Biomedical subjects

H Hecker

Publications and source records attributed to H Hecker.

At least 37 records · Page 2Linked to original sources

PubMed2000

Succinylcholine metabolite succinic acid alters steady state activation in muscle sodium channels.

BACKGROUND: Animal experiments revealed that succinylcholine produced masseter muscle rigidity and activated myotonic discharges despite neuromuscular blockade with a nondepolarizing blocker. These results suggest that either succinylcholine or its metabolites might interfere directly with voltage-operated ion channels of the sarcolemma. The aim of this study was to examine effects of one product of succinylcholine hydrolysis, succinic acid, on voltage-gated muscle sodium (Na+) channels. METHODS: Alpha subunits of human muscle sodium channels were heterologously expressed in HEK293 cells. Activation of Na+ currents was examined applying standard whole-cell voltage-clamp protocols in the absence (control and washout) and presence of succinic acid in different concentrations (0.05-10 mm). RESULTS: Succinic acid shifted the midpoints of steady state activation plots in the direction of more negative test potentials, indicating that channels open during smaller depolarizations in the presence of the drug. The maximum amount of the negative shift in 10 mm succinic acid was -6.3 +/- 1.7 mV; the EC50 for this effect was 0.39 mm. In addition, succinic acid (10 mm) significantly enhanced maximum currents after depolarizations with respect to a series of control experiments. CONCLUSION: Succinic acid facilitates voltage-dependent activation in muscle sodium channels in vitro. This might lead to muscle hyperexcitability in vivo.

Anti-Ulcer Agents↗

PubMed2000

Discrimination of sepsis and systemic inflammatory response syndrome by determination of circulating plasma concentrations of procalcitonin, protein complement 3a, and interleukin-6.

OBJECTIVE: To evaluate whether plasma concentrations of procalcitonin (PCT), interleukin-6 (IL-6), protein complement 3a (C3a), leukocyte elastase (elastase), and the C-reactive protein (CRP) determined directly after the clinical onset of sepsis or systemic inflammatory response syndrome (SIRS) discriminate between patients suffering from sepsis or SIRS and predict the outcome of these patients. DESIGN: Prospective study. SETTING: Medical intensive care unit at a university hospital. PATIENTS: Twenty-two patients with sepsis and 11 patients with SIRS. MEASUREMENTS AND MAIN RESULTS: The plasma concentrations of PCT, C3a, and IL-6 obtained < or =8 hrs after clinical onset of sepsis or SIRS but not those of elastase or CRP were significantly higher in septic patients (PCT: median, 16.8 ng/mL, range, 0.9-351.2 ng/mL, p = .003; C3a: median, 807 ng/mL, range, 422-4788 ng/mL, p < .001; IL-6: median, 382 pg/mL, range, 5-1004 pg/mL, p = .009, all Mann-Whitney rank sum test) compared with patients suffering from SIRS (PCT: median, 3.0 ng/mL, range, 0.7-29.5 ng/mL; C3a: median, 409 ng/mL, range, 279566 ng/mL; IL-6: median, 98 pg/mL, range, 23-586 pg/mL). The power of PCT, C3a, and IL-6 to discriminate between septic and SIRS patients was determined in a receiver operating characteristic analysis. C3a was the best variable to differentiate between both populations with a maximal sensitivity of 86% and a specificity of 80%. An even better discrimination (i.e., a maximal sensitivity of 91% and a specificity of 80%) was achieved when PCT and C3a were combined in a "sepsis score." C3a concentrations also helped to predict the outcome of patients. Based on the sepsis score, a logistic regression model was developed that allows a convenient and reliable determination of the probability of an individual patient to suffer from sepsis or SIRS. CONCLUSIONS: Our data show that the determination of PCT, IL-6, and C3a is more reliable to differentiate between septic and SIRS patients than the variables CRP and elastase, routinely used at the intensive care unit. The determination of PCT and C3a plasma concentrations appears to be helpful for an early assessment of septic and SIRS patients in intensive care.

Adult↗

PubMed2000

Disruption of intracerebral progression of C6 rat glioblastoma by in vivo treatment with anti-CD44 monoclonal antibody.

