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Biomedical subjects

R Gust

Publications and source records attributed to R Gust.

At least 37 records · Page 2Linked to original sources
PubMed1999

Role of cyclooxygenase-2 in oleic acid-induced acute lung injury.

Eicosanoid production appears to be important to both edemagenesis and the pattern of pulmonary perfusion in experimental acute lung injury (ALI). We hypothesized that these effects could be mediated by the inducible form of cyclooxygenase (COX-2). We used positron emission tomography to evaluate the pulmonary perfusion pattern in dogs given oleic acid (OA) only (n = 6), the novel COX-2 inhibitor SC-236 50 min before OA (n = 3), and SC-236 given 20 min before endotoxin (Etx), followed by OA given 30 min after Etx (n = 5). Thromboxane B(2) (TXB(2)) and prostacyclin (6-keto prostaglandin F(1alpha); 6-keto PGF(1alpha)) metabolite concentrations in plasma and lung tissue were measured in these groups and in another group given Etx + OA (n = 4). Inhibition of COX-2 before administration of OA alone or before administration of Etx and OA did not have any significant effect on plasma or lung tissue concentrations of TXB(2). However, inhibition of COX-2 prior to Etx and OA significantly reduced the plasma and lung tissue concentrations of 6-keto PGF(1alpha) as compared with those in the group given only Etx + OA. Moreover, SC-236 prevented the expected loss of perfusion redistribution associated with Etx + OA only. The effect of endotoxin on pulmonary perfusion in ALI is therefore the result of a COX-2-mediated increase in prostacyclin production in lung tissue.

6-Ketoprostaglandin F1 alpha↗
PubMed1998

Synthesis and antitumor activity of [1,2-bis(4-fluorophenyl)ethylenediamine][dicarboxylato]platinum(II) complexes.

The synthesis of the diastereomeric [1,2-bis(4-fluorophenyl)-ethylenediamine][dicarboxylato]platinum(I I) complexes, rac- and meso-4F-Pt(X) [X: oxalato (Ox), malonato (Mal), hydroxymalonato (OHMal), phenylmalonato (PhMal), tetrahydro-4H-pyran-4,4-dicarboxylato (Thpdc)], the evaluation of their structure, water solubility, resistance against attack by nucleophiles, and growth inhibiting properties on the human MCF-7 breast cancer cell line are described [parent compounds: rac-4F-Pt(CBDC) and meso-4F-Pt(CBDC); reference complexes: carboplatin, cisplatin, rac- and meso-4F-PtCl2]. The most active 4F-Pt(X) complexes, rac-4F-Pt(Mal), rac-4F-Pt(OHMal) and rac-4F-Pt(Thpdc), equal the parent compound rac-4F-Pt(CBDC) as well as cisplatin and surpass carboplatin in their effect on the MCF-7 breast cancer cell line. Their water solubility, which is of importance for an application in the cancer chemotherapy, is higher than that of rac-4F-Pt(CBDC), especially in the case of rac-4F-Pt(OHMal) and rac-4F-Pt(Thpdc). In comparison to the dichloroplatinum(II) analogue (4F-PtCl2) the stability of the three compounds in the presence of the strong nucleophile iodide is markedly enhanced, which means a reduction of the protein bound drug fraction in the blood and tissue compartments accompanied by an increase of the active, free drug level. The found physiochemical properties of these compounds meet the requirements for the transferability of their promising breast cancer inhibiting effects detected in cell culture experiments to in vivo conditions.

Antineoplastic Agents↗
PubMed1998

Stability and cellular studies of [rac-1,2-bis(4-fluorophenyl)-ethylenediamine][cyclobutane-1,1- dicarboxylato]platinum(II), a novel, highly active carboplatin derivative.

