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Biomedical subjects

L Bauer

Publications and source records attributed to L Bauer.

At least 55 records · Page 3Linked to original sources
PubMed1992

A phase I trial of 5-fluorouracil, folinic acid, and alpha-2a-interferon in patients with metastatic colorectal carcinoma.

The mechanisms of biochemical modulation of 5-fluorouracil (5-FU) cytotoxicity by folinic acid (FA) have been elucidated, and the clinical use of this combination has improved response rates and survival in patients with metastatic colorectal cancer. Recently, Phase II trials also showed potential synergism between alpha-2a-interferon (rHuIFN-alpha 2a) and 5-FU. Therefore, a Phase I trial of these three agents 5-FU, FA, and rHuIFN-alpha 2a was conducted in patients with metastatic colorectal cancer. The drugs were given over 5 days, with dose escalation of either rHuIFN-alpha 2a or 5-FU. Fifty-five eligible patients were treated at eight dosing levels. The maximal tolerated dose (MTD) was as follows: 5-FU 430 mg/m2/d intravenously (IV) on days 1 to 5, FA 200 mg/m2 IV on days 1 to 5, and rHuIFN-alpha 2a 4.0 x 10(6) U/m2/d subcutaneously on days 1 to 5. The dose-limiting toxicities were mucositis and neutropenia. Objective responses were seen at most dosing levels, and overall 15 of 55 patients (27%; 95% confidence interval, 16% to 41%) responded (median duration, 6.5 months). A Phase II trial using the MTD is ongoing.

Adult↗
PubMed1992

Variation in evoked potential measures over the menstrual cycle: a pilot study.

The P3 component of a visual event related potential (ERP) was studied for five consecutive weeks in six women with normal menstrual cycles. Serum concentrations of luteinizing hormone (LH), estradiol (E2) and progesterone were studied during the same period. Increases in P3 amplitude, although nonsignificant, were noted in the week preceding onset of menses. No significant changes in reaction times to target/nontarget stimuli were noted over the same time period.

Adult↗
PubMed1992

Functional equivalence of end and loop ileal conduit stomas.

A total of 458 patients underwent ileal conduit urinary diversion between 1970 and 1984. An end stoma was constructed in 44% of the patients and a Turnbull loop stoma in 56%. The median interval between appliance changes for all patients was 5 days. Patients with an end stoma had a longer median interval between appliance changes than those with a loop stoma. A total of 51 patients had 66 complications. Operations for stomal revisions were required in 5.5% of the patients. There was no difference in interval until initial complication between the end and loop stoma groups, although the end stoma was more prone to ischemic complications than the loop stoma. We conclude that the ileal conduit stoma constructed in an end or loop fashion yielded clinically equivalent long-term function.

Adolescent↗
PubMed1991

Clinical results and characterization of tumor-infiltrating lymphocytes with or without recombinant interleukin 2 in human metastatic renal cell carcinoma.

A Phase I trial of tumor-infiltrating lymphocytes (TIL) expanded in vitro and administered on Days 1 and 8, with or without continuous infusion recombinant interleukin 2 (rIL-2) in 25 patients with metastatic renal cell carcinoma, was conducted. Eighteen of the 25 eligible patients were treated with TIL and escalating doses of rIL-2 (0.0, 3.0, 4.5 x 10(6) units/m2) on Days 1 to 5 and 8 to 12. Dose-limiting toxicity was pulmonary, and the maximum tolerated dose of rIL-2 was 3.0 x 10(6) units/m2. No clinical responses were observed. Immunological monitoring of peripheral blood lymphocytes demonstrated significant increases in CD3+ and CD56+ cells, including the activated T-cell subsets. Phenotypic analysis of cultured TILs demonstrated significant heterogeneity and the presence of CD3+CD4+ and CD3+CD8+ T-cells, with CD3-CD56+ and CD3+CD56+ populations also present. The majority of cultured TILs expressed HLA-DR and CD45RO, with a variable number expressing CD25. The rIL-2-expanded TILs possessed cytotoxicity against allogeneic and autologous tumor, with cytolytic activity against only autologous tumor seen in one patient. Results demonstrate that in vitro expansion of TILs is possible, but further studies are needed to define the biology of TILs in renal cancer and to isolate and expand tumor-specific T-cells.

