Biomedical subjects

J Beitz

Publications and source records attributed to J Beitz.

At least 37 records · Page 2Linked to original sources

PubMed1993

Lipoproteins from normolipidemic and dyslipidemic subjects modify the thromboxane A2 generation by platelets in clotting human blood.

The study was performed to investigate the influence of lipoproteins (LP) on the thromboxane (TX) A2 formation capacity of platelets in clotting whole blood in vitro. The different lipoprotein fractions VLDL, LDL, HDL2 and HDL3 were isolated from blood of normo- or dyslipidemic volunteers by ultracentrifugation. These lipoproteins were incubated in blood with different levels of serum total cholesterol (TC) taken from normolipidemics (TC < 200 mg/dl), moderate hypercholesterolemics (TC: 200-250 mg/dl) or subjects with high cholesterol level (TC > 250 mg/dl), respectively. The amount of serum TXA2 formed within 60 min at 37 degrees C was measured by enzyme immunoassay. The results obtained show that the efficacy of separate LP fractions to influence the TXA2 production depends not only on the type of LP fraction but also on the source of plasma used for isolation of LP and on the cholesterol level in the blood for incubation: LDL taken from normolipidemics or moderate hyperlipidemics inhibited the TXA2 formation in blood from normolipidemics (P < 0.02, respectively), but enhanced it in blood from persons with moderate hypercholesterolemia (P < 0.05). LDL from hyperlipidemics enhanced TXA2 production in blood from hyperlipidemics (P < 0.05). The HDL2 fractions inhibited the TXA2 formation in blood from normo- and hypercholesterolemics (P < 0.02, resp.), but there was no effect of HDL2 in clotting blood from persons with moderate hypercholesterolemia. All HDL3 fractions tested inhibited the TXA2 formation in all types of blood used for clotting (P < 0.02, resp.), probably due to their great cholesterol accepting capacity.

Blood Coagulation↗

PubMed1993

Combined modality therapy for stage IIIA non-small cell carcinoma of the lung.

53 patients with stage IIIA non-small cell carcinoma of the lung (NSCCL) were treated with multimodality therapy consisting of induction radiotherapy (55.8 Gy) and two cycles of concurrent chemotherapy with cisplatin, 25 mg/m2 for 4 days by continuous infusion and bolus etoposide, 100 mg/m2 on days 2 and 4 of each cycle followed by surgery and adjuvant chemotherapy. Of 53 evaluable patients, 47 achieved clinical responses (9 complete response, 38 partial response) after induction therapy for a response rate of 89%. 47 patients were resectable after induction therapy, but 8 patients refused surgery and 6 patients were not eligible for surgery based on poor pulmonary function (medical contraindications). 33 patients underwent thoracotomy and in 6 patients, resection was technically unfeasible. Thus complete surgical resection was accomplished in 27 patients. After all therapy, 28 patients achieved a complete response (53%) and 19 patients a partial response (36%). Toxicities were mild. At a maximum of 75 months (median, 28 months) of follow-up, the median survival of the entire group is 24 months. The median survival of resected patients has not been reached; their 6-year survival rate is 55%. Unresected patients survived for a median of 11 months. This multimodality regimen is well-tolerated, induces a high response and resectability rate and prolongs survival in resected patients.

Adult↗

PubMed1993

Effect of trapidil derivative AR 12456 on intracellular cholesterol homeostasis in human hepatoma cell line Hep G2.

The effect of trapidil derivative AR12456 on intracellular cholesterol metabolism was investigated in human hepatoma cell line HepG2. AR12456 enhanced the uptake and degradation of 125I-LDL in a dose-dependent manner. The drug inhibited cholesterol synthesis and esterification without affecting cellular cholesterol content and bile acid synthesis; cholesterol efflux was slightly increased. These results show that the inhibition of cholesterol synthesis together with the enhanced expression of LDL receptors may partially explain the hypocholesterolemic activity of compound AR12456.

Anticholesteremic Agents↗

PubMed1992

Influence of a cholesterol rich diet in rabbits on the formation of PGI2 and TXA2.

In the study was investigated whether the formation of prostanoids is changed in the different regions of aorta or in clotting whole blood in dependence on development of atherosclerosis. For this question New Zealand rabbits were fed for different periods with a cholesterol rich diet (0.5%). At the end of the different dietary periods the animals were killed and the following parameters estimated: blood: levels of total cholesterol, HDLcholesterol, VLDLcholesterol, cholesterol in the beta-migrating lipoprotein fraction, serum lipid peroxides, TXB2 formation capacity of clotting whole blood; aorta: surface of intima covered with fatty streaks, free and esterified cholesterol, triglycerides, collagen, formation of 6-keto-PGF1a and TXB2 by abdominal and thoracic aortas. The lipid parameter demonstrated a relatively strong correlation with the duration of cholesterol rich diet or the macroscopically detectable atherosclerosis, but the prostanoid formation remained unchanged.

