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Background: Despite the worldwide obesity epidemic, there have been very few studies investigating the influence of body weight on treatment dosing and outcomes in patients with hereditary angioedema (HAE)., Objective: The purpose of this analysis was to determine whether the standard weight-based dosing recommendation of C1 esterase inhibitor (C1-INH) concentrate (20 IU/kg) is adequate in HAE patients with a high body mass index (BMI)., Methods: Data from patients treated for HAE attacks with 20 IU/kg of C1-INH concentrate were retrospectively analyzed from the open-label IMPACT2 study (International Multicenter Prospective Angioedema C1-INH Trial). Patients were categorized according to BMI as being normal body weight, overweight, or obese. Efficacy end points were time to onset of symptom relief and time to complete resolution of symptoms. The safety profile was evaluated according to adverse events occurring within 7 to 9 days of treatment., Results: Of 57 patients, 24 (42%) were of normal body weight, 20 (35%) were overweight, and 13 (23%) were obese. Median (95% CI) time to onset of symptom relief was 0.37 hour (0.29-0.57) in normal-weight patients, 0.48 hour (0.39-0.53) in overweight patients, and 0.58 hour (0.41-0.94) in obese patients. Median time (95% CI) to complete resolution of symptoms was 15.2 hours (9.3-23.2) in normal-weight patients, 22.6 hours (11.3-44.6) in overweight patients, and 11.0 hours (5.6-23.6) in obese patients (differences not significant). There were no relevant differences in the incidence of adverse events in normal-weight patients (54%), overweight patients (30%), and obese patients (54%)., Conclusions: Treatment of HAE attacks with weight-based doses of C1-INH concentrate provided reliable treatment response, regardless of body weight, in these patients with HAE., (Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.) more...

Background: C1 esterase inhibitor (C1-INH) concentrate is well established as effective therapy for hereditary angioedema (HAE). It is thought that treatment of an acute HAE attack with C1-INH as early as possible improves efficacy, but there are limited data from prospective studies supporting this recommendation., Objective: To assess the effect of time to treatment (<6 vs ≥6 hours after start of an attack) with 20 U/kg of C1-INH concentrate on efficacy., Methods: A post hoc analysis of time to treatment after start of an attack was performed for 2 studies with C1-INH concentrate: International Multicenter Prospective Angioedema C1-INH Trial (IMPACT) 1 (randomized, placebo-controlled) and IMPACT 2 (open-label, uncontrolled extension). Because of differences in study design, the data sets were analyzed separately. IMPACT 1 data were analyzed using Cox regression with hazard ratios (HRs). For IMPACT 2 data, linear regression was applied to evaluate whether earlier treatment leads to faster recovery. Descriptive statistics for treatment response were calculated for both studies., Results: In IMPACT 1, treatment with C1-INH within less than 6 hours after start of an attack resulted in considerably shorter times to onset of symptom relief (HR, 3.36) and complete resolution (HR, 4.30) vs placebo. The benefit of C1-INH compared with placebo was reduced when administered after 6 or more hours (HRs, 1.18 for times to onset of symptom relief and 1.61 for complete resolution). Analysis of IMPACT 2 data indicated slower complete resolution of symptoms with later start of treatment., Conclusion: Early treatment with C1-INH (<6 hours) provides a better treatment response than late treatment (≥6 hours), supporting the international recommendation to treat HAE attacks as early as possible., Trial Registration: ClinicalTrials.gov Identifiers: NCT00168103 and NCT00292981., (Copyright © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.) more...