The synthesis of the diastereomeric [1,2-bis(4-fluorophenyl)ethylenediamine][cyclobutane-1, 1-dicarboxylato]platinum(II) complexes, rac- and meso-4F-Pt(CBDC), the evaluation of their structures, their tumor-inhibiting properties and their stability in physiological environment are described (reference complexes: the dichloro- and sulfatoplatinum(II) analogues, carboplatin and cisplatin). The most interesting diastereomer, rac-4F-Pt(CBDC), equals cisplatin and surpasses carboplatin in its effect on human breast cancer cell lines (MCF-7 and MDA-MB-231). Rac-4F-Pt(CBDC) is largely insensitive against attack of nucleophiles e.g. Cl-, a prerequisite for sufficient stability in vivo and for fewer side effects. In accordance with this, in vitro studies on the binding of rac-4F-Pt(CBDC) to albumin, the main plasma protein, show that the free, non-protein-bound fraction is relatively high, coming close to that of carboplatin. These properties are of importance for the transferability of the promising effects found in the cell culture experiments to in vivo conditions. The distinctly better anti-breast cancer activity of rac-4F-Pt(CBDC) than of carboplatin has been attributed to its ability to accumulate in the tumor cells. The human ovarian cancer cell line NIH-OVCAR-3 is also strongly inhibited by rac-4F-Pt(CBDC).

Breast Neoplasms↗
PubMed1998

Cardiac output measurement by transpulmonary versus conventional thermodilution technique in intensive care patients after coronary artery bypass grafting.

OBJECTIVE: The aim of the present study was to evaluate the correlation, accuracy, and precision of transpulmonary thermodilution cardiac output (CO) measurement. For this purpose, this technique was compared with the clinical gold standard, the CO measurement by pulmonary artery catheter in patients after coronary artery bypass grafting (CABG). DESIGN: A prospective clinical study. SETTING: A university medical center. PARTICIPANTS: Seventy-five patients in an intensive care unit (ICU) after CABG. INTERVENTIONS: Standard (SCO) and transpulmonary thermodilution CO measurement (TPCO) measurements were simultaneously performed in triplicate by central venous injection of cooled saline solution. All variables were recorded at five different time points of measurement during weaning from mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: CO measurements yielded 375 data pairs. SCO ranged from 2.0 to 10.2 L/min, and TPCO from 1.3 to 10.6 L/min. During the entire observation period, TPCO measurements tended to yield relatively high values, whereas SCO measurements resulted in lower values. Correlation between TPCO and SCO measurements was significant (r = 0.73; p < 0.05), accompanied by an accuracy with a bias of 0.456 L/min (7.3%) and a precision of 1.156 L/min (18.5%). CONCLUSION: In most patients, TPCO measurement will not replace the conventional technique by pulmonary artery catheter, but in some patients it offers an attractive, reliable, and safe method to determine CO.

Aged↗
PubMed1998

Bedside troponin T testing is not useful for early out-of-hospital diagnosis of myocardial infarction.

BACKGROUND: A new commercially available rapid qualitative bedside immunoassay for cardiac troponin T has been developed. The aim of the study was to investigate whether this new rapid bedside cardiac troponin T assay facilitates diagnosing myocardial infarction in a pre-hospital setting. METHODS: We evaluated the sensitivity and specificity of the new rapid bedside troponin T assay for myocardial infarction. In 68 patients with acute, central, crushing chest pain, who were strongly suspected of having myocardial infarction, the emergency doctor performed preclinically a bedside cardiac troponin T test. The results were compared with the diagnosis after admission to hospital, using the criteria of the World Health Organization. RESULTS: The diagnosis of myocardial infarction was confirmed in 16/68 (24%) patients after admission to hospital, but only in 4/16 (25%) patients with myocardial infarction was a positive result observed preclinically with this test. The result was false positive in 1/5 patients (20%). CONCLUSIONS: In contrast to an excellent specificity (0.98), sensitivity (0.25) of the rapid troponin T assay was poor. Thus, we conclude that this test cannot improve the distinction between myocardial infarction and angina pectoris in a pre-hospital setting.

Aged↗
PubMed1998

Synergistic hemodynamic effects of low-dose endotoxin and acute lung injury.

