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L A Frenken

Publications and source records attributed to L A Frenken.

At least 19 recordsLinked to original sources
PubMed1997

Role of polymorphic Fc receptor Fc gammaRIIa in cytokine release and adverse effects of murine IgG1 anti-CD3/T cell receptor antibody (WT31).

Anti-CD3 monoclonal antibody (mAb) OKT3 is immunosuppressive, but causes severe adverse effects during the first administration ("first-dose reaction"). These adverse effects are presumably caused by cytokine release that results from T-cell activation. In vitro, T-cell activation by anti-CD3 mAb requires interaction with monocyte Fc receptors. The Fc receptor for murine IgG1, Fc gammaRIIa, is polymorphic. In some individuals, murine IgG1 anti-CD3 mAb causes T-cell proliferation and cytokine release in vitro (high responders [HR]), whereas in individuals with the low-responder (LR) phenotype it does not. We have now investigated the role of this Fc gammaRIIa polymorphism in the release of cytokines in vivo and the occurrence of adverse effects after the administration of WT31, a murine IgG1 anti-CD3/T cell receptor mAb. WT31 caused an increase of plasma tumor necrosis factor-alpha in all four HR patients and none of the five LR patients. In all HR patients except one, plasma gamma-interferon and interleukin 6 also increased, and a first-dose response was observed, whereas no cytokine release or adverse effects occurred in any of the LR patients. WT31 caused lymphopenia in all HR and none of the LR patients. FACS analysis demonstrated that in HR patients, after the initial disappearance of CD3+ cells from peripheral blood, modulation of CD3 occurred, whereas in LR patients a high degree of coating of the lymphocytes was observed. Surprisingly, WT31 also induced a marked granulocytopenia, as well as a decrease of thrombocytes, in three of the four HR patients (and in none of the LR patients). These data provide direct clinical evidence that Fc receptor interaction determines the release of cytokines and the occurrence of adverse effects after administration of anti-CD3/T cell receptor mAb. Furthermore, these data suggest that tumor necrosis factor-alpha by itself is not sufficient to induce the first-dose reaction.

Antibodies, Monoclonal↗
PubMed1994

Analysis of the efficacy of measures to reduce pain after subcutaneous administration of epoetin alfa.

Pain at the injection site with subcutaneous administration of epoetin alfa preparations is a common adverse event, and sometimes precludes self-administration. The pain is caused mainly by the vehicle. The present studies were designed to assess whether pain after subcutaneous administration of the vehicle can be influenced by making the solution iso-osmotic, or by diluting the vehicle by the bacteriostatic agent benzyl alcohol saline (BAS). The volumes injected were 1 ml. We also determined whether reduction of the injected volume of 1 ml to 0.33 ml or to 0.1 ml could be of clinical importance. One millilitre of normal saline served as a placebo control. The studies were done in a double-blind, placebo-controlled, randomized order, cross-over fashion in healthy volunteers. Pain scores were obtained from visual analogue pain scales with no divisions and from 5-point verbal descriptive pain scales. Dilution of the vehicle with BAS resulted in significantly less pain (P < 0.0001) after subcutaneous injection, comparable to levels obtained with normal saline. Making the vehicle iso-osmotic had no effects. Injection of smaller volumes of the vehicle was beneficial with 0.1 ml (P < 0.0001), but the reduction to 0.33 ml was not statistically significant.

Adult↗
PubMed1993

Identification of the component part in an epoetin alfa preparation that causes pain after subcutaneous injection.

The subcutaneous administration of epoetin alfa preparations may cause pain at the injection site. To identify the pain-causing substance in these formulations we performed two double-blind, placebo-controlled, randomized order, cross-over studies. Differences in pain experienced after subcutaneous injection of an epoetin alfa solution and its vehicle were assessed in 36 patients. The vehicle and its component parts, albumin and citrate, were compared in 36 volunteers. Normal saline served as a placebo control in both studies. Pain scores were obtained from visual analogue pain scales with no divisions and from five point verbal descriptive pain scales. Both the epoetin alfa solution and its vehicle caused significantly more pain than normal saline (P < 0.0001) in the patients studied. In volunteers the pain scores with the vehicle or its citrate component were significantly higher (P < 0.0001) when compared with normal saline or with the albumin component of the vehicle. In conclusion, the local pain experienced after subcutaneous administration of epoetin alfa preparations is mainly caused by the citrate component of the buffered solution. Epoetin alfa and the albumin component of the preparation do not play a role in this phenomenon.

Adolescent↗
PubMed1993

Erythropoietin: mechanisms of action and indications for treatment.

We review data concerning site and regulation of erythropoietin (EPO) production, its effects on target tissue, routes of administration and clinical applications. In the anaemia of chronic renal failure (ACRF) treatment with recombinant human erythropoietin (r-Hu-EPO) has been shown to be effective in both improvement of the anaemia and increase in quality of life. In the anaemia of chronic disease (ACD), associated with various malignant, infectious and inflammatory disorders, many investigators have demonstrated an inappropriately low EPO response to anaemia. Therapeutic trials in patients with ACD mostly lacked sufficient numbers of patients for evaluation of the effects. The results obtained from some studies in AIDS and rheumatoid arthritis and the effect on the number of units of autologous blood obtained from patients planned for elective surgery are encouraging, however. Adverse reactions of r-Hu-EPO treatment are mainly confined to the ACRF population and include hypertension, shunt thrombosis and pain at the injection site. The exact mechanism of action of EPO is not yet fully understood. Large scale clinical trials are required to establish its effects on both the anaemia and quality of life in anaemias other than ACRF.