Placebo-controlled studies established the efficacy of replacement therapy with C1 esterase inhibitor (C1-INH) concentrate for treating single acute hereditary angioedema (HAE) attacks, but only limited data from prospective studies are available on repeated treatment of successive HAE attacks. This study evaluates the association between repeated treatments with 20 U/kg of C1-INH concentrate (Berinert; CSL Behring, Marburg, Germany) for HAE attacks at any body location and treatment response. In a post hoc analysis of an open-label extension study (International Multicenter Prospective Angioedema C1-INH Trial [I.M.P.A.C.T.2]), the association between repeated treatment with C1-INH and times to onset of symptom relief and complete resolution of HAE symptoms was assessed in patients who were treated for at least 15 attacks by linear regression on the ordinal attack number. Eighteen patients received C1-INH concentrate for at least 15 HAE attacks over a mean duration of 34 months. Demographic and baseline characteristics of these patients were similar to those of all patients in the study. The distribution of body locations and the intensity of HAE attacks were similar for each of the first 15 attacks and subsequent attacks. The extent of previous use of C1-INH concentrate had no effect on the time to onset of symptom relief, the time to complete resolution of HAE symptoms, or the time between attacks treated with C1-INH concentrate; the median of individual linear regression coefficients was not statistically significantly different from 0. Treatment with 20 U/kg of C1-INH concentrate provided consistent treatment response in patients treated for multiple successive HAE attacks at any body location. (Clinicaltrials.gov identifier: NCT00292981). more...

Background: The placebo-controlled study International Multicentre Prospective Angioedema C1-INH Trial 1 (I.M.P.A.C.T.1) demonstrated that 20 U/kg C1 esterase inhibitor (C1-INH) concentrate (Berinert®; CSL Behring, Marburg, Germany) is effective in treating acute abdominal and facial Hereditary Angioedema (HAE) attacks., Methods: I.M.P.A.C.T.2 was an open-label extension study of I.M.P.A.C.T.1 to evaluate the safety and efficacy of long-term treatment with 20 U/kg C1-INH for successive HAE attacks at any body location. Efficacy outcomes included patient-reported time to onset of symptom relief (primary) and time to complete resolution of all symptoms (secondary), analysed on a per-patient and per-attack basis. Safety assessments included adverse events, vital signs, viral safety and anti-C1-INH antibodies., Results: During a median study duration of 24 months, 1085 attacks were treated in 57 patients (10-53 years of age). In the per-patient analysis, the median time to onset of symptom relief was 0.46 h and was similar for all types of attacks (0.39-0.48 h); the median time to complete resolution of symptoms was 15.5 h (shortest for laryngeal attacks: 5.8 h; 12.8-26.6 h for abdominal, peripheral and facial attacks). Demographic factors, type of HAE, intensity of attacks, time to treatment, use of androgens and presence of anti-C1-INH antibodies had no clinically relevant effect on the efficacy outcomes. There were no treatment-related safety concerns. No inhibitory anti-C1-INH antibodies were detected in any patient., Conclusions: A single dose of 20 U/kg C1-INH concentrate is safe and provides reliable efficacy in the long-term treatment of successive HAE attacks at any body location., (© 2011 John Wiley & Sons A/S.) more...

Background: hereditary angioedema (HAE) is a rare disorder characterized by a quantitative or functional deficiency of C1 esterase inhibitor (C1-INH), resulting in periodic attacks of acute edema at various body locations. The symptoms of these painful attacks can be treated effectively with C1-INH concentrate., Objective: to document the efficacy and safety of a weight-based dose of C1-INH concentrate in the treatment of successive HAE attacks at abdominal and facial locations., Methods: acute facial and abdominal attacks were each treated with C1-INH concentrate using a single intravenous dose of 20 U/kg body weight. Efficacy end points included patient-reported time to onset of symptom relief and time to complete resolution of all symptoms. Safety was assessed by monitoring adverse events and assaying for markers of viral infection., Results: we treated 663 abdominal attacks in 50 patients and 43 facial attacks in 16 patients (a total of 706 attacks in 53 patients). The median time to onset of relief for all attacks was 19.8 minutes, with a median time to complete resolution of 11.0 hours. The median time to onset of relief was 19.8 minutes for abdominal attacks and 28.2 minutes for facial attacks, indicating efficacy for both types of attack. No treatment-related serious adverse events occurred, and C1-INH concentrate was well tolerated. No human immunodeficiency virus, hepatitis virus, or parvovirus B19 infections arose during the study., Conclusion: the C1-INH concentrate dose of 20 U/kg provides rapid, effective, and safe treatment for successive HAE attacks at abdominal and facial locations. more...