Adult↗
PubMed1991

Phase I trial of natural human interferon beta in metastatic malignancy.

A phase I trial of natural human beta-interferon (nHuIFN-beta) was initiated to evaluate its biological activity, maximum tolerated dose, and toxicity in patients with refractory malignancies. nHuIFN-beta was administered to successive groups of 4-6 patients as an i.v. bolus on days 1 and 4, for 4 consecutive weeks. Dose levels were 0.1, 1.0, 10, 30, 60, 100, and 200 x 10(6) units/m2. Thirty-five patients were entered, and 34 patients were evaluable for toxicity, immunomodulatory, and antitumor effects. Toxicity was mild to moderate and included fever and chills, fatigue, arthralgias, nausea, transient renal and hepatic dysfunction, and leukopenia. No dose-limiting toxicity was observed, and no responses were seen. Significant immunological changes included the following: an increase in natural killer activity on day 5 when compared to pretreatment values (P less than 0.01) and an increase in activated T-cells (CD3+/HLA-DR+) with increasing doses of nHuIFN-beta (P less than 0.01). Pharmacokinetic data demonstrated a short alpha half-life of 12.1 +/- 2.5 (SE) min and a beta half-life of 129.7 +/- 14.7 min. Neutralizing serum antibodies were detected in 2 of 27 patients receiving nHuIFN-beta. In conclusion, toxicity of nHuIFN-beta given twice weekly was moderate, and further dose escalation is possible. The immunological changes and pharmacokinetic behavior of nHuIFN-beta resemble those reported with rHuIFN-beta ser.

Adult↗
PubMed1991

Induction of cytokine messenger RNA and secretion in alveolar macrophages and blood monocytes from patients with lung cancer receiving granulocyte-macrophage colony-stimulating factor therapy.

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes the proliferation and differentiation of hematopoietic progenitor cells. Although preliminary data are available from clinical trials, the effect of GM-CSF on gene expression of immunocompetent cells in treated patients has not been studied. We previously demonstrated that in vitro treatment with GM-CSF also enhances maturation-related anti-tumor activities in mononuclear phagocytes. The purpose of the present study was to examine the effects of in vivo recombinant GM-CSF therapy on alveolar macrophages and blood monocytes, to determine if these cells demonstrated differential expression of cytokine genes, cytokine production, and tumoricidal activity. Alveolar macrophages and blood monocytes were isolated from 13 patients receiving a range of GM-CSF doses (60-250 micrograms/m2/day) by continuous infusion over a 2-week period. Both monocytes and macrophages were isolated prior to therapy and at day 10 of the infusion. Monocytes, in addition, were isolated on day 3 of infusion. Results indicated that GM-CSF therapy enhanced expression of tumor necrosis factor, interleukin 1, and interleukin 6 mRNA in both monocytes and alveolar macrophages. Differential responses, however, were observed in cytokine secretion; monocytes demonstrated enhanced secretion of all three cytokines by day 3 of treatment, but alveolar macrophages showed only enhanced interleukin 6 secretion at day 10. Monocyte tumoricidal activity after in vitro lipopolysaccharide stimulation was also significantly elevated by day 3 of treatment, but at day 10 activity was not statistically different from pretreatment values in either monocytes or alveolar macrophages. These data indicate that GM-CSF exerts striking time-dependent modulatory effects on gene expression and functional activities of monocytes and alveolar macrophages in vivo, although the responses of the two cell types differ with respect to cytokine secretion.

Gene Expression Regulation, Neoplastic↗
PubMed1991

Phase I trial of continuous infusion interleukin-2 and doxorubicin in patients with refractory malignancies.