Anemia↗
PubMed1992

Evidence for renal vasodilation in pre-dialysis patients during correction of anemia by erythropoietin.

Results from animal experiments have suggested that treatment with recombinant human erythropoietin (rHuEPO) causes changes in renal hemodynamics which are detrimental to renal function. Therefore, the effects of correction of the anemia by rHuEPO on glomerular filtration rate (GFR; inulin clearance) and effective renal plasma flow (ERPF; PAH clearance) were studied in eight pre-dialysis patients. The studies were done before (Hct 0.24 +/- 0.05 liter/liter) and at 89 +/- 19 days after the start of rHuEPO therapy (Hct 0.39 +/- 0.03 liter/liter). To further evaluate the effects of ACE inhibition, 25 mg of captopril was given orally after baseline values had been obtained. Baseline GFR, renal blood flow (RBF) and filtration fraction (FF) did not change during rHuEPO therapy. At low hematocrit (Hct) captopril induced a significant increase in ERPF and RBF, and a decrease in MAP. After correction of the hematocrit the blood pressure lowering effect of captopril remained unchanged. However, captopril no longer induced changes in ERPF and RBF. We conclude that the increase in hematocrit had no adverse effects on GFR. The results suggest that changes in hematocrit may influence the effects of ACE inhibition on efferent vascular resistance. Therefore, the hematocrit should be taken into account when evaluating studies on the effects of ACE inhibition in the progression of chronic renal failure.

Adult↗
PubMed1992

Intraperitoneal administration of recombinant human erythropoietin.

OBJECTIVE: To determine the efficacy and safety of intraperitoneal administration of recombinant human erythropoietin (rHuEPO) in continuous ambulatory peritoneal dialysis (CAPD) patients compared to subcutaneous rHuEPO. DESIGN: Prospective analysis of an open, nonrandomized investigation. SETTING: Outpatient CAPD clinics in two university hospitals. PATIENTS: Nine adult CAPD patients receiving rHuEPO intraperitoneally and 8 patients receiving rHuEPO subcutaneously. INTERVENTION: One hundred units of rHuEPO per kilogram of body weight were administered three times a week for 8 weeks or until the target hematocrit of 35% was reached. Thereafter, dosages of rHuEPO were adjusted for response. Intraperitoneal rHuEPO was administered in 1 L of dialysis solution during the night. MEASUREMENTS: Efficacy was assessed by measuring the increase in hemoglobin. Tolerance was assessed by monitoring side effects. RESULTS: In the first 8 weeks of treatment hemoglobin concentration increased from 64.5 +/- 12.9 g/L to 98.3 +/- 16.1 g/L (p < 0.0005) in the intraperitoneally treated group. In the subcutaneously treated group hemoglobin increased significantly faster (p < 0.05) from 72.5 +/- 4.8 g/L to 119.2 +/- 11.3 g/L (p < 0.0005) in the same period. Antihypertensive medication had to be increased or instituted in most of the patients in both groups. The incidence of peritonitis in the intraperitoneally treated group was not increased when compared to the pretreatment incidence. CONCLUSIONS: Subcutaneously administered rHuEPO is superior to intraperitoneally administered rHuEPO with regard to the required dosages. However, the results of this study show that intraperitoneal administration of rHuEPO might be a convenient and safe alternative when subcutaneous administration is undesirable.

Adult↗
PubMed1991

The role of antibody isotype in IFN-gamma and IL-2 production during anti-CD3-induced T cell proliferation.

Murine anti-CD3 mAb of the IgG2a isotype are effective in the reversal of graft rejection. However, the first injection of these mAb causes a transient T cell activation in vivo, resulting in the release of cytokines that are held responsible for the sometimes severe febrile and adverse circulatory reactions associated with this therapy. Previously, we and others have reported that there is a polymorphism in the interaction of human Fc gamma R with mouse IgG1 and mouse IgG2b. This polymorphism implies that IgG1 and IgG2b mAb are mitogenic for T cells from respectively 70% and less than 5% of healthy individuals. By contrast, Fc gamma R interact with murine IgG2a and IgG3 mAb in virtually all individuals. We have now investigated the role of the isotype of the anti-CD3 mAb with respect to in vitro T cell proliferation and production of IFN-gamma and IL-2. IFN-gamma and IL-2 production always accompanied IgG2a- and IgG3-induced mitogenesis, whereas with IgG1 mAb the polymorphism in mitogenic effects completely correlated with IFN-gamma and IL-2 production. With IgG2a, IgG3, and IgG1 mAb, proliferation and IFN-gamma production were, at least in part, dependent on IL-2 production. On the other hand, IgG2b-induced proliferation was not accompanied by measurable IFN-gamma or IL-2 production. This suggests a fundamental difference in the way T cells are activated by IgG2b mAb. Given the role of IFN-gamma and IL-2 in the generation of adverse events during in vivo administration of anti-CD3 mAb, the use of IgG1 anti-CD3 or anti-TCR mAb offers a tool to further analyze the role of isotype in this respect. Moreover, the clinical use of IgG2b might result in immunosuppression without side effects.

Antibodies↗