Time to onset of symptom relief in hereditary angioedema (HAE) is a common primary end point in clinical studies but it has never been validated by correlation with the course of HAE symptoms. This study was designed as a retrospective validation of the primary end point for a placebo-controlled phase II/III study in patients with HAE. Ninety-eight abdominal attacks were treated with 10 or 20 U/kg of a highly purified C1 esterase inhibitor (C1-INH) concentrate or placebo. The primary end point was the time to onset of symptom relief, as determined by the patients. Patients assessed the intensity of the symptoms of pain, nausea, vomiting, cramps, and diarrhea over time. By Spearman rank correlation, the primary end point was compared with the time to first reduction of (1) any symptom intensity, (2) the sum of symptom intensity scores, and (3) the intensity of the last symptom present at baseline. The C1-INH, 20 U/kg, and placebo groups were compared by one-sided two-sample Wilcoxon tests. The time to first reduction in intensity of the last symptom present at baseline had the highest correlation with the primary end point (r = 0.77). The time to onset of symptom relief and the time to the first reduction in intensity of the last symptom were significantly shorter for the C1-INH, 20 U/kg, group compared with placebo (p = 0.009 and p = 0.0036, respectively). The association with the intensity of single symptoms confirmed that the time to onset of symptom relief is an appropriate end point for assessing the efficacy of C1-INH therapy. more...

Introduction: Hereditary angioedema (HAE) is a rare disorder characterized by C1 esterase inhibitor (C1-INH) deficiency, resulting in periodic attacks of acute edema that can be life-threatening if they occur in the laryngeal region. We assessed the efficacy of C1-INH concentrate in the emergency treatment of rarely occurring acute laryngeal HAE attacks in a prospective, open-label clinical study., Methods: Acute laryngeal attacks were each treated with C1-INH concentrate (Berinert) at a single dose of 20 U/kg body weight. Efficacy endpoints included time to onset of symptom relief and time to complete resolution of all symptoms, each based on the patient's assessment., Results: All 39 laryngeal attacks in 16 patients were treated successfully. The median time to onset of symptom relief was 15 min. The median time to complete resolution of all symptoms was 8.25 h. No treatment-related serious adverse events occurred, and the treatment was well tolerated. The administration of C1-INH concentrate was not associated with any viral infections., Conclusion: C1-INH concentrate is an effective and safe emergency treatment for providing reliable and rapid relief from the potentially life-threatening symptoms of laryngeal HAE attacks. more...

Background: Hereditary angioedema caused by C1 esterase inhibitor deficiency is a rare disorder., Objective: To compare the efficacy of pasteurized C1 esterase inhibitor concentrate (Berinert, CSL Behring) at intravenous doses of 10 or 20 U/kg body weight with placebo in the treatment of single, acute abdominal or facial attacks in patients with hereditary angioedema., Methods: This was a randomized, double-blind, placebo-controlled study in 125 patients with type I or II hereditary angioedema. The primary outcome was time from start of treatment to onset of symptom relief. Secondary outcomes were time to complete resolution, proportion of patients with worsened intensity of angioedema symptoms between 2 and 4hours after treatment, and number of vomiting episodes within 4 hours., Results: Median time to onset of relief was significantly shorter with C1 esterase inhibitor concentrate at a dose of 20 U/kg than with placebo (0.5 vs 1.5 hours; P = .0025), whereas with 10 U/kg, the time to onset of relief was only slightly shorter than with placebo (1.2 vs 1.5 hours; P = .2731). Compared with placebo, the reduction in time to onset of relief was greatest for severe attacks (0.5 vs 13.5 hours). The secondary outcomes consistently supported the efficacy of the 20 U/kg dose. C1 esterase inhibitor concentrate was safe and well tolerated. No seroconversions were observed for HIV, hepatitis virus, or human B19 virus., Conclusion: C1 esterase inhibitor concentrate given intravenously at a dose of 20 U/kg is an effective and safe treatment for acute abdominal and facial attacks in patients with hereditary angioedema, with a rapid onset of relief. more...

