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Biomedical subjects

H Bernhard

Publications and source records attributed to H Bernhard.

54 records · Page 3Linked to original sources
PubMed1992

Immunorecognition of ganglioside epitopes: correlation between affinity and cytotoxicity of ganglioside antibodies.

Cell-surface gangliosides have immunomodulatory effects that are presumed to play a role in tumour growth, progression, metastasis and therapy. To study the epitopes of gangliosides on human malignant melanomas and to search for monoclonal antibodies (Mabs) with superior immunological effector functions, 19 ganglioside antibodies were established. Specificity and affinity of nine antibodies of IgG3 isotype were evaluated by enzyme linked immunosorbent assay and thin layer chromatography with a panel of purified gangliosides. All antibodies recognised the ganglioside GD3, but their epitope specificity divided them into five groups. Their affinity constants for ganglioside GD3 ranged from 4.7 x 10(6) to 2.3 x 10(8), with 2 x 10(7) for Mab R-24. Two antibodies possessed a higher affinity for GD2 than for GD3. The functional properties of the antibodies were investigated in vitro. Differences in the degree of tumour lysis by complement fixation correlated with the affinity constants. Every ganglioside antibody differed in epitope recognition, affinity and cytotoxicity. Therefore some of these antibodies might even be more useful in the immunotherapy of malignant melanoma than Mab R-24.

Antibodies, Monoclonal↗
PubMed1992

Treatment of refractory colorectal carcinomas with fluorouracil, folinic acid, and interferon alfa-2a.

Interferon has been shown to augment the cytotoxic effects of fluorouracil (5-FU) against colon cancer in vitro and possibly in vivo. Therefore a pilot study was initiated to evaluate the effects of the combination 5-FU/FA/interferon alfa (IFN-alpha) in colorectal adenocarcinomas refractory to first-line therapy with 5-FU/FA. Eleven patients with rectum cancer and four patients with colon cancer were treated according to the following schedule: 9 million units IFN-alpha subcutaneous three times a week; 500 mg/m2 5-FU via an intravenous bolus 1 hour after the initiation of a 2-hour infusion of 500 mg/m2 of FA, once a week. Of 15 patients, one had a minor response, one had a disease stabilization, and three had a mixed response. No complete or partial remissions were seen. Looking at the sensitivity of lung metastases (three of three), the regressions can be explained through the additive effect of IFN-alpha to 5-FU/FA. Although minimal side effects (World Health Organization classification) were observed, most patients experienced a reduction of well-being.

Adult↗
PubMed1992

Combination fluorouracil, folinic acid, and interferon alfa-2a: an active regimen in advanced pancreatic carcinoma.

Based on promising results with 5-FU/FA or 5-FU/IFN-alpha in colorectal cancer, a pilot study was initiated to evaluate the effects of the combination 5-FU/FA/interferon alfa (IFN-alpha) in patients with advanced pancreatic cancer. Patients received 9 million units (MU) IFN-alpha subcutaneously three times a week or 6 MU IFN-alpha once a week; 500 mg/m2 5-FU via an intravenous bolus 1 hour after the initiation of a 2-hour infusion of 500 mg/m2 of FA, once a week. Fourteen patients, all previously untreated with chemotherapy, were enrolled; 13 (two females/11 males) were evaluable for response and toxicity (one too early). The median performance status was 80% (range, 60 to 100) and the median age 62 years. Besides the inoperable primary tumor, metastatic sites were liver, lung, and peritoneum. Three of 13 patients had a partial remission, three of 13 patients a minor response, and four of 13 patients no change. Three patients had progressive disease. Until now, no complete remission was seen. Median duration of response was 4+ months; median survival has not been reached yet. Of all patients there were three instances of World Health Organization grade 3 toxicity: fatigue (one of 13), nausea (one of 13), and diarrhea (one of 13); grade 4 toxicity did not occur. Although overall toxicity was moderate, most patients experienced a reduction of well-being. Therefore in all patients the dose of IFN was reduced (from 3 x 9 MU/week to 1 x 6 MU/week). Our preliminary data suggest that biochemical modulation of 5-FU with FA and IFN-alpha (reduced dosage) is effective in pancreatic cancer with moderate toxicity, warranting further study.