We evaluated the effects of low-dose endotoxin (15 microg/kg) on the pulmonary and systemic responses to oleic acid (OA)-induced acute lung injury in dogs. Animals given endotoxin alone (n = 5) showed a modest decrease in arterial blood pressure, but no effects on pulmonary hemodynamics, blood gases, cardiac output, or lung water accumulation. Animals (n = 6) given only OA (0.08 ml/kg) showed the expected development of mild-moderate pulmonary hypertension, a comparable reduction in arterial blood pressure, hypoxemia, increased lung water concentration, and an altered intrapulmonary perfusion pattern, as assessed by positron emission tomography. Animals (n = 7) given the same dose of endotoxin, followed 30 min later by the same dose of OA, developed a similar increase in lung water concentration as the group given OA alone, but failed to develop pulmonary hypertension or to redistribute pulmonary blood flow away from the edematous lung regions. In addition, arterial blood pressure fell significantly more than in the other groups. These responses were associated with a 30-fold increase in circulating prostacyclin (assayed as 6-keto prostaglandin F1 alpha [PGF1alpha]). The effects on systemic blood pressure, intrapulmonary blood flow redistribution, and eicosanoid production were eliminated by pretreating (n = 5) animals with meclofenamate (2 mg/kg). The results are consistent with a "priming" effect of low-dose endotoxin on the pulmonary endothelium, with exaggerated prostacyclin production in response to a subsequent lung injury. This interaction leads to altered intrapulmonary hemodynamics that exacerbate the development of hypoxemia, and to significant decreases in systemic blood pressure. To the extent that the lung is the most likely source of the increased prostacyclin production, the synergistic effects of low-dose endotoxin and lung injury may produce a kind of "lung shock."

6-Ketoprostaglandin F1 alpha↗
PubMed1997

Gastric intramucosal pH: a predictor of survival in cardiac surgery patients with low cardiac output?

OBJECTIVE: To assess the value of gastric intramucosal pH measurement in patients with low output after cardiac surgery. DESIGN: Prospective clinical study. SETTING: University hospital. PARTICIPANTS: Fifteen patients with low output after cardiac surgery were included. Those who survived the first postoperative day (n = 14) remained in the study. INTERVENTIONS: Gastric intramucosal pH and arterial lactate concentrations were measured 6, 12, and 24 hours after admission to the intensive care unit. Intravenous infusion of buffer solutions was strictly avoided during the equilibration period and in the half hour before injection of saline into the gastric balloon of the tonometer. MEASUREMENTS AND MAIN RESULTS: Eight patients survived during the 28-day observation period, and six patients died. On admission to the intensive care unit, no difference in cardiac index (1.56 v 1.54 L/min/m2) or pulmonary capillary wedge pressure (17.3 v 17.7 mmHg) was found between survivors and nonsurvivors. During the first 24 hours after surgery, arterial lactate was significantly higher in the nonsurvivor group (61 v 23 mg/dL), but there was no difference between the gastric intramucosal pH of survivors and nonsurvivors (7.41 v 7.42 on admission). CONCLUSIONS: Calculated gastric mucosal pH is not an early predictor of survival in cardiac surgery patients with postoperative low cardiac output syndrome. Further studies are required to assess whether the gradient between arterial and intramucosal partial pressure of carbon dioxide (PCO2) might be a more useful predictive value.

Adult↗
PubMed1996

Effects of continuous (CPAP) and bi-level positive airway pressure (BiPAP) on extravascular lung water after extubation of the trachea in patients following coronary artery bypass grafting.