Animals↗

PubMed1992

Does a HDL injection reduce the development of serum hyperlipidemia and progression of fatty streaks in cholesterol fed rabbits?

The influences of homologous (rabbit) or heterologous (human) high density lipoprotein (HDL) on the development of serum hyperlipidemia and progression of fatty streaks were studied in cholesterol fed rabbits. Three groups of New Zealand rabbits were fed a 0.5% cholesterol rich diet for 8 weeks. Additionally into these animals the following solutions were injected intravenously two times per week: group 1 (control): saline; group 2: human HDL dissolved in saline; group 3: rabbit HDL dissolved in saline. The animals of group 2 had lower serum cholesterol levels during the dietary period than rabbits of group 1 (p < 0.05) but the surface of intima covered with fatty streaks was the same as in group 1. On the other hand, the serum cholesterol level in rabbits of group 3 was the same as in group 1 during the whole experimental period, but the surface of aorta covered with fatty streaks was significantly lower (p < 0.05) in group 3 than in group 1. The results of this study support the hypothesis of an antiatherogenic action of HDL, which seems to be independent of the influence of HDL on the serum lipids but depends on the source of HDL.

Animals↗

PubMed1992

Influence of HDL on the formation of 6-keto-PGF1 alpha and TXB2 in vitro: the importance of the source of HDL.

The influence of HDL, isolated from normolipidemic human blood and blood of normo- and hyperlipidemic rabbits, on in vitro 6-keto-PGF1 alpha synthesis by rabbit aorta and on TXB2 synthesis by platelets of clotting human and rabbit blood was tested. The HDL fraction from normolipidemic subjects, when incubated with blood from normolipidemic humans or rabbits, inhibited TXB2 formation. The same fraction stimulated the formation of 6-keto-PGF1 alpha after incubation with rabbit aorta taken from normolipidemic animals. HDL taken from hyperlipidemic rabbits inhibited 6-keto-PGF1 alpha formation in rabbits and had no influence on TXB2 formation. These results support the hypothesis that not only is the absolute amount of HDL important for its influence on prostanoid formation, but also the origin and the composition of the HDL fraction.

6-Ketoprostaglandin F1 alpha↗

PubMed1991

Influence of trapidil and derivatives on cholesterol synthesis and esterification in cultured cells.

The effect of trapidil (Rocornal) and its derivatives AR 12456 and AR 12463 on endogenous cholesterol synthesis and on cholesterol esterification rate was studied in human skin fibroblasts (HSF), in human hepatoma cell line Hep G2 and in primary culture of peritoneal macrophages from mouse (PMM). The cholesterol esterification rate was not influenced by the drugs in the tested cell lines. The incorporation of [14C]acetate into cholesterol in HSF was inhibited by AR 12463 and AR 12456, but not by trapidil. The inhibitory potency of AR 12456 in HSF was enhanced after preincubation of the drug with Hep G2 and removal of the medium to HSF, suggesting that the formed metabolite(s) are more potent inhibitors than the parent substance. The metabolite(s) formed seem(s) to influence the first steps in the endogenous formation of cholesterol, because the incorporation of [14C]mevalonate into cholesterol was not significantly inhibited. These findings suggest that the demonstrated inhibition of the endogenous cholesterol synthesis by AR 12456, especially after transformation into a probably more active substance(s), together with the recently described enhanced expression of LDL receptors in Hep G2 cells may partially explain the hypocholesterolaemic activity of AR 12456.

Acetates↗

PubMed1991

Influence of the trapidil derivative AR 12463 on serum and tissue lipids and development of aortic lesions during experimental atherosclerosis in rabbits.

Daily administration of the trapidil derivative AR 12463 (20 mg/kg body weight i.p.) to cholesterol-fed rabbits diminished statistically significantly the increase in serum total cholesterol. After 8 weeks of treatment all measured lipoprotein fractions were significantly lower in animals treated with AR 12463 (group 3) compared with the values of the untreated control (group 1) or vehicle-treated group (group 2). The reduction of serum levels was associated with statistically significantly reduced levels of cholesterol esters in kidney, liver and aorta. The levels of free cholesterol in the liver of group 3 animals were statistically significantly lower compared with the levels in the two other groups, whereas in kidney and aortas the levels of free cholesterol remained unchanged under the influence of AR 12463. The area of aorta covered with fatty streaks was significantly smaller in group 3 versus group 1. The results of this study indicate that treatment of rabbits with AR 12463 while feeding a cholesterol-rich diet prevents hypercholesterolemia as well as the cholesterol incorporation into tissues. The mode of action of AR 12463 on serum and tissue lipids as well as on the development of atherosclerosis is discussed.