A phase I trial was performed to assess the immunomodulatory activities, maximum tolerated doses, and the toxicity of recombinant interleukin-2 (rIL-2) administered in combination with doxorubicin to patients with refractory malignancies. Therapy was administered to successive cohorts of four to six patients who were treated at three different dose levels (1A, 1B, 2A). Levels 1-2 refer to doxorubicin (40 or 60 mg/m2) given as an intravenous (i.v.) bolus on day 1, and levels A-B refer to rIL-2 (1.0 or 3.0 x 10(6) U/m2) given as a continuous i.v. infusion on days 2-5, 9-12, and 16-19. Cycles were repeated every 28 days. Seventeen patients were entered in the trial. Dose limiting toxicity consisted of neutropenia, and the maximum tolerated dose (MTD) of the combination was doxorubicin 40 mg/m2 and rIL-2 3.0 x 10(6) U/m2. No objective responses were observed. Lymphocytosis related to rIL-2 occurred and flow cytometry demonstrated significant increases in the following subsets: CD3+CD25+HLADr+ and CD11b-CD16c+CD8-. Natural killer cell activity and lymphokine-activated killer (LAK) cell precursors were increased in patients treated at dose levels 1A and 1B (40 mg/m2 doxorubicin), but no consistent changes in LAK activity were noted. No clinical responses were seen and the overall toxicity of this combination was moderate to severe. Administration of doxorubicin prior to rIL-2 does not enhance the immunologic effects of rIL-2.

Adult↗
PubMed1991

[Fatty degeneration of liver sinusoids in fetal asphyxia].

The fat content of the liver sinusoidal cells was examined partly systematically partly by selected case groups from 297 cases. While minor grades of lipid content within these cells was found nearly equally spread at all causes of death the most intensive fat accumulation was seen at cases of violent asphyxia.

Asphyxia↗
PubMed1990

Phase I trial of dipyridamole with 5-fluorouracil and folinic acid.

We have performed two Phase I trials of the combination of dipyridamole, 5-fluorouracil (5-FU), and folinic acid in patients with advanced refractory malignancy, based upon in vitro evidence that dipyridamole can modulate the cytotoxicity of 5-FU. In the first trial, patients were treated every 4 wk with dipyridamole (50 mg/m2) p.o. every 6 h on Days 0 to 6, beginning 24 h prior to the i.v. administration of folinic acid (200 mg/m2) and escalating doses of i.v. 5-FU on Days 1 to 5. The maximum tolerated daily dose of 5-FU that could be given with this combination was 375 mg/m2. Because dipyridamole is extensively bound to plasma proteins, it was hypothesized that the concentrations of free dipyridamole achieved with a dose of 50 mg/m2 were inadequate to modulate the cytotoxicity of 5-FU and folinic acid. Therefore, a second Phase I trial of escalating dose of p.o. dipyridamole was performed. Folinic acid (200 mg/m2) and 5-FU (375 mg/m2) were given i.v. on Days 1 to 5 every 4 wk, beginning 24 h after the start of therapy with dipyridamole; dipyridamole was administered p.o. on Days 0 to 6 at doses of 75, 100, 125, 150, 175, or 200 mg/m2/dose to successive cohorts of patients. Dose-limiting neutropenia, mucositis, and nausea were produced at a dose of 200 mg/m2/dose; the recommended dose of dipyridamole for use in Phase II studies is 175 mg/m2 p.o. every 6 h, or 700 mg/m2/day. At this dose, a mean peak plasma concentration of total dipyridamole of 16.32 mumol and a mean peak plasma concentration of free dipyridamole of 38.30 nmol were observed. Trough concentrations of free dipyridamole averaged 60% of the peak concentrations. Objective antitumor responses were seen in a number of tumor types; five of 13 patients with breast cancer treated with high-dose p.o. dipyridamole, 5-FU, and folinic acid responded. High-dose p.o. dipyridamole can produce plasma concentrations of free dipyridamole within the range shown to modulate the cytotoxicity of 5-FU and other agents. Phase II trials of this combination are justified.

Adult↗
PubMed1990

[Quantitative analysis of cell density and pattern of chondrocytes in transitory hyaline cartilage anlagen of human tarsal bones].