OBJECTIVE: To evaluate the effects of continuous positive airway pressure (CPAP) and bi-level positive airway pressure (Bi-PAP) on extravascular lung water during weaning from mechanical ventilation in patients following coronary artery bypass grafting. DESIGN: Prospective, randomized clinical study. SETTING: Intensive care unit at a university hospital. PATIENTS: Seventy-five patients following coronary artery bypass grafting. INTERVENTIONS: After extubation of the trachea, patients were treated for 30 min with CPAP via face mask (n = 25), with nasal BiPAP (n = 25), or with oxygen administration via nasal cannula combined with routine chest physiotherapy (RCP) for 10 min (n = 25). MEASUREMENTS AND RESULTS: Extravascular lung water (EVLW), pulmonary blood volume index (PBVI) and cardiac index (CI) were obtained during mechanical ventilation (T1), T-piece breathing (T2), interventions (T3), spontaneous breathing 60 min (T4) and 90 min (T5) after extubation of the trachea using a combined dye-thermal dilution method. Changing from mechanical ventilation to T-piece breathing did not show any significant differences in EVLW between the three groups, but a significant increase in PBVI from 155 +/- 5 ml/m2 to 170 +/- 4 ml/m2 could be observed in all groups (p < 0.05). After extubation of the trachea and treatment with BiPAP. PBVI decreased significantly to 134 +/- 6 ml/m2 (p < 0.05). After treatment with CPAP or BiPAP, EVLW did not change significantly in these groups (5.5 +/- 0.3 ml/kg vs 5.0 +/- 0.4 ml/kg and 5.1 +/- 0.4 ml/kg vs 5.7 +/- 0.4 ml/kg). In the RCP-treated group, however, EVLW increased significantly from 5.8 +/- 0.3 ml/kg to 7.1 +/- 0.4 ml/kg (p < 0.05). Sixty and 90 min after extubation, EVLW stayed at a significantly higher level in the RCP-treated group (7.5 +/- 0.5 ml/kg and 7.4 +/- 0.5 ml/kg) than in the CPAP-(5.6 +/- 0.3 ml/kg and 5.9 +/- 0.4 ml/kg) or BiPAP-treated groups (5.2 +/- 0.4 ml/kg and 5.2 +/- 0.4 ml/kg). No significant differences in CI could be observed within the three groups during the time period from mechanical ventilation to 90 min after extubation of the trachea. CONCLUSIONS: Mask CPAP and nasal BiPAP after extubation of the trachea prevent the increase in extravascular lung water during weaning from mechanical ventilation. This effect is seen for at least 1 h after the discontinuation of CPAP or BiPAP treatment. Further studies have to evaluate the clinical relevance of this phenomenon.

Aged↗
PubMed1995

Investigation of the configurational and conformational influences on the hormonal activity of 1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamines and of their platinum(II) complexes. 1. Synthesis, estradiol receptor affinity, and estrogenic activity of diastereomeric [N-alkyl- and N,N'-dialkyl-1,2- bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]dichloroplatinum(II) complexes.

N-Monoalkylated (Et) and N,N'-dialkylated (Me and Et) 1,2-bis(2,6-dichloro-4-hydroxyphenyl)-ethylenediamines and their dichloroplatinum(II) complexes were synthesized, and their configuration and conformational behavior were 1H-NMR spectroscopically clarified. The latter was brought in relation to their relative binding affinity (RBA) to the estrogen receptor as well as to their estrogenic potency. In contrast to the RR/SS-configurated diamines, the R/S-configurated ones showed marked estrogenic properties which correlate with the RBA's. In the related R/S-configurated complexes the estrogenic activity is determined by the same structural requirements as in the diamine series. However, a correlation between RBA's and estrogenic potencies is missing. The connection between spatial structure and activity is discussed by use of a drug-receptor model recently proposed by Höltje and Dall.

Animals↗
PubMed1995

Reduction of the estrogenic side effects of the mammary tumor-inhibiting drug [1,2-bis(2,6-dichloro-4-hydroxyphenyl)- ethylenediamine]dichloroplatinum(II) by variation of ring substituents.