Objective: To explore if patients with severe sepsis and with a predicted high risk of death (according to the Simplified Acute Physiology Score II) might have a treatment benefit from high-dose antithrombin III., Design: Subgroup analysis of a randomized, placebo-controlled, double-blind, prospective phase III study., Setting: Unifactorial and multifactorial reanalysis of prospectively defined populations from the KyberSept trial., Patients: We studied 1,008 patients (43.6% of the overall intention-to-treat population, n = 2,314) with a predicted mortality rate of 30-60% at study entry as defined by the Simplified Acute Physiology Score II., Interventions: Patients were randomized in a 1:1 fashion to receive either high-dose antithrombin III (30,000 IU intravenously over the period of 4 days) or placebo., Measurements and Main Results: In a Kaplan-Meier analysis of patients with a predicted mortality of 30-60%, the survival time when followed up for 90 days after admission was increased in the high-dose antithrombin III group compared with placebo (p = .04). If heparin was avoided during the 4-day treatment phase with high-dose antithrombin III (n = 140) or placebo (n = 162), the treatment effect appeared to be even more pronounced: 28-day mortality rate, 35.7% vs. 44.4% (risk ratio, 0.804; 95% confidence interval, 0.607-1.064); 56-day mortality rate, 39.9% vs. 52.2% (risk ratio, 0.764; 95% confidence interval, 0.593-0.984); 90-day mortality rate, 42.8% vs. 55.1% (risk ratio, 0.776; 95% confidence interval, 0.614-0.986). Like in the overall population, the percentage with any bleeding was increased in patients receiving high-dose antithrombin III compared with placebo. Survival rates were in favor of high-dose antithrombin III in patients both with and without bleeding complications., Conclusions: Treatment with high-dose antithrombin III may increase survival time up to 90 days in patients with severe sepsis and high risk of death. This benefit may even be stronger when concomitant heparin is avoided. more...

Background: Disseminated intravascular coagulation (DIC) is a serious complication of sepsis that is associated with a high mortality., Objectives: Using the adapted International Society on Thrombosis and Haemostasis (ISTH) diagnostic scoring algorithm for DIC, we evaluated the treatment effects of high-dose antithrombin (AT) in patients with severe sepsis with or without DIC., Patients and Methods: From the phase III clinical trial in severe sepsis (KyberSept), 563 patients were identified (placebo, 277; AT, 286) who did not receive concomitant heparin and had sufficient data for DIC determination., Results: At baseline, 40.7% of patients (229 of 563) had DIC. DIC in the placebo-treated patients was associated with an excess risk of mortality (28-day mortality: 40.0% vs. 22.2%, P < 0.01). AT-treated patients with DIC had an absolute reduction in 28-day mortality of 14.6% compared with placebo (P = 0.02) whereas in patients without DIC no effect on 28-day mortality was seen (0.1% reduction in mortality; P = 1.0). Bleeding complications in AT-treated patients with and without DIC were higher compared with placebo (major bleeding rates: 7.0% vs. 5.2% for patients with DIC, P = 0.6; 9.8% vs. 3.1% for patients without DIC, P = 0.02)., Conclusions: High-dose AT without concomitant heparin in septic patients with DIC may result in a significant mortality reduction. The adapted ISTH DIC score may identify patients with severe sepsis who potentially benefit from high-dose AT treatment. more...