OBJECT: Glioblastoma multiforme (GBM) invasiveness is a complex process that involves recognition and attachment of GBM cells to particular extracellular matrix (ECM) molecules before migrating into proteolytically modified matrix and inducing angiogenesis. The CD44 molecule, which is a transmembrane adhesion molecule found on a wide variety of cells including GBM, has been suggested as the principal mediator of migration and invasion. The aim of the present study was to demonstrate whether an antibody specific to the standard form of CD44 (CD44s, 85-90 kD) might prevent invasion and thus disrupt progression of C6 GBM in vivo. METHODS: Immunostaining demonstrated homogeneous expression of CD44s on the surface of C6 GBM cells and tumors. Flow cytometric analysis demonstrated binding saturation of anti-CD44s monoclonal antibody (mAb) to the receptor at 1 microg/5 x 10(5) cells. Blocking of CD44s in vitro resulted in a dose-dependent progressive (up to 94+/-2.7%; mean +/- standard deviation [SD]) detachment of C6 cells from ECM-coated culture. Blocking of CD44s in vivo resulted in significantly reduced C6 brain tumors (3.6+/-0.4% [SD])--measured as the quotient: tumor surface (mm2)/brain surface (mm2) x 100--compared with untreated (19.9+/-0.9%) or sham-treated (19.2+/-1.1 to 19.3+/-2.5% [SD]) rats. Disruption of C6 GBM progression correlated with an improved food intake; treated rats were significantly less cachectic (166.6+/-16.4 g [SD]) than those that were untreated (83+/-2.7 g [SD]) or sham-treated (83.4+/-1.1 to 83+/-2.2 g [SD]) rats. CONCLUSIONS: The authors conclude that CD44s-targeted treatment with specific mAb may represent an effective means for preventing progression of highly invasive GBMs.

Animals↗

PubMed2000

Bidirectional classification procedures: double tree and double cluster.

Partition based prediction rules as derived in CART, RECPAM or CBR, relating multivariate predictor variables X to a response variable Y, may be extended to bidirectional classification procedures. Tree or clustering algorithms are simultaneously applied to X and Y resulting in a double partition classification table that should be able to detect existing characteristic patterns of predictor and response values and relate them to each other.

Algorithms↗

PubMed1999

CD44s-targeted treatment with monoclonal antibody blocks intracerebral invasion and growth of 9L gliosarcoma.

Glioma invasiveness is a complex process involving recognition and attachment of tumor cells to particular extracellular matrix (ECM) molecules prior to migrating into proteolytically modified matrix and inducing angiogenesis. CD44 is a group of transmembrane adhesion molecules found on a wide variety of cells including gliomas that has been suggested as the principal mediator of migration/invasion. The aim of the present study was to demonstrate whether antibody specific for the standard form of CD44 (CD44s, 85-90 kDa) might prevent invasion, thus blocking growth of the 9L gliosarcoma in vivo. High expression of CD44s on the surface of 9L cells and brain tumors was demonstrated by immunochemistry. Fluorescence-activated cell sorting (FACS) demonstrated binding saturation of anti-CD44s monoclonal antibody (mAb) to the receptor at 1 microg/5 x 10(5) cells. Blocking of CD44s in vitro resulted in a dose-dependent progressive, up to 95%+/-2.5% detachment of 9L cells from ECM-coated culture surfaces. Blocking of CD44s in vivo resulted in significantly reduced 9L brain tumors (2.5%+/-0.4%)--measured as the quotient: tumor surface (mm2)/brain surface (mm2) x 100--as compared to untreated (16.1%+/-2.2%) or sham-treated rats (16%+/-3.7% to 16.1%+/-3%). We conclude that CD44s-targeted treatment with specific mAb may be an effective means for preventing glioma progression.

Animals↗

PubMed1999

[Performance of different CT angiography imaging modalities in detecting renal artery stenoses].