Adult↗
PubMed1991

Surgical treatment of primary aortoduodenal fistula.

Primary aortoduodenal fistula is a rare and potentially fatal condition. Awareness of its existence, precise diagnostic evaluation, and early surgical intervention are essential for the survival of the patient. Although early experience indicated that interruption of the fistula, repair of the enteric defect, oversewing of the aorta and extraanatomic bypass was the procedure of choice, in situ aortic replacement with a prosthetic graft seems to be a viable option. This article includes a case report of a primary aortoduodenal fistula and review of the literature.

Aged↗
PubMed1989

Ganglioside GD3 shedding by human malignant melanoma cells.

Gangliosides appear to be important target molecules for immunological effector mechanisms on neuro-ectodermal tumors. Therefore in vitro studies were performed to examine whether ganglioside GD3, which is highly expressed on the cell surface of cultured human melanoma cells, is being shed into the culture medium. Measurable quantities of gangliosides GM3 and in particular GD3 were shed by the melanoma cells we have tested as detected on thin-layer chromatograms (TLC) stained with orcinol. Ganglioside GD3 was also evidenced by immunostaining with anti-GD3 MAb and by ELISA. The concentration of GD3 in the supernatant of human melanoma cells depended on the ganglioside pattern of the cell line. Cells containing high levels of GD3 shed large amounts, cells with low levels shed no detectable GD3. Ganglioside GD3 was detectable in sera, but no major quantitative differences were observed in sera of patients with GD3-positive tumors and normal controls. This points to a local accumulation of ganglioside GD3 at the tumor site.

G(M3) Ganglioside↗
PubMed1989

[Chronic paranoid-hallucinatory psychosis as the initial manifestation of an HIV infection?].

In a 36-year-old patient an acute onset of psychosis occurred, probably due to HIV infection. For one year HIV-infection with reduced T4/T8 ratio had been known without clinical manifestation (stage IV B of the CDC-classification). He developed chronic delusional hallucinations, which persisted for more than one year in spite of adequate psychoactive drug therapy. So far AIDS-related dementia has not become evident. Focal lesions caused by opportunistic infections or tumour were excluded by computed tomography and magnetic resonance imaging. The latter revealed several small lesions and the brain scan showed a nonhomogeneous pattern of cerebral blood flow. CSF-examination disclosed a mild lymphocytosis and raised protein concentration. A classification as an organic, HIV-induced delusional hallucination seems to be justified.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Antibodies to cell surface ganglioside GD3 perturb inductive epithelial-mesenchymal interactions.

Most epithelial sheets emerge during embryogenesis by a branching and growth of the epithelium. The surrounding mesenchyme is crucial for this process. We report that branching morphogenesis and the formation of a new epithelium from the mesenchyme in the embryonic kidney can be blocked by a monoclonal antibody reacting with a surface glycolipid, disialoganglioside GD3. In contrast, a more than 10-fold excess of antibodies to adhesive glycoproteins (N-CAM, L-CAM, fibronectin) fails to inhibit morphogenesis. Although the anti-GD3 antibody affected epithelial development, the disialoganglioside GD3 was expressed not in the epithelium, but in the mesenchyme surrounding the developing epithelia. The data raise the intriguing possibility that the anti-GD3 antibody inhibits epithelial development by interfering with epithelial-mesenchymal interactions.

Animals↗
PubMed1987

A common epithelial cell surface antigen (EPM-1) on gastrointestinal tumors and in human sera.

