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Biomedical subjects

M Stahl

Publications and source records attributed to M Stahl.

At least 19 recordsLinked to original sources
PubMed1995

Two unrelated children with developmental delay, short stature and anterior chamber cleavage disorder, cerebellar hypoplasia, endocrine disturbances and tracheostenosis: a new entity?

Two unrelated children with developmental delay, anterior chamber-cleavage disorder, proportionate short stature and striking similarity in facial appearance appear to have an identical syndrome. Peters' plus syndrome has to be considered but additional abnormalities not described in this syndrome and their apparently different facies may be evidence for a hitherto undescribed condition. The further malformations both children have in common are cerebellar hypoplasia, hypothyroidism, tracheostenosis and dislocated hips.

Abnormalities, Multiple↗
PubMed1994

Inactivation of a cytosolic phospholipase A2 by thiol-modifying reagents: cysteine residues as potential targets of phospholipase A2.

The cytosolic phospholipase A2 (cPLA2) from the human monocytic cell line U937 contains nine cysteine residues and is subject to oxidation. Iodoacetamide and 5,5'-dithiobis(2-nitrobenzoic acid) were used to explore the susceptibility of cysteine residues to thiol modification agents as outlined in Schemes 2 and 3. In the absence of thiol reducing agents such as DTT, cPLA2 takes up only 2.8 equiv of [1-14C]iodoacetamide at pH 8.03/37 degrees C. With DTT present, cPLA2 is in its fully reduced form, and 4-5 equiv of acetamide are taken up without altering enzyme activity to give IA-cPLA2. A single equivalent of DTNB suffices to inactivate IA-cPLA2, giving a TNB-labeled enzyme, with the loss of activity correlating with release of an equivalent of 5-thio-2-nitrobenzoate. The TNB-labeled enzyme is quite stable up to 33 degrees C; enzyme activity is recoverable with DTT, even after this disulfide-enzyme adduct is incubated with iodoacetamide at pH 9.5, conditions that inactivate the free enzyme. At pH 9.5/37 degrees C, a single equivalent of 14C-labeled iodoacetamide is incorporated by IA-cPLA2 concomitant with complete loss of enzyme activity. Amino acid analysis of the 14C-labeled enzyme indicates that only cysteine residues are labeled. Lys-C digestion of labeled enzyme with 2 M guanidine at pH 8.0 yields a 40-mer peptide. Amino acid sequencing establishes that the label resides primarily in Cys324, although Cys331 is also labeled. These results identify a region of the enzyme that is susceptible to labeling by group modification reagents and may represent a suitable target for small molecule inhibitors.

Amino Acid Sequence↗
PubMed1994

Weekly high-dose 5-fluorouracil and folinic acid as salvage treatment in advanced gastric cancer.

BACKGROUND: A weekly schedule of a 24-h high-dose 5-FU infusion in combination with folinic acid was investigated as salvage therapy in patients with advanced gastric cancer. PATIENTS AND METHODS: Seventeen patients with progressive disease after chemotherapy were treated with a weekly schedule of 500 mg folinic acid/sqm by i.v. 2-h infusion followed by an i.v. 24-h infusion of 2.6 g 5-FU/sqm times six. Fourteen of the 17 patients (82%) had been pretreated in regimens which included 5-FU/folinic acid i.v. bolus. RESULTS: Toxicity was mild, with diarrhea, mucositis and nausea; WHO grade III/IV diarrhea was observed in only two patients. Three patients achieved partial remissions (18%; 95% confidence interval: 0%-38%) and 7 patients stable disease (41%; 95% confidence interval: 17%-64%). Their median survival time was five months (range 1.5-10 months) after the onset of salvage therapy. CONCLUSIONS: This schedule of weekly 24-h infusions of high-dose 5-FU and folinic acid is effective, even in patients pretreated with or resistant to regimens including 5-FU/folinic acid i.v. bolus. Based on these data, it appears that this schedule of high-dose 5-FU/folinic acid in first-line combination chemotherapy merits investigation.

Adult↗
PubMed1994

Congenital rubella syndrome despite repeated vaccination of the mother: a coincidence of vaccine failure with failure to vaccinate.