PURPOSE: Purpose of the study was to compare the sensitivity and specificity of various display modalities in the detection of renal artery stenosis. In particular, the difference between hard-copy reading and interactive analysis at the workstation was assessed. MATERIALS AND METHODS: Selected patients (n = 31) with expected suboptimal conditions for CT angiography due to long-standing hypertension and compromised renal function were included. Six radiologists evaluated independently a total of 77 renal arteries with 49 renal artery stenoses proven by angiography. Image analysis included: mode A: interactive display, analysis of multiplanar reformats and axial sections at the workstation, mode B: visualization of MIPs in the coronal and axial planes as hard copies only, mode C: visualization of MIPs and axial sections as hard copies only. RESULTS: The following sensitivities and specificities were found for internal readers and (readers from outside institutions): mode A: 94.8%, 87.9%, mode B: 97.7% (95.1%), 80.3% (75.4%); mode C: 97.0% (95.3%), 78.8% (76.6%). The differences were statistically not significant (p > 0.05). CONCLUSIONS: Standardized hard copies of MIPs plus axial CT provide sufficient accuracy to detect renal artery stenosis compared to interactive imaging even in this highly selected group of patients.

Adult↗

PubMed1998

Increased susceptibility to postoperative sepsis in patients with impaired monocyte IL-12 production.

IL-12 is a potent immunoregulatory cytokine that is essential for the development of protective immunity, as demonstrated by numerous animal models of infection. Here, we provide evidence for a critical role of IL-12 in human sepsis. The results of a prospective study of 184 patients undergoing major elective surgery of the upper and lower gastrointestinal tract revealed that, in contrast to patients showing uneventful recovery, monocyte IL-12 production was severely and selectively impaired in patients developing postoperative sepsis. Moreover, the extent of monocyte IL-12 suppression correlated with the severity of postoperative sepsis. Monocyte IL-12 secretion was suppressed before surgery and remained low until the onset of sepsis. Therefore, the suppression of IL-12 secretion preceded the onset of postoperative sepsis but did not occur as a consequence of major surgery. In contrast, IL-1beta production was only reduced during the late postoperative course in patients developing postoperative sepsis, and TNF-alpha release was even increased at different time intervals before the onset of sepsis. Thus, reduced IL-12 release does not reflect a general defect in monocyte cytokine production. Consequently, these results establish a critical role for IL-12 in early resistance to postoperative infection and may allow for the development of novel therapeutic strategies designed to stimulate host defense mechanisms and to reduce the incidence and severity of septic complications.

Aged↗

PubMed1998

Safety and toxicity of amphotericin B in glucose 5% or intralipid 20% in neutropenic patients with pneumonia or fever of unknown origin: randomised study.

OBJECTIVE: To compare the feasibility of treatment, safety, and toxicity of intravenous amphotericin B deoxycholate prepared in either glucose or intralipid for empirical antimycotic treatment of neutropenic cancer patients. DESIGN: Single centre stratified, randomised non-blinded phase II study. SETTING: University hospital providing tertiary clinical care. SUBJECTS: 51 neutropenic patients (leukaemia (35), lymphoma (11), solid tumours (5)) with refractory fever of unknown origin (24) or pneumonia (27). INTERVENTIONS: Amphotericin B 0.75 mg/kg/day in 250 ml glucose 5% solution or mixed with 250 ml intralipid 20%, given on eight consecutive days then alternate days, as a 1-4 hour infusion. MAIN OUTCOME MEASURES: Feasibility of treatment, subjective tolerance (questionnaire), and objective toxicity (common toxicity criteria of the National Cancer Institute). RESULTS: Study arms were balanced for age, sex, underlying malignancy, renal and liver function, and pre- and concomitant treatment with antibiotics and nephrotoxic agents. No statistically significant or clinically relevant differences were found between the treatment groups for: daily or cumulative dose and duration of treatment with amphotericin B; incidence and time of dose modifications or infusion duration changes related to toxicity; dose or duration of symptomatic support with opiates, antipyretics, or antihistamines; renal function; subjective tolerance; most common toxicity scores; course of infection; and incidence of treatment failures. Patients treated with amphotericin B in intralipid were given fewer diuretics (P<0.05) and therefore had more peripheral oedema (P<0.01) and needed less potassium supplementation (P<0.05) than patients given amphotericin in glucose. Acute respiratory events were more common in the intralipid arm (P<0.05). CONCLUSIONS: Amphotericin B 0.75 mg/kg/day in intralipid given on eight consecutive days then alternate days provides no benefit and is associated with potential pulmonary side effects possibly because of fat overload or an incompatibility of the two drugs.