Primary antibody deficiencies are the most common forms of primary immunodeficiencies. Substitution therapy with polyvalent immunoglobulins has been established as the standard therapy for antibody deficiencies for several decades. Until now mainly intravenous immunoglobulins (IVIG) have been used in Germany, and the majority of patients receive treatment in hospital outpatient clinics. In recent years subcutaneous administration of immunoglobulins (SCIG) has been developed which is administered as home self-infusion. Studies indicate no significant differences in immunoglobulin substitution therapy between SCIG and IVIG concerning outcome. We carried out a cost-minimization analysis to compare the two treatment alternatives in Germany. Under base case assumptions the treatment with SCIG is cost saving from the perspective of the German statutory health insurance. The main cost drivers are IVIG and SCIG; the incremental cost of SCIG compared to IVIG is most sensitive to changes in the immunoglobulin price and changes in the body weight of the patient. more...

Introduction: Treatment of sepsis is aimed at increasing both the duration and quality of survival. A long-term focus on quality of life (QoL) in clinical trial evaluations of sepsis care should be a priority., Method: QoL data were used to evaluate the effects of intravenous antithrombin III treatment for severe sepsis measured for up to 90 days during the follow-up phase of the KyberSept phase III clinical trial. A visual analog scale and a Karnofsky scale were used to measure physical, psychologic, and social QoL at regular intervals. Changes from baseline between placebo and antithrombin III groups were assessed using Wilcoxon statistical tests, with additional analyses by severity of illness and admitting diagnosis., Results: Among all sepsis survivors in the trial, there was a significant advantage on some attributes of QoL in the antithrombin III subgroup of patients who did not receive heparin as compared with the corresponding placebo group., Discussion: The present study represents the first attempt to evaluate patient QoL over a relatively long period in a large, randomized, placebo-controlled sepsis trial. Over a 90-day period, survivors of severe sepsis receiving antithrombin III experienced significant improvements as compared with placebo on several attributes of QoL. In conclusion, the present study demonstrated that clinical improvements over an extended time period with antithrombin III were complemented by improvements in QoL, particularly in social and psychologic functioning, in many patients. more...

Context: Activation of the coagulation system and depletion of endogenous anticoagulants are frequently found in patients with severe sepsis and septic shock. Diffuse microthrombus formation may induce organ dysfunction and lead to excess mortality in septic shock. Antithrombin III may provide protection from multiorgan failure and improve survival in severely ill patients., Objective: To determine if high-dose antithrombin III (administered within 6 hours of onset) would provide a survival advantage in patients with severe sepsis and septic shock., Design and Setting: Double-blind, placebo-controlled, multicenter phase 3 clinical trial in patients with severe sepsis (the KyberSept Trial) was conducted from March 1997 through January 2000., Patients: A total of 2314 adult patients were randomized into 2 equal groups of 1157 to receive either intravenous antithrombin III (30 000 IU in total over 4 days) or a placebo (1% human albumin)., Main Outcome Measure: All-cause mortality 28 days after initiation of study medication., Results: Overall mortality at 28 days in the antithrombin III treatment group was 38.9% vs 38.7% in the placebo group (P =.94). Secondary end points, including mortality at 56 and 90 days and survival time in the intensive care unit, did not differ between the antithrombin III and placebo groups. In the subgroup of patients who did not receive concomitant heparin during the 4-day treatment phase (n = 698), the 28-day mortality was nonsignificantly lower in the antithrombin III group (37.8%) than in the placebo group (43.6%) (P =.08). This trend became significant after 90 days (n = 686; 44.9% for antithrombin III group vs 52.5% for placebo group; P =.03). In patients receiving antithrombin III and concomitant heparin, a significantly increased bleeding incidence was observed (23.8% for antithrombin III group vs 13.5% for placebo group; P<.001)., Conclusions: High-dose antithrombin III therapy had no effect on 28-day all-cause mortality in adult patients with severe sepsis and septic shock when administered within 6 hours after the onset. High-dose antithrombin III was associated with an increased risk of hemorrhage when administered with heparin. There was some evidence to suggest a treatment benefit of antithrombin III in the subgroup of patients not receiving concomitant heparin. more...