Changes in the distribution patterns of chondrocytes in the embryonic transitory hyaline cartilage of the tarsus were studied using 56 sagittal section of tarsi from 28 human embryos, with a vertex-foot length from 7.0 to 44.0 cm. The os naviculare and os cuboideum were not sliced in all sections. A total of 93,931 cells were transferred via a mirror to paper, and the resulting patterns were analyzed. Determinations included the numerical surface and volume density of the chondrocytes and the cell distribution patterns using the dispersion index. In the case of the calcaneus, talus, os naviculare and os cuboideum, the number of sliced cells found over a constant area decreases at a continuous linear rate in the course of the embryonic period. In all tarsal primordia the distribution pattern developed from regular to random. Particular conditions prevail immediately below the perichondrium and near the ossification centers which can be found in the calcaneus from the 6th month onwards.

Ankle↗
PubMed1988

Pharmacological investigations on Achyrocline satureioides (LAM.) DC., Compositae.

Achyrocline satureioides (Lam.) DC. inflorescences have been used as remedies in folk medicine for the treatment of a variety of human ailments, particularly those of the gastrointestinal tract. Different extracts of inflorescences have been tested for anti-inflammatory, analgesic, antispasmodic, constipating and sedative activities. The aqueous extracts (maceration and decoction) and ethanolic macerate exhibited an inhibition of the carrageenan-induced rat paw oedema at a dose range of 75-500 mg kg-1 i.p., and also showed analgesic effect with the acetic acid-induced writhing test in mice. The gastrointestinal propulsion of a charcoal suspension was not affected significantly by any extract, at a dose of 200 mg kg-1 p.o., in mice. The aqueous decoction increased pentobarbital-induced sleeping time, at doses of 200 and 500 mg kg-1 i.p. and p.o., in mice. The ethanolic macerate inhibited contractions induced by acetylcholine, histamine, noradrenaline and barium chloride in four different smooth muscle tissues. The antispasmodic and anti-inflammatory activities were reproduced with quercetin, luteolin and quercetin 3-methyl ether, flavonoids that have been isolated from this plant. A partial evaluation of the toxicity of the extracts was also performed. The pharmacological effects assayed are discussed in relation to the chemical constituents of this plant and its popular use in gastrointestinal disturbances, and inflammatory conditions could be related to the presence of the flavonoids.

Analgesics↗
PubMed1988

Occult carcinomas of the thyroid. Evaluation of 1,020 sequential autopsies.

In a sequence of 1,020 autopsies, all thyroid glands were thoroughly examined during a two-year period. Fifty-seven percent of the thyroid glands had no gross or histologic changes; approximately 22% were more or less goitrous. In 63 of 1,020 (6.2%) thyroid glands, a clinically latent carcinoma was detected. The greatest diameter of tumors measured microscopically ranged between 0.5 and 10.5 mm. Sixty-nine percent of the carcinomas were found by excision of a local change of tissue visible through close examination by the naked eye. All but one carcinoma were of papillary type, the one exception being a C-cell carcinoma. Multicentricity was found in 46% and regional lymph node metastases in 14%. There was no significant predilection of sex or age. It was concluded that these tumors have no propensity to increase to a clinically apparent thyroid disease.

Adenoma↗
PubMed1986

Synthesis and inhibition of human acrosin and trypsin and acute toxicity of aryl 4-guanidinobenzoates.

The aryl 4-guanidinobenzoate, 4'-nitrophenyl 4-guanidinobenzoate (NPGB), is a potent inhibitor of sperm acrosin, an enzyme with an essential function in the fertilization process. NPGB prevents fertilization in a number of animal species and is a good lead compound for the development of contraceptive agents. In order to assess the efficacy of other aryl 4-guanidinobenzoates as acrosin inhibitors, 24 of these compounds were synthesized. Their inhibitory activity toward human acrosin was determined and compared with their activity toward human pancreatic trypsin in order to assess whether inhibitor sensitivity differed between these similar enzymes. Nine of the inhibitors were synthesized from phenols approved by the FDA for therapeutic use. The acute toxicity of these inhibitors in mice was determined and compared to that of nonoxynol-9, the most commonly used active ingredient in today's vaginal contraceptive preparations. All of the compounds proved to be potent inhibitors of human acrosin although 3 orders of magnitude difference were observed between the most and least effective inhibitors. Little specificity was present in regard to their inhibition of acrosin and trypsin. All the aryl 4-guanidinobenzoates synthesized from FDA-approved phenols were less toxic than nonoxynol-9, and it is concluded that these 4-guanidinobenzoates are of interest for further development and testing as nonhormonal contraceptive agents.