Adolescent↗

PubMed1998

Standard calculation of ethanol elimination rate is not sufficient to provide ethanol substitution therapy in the postoperative course of alcohol-dependent patients.

OBJECTIVE: Alcohol withdrawal syndrome (AWS) is a severe complication during postoperative treatment of alcohol-dependent patients. Besides the use of clomethiazole, clonidine, and benzodiazepines, there is another possible way to prevent AWS by deliberate administration of ethanol. The appropriate dosage of ethanol has not been known up to now and it could be defined according to the average ethanol elimination rate (EER) which, from forensic analysis, is known to be 15 mg/dl per h in a normal population. However, it is questionable whether these data are suitable for the calculation of the correct dosage in alcohol-dependent patients. DESIGN: Preliminary retrospective descriptive study. SETTING: Intensive care unit of a university teaching hospital. PATIENTS: 11 alcohol-dependent patients (9 males, 2 females, mean age 50.8 years, range 33 to 60 years). INTERVENTIONS: Ethanol substitution (ES) by parenteral application. MEASUREMENTS AND RESULTS: Ethanol kinetics were evaluated by repeated measurement of the blood ethanol concentration (BEC) over a period of at least 6 h parallel to the administration of ethanol. The average EER was found to be 28 mg/dl per h with a standard deviation of 11 mg/ dl per h. The minimum value was 18 mg/dl per h and the maximum 50 mg/dl per h. These EERs were significantly higher than the EERs known from forensic analysis. AWS was prevented in all 11 patients. CONCLUSIONS: Close control of BEC and precise adjustment of ethanol administration are necessary prerequisites for ES. The standard EER is not sufficient to define the appropriate ethanol dosage due to enormous variations in the ethanol metabolism of alcohol-dependent patients.

Adult↗

PubMed1998

Predictors of respiratory function deterioration after transfer of critically ill patients.

OBJECTIVES: Critically ill patients are often transferred due to the growing number of diagnostic procedures required to be performed outside the intensive care unit. These transfers have proved to be very critical. The aim of this study was to evaluate predictors for the deterioration of respiratory function in critically ill patients after transfer. DESIGN: Prospective, clinical, observational study. SETTING: 1800-bed university teaching hospital. SUBJECTS: 98 mechanically ventilated patients were investigated during transfer. MEASUREMENT AND MAIN RESULTS: Before transfer, all patients were classified according to the Acute Physiology and Chronic Health Evaluation (APACHE) II score and the Therapeutic Intervention Scoring System (TISS). Haemodynamics and arterial blood gases were measured at 11 different times. Arterial oxygen tension (PaO2), fractional inspired oxygen (FIO2), PaO2/FIO2 ratio, lowest PaO2/FIO2 ratio, minimal PaO2 and maximal FIO2, APACHE II score, TISS before transfer, age and duration of transfer were analysed as potential predictors for deterioration of respiratory function after transfer. Variables were analysed using Classification and Regression Trees and Clustering by Response. In 54 transports (55%) there was a decrease in the PaO2/FIO2 ratio, and a decrease of more than 20% from baseline was noted in 23 of the transferred patients (24%). Age > 43 years and FIO2 > 0.5 were identified as predictors for respiratory deterioration. CONCLUSIONS: Our predictors were able to indicate deterioration after transfer correctly in 20 of 22 patients (91%), combined with a false-positive rate in 17 of 49 (35%).

APACHE↗

PubMed1998

The number connection tests A and B: interindividual variability and use for the assessment of early hepatic encephalopathy.