Objectives: To evaluate the safety, pharmacokinetics, and the practicability of two different antithrombin III (AT III) high-dose regimens in patients with severe sepsis., Design: Prospective, open, randomized, 2 parallel groups, multinational clinical trial., Setting: Eleven academic medical center intensive care units (ICU) in Austria, Belgium, Denmark, Germany, Norway and Sweden., Patients: Thirty-three patients with severe sepsis who received standard supportive care and antimicrobial therapy, in addition to the administration of AT III., Interventions: Patients received an intravenous loading dose of 6,000 IU AT III followed by either intermittent bolus infusions of 1,000 IU AT III every 4 h or a continuous infusion of 250 IU AT III/h for 4 days, resulting in a total dose for both dosage regimens of 30,000 IU AT III., Measurements: All patients were evaluated for safety and all but one for pharmacokinetics., Results and Conclusions: The administration of AT III was safe and well tolerated. The overall 28-day all-cause mortality was 30% (43% intermittent bolus infusions; 21% continuous infusion). The mean probability of dying according to the SAPS II was 48%. The difference in mortality between both groups was within the range of chance. AT III plasma levels were elevated from low baseline levels to above 120% soon after onset of AT III therapy and remained at these levels for the treatment phase of 4 days. Functional and immunologic levels of AT III corresponded very well. With an overall median volume of distribution of 4.5 l (range: 2.4-6.5 l), AT III only moderately extended beyond plasma. The overall median elimination half-life was 18.6 h (range: 5.1-37.4). Overall, median response was 1.75% per IU/kg (range: 1.14-2.8). The variability of elimination parameters was quite noteworthy (CV = 41-59%), whereas distribution-related parameters showed a moderate variability (CV = 24%). In spite of this variability, both high-dose IV regimens reliably provided AT III levels above 120% for all but one patient. An increased mortality was observed for patients with a distribution volume exceeding 4.5 l (or a response < 1.7% per IU/kg). AT III distribution volumes above 4.5 l might indicate a capillary leak phenomenon. The continuous infusion regimen was slightly preferred by the investigators with regard to practicability. more...

Objectives: To evaluate the safety and potential efficacy of antithrombin III (AT III) in reducing mortality in patients with severe sepsis., Design: Prospective, randomized, placebo-controlled, double-blind, phase II, multicenter, multinational clinical trial., Setting: Seven academic medical center intensive care units (ICU) in Belgium, Denmark, the Netherlands, Norway and Sweden., Patients: 42 patients with severe sepsis who received standard supportive care and antimicrobial therapy, in addition to the administration of AT III or placebo., Interventions: Patients received either an intravenous loading dose of 3000 IU AT III followed by a maintenance dose of 1500 IU every 12 h for 5 days or equivalent amounts of placebo., Measurements and Results: All patients were evaluated for safety and for 30-day all-cause mortality., Conclusions: The administration of AT III was safe and well-tolerated. It was followed by a 39 % reduction in 30-day all-cause mortality (NS). The reduction in mortality was accompanied by a considerably shorter stay in the ICU. Patients treated with AT III exhibited a better performance in overall severity of illness and organ failure scores (Acute Physiology and Chronic Health Evaluation II, multiple organ failure, organ system failure), which was noticeable soon after initiation of treatment. Patients treated with AT III demonstrated a better resolution of pre-existing organ failures and a lower incidence of new organ failures during the observation period. A meta-analysis comprising this and two other double-blind, placebo-controlled trials with AT III with a total of 122 patients suffering from severe sepsis confirms the positive trend. The results of the meta-analysis demonstrate a 22.9 % reduction in 30-day all-cause mortality in patients treated with AT III. Although still too small to be confirmative, the meta-analysis clearly points to the fact that a sufficiently powered phase III trial is warranted to prove whether AT III has a beneficial role in the treatment of severe sepsis. more...