[1,2-Bis(4-methoxy/4-hydroxyphenyl)ethylenediamine]dichloroplatinum-(II) complexes with Cl-, CH3-, or OCH3-substituents in the ortho-positions of the aromatic rings (meso-1-PtCl2, D,L-1-PtCl2, meso-2-PtCl2, D,L-2-PtCl2, meso-3-PtCl2, meso-4-PtCl2, meso-5-PtCl2) were tested on the MDA-MB 231 breast cancer cell line, the lymphocytic leukemia P388, and the estrogen receptor-positive and -negative MXT mammary carcinoma of the mouse (MXT,ER(+)-MC, MXT,ER(-)-MC). The comparison of the effects of methoxy-substituted complexes (meso-1-PtCl2, D,L-1-PtCl2, meso-3-PtCl2) with those of the respective hydroxy-substituted ones (meso-2-PtCl2, D,L-2-PtCl2, meso-4-PtCl2) shows that a reduction of estrogenic effects as well as a total loss of the mammary tumor-inhibiting activity takes place on methylation of the 4-OH group. The exchange of the 2,6-standing chlorine atoms by methyl groups in meso-2-PtCl2 led to the non-estrogenic, but on the MXT,ER(+)-MC highly effective derivative meso-4-PtCl2 which proved to be also cytotoxic on ER(-)-tumors such as MXT,ER(-)-MC, and the P388 leukemia.

Animals↗
PubMed1995

Development of a parenterally administrable hydrosol preparation of the "third generation platinum complex" [(+/-)-1,2-bis(4-fluorophenyl)ethylenediamine]dichloroplatinum(II). Part 1. Preparation and studies on the stability and antitumor activity.

The development of a galenical formulation for poorly water soluble dichloroplatinum(II) complexes suitable for the parenteral administration in cancer chemotherapy is described. The procedure, which we elaborated for [(+/-)-1,2-bis(4-fluorophenyl)ethylenediamine]dichloroplatinum(II) (rac-4F-PtCl2), is based on the reaction of a soluble diaquaplatinum(II) salt with sodium chloride in water in the presence of pluronic F 68 as stabilizer and results in a sufficiently stable colloidal solution (i.e. hydrosol). In contrast to the poorly water soluble synthetic rac-4F-PtCl2, which was ineffective towards the hormone sensitive MXT-M-3.2 breast cancer of the mouse, its hydrosol formulation proved to be highly active and was very well tolerated.

Animals↗
PubMed1994

Aqua[1,1-bis(4-hydroxyphenyl)-1,2-diamino-2-phenylethane]- sulfatoplatinum(II), a new compound for the treatment of the mammary carcinoma.

The highly estrogen receptor(ER)-affinic compound 1,1-bis(4-hydroxyphenyl)-2-phenylethane (BHPE) was used as carrier ligand for a new cisplatin derivative, aqua[1,1-bis(4-hydroxyphenyl)-1,2-diamino-2-phenylethane]sulfatoplati num (II) (3-PtSO4) for the therapy of the ER-positive (i.e. hormone sensitive) breast cancer. The diamine ligand 1,1-bis(4-hydroxyphenyl)-1,2-diamino-2-phenylethane (3) was synthesized by transformation of the O-methyl ether derivative of BHPE into the 1,2-bisazido compound 3b with IN3/NaN3, reduction of both N3 residues into NH2 groups [3a] and subsequent ether cleavage with BBr3. From the diamine ligand 3 and K2PtI4 a five-membered chelate 3-PtI2 was obtained which was transformed into 3-PtSO4 with Ag2SO4. In comparison to BHPE the ER-affinity of 3-PtSO4 is markedly reduced. 3-PtSO4 possesses, however, weak cytotoxic activity (P388) and antiestrogenic, but no estrogenic properties. 3-PtSO4 is comparable with BHPE in terms of its activity on the hormone sensitive MXT-M 3.2 breast cancer of the mouse.

Animals↗
PubMed1994

Investigation of the conformational influences on the estrogenic activity of 1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamines and of their platinum(II) complexes, II: Synthesis and studies on the estrogenic activity of cis- and trans[bis(2,6-dichloro-4-hydroxybenzylamine)]dihaloplatinum(II)-c omplexes.