Congenital rubella syndrome occurred in a boy born to a mother who had been properly vaccinated three times before conception, but developed only low titers of rubella antibody. The non-vaccinated father most likely infected the mother on a home visit during the third to fifth weeks of gestation. He served in the army and fell ill during an outbreak of a rubella-like disease in his military unit. The mother subsequently developed a slight rash, but rubella IgM antibodies were lacking and rubella infection was not suspected. This incidence demonstrates the necessity of vaccinating all children, including boys and young men, in order to reduce the number of infections and prevent further cases of congenital rubella syndrome.

Adult↗
PubMed1994

Angiotensin I is converted to angiotensin II by a serine protease in human detrusor smooth muscle.

The aim of the present study was to investigate whether a pathway for conversion of angiotensin I (ANG I) to angiotensin II (ANG II) other than that via angiotensin-converting enzyme (ACE) is present in the smooth muscle of the human detrusor. Isolated detrusor strips from 11 patients were contracted by ANG I (1 microM) in the absence or presence of enalaprilat (10 microM), soybean trypsin inhibitor (STI, 200 micrograms/ml), or both. The metabolic activity in detrusor membranes from four patients was studied separately using Hip-Gly-Gly or ANG I as a substrate, with or without various protease inhibitors. The contractile response to ANG I (1 microM) was depressed by enalaprilat from 66 +/- 22 (mean +/- SD) to 39 +/- 13% of the K+ (124 mM)-induced response (P < 0.01, n = 11), and the combination of enalaprilat and STI resulted in a further reduction in contractile amplitude to 25 +/- 14% (P < 0.01 vs. K+, and P < 0.05 vs. enalaprilat alone) and a significantly slower developing contraction with a time to peak of 3.7 +/- 1.7 vs. 1.1 +/- 0.3 min for ANG I alone (P < 0.01). In detrusor membranes, a low ACE activity, inhibitable by captopril, was demonstrated by the formation of hippuric acid (0.70 nmol.min-1.mg protein-1) from the synthetic ACE substrate, Hip-Gly-Gly. However, the conversion of ANG I (166 nmol.min-1.mg protein-1) to ANG II was not affected by ACE inhibition, while serine protease inhibitors, e.g., STI and chymostatin, completely prevented ANG II formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Phase II study of single-agent etoposide in patients with metastatic squamous-cell carcinoma of the esophagus.

A total of 26 evaluable patients presenting with advanced or metastatic squamous-cell carcinoma of the esophagus were entered in a phase II trial to assess the single-agent activity of etoposide. Etoposide was given at a dose of 200 mg/m2 on 3 consecutive days every 3 weeks. Five patients (19%) achieved a partial response and seven (27%) experienced stabilisation of their disease. The median duration of response was 4 months (range 3-8 months). The major toxicity was leukopenia, which reached WHO grade 3 in 46% of patients and grade 4 in 11% of cases, with five instances of leukopenic fever and one therapy-associated death being recorded. Etoposide given at this dose and on this schedule seems to have considerable activity against non-pretreated metastatic esophageal carcinoma.

Adult↗
PubMed1992

Antitumour effect and symptomatic control with interferon alpha 2b in patients with endocrine active tumours.

26 patients with progressive neuroendocrine tumours received 3 x 10(6)U/m2 interferon alfa (IFN-alpha 2b) subcutaneously thrice weekly, until progression, as outpatients with moderate toxicity. 4/16 carcinoids and none out of 10 endocrine pancreatic tumours showed objective regression. Another 17 patients (68%) had no change. For a median of 34 weeks symptom control was excellent: 9 of 17 patients had major relief from pain, 11 of 13 from diarrhoea, and 7 of 7 from flushing. Thus, low-dose INF-alpha 2b given thrice weekly might be as effective as daily treatment with higher dosages. Treatment was only administered to patients with progression or major symptoms and this did not seem to adversely affect remission quality and survival.

Adult↗
PubMed1992

A phase II study of high dose tamoxifen in progressive, metastatic renal cell carcinoma.

Thirty-four patients with progressive advanced renal cell carcinoma (RCC) were treated with high-dose tamoxifen (HD-TAM) 100 mg/m2 p.o. daily until progression. The overall remission rate was 12%, including 1 complete remission. Seventeen of the thirty-four (50%) patients had minor remission or no change. Taking into consideration the documented progression prior to tamoxifen therapy, further tumour growth could be arrested in 62% (1 CR, 3 PR, 17 MR/NC) of the patients. Median response duration for CR/PR was 20 months (range 6-21+) and median progression-free survival for MR/NC was 6 months (range 2-15). The one-year survival rate was 41%. Patients with only pulmonary metastases, good performance status and prior nephrectomy seemed to have a better survival. Side effects were comparable to those of conventional doses of tamoxifen (20-30 mg p.o. daily). These data suggest that HD-TAM may be a useful therapeutic approach with low toxicity, considering that, in metastatic RCC, the treatment intent is at best palliative.