Acrosin↗
PubMed1986

A randomized, double-blind, crossover study of phenobarbital and mephobarbital.

Some pediatric neurologists maintain that mephobarbital (Mebaral) causes fewer behavioral side effects than phenobarbital. Because this hypothesis has not been previously tested, we conducted a prospective, double-blind, randomized, crossover study of these two anticonvulsants. Both drugs were equally effective in reducing the frequency of seizure, although serum phenobarbital levels were significantly higher when the patients were taking phenobarbital compared to mephobarbital. As measured by the Abbott Parent Questionnaire, there was no significant deterioration of behavior with either phenobarbital or mephobarbital, regardless of which drug was administered first.

Child↗
PubMed1985

Vaginal contraceptive activity of aryl 4-guanidinobenzoates (acrosin inhibitors) in rabbits.

Nine aryl 4-guanidinobenzoates were synthesized as inhibitors of the sperm enzyme acrosin. These esters were prepared from 4-guanidinobenzoic acid and a number of phenols which had been approved by the FDA for clinical use. The vaginal contraceptive activity of the inhibitors was evaluated in the rabbit at nonspermicidal concentrations (0.1 mg/ml). All the inhibitors except the 2'-carboxamidophenyl and the 2'-isopropyl-5'-methylphenyl 4-guanidinobenzoates caused significant reductions in fertilization compared to the controls. Several of the aryl 4-guanidinobenzoates appeared to be particularly effective. Nonoxynol-9, under the same conditions but at 10- and 100-fold higher concentrations, also showed an antifertility effect. However, even at these increased dose levels, the contraceptive efficacy of nonoxynol-9 was no higher than that of most of the inhibitors and was less consistent than that of the most active aryl 4-guanidinobenzoates. The relatively high in vivo antifertility activity exhibited by several of the aryl 4-guanidinobenzoates encourages their further evaluation as vaginal contraceptive agents.

Acrosin↗
PubMed1985

Inhibition of human sperm penetration into zona-free hamster oocytes by proteinase inhibitors.

The potential role of serine proteinase in the penetration of human spermatozoa into denuded (zona-free) hamster oocytes was investigated. Aryl 4-guanidinobenzoates (10(-4) to 10(-6) M) and 4-aminobenzamidines (10(-3) and 10(-4) M) decreased oocyte penetration when present throughout the assay system. More detailed studies with 8-quinolyl 4-guanidinobenzoate showed that this inhibitor also caused a large decrease in the penetration rate even when only present during the preincubation period of the spermatozoa to induce capacitation. Much smaller decreases were observed when this inhibitor was only present during sperm/egg incubation. By contrast, 4-aminobenzamidine caused a large decrease in the penetration rate when present during sperm/egg incubation but a much smaller one when present during the sperm's preincubation period. The primary action of the inhibitors was not due to a visible effect on sperm motility or forward progression, or to an effect on the oocyte, although treatment of oocytes with inhibitor caused a small decrease in penetration. Inhibition of sperm binding to the oolemma occurred also at times, but this was not directly correlated to the decrease in oocyte penetration. The results are consistent with the fact that a serine proteinase, presumably acrosin, is important for the capacitation, acrosome reaction, and/or oocyte penetration of human spermatozoa. The synthesized aryl 4-guanidinobenzoates are of interest as contraceptive agents because they possess phenols approved by the Food and Drug Administration (United States) for human use and should be relatively nontoxic.

Animals↗