2,6-Dichloro-4-hydroxybenzylamine (1) and its N-methyl (2) and N-ethyl (3) derivatives were synthesized and tested for estrogen receptor affinity as well as for estrogenic activity. In contrast to their related highly active 1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamines (meso-4 - meso-6) none of the benzylamines showed hormonal activity. The coordination of the benzylamine 1 to platinum did not lead to an estrogenic compound. The reasons for the different activity of [meso- 1,2(bis-2,6-dichloro-4-hydroxyphenyl)ethylenediamine]dichloroplatinum(II ) (meso-4-PtCl2) and cis[bis(2,6-dichloro-4-hydroxybenzylamine)]dichloroplatinum(II) (cis-1-PtCl2), the latter of which can be considered as a ring-opened counterpart of the highly active meso-4-PtCl2, are thoroughly discussed under inclusion of conformational facts. The results of this and the preceding work show, that the pharmacophore meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine (meso-4) which is exclusively responsible for the estrogenic activity of meso-4-PtCl2 causes comparable hormonal effects in two different conformations with O-O distances of about 8 A (complex) and of about 12 A (diamine). Therefore, we discuss two binding sites for estrogens in their receptor.

Animals↗
PubMed1994

[Anesthesia in carotid surgery].

Carotid endarterectomy has become a standard surgical procedure in the therapy of cerebrovascular insufficiency. An important consideration in this form of therapy is to maintain a low perioperative morbidity and mortality. In planning the procedure the two most frequent complications deserve special consideration. Thromboembolism is the major cause of new neurological deficits and prevention should be emphasized as therapeutic interventions are of limited value. The cardiovascular status needs special attention, since the long-term prognosis is predominantly influenced by concomitant coronary artery disease. Regional anaesthesia provides good cardiovascular stability and the chance to monitor neurological changes in an awake patient. Patient discomfort and limited control of vital functions are obviated by general anaesthesia raising the challenge of maintaining cardiovascular stability and establishing adequate cerebral monitoring. Both electroencephalography and somatosensory evoked potentials monitor cerebral function continuously and enable detection of cerebral ischaemia secondary to inadequate blood flow. Another continuous technique is transcranial Doppler sonography; this, however, does not monitor brain function and its role in carotid surgery is still under investigation. Carotid stump pressure or cerebral blood flow measurements provide intermittent data and should therefore only be used as an adjunct. The goal to find an approach that minimizes the risk for the individual patient can only be attained by close cooperation between anaesthesiologists and surgeons.

Anesthesia, General↗
PubMed1993

Mammary tumor inhibiting [1,2-bis(2,6-dihalo-3-hydroxyphenyl)ethylenediamine]platinum(II) complexes, III: Relationship between structure and estrogenic activity of the diamine ligands, their sulfatoplatinum(II) and diiodoplatinum(II) complexes.

1,2-Bis(2,6-dihalo-3-hydroxyphenyl)ethylenediamines with 2,6-Cl2, 2-F-6-Cl, 2-Cl,6-F, and 2,6-F2 substituents (meso-1 to meso-4, D,L-1 and D,L-4) and their sulfatoplatinum(II) complexes were tested in the immature mouse uterine weight test. The only complex with marked estrogenic properties proved to be meso-1-PtSO4. Surprisingly its diamine ligand meso-1 was only marginally active. 1H-NMR spectroscopic studies on the 1,2-diphenylethylenediamine ligand reveal that the 2,6-standing Cl-atoms in meso-1 (antiperiplanar phenyl residues) hinder the rotation of the aromatic rings, which results in very stable conformers with different O-O distances owing to the unsymmetric arrangement of the ring substituents. On transformation into the Pt(II) complex the conformations of meso-1 change (synclinal phenyl residues) and a delta and lambda interconversion takes place already at physiological temp. (37 degrees C). This process is accompanied by a rotation of phenyl rings, which is supposed to allow an optimal fit for the formation of hydrogen bridges to the estrogen receptor, resulting in a marked estrogenic activity. The other ligands and complexes are inactive presumably due to a diminished hydrophobic interaction with the estrogen receptor, resulting from their R,R/S,S-configuration or the reduced number of Cl-atoms.

Animals↗