Adult↗
PubMed1992

Contractions induced by angiotensin I, angiotensin II and bradykinin in isolated smooth muscle from the human detrusor.

In isolated human detrusor preparations angiotensin (At)II 10(-9)-10(-5) M caused concentration-dependent contractions. The contractile effect was immediate, and had an amplitude which at the highest concentration used, 10(-5) M, reached 103 +/- 16% of the mean contraction produced by K+ 124 mM (27.6 +/- 1.4 mN). The AtII effect was completely blocked by saralasin 10(-6) M, but was not affected by pre-treatment of the preparations with captopril or enalaprilate. There was a marked tachyphylaxis to the actions of the peptide. AtI (10(-8)-10(-5) M) also caused contractions which were rapidly developing, and subject to a marked tachyphylaxis. At a concentration of 10(-5) M, the mean amplitude was 66 +/- 9% of the K(+)-induced contraction. The contractions were blocked by saralasin 10(-6) M, but not by captopril or enalaprilate 10(-5) M. In contrast, contractions produced by AtI in rabbit mesenteric arteries were practically abolished by the angiotensin converting enzyme (ACE) inhibitors. The contractions induced by both AtI and AtII were practically abolished after pre-treatment in a nominally calcium-free Krebs solution. However, blockade of L-type calcium channels by nifedipine 10(-6) M reduced the responses to both AtI 10(-6) M (by 38 +/- 4%) and AtII 10(-6) M (by 39 +/- 7%), but never abolished the contractions. Bradykinin (Bk; 3 x 10(-8)-10(-5) M) had a contractile effect in detrusor preparations which varied widely between strips. At a concentration of 3 x 10(-6) M, a maximum was reached amounting to 30 +/- 10% of the K(+)-induced contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

The role of schedule dependency of 5-fluorouracil/leucovorin combinations in advanced colorectal cancer.

The dose intensity in cancer monochemotherapy is probably the most important prognostic factor. In combination chemotherapy, in which interactions between agents do occur, response, survival, and toxicity might vary between different schedules. In a literature review of all published data of folinic acid and 5-fluorouracil intravenous bolus therapy in colorectal cancer with comparable dose intensity, an attempt was made to characterize the possible differences of the variations of schedules used. The antitumor activity increased significantly from 19% to 30%-35% when the two drugs were used concomitantly in multiple fractions per cycle rather than on a single day. However, fractionation changed the type of dose-limiting toxicity from hematologic and neurologic to gastrointestinal side effects. The different schedules did not differ significantly in the overall frequency of severe toxicities; however, recommending a certain schedule outside of controlled trials should be done cautiously.

Clinical Trials as Topic↗
PubMed1992

A 3-day schedule of 5-fluorouracil and folinic acid in metastatic progressive colorectal cancer and its impact in terms of palliation.

Treatment results in advanced colorectal cancer have improved during the last decade since the incorporation of agents like folinic acid, PALA, or interferon as active biomodulation of 5-fluorouracil (5-FU), the most potent drug in this disease. But essential prolongation of survival could not be demonstrated. To better define the need to initiate therapy and duration of treatment, a phase II study of high-dose folinic acid and 5-FU was initiated in patients with documented progression or severe tumor-related symptoms prior to start of therapy until best response was observed. The treatment plan was folinic acid 300 mg/m2 as a 10-minute intravenous infusion followed 50 minutes later by 5-FU 600 mg/m2 intravenous bolus days 1 to 3 every 3 to 4 weeks. Thirty-seven consecutive patients were treated during November 1986 and October 1987. Because of severe tumor-related symptoms, immediate treatment was considered mandatory in only eight patients. In the remaining 29 primarily asymptomatic patients, an observational period of a median duration of 8 weeks (range, 1-56) was possible before treatment seemed to be indicated. Most patients experienced some toxicity, mostly leukopenia and gastrointestinal side effects, of World Health Organization grades 3 and 4 during 156 treatment cycles (range, one to eight cycles). The calculated dose intensity was 535 mg/m2 5-FU per week. Of 36 evaluable patients, 14 responded at least with a partial remission (39%; confidence interval, 23% to 55%) of 7 months median duration. An additional 13 patients (36%) had stable disease, giving a rate of tumor stabilization in these progressive patients of 75%, for a median duration of 5.5 months. Median survival since start of therapy was 11 months. Results are comparable to data reported in the literature; survival and remission duration seem not to be mitigated in a patient population in which therapy was withheld until progression or symptoms occur. This patient population might be characterized by more homogeneously distributed risk factors.