Animals↗

PubMed1990

Oral zidovudine, continuous-infusion fluorouracil, and oral leucovorin calcium: a phase I study.

A phase I clinical, pharmacologic, and biochemical evaluation of escalating oral zidovudine (AZT) given over 2 days with a fixed dose of continuous-infusion fluorouracil (800 mg/m2 per day X 3 days) and oral leucovorin calcium was performed. Eighteen patients were treated with doses of AZT ranging from 1.0 to 9.0 g/m2 per day. Nausea and vomiting were dose limiting, with a maximally tolerated dose of 7.5 g/m2 per day. Rash and mucositis occurred but were not dose limiting. A dose-related increase in peak plasma levels of AZT was observed, and the alpha half-life of AZT in plasma (75 min) was unaffected by these high doses. At doses above 4.0 g/m2 per day, trough levels significantly increased, perhaps reflecting prolonged absorption from the gut. No responses were observed; however, a significant increase in DNA single-strand breaks was observed in peripheral blood cells after a threshold dose of 4.0 g/m2 per day, confirming a biological effect of AZT in this regimen. Further trials with an intravenous formulation capable of maintaining plasma levels and circumventing dose-limiting toxicity are warranted.

Administration, Oral↗

PubMed1990

Influence of high density lipoprotein (HDL), prepared from human blood, on prostanoid formation, serum and tissue lipids and development of arteriosclerosis in cholesterol rich fed rabbits.

The i.v. administration of high density lipoprotein (HDL) into cholesterol fed rabbits decreased statistically significantly the serum level of total cholesterol and of low density lipoprotein cholesterol after a feeding period of 8 weeks. These diminished levels of cholesterol were associated with a statistically significant reduction in the levels of cholesterol esters in kidneys and platelets but not in hepatic tissue or in aorta. Macroscopically detectable arteriosclerosis was not statistically significantly diminished. The formation of prostanoids by the aorta remained unchanged. The atherogenic role of immunologic factors acting against the heterologous HDL may have compensated for the antiatherogenic HDL action on plasma and tissue lipids.

Animals↗

PubMed1990

Modulation of TXA2 generation of platelets by human lipoproteins.

The lipoprotein (LP) fractions VLDL, LDL, HDL2 and HDL3 were prepared by ultracentrifugation of plasma from healthy volunteers and from patients with coronary heart disease (CHD). We investigated the capacity of platelets from healthy volunteers and patients with atherosclerosis to generate thromboxane A2 (TXA2) during spontaneous clotting of whole blood under the influence of the lipoprotein fractions. In our experiments the serum concentration of TXB2, reflecting the capacity of platelets to generate TXA2 during clotting, depends on several factors: the type of LP fraction used, the blood used for generation of TXA2, and for the same LP fraction whether it was taken from plasma of healthy volunteers or patients with CHD. VLDL prepared from plasma of healthy volunteers inhibited but VLDL prepared from plasma of patients with CHD enhanced the TXA2 formation of platelets from healthy volunteers (p less than 0.05, resp.). LDL from CHD patients inhibited the TXA2 formation of platelets from atherosclerotic patients (p less than 0.01). The HDL subfractions HDL2 and HDL3 from healthy volunteers inhibited TXA2 formation by platelets from healthy volunteers as well as those from atherosclerotic patients (p less than 0.05; p less than 0.01, respectively). HDL2 from patients with CHD inhibited only the TXA2 formation of platelets from healthy volunteers (p less than 0.01), whereas HDL3 from CHD patients inhibited only the TXA2 formation of platelets from atherosclerotic patients (p less than 0.01).

Adult↗

PubMed1990

[Changes in the spongiosa density in the femoral head of rabbits in atherosclerosis].

Modulations of spongiosa density in the femoral head of rabbits by atherosclerosis. In a long-term study 31 rabbits (+5 control animals) were fed about 20 weeks on a diet rich in cholesterol. An important observation in this study was, that spongiosa density in the femoral head decreases after cholesterol rich diet in contrast to the control group. This effect could be modulated by the Trapidil AR 12463 content (50 mg/die) of the diet, but not by the high density lipoprotein application. Serum cholesterol levels and induced atherosclerosis were determined. Correlations between spongiosa density and atherosclerosis were discussed.

Animals↗

PubMed1989

Influence of a plasma fraction of human blood, rich in high density lipoprotein, on in vitro formation of prostaglandin I2 (PGI2) and thromboxane A2 (TXA2).