A common epithelial cell surface marker (EPM-1) was defined by two monoclonal antibodies (Pa-25 and Pa-42), raised against a pancreatic tumor cell line (Capan-1). Both monoclonal antibodies were tested on 49 cultured human cell lines and 244 tissue samples and reacted with all 76 tissue samples of 20 different normal epithelial cell types and with 57 of 63 epithelial tumor tissue samples of nonendocrine origin. Included were eight exocrine pancreatic carcinomas. There the percentage of EPM-1 positive tumor cells correlated with tumor grading. EPM-1 was detectable on the cell surface of cultured human cell lines of the pancreas, liver, colon, and mamma. Some epithelial tumor cell lines did not express EPM-1 on the cell surface, but in the cytoplasm. 100 nonepithelial and epithelial endocrine tissue samples as well as 25 nonepithelial cultured tumor and normal cells were unreactive with monoclonal antibodies Pa-25 and Pa-42. These included cells of neuronal, endocrine, and mesenchymal origin. EPM-1 activity was purified from pancreas tumor cells Capan-1 and from human sera by high-performance liquid chromatography and its molecular weight amounts to about Mr 400,000. EPM-1 was detectable in bronchial, intestinal, and pancreatic secretions and saliva and serum by an enzyme-linked immunosorbent assay test. EPM-1 values were high in the sera of normal individuals, but low or not detectable in most sera (21 of 31) of patients with gastrointestinal tumors. EPM-1 represents a novel differentiation marker for epithelial cell types, which should have a central role in the biology of normal and tumorous epithelial cells.

Animals↗
PubMed1987

Secretory epithelial cell marker on gastrointestinal tumors and in human secretions defined by a monoclonal antibody.

A new marker for human secretory epithelial cell types (Exo-1) has been defined by a mouse monoclonal antibody (Pa-G14). The antibody was raised against a human exocrine pancreatic tumor cell line (Capan-1) and tested against 46 cultured human cell types and 228 freshly frozen human tissue sections. It reacted specifically with 28 normal and 55 secretory neoplastic epithelial tissues tested. Eleven different secretory epithelial cell types expressed this antigen, as well as human fetal tissues of the gut and bronchi. One hundred and twenty samples of normal tissues, cells, and tumors of nonexocrine origin were Exo-1 negative. In normal secretory tissues staining was most pronounced at the apical poles and as shown by immunoelectron microscopy in the case of the duodenum, at the microvilli. In cultured Exo-1 positive tumor cells the antigen was not demonstrable on the cell surface but in the cytoplasm after acetone/methanol fixation only. The antigen was identified biochemically as a polar neutral glycolipid and detected in human salivary, bronchial, pancreatic, and intestinal secretions by an enzyme-linked immunosorbent assay, but was not found in sera of healthy controls or patients with gastrointestinal and other tumors. Antigen Exo-1 represents a novel common antigen for normal and tumorous glandular epithelial cells.

Animals↗
PubMed1987

Nimodipine disposition and haemodynamic effects in patients with cirrhosis and age-matched controls.

Six biopsy proven cirrhotics and five age-matched controls (mean 55.3 vs 52.4 years) were randomly given single 60 mg p.o. and 30 mg s.l. doses of nimodipine. Serum concentrations and blood pressure were measured regularly over the subsequent 24 h period. The clearance of nimodipine was reduced in the patients with cirrhosis. Apparent oral clearance of nimodipine in the cirrhotic group was significantly lower than that observed in the normal group (187 +/- 163 l h-1 vs 469.6 +/- 198.4 l h-1, P less than 0.01). There were no significant changes in mean arterial pressure (MAP) in the normal subjects. There were, however, significant reductions in MAP following oral nimodipine in the cirrhotics. These reductions were significantly related to nimodipine concentrations in individual patients (P less than 0.05).

Adult↗
PubMed1984

Ranitidine disposition and systemic availability in hepatic cirrhosis.

Single-dose ranitidine kinetics were studied in 10 patients with cirrhosis as proved by liver biopsy. All were clinically stable. After an overnight fast, ranitidine was given in a randomized crossover order as a bolus intravenous injection (50 mg) or was taken by mouth (150 mg). Terminal t1/2 was 2.7 +/- 0.4 hr after oral dosing and 2.9 +/- 0.4 hr after intravenous injection. Total plasma clearance was 470 +/- 170 ml/min and the steady-state volume of distribution was 1.2 +/- 0.2 l/kg. There was considerable intersubject variability in the ranitidine serum concentration-time profile after oral dosing. Systemic availability as assessed by AUC analysis was 58% +/- 11%. Not all of the dose could be recovered in the urine as unchanged ranitidine and its known metabolites after intravenous injection. At 0.5 microgram/ml the serum protein binding of ranitidine was 4.6% +/- 1.3%. It is concluded that disposition of ranitidine in these 10 stable subjects with cirrhosis was not significantly altered. The minor changes observed in some were as likely to be the result of secondary perturbations in physiologic status as to effects of cirrhosis on drug metabolism.