Adult↗
PubMed1992

Biochemical modulation of 5-fluorouracil by folinic acid or alpha-interferon with and without other cytostatic drugs in gastric, esophageal, and pancreatic cancer.

5-Fluorouracil (5-FU) is one of the important antineoplastic agents for the treatment of gastrointestinal cancers. The biochemical modulation of 5-FU by various drugs has brought about the two combinations of 5-FU/folinic acid (FA) and 5-FU/alpha-interferon (IFN), which have shown clinical activity in phase II and III trials, especially in colorectal cancer. The experience with both combinations in upper gastrointestinal cancers, however, is limited. In esophageal cancer, two phase II studies with 5-FU/IFN reported seven (27%) objective remissions in 26 patients, indicating superiority of 5-FU/IFN over 5-FU monotherapy. Trials with 5-FU/FA alone are lacking in esophageal cancer. The modulation of 5-FU by IFN or FA failed to show clinically significant activity in pancreatic cancer. However, in gastric cancer, 5-FU/FA and 5-FU/IFN seem to induce higher complete and overall remission rates in advanced gastric cancer compared with 5-FU alone. With the daily times five schedule of 5-FU/FA, 27% objective remissions were achieved; in combination with other cytotoxic drugs, such as etoposide, anthracyclines, cisplatin, mitomycin, or methotrexate, objective response rates up to 50% and more were reported.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

New developments in the treatment of gastric carcinoma.

The recent successes being achieved with combination chemotherapy regimens strongly indicate that gastric cancer is chemosensitive. With these regimens, objective remission rates of more than 50% were recorded, including approximately 10% complete remission (CRs). The finding that locally advanced disease (LAD) and technically unresectable disease could be rendered resectable by preoperative chemotherapy (EAP) was important. The median survival time was 18 months for all patients and 24 months for disease-free patients. At 30+ months, 21% of all patients are still living disease free. The expected survival of patients with unresectable LAD is approximately 4-6 months without any treatment and 6-9 months with standard chemotherapy. Compared with the latter results, the preoperative use of etoposide, adriamycin, and platinum (EAP) seems to improve the prognosis of patients with LAD. Moreover, such a multimodal approach may increase the number of long-term survivors among patients with resectable gastric cancer, especially those whose stage indicates a high risk of relapse (stage IIIa or IIIb). However, partly because of the severe toxicities (myelo-suppression, nausea/vomiting), a considerable number of patients cannot be treated with these new regimens. Considering the predominantly palliative treatment intentions in far-advanced (metastasized) gastric cancer, regimens with low toxicities and acceptable activity should be preferred. For these reasons, we developed and investigated the combination etoposide, leucovorin, and 5-FU (ELF) in a phase II trial in elderly patients (greater than 65 years) and in patients with cardiac risks who could not be treated with anthracyclines. The overall response rate in 51 evaluable patients was 53%, including six clinical CRs (12%). The median remission duration was 9.5 months and the median survival time was 11 months. Tolerability was excellent. The high remission rate and long medical survival time achieved with ELF, plus its good tolerability, make this combination a valuable alternative to anthracycline-containing regimens. In addition to developing new treatment plans and strategies, it is also desirable to predict treatment outcome with an acceptable degree of certainty. Combinations of variable defined patient subgroups with significantly different probabilities for achieving objective response and for survival. The results of this analysis may contribute to a more patient-oriented and risk-adapted chemotherapy and to better comparability of future studies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Etoposide, folinic acid, and 5-fluorouracil in carboplatin-pretreated patients with advanced gastric cancer.

A group of 20 patients with gastric cancer, refractory to or with no change after two or three cycles of carboplatin were treated with etoposide/folinic acid/5-fluorouracil (ELF). An objective remission rate of 45% (9/20), a median remission duration of 8 months and a median survival time of 11 months were achieved. Toxicities were mild to moderate only. These results are comparable to those being achieved with ELF in previously untreated gastric cancer patients and confirm its efficacy and good tolerability.

Antineoplastic Combined Chemotherapy Protocols↗