BACKGROUND/AIMS: The number connection tests A and B are regarded as sensitive psychometric measures for the assessment of early hepatic encephalopathy. Review of the studies dealing with the diagnostic sensitivity of the number connection tests, however, shows that the scoring of the number connection tests results differs between studies. Most groups define the limits of the normal range by studying small control groups. Others use scores given in the literature without ensuring the comparability of the test versions used. Thus, there is a need for normative data for the number connection test results and for re-evaluation of the sensitivity of the tests using valid scores. METHODS: In this study the number connection tests A and B were administered to 249 healthy volunteers (age: 18 to 76 years) to analyze the influence of age, education and occupation on their results. In addition, the age-corrected normative data were applied to 169 patients with grade 0-I hepatic encephalopathy. The specificity and sensitivity of age-corrected and age-independent normative data of the number connection tests were compared. RESULTS: There was a significant influence of age and education on the number connection test results, but only a negligible effect of occupation. Application of the age-corrected normative data to the test results of the patients with grade I hepatic encephalopathy significantly decreased the sensitivity of the number connection tests for hepatic encephalopathy compared to widely used age-independent normal ranges, but also increased the specificity. CONCLUSION: The use of standardized versions of the number connection tests and age-related normative data is recommended.

Acute Disease↗

PubMed1998

Trypanosoma evansi and T. equiperdum: distribution, biology, treatment and phylogenetic relationship (a review).

Trypanosoma evansi and T. equiperdum were compared regarding their ultrastructure, their mammalian hosts, way of transmission, pathogenicity, diagnosis and treatment, and biochemical and molecular characteristics. Electron microscopic investigation revealed no ultrastructural differences between the two species except that there were more coated vesicles in the flagellar pocket of T. equiperdum. Biological, biochemical and molecular studies were reviewed and exhibited many similarities between T. evansi and T. equiperdum. The most prominent differences between the two species are the presence of maxicircles in T. equiperdum, which are missing in T. evansi, and the route of transmission. While T. evansi is transmitted by biting flies, T. equiperdum is transmitted from one equine host to another during copulation when mucous membranes come into contact. Otherwise the two species are remarkably similar. The phylogenetic relationship between the two species and T. b. brucei is being discussed, and the hypothesis is proposed that T. evansi arose from a clone of T. equiperdum which lost its maxicircles.

Animals↗

PubMed1998

Effective biomodulation by leucovorin of high-dose infusion fluorouracil given as a weekly 24-hour infusion: results of a randomized trial in patients with advanced colorectal cancer.

PURPOSE: To determine whether high-dose infusional fluorouracil (FU) is effectively modulated by leucovorin (LV), interferon (IFN) alpha-2b, or both when given to patients with metastatic colorectal cancer. PATIENTS AND METHODS: Patients (n = 236) with progressive, measurable disease were randomized to three groups and received FU 2,600 mg/m2 as a 24-hour continuous infusion (CI) weekly for 6 weeks with 2 weeks rest (FU24h) and LV 500 mg/m2 as a 2-hour infusion before FU or IFN 3 x 10(6) U subcutaneously 3 times weekly or both. Treatment continued until progressive disease or unacceptable toxicity was observed. Pairs of treatment arms were analyzed sequentially to detect equivalence or a 25% difference in response rates. RESULTS: The rate of objective remission in patients who received FU24h/LV (44%; 40 of 91) was significantly higher than in patients who received FU24h/IFN (18%; 16 of 90; P < .05). The response rates of patients who received FU24h/LV versus FU24h/LV/IFN (27%; 13 of 49) were statistically equivalent. Significant differences were observed for time to tumor progression (TTP) (FU24h/LV, 7.1 months; FU24h/IFN, 3.9 months; FU24h/LV/IFN, 6.3 months; global P value < .009) and survival (16.6 months, 12.7 months, 19.6 months, respectively; global P value < .04). Unpredictable and life-threatening toxicity in the FU24h/LV/IFN arm required dose reduction of FU to 2,000 mg/m2/day and early stoppage of this arm. Toxicity was manageable in patients who received both FU24h/LV (grade 3 to 4 diarrhea, 21%) and FU24h/IFN (grade 3 to 4 diarrhea, 15%). CONCLUSION: Response rate, TTP, and overall survival were superior for LV-containing regimens compared with IFN modulation alone. The addition of IFN to high-dose infusional FU plus LV offers no advantage and may increase toxicity. The regimen of high-dose infusional FU24h/LV warrants further evaluation in patients with metastatic colorectal cancer.

Adult↗

PubMed1997

Prognostic factors and staging systems in childhood hepatoblastoma.