Administration, Oral↗
PubMed1983

Hepatic encephalopathy and altered cimetidine kinetics.

Cimetidine kinetics were followed in 16 cirrhotic patients after a single IV 300-mg dose. The patients were grouped according to a history of portal systemic encephalopathy (PSE). There were no differences among the groups in volume of distribution, biologic t 1/2, or distributional clearance. In cirrhotic patients with no history of PSE, cimetidine kinetics and metabolism were the same as in healthy subjects. Patients with a history of PSE (n = 8) had lower cimetidine total body clearance than cirrhotic patients without a history of PSE and healthy subjects. Cirrhotic patients with a history of PSE also had decreased formation of cimetidine sulfoxide (as judged by differences in the sulfoxide serum concentration-time AUC). Because of the 40% decrease in total clearance, dosage in cirrhotic patients with a history of PSE should be reduced to minimize the risk of CNS side effects associated with cimetidine.

Adult↗
PubMed1981

Age, disease, and cimetidine disposition in healthy subjects and chronically ill patients.

Cimetidine induces reversible dose-related central nervous system (CNS) toxicity. Trough serum concentrations and the development of CNS toxicity correlate. We compared cimetidine kinetics in 12 healthy subjects and 31 patients. Six of the latter had normal renal and liver function, five had renal disease only, 12 had liver disease only, and eight had both renal and liver disease. Postmortem tissue distribution was assessed in 11 patients, and expressed as tissue:serum ratio. Average cimetidine total clearance (ClB) in milliliters per minute for each group was as follows: patients with renal and liver disease (182 +/- 105), renal disease only (193 +/- 24), liver disease only (463 +/- 145), normal patients (510 +/- 93), and healthy subjects (583 +/- 140). Renal function was the major determinant for ClB, and the relationship was described by ClB = 4.2(CCr) + 140, r = 0.87, where CCr is creatinine clearance. Cimetidine clearance was affected little by age. Tissue:serum ratios from highest to lowest were as follows: kidney greater than stomach greater than liver greater than bone greater than brain greater than fat. Central and steady-state distribution volumes were not influenced by age or disease. There was enchanced CNS penetration in liver disease patients; their cerebrospinal fluid (CSF):serum ratio was twice the normal. Our kinetic studies identify patient characteristics likely to result in elevated blood levels, and suggest that the greatest risk of CNS toxicity is in those with liver disease.

Adolescent↗
PubMed1981

Cimetidine in systemic mastocytosis.

54-year-old caucasian women with systemic mastocytosis manifested by gastrointestinal and dermatological symptoms that were treated with cyproheptadine, Lomotil (diphenoxylate-atropine), and cimetidine was studied. The patient consented to discontinue the H2-receptor antagonist, and to have the following values measured: serum and urine concentrations of cimetidine: complete blood count (CBC) with differential, serum chemistry, and urinalysis; and systemic mastocytosis symptomatology. The patient experienced prompt recurrence of gastrointestinal and dermatological symptoms after stopping the cimetidine; the drug was restarted in three days and the symptoms subsided. The preceding laboratory and symptomatological values were recorded for 11 days after the reinstitution of cimetidine therapy. Histamine, gastrin, CBC, serum chemistry, and urinalysis remained normal, with and without cimetidine. Exacerbations of her symptoms were worst when no drug was detected in the serum. Therefore, it appears that cimetidine has a role in treating the symptoms of systemic mastocytosis.

Adult↗
PubMed1981

Alteration of theophylline clearance and half-life by cimetidine in normal volunteers.

