsA levels in the early posttransplant period--predictive of chronic rejection in liver transplantation?

The increasing success of clinical liver transplantation has brought rejection to the forefront as a cause of morbidity and graft loss. The relationship of immunosuppressive drug doses and levels to acute and chronic rejection remains a matter of debate. The effect of blood CsA levels and drug doses on the incidence of acute and chronic rejection and the impact of acute rejection episodes on the occurrence of chronic rejection were studied in 146 grafts in 132 patients. These patients were transplanted in the 4-year period from June 1989 using CsA-based immunosuppression (CsA, azathioprine, prednisolone). Liver grafts in patients maintained on median CsA levels (whole blood, trough level) of > or = 175 micrograms/L in the first 28 days posttransplant had a significantly lower incidence of chronic rejection (2 out of 49 vs. 22 out of 97; P = 0.002). There was no significant difference in incidence of graft loss due to fatal sepsis (6% vs. 5%) or nephrotoxicity between the high and low CsA level groups. The overall graft loss rate was lower in the higher CsA level group (22% vs. 37%). The total doses of the individual drugs did not correlate with the incidence of acute or chronic rejection. Although the occurrence of acute rejection itself did not determine later chronic rejection, late occurrence (P < 0.00001) and multiple episodes (two or more; P = 0.0002) of acute rejection were significant risk factors for the occurrence of chronic rejection. We conclude that to minimize graft loss to rejection, CsA levels should be maintained at greater than 175 micrograms/L in the early posttransplant period, and late and recurrent episodes of acute rejection should be prevented.     

Gene expression of syndecans and betaglycan in isolated rat liver cells

Competence as communication skills and as skilled practice of asepsis were studied by observing four nurses while interacting with patients and performing intravenous procedures. Nurses were observed using sterile equipment for methods of intravenous therapy. Asepsis is performed frequently, but through misunderstanding in the learning of asepsis or improper model learning the nurses may establish incorrect routines. When performing procedures, unexpected factors can distract both the expert and the inexperienced, resulting in a failure to apply basic aseptic techniques. The nurses showed an interest in the patient by listening and giving responses. Nurses may control interactions with the patient by using undesirable communication skills which include incomplete sentences, incomplete explanations and closed questions. Asked to evaluate their own behavior, the nurses did not estimate whether or not the appropriate skills were applied in observed situations. To improve the quality of nursing care performance it is recommended to further develop and apply skill training programs.     

Discharge planning for the patient requiring home intravenous antimicrobial therapy

Home intravenous (IV) antimicrobial therapy is a well accepted and widely practiced form of home infusion therapy. Orthopaedic-related infections, often requiring long courses of therapy, are commonly treated in the home setting after a brief hospitalization. Hospital orthopaedic nurses play an important role in preparing patients for home care. This article addresses patient selection for home IV therapy, the discharge planning process, and educational preparation of the patient. The role of the home care nurse is briefly presented to enhance the orthopaedic nurse's knowledge of the continuum of care.     

Are fathers helpful, harmful or superfluous for the development of adolescents?

Presented is the first reported case of an anaphylactoid reaction following Norplant contraceptive implant insertion. The 19-year-old UK woman denied any history of allergic reaction to local anesthesia. After subcutaneous infiltration with 50 mg of 1% lidocaine (without adrenalin), 6 Norplant capsules were inserted through use of the standard insertion technique. Shortly after completion of the procedure, the patient collapsed and had 2 short convulsions. Her blood pressure dropped to 80/40 mm Hg and her radial pulse was 60 beats/minute and thready. Recovery was rapid following administration of intramuscular adrenalin and intravenous hydrocortisone. The woman later recalled a similar episode during a visit to her dentist. An estimated 3 in every 100,000 patients receiving lignocaine hydrochloride have an episode of anaphylaxis in the hospital. In type I hypersensitivity reactions, there is often a history of previous exposure to the allergen, as occurred in this patient. Those undertaking Norplant insertion and removal should be aware of the potential for serious allergic reactions and have access to resuscitative equipment.     

Dermatology and the Internet--uses for the clinic and research

Improvement brought to iodinated molecules aims to obtain an optimal enhancement effect together with a lower toxicity. However, benign adverse events remain a common risk, and anaphylactoid reactions from the intravascular administration of iodinated contrast media may occur at random and are unpredictable. Although most contrast reactions are mild and self-limited, severe and even life-threatening reactions can occur at any time and for any kind of agent. Physicians must be aware of possible complications related to administration of this kind of agents and must be able to identify patients at risk, to care for prevention and prescribe an appropriate premedication regimen.     

Effect of different immunosuppressive agents on acute pancreatitis: a comparative study in an improved animal model

BACKGROUND: Immunosuppressive drugs have been associated with the development and progression of acute pancreatitis after organ transplantation. Consequently, a reduction or a change in immunosuppressive therapy has been recommended once posttransplantation pancreatitis has been suspected. However, it is not known which of the available immunosuppressive agents is most harmful to the pancreas and which may be used safely in this situation. The objective of this study was to investigate the effect of different immunosuppressive drugs in various dosages on intrapancreatic protease activation, acinar cell necrosis, and mortality in an improved model of acute necrotizing pancreatitis in the rat. The rat model of acute necrotizing pancreatitis, like posttransplantation pancreatitis, is characterized by ischemia and microcirculatory disorders. METHOD: Acute pancreatitis was induced in rats by using a combination of low-dose controlled intraductal glycodeoxycholic acid superimposed on intravenous cerulein hyperstimulation. Six hours thereafter, animals were randomized to intravenous therapy with 2, 10, or 50 mg/kg/day prednisolone (PRED); 3, 15, or 60 mg/kg/day cyclosporine A (CsA); 10 mg/kg/day azathioprine (AZA); 0.6 mg/kg/day orthoclone OKT3 (OKT3); or saline. After 36 hr, surviving animals were killed to determine acinar cell necrosis and trypsinogen activation peptides levels (TAP) in blood and ascites. RESULTS: Compared with saline-treated control rats, animals treated with 60 mg/kg/day CsA developed significantly more acinar cell necrosis and had increased amounts of TAP in ascites. Likewise, there was more extensive acinar cell necrosis in animals subjected to AZA therapy. However, this was not associated with incremental TAP. Animals treated with 3 or 15 mg/kg/day CsA, OKT3, or PRED showed no significant changes in these target parameters. Animals given 10 or 50 mg/kg/day PRED even had decreased hematocrit values and produced significantly less ascites than animals in the other groups. CONCLUSION: The present results suggest that AZA and high doses of CsA aggravate acute pancreatitis and should, therefore, be avoided once posttransplantation pancreatitis has been suspected, whereas lower doses of CsA, OKT3, and PRED may be used safely. PRED can even be used at higher doses as may be required when graft rejection is suspected.