The objectives of this study were to investigate clinical and patho-histological characteristics of childhood hepatoblastoma on their value as prognostic factors, and to evaluate the predictive impact of different staging systems for liver tumors on 72 patients treated in the German Pediatric Liver-Tumor Study HB89. Statistical analysis was performed by comparing patients' disease-free survival with characteristics and stages. Multivariate analysis was done by the Cox proportional-hazards model, the recursive partitioning and amalgamation model (RECPAM) and the model of clustering by response (CBR). The following characteristics were significantly related with prognosis: tumor involvement of one vs. both liver lobes, multifocal disseminated vs. unifocal growth pattern in the liver, distant metastases, vascular invasion, fetal vs. embryonal differentiation, and serum alpha-fetoprotein; patients with values of < or = 100 ng/ml or > or = 1,000,000 ng/ml had a worse outcome than those with 100 to 1,000,000 ng/ml. Multivariate analysis with the 3 models revealed that tumor-growth pattern, serum alpha-fetoprotein and, in the Cox and CBR models, vascular invasion also are independent prognostic factors, permitting the allocation of hepatoblastoma patients to 1 of 2 prognostic groups for differential therapy. Post-surgical staging and the conventional TNM system for liver carcinoma had a high predictive value, in contrast to a TNM system proposed by the UICC for testing on childhood liver tumors. We therefore propose that the TNM system for liver carcinoma be applied for comparison of treatment results in hepatoblastoma.

Child↗

PubMed1997

[Total cavopulmonary anastomosis for definitive palliation of complex univentricular cardiovascular systems--potential preoperative risk factors].

The modified Fontan operation for definitive palliation has been performed in an increasing number of patients with various forms of a functionally univentricular heart. To eliminate the influence of different surgical techniques only patients after total cavopulmonary anastomosis (TCPA) were included in this retrospective analysis of preoperative risk factors. The age at operation in 72 patients varied from 7 to 219 months (median 54 months); 29 patients had been younger than 4 years. Forty-nine patients presented with a complex form of a functionally univentricular heart; associated systemic- or pulmonary venous anomalies were found in 22 patients, AV valve abnormalities in 42 patients with AV valve incompetence in 21 patients. Preoperative hemodynamic data revealed an elevated mean pulmonary artery pressure (> 15 mm Hg), increased pulmonary arteriolar resistance (> 3 U.m2) or end-diastolic ventricular pressure (> 12 mm Hg) in 23 patients. The overall mortality was 9.7% (7/72 patients). Variables with significant influence on postoperative mortality were associated systemic- and pulmonary venous anomalies. AV-valve incompetence and prolonged cardio-pulmonary bypass time. Age at operation, preoperative pulmonary arteriolar resistance, systemic- and pulmonary blood flow did not influence postoperative mortality. Even in patients with a complex form of a univentricular heart with associated anomalies and borderline preoperative hemodynamics TCPA can be performed with an acceptable risk.

Adolescent↗

PubMed1997

Efficiency and toxicity of ifosfamide, cisplatin and doxorubicin in the treatment of childhood hepatoblastoma. Study Committee of the Cooperative Paediatric Liver Tumour Study HB89 of the German Society for Paediatric Oncology and Haematology.

The Cooperative German Paediatric Liver Tumour Study HB89 was conceived to evaluate the efficiency and toxicity of ifosfamide, cisplatin and doxorubicin (IPA) in children with resectable and non-resectable hepatoblastoma (HB) and to determine late sequelae including tubular nephropathy of tumour treatment. The study also assessed the results of a surgical strategy, which adapts the procedure at the initial operation to the tumour's extension in the liver. The relationship of the tumours' histological differentiation to response to chemotherapy was also examined. Patients with a HB restricted to one liver lobe underwent primary resection. Larger tumours were initially treated with IPA chemotherapy and resected at second-look surgery. All patients received IPA adjuvantly after tumour resection. The IPA regimen consisted of ifosfamide 3.5 g/m2 (over 72 h days 1-3), cisplatin 100 mg/m2 (over 5 days 4-8) and doxorubicin 60 mg/m2 (over 48 h, days 9-10). Median follow-up of survivors was 64 months (range 28-82). Long-term disease-free survival (DFS) was for stage I: 21/21; stage II: 3/6; stage III: 28/38; and stage IV: 2/7 (overall 75%). Severe surgical complications occurred in 15% (4/27) of primary and 21% (8/38) of secondary resections with no lethality. 44/45 stage III/IV HB displayed PR after two IPA courses. Drug resistance developed in 8/12 tumours after four or five chemotherapy courses. Acute toxicity was observed in 34/242 (14%) IPA courses. Late sequelae were found in 7/54 (13%) of survivors, and subclinical renal tubulopathy occurred in 7/41 investigated patients (17%). Despite a more favourable prognosis in pure fetal and predominantly fetal histology, statistical analysis revealed no relationship between tumour differentiation and response to chemotherapy. In conclusion, IPA chemotherapy in combination with delayed surgery was highly effective in the treatment of HB.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1997