Interaction between cimetidine and theophylline was studied in six male volunteers, who were randomly divided into two groups to eliminate temporal effects. The effect of cimetidine on theophylline elimination was immediate and progressed as cimetidine treatment was continued. Cimetidine prolonged theophylline half-life compared to that in control periods an average of 36.2% (range, 0 to 103%) on the first day of cimetidine exposure (p less than 0.05). Theophylline clearance was decreased an average of 18.5% (range, 4.9% to 36%), whereas theophylline volume of distribution was unchanged by cimetidine. After 8 days of cimetidine treatment at the usually recommended dosage, theophylline half-life further increased to 64.3% (range, 9% to 128%) of control values, whereas clearance declined an average of 30% (range, 5% to 50%) (p less than 0.01). Theophylline volume of distribution remained unchanged. Although cimetidine-theophylline interaction needs confirmation in a patient population, we advise caution when these agents are coadministered. Some adjustment in theophylline dosage may be needed in treated patients who are also given cimetidine, and these patients who are also given cimetidine, and these patients should be studied closely with theophylline serum concentration measurements and careful clinical assessments.

Adult↗
PubMed1979

Pharmacokinetic and clinical studies in patients with cimetidine-associated mental confusion.

15 cases of cimetidine-associated mental confusion have been reported. In order that this syndrome might be investigated changes in mental status (M.S.) were correlated with serum concentrations and renal and hepatic function in 36 patients, 30 patients had no M.S. change on cimetidine and 6 had moderate to severe changes. These 6 patients had both renal and liver dysfunction (P less than 0.05), as well as cimetidine trough-concentrations of more than 1.25 microgram/ml (P less than 0.05). The severity of M.S. changes increased as trough-concentrations rose, 5 patients had lumbar puncture. The cerebrospinal fluid: serum ratio of cimetidine concentrations was 0.24:1 and indicates that cimetidine passes the blood-brain barrier; it also raises the possibility that M.S. changes are due to blockade of histamine H2-receptors in the central nervous system. Patients likely to have both raised trough-concentrations and mental confusion are those with both severe renal and hepatic dysfunction. They should be closely observed and should be given reduced doses of cimetidine.

Aged↗
PubMedDate not supplied

Combination of 5-fluorouracil, adriamycin, ifosfamide and cisplatin in metastatic adult soft tissue sarcoma: results of a phase II study.

Treatment results of advanced soft tissue sarcomas are still suboptimal. To evaluate the clinical effects of a combination therapy (FADIP) with Adriamycin (ADM), ifosfamide (IFO), cisplatin (DDP) plus continuous infusion of 5-fluorouracil (FU) as a synergistic factor for alkylating agents, a phase II study was initiated in patients with advanced soft tissue sarcomas of different histological subtypes. Fifty-six previously untreated patients with advanced soft tissue sarcomas of different histological subtypes (24 females, 31 males, median age 51.3 years, median Karnofsky performance status 80%) were included in this study. Treatment consisted of ADM 50 mg/m2 i.v. on day 1, IFO 4,000 mg/m2 i.v. on day 1, mesna 800 mg/m2 i.v. 3 x with 8-hour intervals on day 1 starting with IFO administration, FU 500 mg/m2 i.v. as 24-hour infusion on days 1 + 2, DDP 100 mg/m2 i.v. on day 2. This regimen was repeated every 4 weeks for at least 2 cycles. Major WHO grade III/IV hematological toxicity was observed in 35/56 patients. One toxic death due to severe neutropenia and fungal pneumonia occurred. Granulocyte colony-stimulating factor was administered in 8/35 neutropenic patients. Time to recovery was significantly reduced and no infectious complication was observed. WHO grade III/IV toxic diarrhea was observed in 8 patients requiring intravenous fluid replacement. WHO grade III/IV nausea occurred in 11 patients, 9/11 responded to symptomatic treatment with ondansetron alone. The overall response rate was 30.3%. The median duration of response (complete/partial response, CR/PR) was 18.1 months, the median progression-free interval was 4.5 months. The median survival time of all patients was 11.8 months, and 18.1 months in responding patients (CR/PR). Tumor-related pain was effectively reduced in 15/31 patients under treatment. FADIP produces comparable response rates to other standard treatment regimens in soft tissue sarcomas. Prolonged duration of response and median survival may be due to the use of continuous infusion of FU as a synergistic factor to alkylating agents. Granulocyte colony-stimulating factor is effective in reducing the otherwise observed high rate of WHO grade III/IV hematological toxicity with severe neutropenia.

Antineoplastic Combined Chemotherapy Protocols↗