The effect of cimetidine, a histamine H2 receptor antagonist, was investigated in 12 healthy volunteers over a period of six weeks. Cimetidine was administered orally in a daily doses of 1,600 mg during the first three weeks of evaluation. Significant alterations in values of immunoglobulins (IgG, IgA), complement (C3), B-lymphocytes and T-helper cell counts were found after cimetidine intake. The in vitro lymphocyte proliferation response to plant mitogens was increased. In contrast to results obtained from a previous study with healthy volunteers who were given 800 mg cimetidine, we found no significant increase in the CD4/CD8 ratio and no decrease in the CD8 but a significant increase in the CD4 cell count. Whereas the peripheral blood immune system showed signs of immune system activation following 800 and 1,600 mg cimetidine intake, reactivity patterns of skin immune system, however, differed in both studies. The data suggests that cimetidine has a dose and time dependent effect on the immune system. more...

To establish whether a general dysfunction, i.e., an increase in permeability, had occurred in 16 trauma patients (6 with adult respiratory distress syndrome [ARDS]), we measured beta 2-microglobulin (beta 2MG), myoglobin (MG), immunoglobulin G (IgG), and transferrin (TF) concentrations in bronchoalveolar lavage fluid (BAL), serum, and urine as well as extravascular lung water content (EVLW) over a period of 14 days. Our results show a positive correlation (p = 0.03) between increases of EVLW, reflecting lung edema, and beta 2MG concentrations in urine of all patients with ARDS, indicating systemically increased permeability. Generalized increase of permeability can also explain the elevation of MG urine concentrations (p = 0.03) together with an EVLW increase, and an increase of BAL protein concentrations (IgG, TF, p less than 0.01) in the early post-trauma phase during the first 48 h after admission. In contrast, commonly used kidney function tests remained unchanged over the time course of 14 days. more...

Lymphocyte subpopulations were determined in blood samples from blood donors (40 women and 45 men) using immunofluorescence microscopy and flow cytometric methodologies. The study demonstrates the value of both methods for the enumeration of lymphocyte subpopulations. The advantages of employing an automated flow cytometer system are better precision and speed. The automated systems require a large initial technical and financial burden and are therefore probably destined to be reserved for the larger laboratory. There is a need for an adequate lymphocyte standard which shows little variation between aliquots and can be used for interlaboratory comparisons. more...

The effect of cimetidine, a histamine H2-receptor antagonist, on the immune system in man was investigated in 11 healthy volunteers. Cimetidine was administered orally in daily doses of 800 mg for a period of 7 days. At the end of the administration period the number of peripheral CD8+ (cytotoxic/suppressor) cells had diminished significantly (P less than 0.05) along with a corresponding increase in the CD4+ (helper/inducer): CD8+ (cytotoxic/suppressor) cell ratio (P less than 0.01). Compared with pretreatment values, a significant in vitro blastogenic response to mitogen stimulation with concanavalin A (P less than 0.005), phytohemagglutinin (P less than 0.01), and pokeweed mitogen (P less than 0.05) was observed in lymphocytes of volunteers after cimetidine intake. The cell-mediated hypersensitivity as assessed by skin testing of seven recall antigens was also enhanced significantly (P less than 0.001). Using Spearman's coefficient of correlation to compare mitogen-stimulation tests and skin tests of delayed hypersensitivity to the CD4+:CD8+ ratio, yielded a positive correlation (r = 0.89; r = 0.85, respectively). These effects were reversible 96 h after the last cimetidine dose. In contrast, leukocytes, total T lymphocytes (CD2+, CD3+), CD4+ (helper/inducer) cells, natural killer cells (Leu7+), immunoglobulins, and total complement, C3, C4 were unaffected by cimetidine administration. more...