Distinct mechanisms of immunosuppression as a consequence of major surgery.

Altered host defense mechanisms after major surgery or trauma are considered important for the development of infectious complications and sepsis. In the present study, we demonstrate that major surgery results in a severe defect of T-lymphocyte proliferation and cytokine secretion in response to coligation of the antigen receptor complex and CD28. During the early postoperative course, reduced cytokine secretion was observed for interleukin-2 (IL-2), gamma interferon, and tumor necrosis factor alpha, which are associated with the Th1 phenotype of helper T lymphocytes, and for IL-4, the index cytokine of Th2 cells. During the late postoperative course, T-cell cytokine secretion increased to normal levels. Production of the anti-inflammatory cytokine IL-10 was altered, with different kinetics being selectively elevated during the late postoperative course. In contrast, the capacity of peripheral blood monocytes to present bacterial superantigens and to stimulate T-cell proliferation was normal or enhanced after surgery despite a significant loss of cell surface HLA-DR molecules. Thus, the level of major histocompatibility complex class II protein expression does not appear to predict the antigen-presenting capacity of monocytes obtained from surgical patients with uneventful postoperative recovery. Secretion of IL-1beta and IL-10 by endotoxin-stimulated peripheral blood monocytes was increased at different time points after surgery. Major surgery therefore results in a distinct pattern of immune defects with a predominant defect in the T-cell response to T-cell receptor- and CD28 coreceptor-mediated signals rather than an impaired monocyte antigen-presenting capacity. Suppression of T-cell effector functions during the early phase of the postoperative course may define a state of impaired defense against pathogens and increased susceptibility to infection and septic complications.

Aged↗

PubMed1996

Diltiazem increases blood concentrations of cyclized cyclosporine metabolites resulting in different cyclosporine metabolite patterns in stable male and female renal allograft recipients.

1. Six male and six female stable renal allograft recipients under cyclosporine immunosuppression and without concomitant therapy with drugs known either to induce or inhibit CYP3A enzymes were included in the study and received 180 mg day-1 diltiazem for 1 week in a two-period cross-over fashion. Cyclosporine (352 +/- 56 mg day-1) was given in two daily oral doses. The daily doses were not changed during the study. Blood samples were collected for 12 h after receiving cyclosporine alone and after receiving diltiazem in addition for 1 week. Cyclosporine and nine of its metabolites were quantified using h.p.l.c. 2. Co-administration of diltiazem caused a 1.6 fold increase of the AUC (0, 12 h) of cyclosporine and a 1.7 fold increase of the AUC(0, 12 h) of its metabolites. Analysis of the metabolite patterns showed an over-proportional increase of the AUC(0, 12 h) of the cyclized metabolites AM1c (2.6 fold) and AM1c9 (2.2 fold). The AUC(0, 12 h) values of cyclosporine and the hydroxylated metabolites increased less than two fold. 3. Differences of the AUC(0, 12 h) values of cyclosporine with and without diltiazem were significantly higher in female than in male patients (P < 0.02). The differences in the AUC(0, 12 h) values of the metabolites, especially AM1c, tended to be higher in female patients as well. 4. It is concluded that coadministration of diltiazem not only increases the blood concentration of cyclosporine but also those of its metabolites, leads to a shift of the metabolite pattern towards cyclized metabolites, and that the pharmacokinetic changes under diltiazem administration are more prominent in female than in male patients.

Adult↗