The influence of a plasma fraction of human blood, rich in high density lipoprotein (HDL), was investigated on the "in vitro" formation of PGI2 and TXA2. The addition of 1 mg HDL-cholesterol per ml incubation fluid stimulated significantly the biotransformation of prostaglandin H2 into PGI2 by the microsomal fraction of pig aorta. The TXB2 formation capacity of whole clotted blood was inhibited by administration of HDL in a dose dependent manner. These results suggest that added HDL is able to enhance the ratio PGI2:TXA2. This did not depend on the preparation of HDL either by ultracentrifugation or by precipitation.

Animals↗

PubMed1989

Influence of iloprost on eicosanoid generation and lipid levels in experimental myocardial ischemia in dogs.

Anaesthetized mongrel dogs were subjected to occlusion of a coronary artery. The resulting myocardial infarction was observed for three hours. One hour after occlusion, infusion of the stable prostacyclin analogue iloprost or saline was started. In the control group myocardial infarction was associated with an increase of the ratio TXB2/6-keto-PGF1a which was abolished by iloprost treatment. After occlusion in the control group, the atherosclerosis index (TC-HDLC): HDLC was increased, but in the iloprost-treated group it was significantly decreased. The results of this study suggest that the administration of iloprost is able to prevent changes in eicosanoid metabolism and lipoprotein pattern after coronary artery occlusion in dogs.

6-Ketoprostaglandin F1 alpha↗

PubMed1989

A phase I/II trial of 5-fluorouracil and etoposide in metastatic colorectal carcinoma.

Twenty-two patients with metastatic colorectal carcinoma were treated in a Phase I-II study of combination therapy with 5-fluorouracil (5-FU) and etoposide (VP-16). Treatment consisted of weekly intravenous VP-16, 100-120 mg/M2, followed by 5-FU, 400-480 mg/M2, in 28-day cycles. Myelosuppression was the dose-limiting toxicity with a mean nadir leukocyte count of 3,600/mm3 and a mean nadir thrombocyte count of 101,000/mm3. There were no episodes of sepsis or bleeding. The tolerable dose for this regimen is VP-16, 110 mg/M2, and 5-FU, 440 mg/M2, weekly. A total of 63 cycles of chemotherapy were given. Although 10 patients had stabilization of disease, no partial or complete responses were documented. We conclude that there is no clinical support for the in vitro synergy observed with this combination. Further trials of this combination using this schedule in colorectal carcinoma are not indicated.

Adenocarcinoma↗

PubMed1988

Influence of drugs on the TXA2/PGI2 balance and on the atherogenic index in myocardial ischemia in dogs.

The effect of drugs on eicosanoid production and on the development of atherogenic index was investigated in canine myocardial ischemia. Iloprost, verapamil, the trapidil derivative AR 12463 or 0.9% NaCl solution were administered 60 min after coronary artery ligation in anaesthetized dogs. Both iloprost and AR 12463 reduced the thromboxane A2/prostacyclin (TXA2/PGI2) ratio in coronary sinus plasma in comparison to controls. The atherogenic index was significantly decreased in the iloprost as well as in the AR 12463-treated group in comparison to the control group. Verapamil had no influence on the investigated parameters.

Animals↗

PubMed1988

Effect of derivatives of trapidil on the expression of LDL receptors.

The influence of trapidil and some of its derivatives (AR 12456, AR 12463, AR 12465) on the LDL receptor mediated uptake and degradation of 125 I-LDL by human skin fibroblasts (HSF) and human hepatic cells (HEP G2) was investigated. AR 12456 enhanced the uptake and degradation of 125 I-LDL in HEP G2, but inhibited this pathway in HSF. When this drug was preincubated with HEP G2 cells, and then the incubation medium was transferred to HSF, a stimulation of specific LDL pathway occurred also in this cell line. Trapidil, AR 12463 and AR 12465 were inactive under the same experimental conditions. These findings suggest that a metabolite of AR 12456 might be responsible for the enhanced expression of LDL receptors in human cells.

Antihypertensive Agents↗

PubMed1988

Is the level of steroid hormones in the low density lipoprotein (LDL) particles responsible for the prostaglandin I2 inhibitory potency of LDL?

In LDL fractions, isolated by ultracentrifugation, sexual hormones are detectable. LDL from male volunteers contained a significantly higher level of testosterone than LDL from female volunteers. This difference, however, is not responsible for the enhanced ability of LDL from men versus LDL from women to inhibit PGI2 formation. The importance of LDL testosterone is contradicted by the following results: Firstly, the PGI2 inhibitory potency of LDL is independent of the age of volunteers and the recentrifugation of isolated LDL fractions, but the level of testosterone is diminished with increasing age of volunteers and after recentrifugation. Secondly, LDL from hyperlipidemic men type II a did not inhibit PGI2 formation, but the level of testosterone in the LDL of these volunteers is significantly higher than in LDL from healthy men.

Adult↗