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Biomedical subjects

R Gust

Publications and source records attributed to R Gust.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1993

Aqua[1-(2,6-dichloro-4-hydroxyphenyl)-2- phenylethylenediamine]sulfatoplatinum(II) complexes with variable substituents in the 2-phenyl ring, II: Correlation of molecular structure and estrogenic activity of breast and prostate cancer inhibiting. [erythro-1-(2,6-dichloro-4-hydroxyphenyl)-2-(2-halo-4- hydroxyphenyl)ethylenediamine]platinum(II) complexes.

Complete three-dimensional X-ray crystal structure analyses of estrogenic [erythro-1-(2,6-dichloro-4-hydroxyphenyl)-2-(2-halo-4- hydroxyphenyl)ethylenediamine]diiodoplatinum(II) complexes (halo = fluoro:erythro-8PtI2 and halo = chloro:erythro-9-PtI2) which were synthesized for application in breast and prostate cancer, have been carried out. 6239 as well as 6521 reflexes were measured and refined to an R-value of 0.105 and 0.066, respectively. The molecules of erythro-8-PtI2 are displaced laterally from a possible Pt-Pt-axis separated, alternatingly, by Pt-Pt-distances of 3.62 A and 6.27 A. A comparable structure possesses erythro-9-PtI2 with Pt-Pt-distances of 3.59 A and 6.32 A. The ethylenediamine ligands of erythro-8-PtI2 and erythro-9-PtI2 are puckered and exist in half chair conformations. For both complexes the 2,6-dichloro-4-hydroxyphenyl ring is equatorially arranged, while the 2-halo-4-hydroxyphenyl ring is nearly perpendicular to the N-Pt-N plane. The O-O-distance between the phenolic oxygens amounts to 8.1 A in erythro-8-PtI2 and to 7.8 A in erythro-9-PtI2. Though these O-O-distances differ strongly from that (12.1 A), which is considered to be necessary for the binding of an estrogen to its receptor, [1-(2,6-dichloro-4-hydroxyphenyl)- 2-(2-halo-4-hydroxyphenyl)ethylenediamine)]platinum(II) complexes show estrogenic effects which are, however, strongly reduced compared to that of therapeutically used estrogens like diethylstilbestrol. The relationship between molecular structure and estrogenicity as well as the significance of the latter for antitumor activity and untoward side effects are thoroughly discussed.

Animals↗
PubMed1993

[meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]- dichloroplatinum(II), a new drug not only parenterally but also orally active in the therapy of breast and prostate cancer.

The platinum complex [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)- ethylenediamine]dichloroplatinum(II),K, was tested for its antitumor activity on hormone-sensitive tumor models under peroral administration. The resorption from the gastrointestinal tract was proved by determining the estrogenic effect of K in a dose/activity study using the immature-mouse uterine weight test. In comparison to the subcutaneous injection, a tenfold peroral dose was administered to achieve identical effects. By peroral treatment of the hormone-sensitive MXT(M3.2) mammary carcinoma of the mouse with K an almost complete inhibition of the tumor growth was obtained. This effect was superior to that of subcutaneously applied cisplatin and significantly better than that obtained by perorally administered ligand L at an equimolar dose, indicating that the antitumor effect is caused by the intact complex K and not by the liberated ligand L. The strong antitumor activity of perorally applied K was also demonstrated on the hormone-sensitive Noble Nb-R prostatic carcinoma of the rat. Histological examinations showed that the platinum complex K did not cause cisplatin-like kidney damage or irritations of gastric or intestinal mucosa when given perorally.

Administration, Oral↗
PubMed1992

[Transient complete AV block as a sequela of Borrelia myocarditis].

A 49-year-old man suddenly developed dyspnoea, sweating, fever (up to 38.5 degrees C), vertigo and angina. After emergency admittance to hospital the ECG showed 3 degrees A-V block, requiring temporary pacemaker insertion. The patient reported that a month before he had been bitten, probably by a tick. Serological tests demonstrated a recent Borrelia infection (rise of IgG antibody titre to 1:2048, IgM antibody titre to 1:128). Coronary angiography excluded any haemodynamically significant coronary heart disease as a cause of the conduction disorder. Myocardial biopsy showed changes pointing to a past myocarditis. This suggested Borrelia infection as the cause of the complete A-V block. Under treatment with broad-spectrum antibiotics for 15 days the fever subsided and the ECG became normal. Shortly before discharge, an elevated pulmonary wedge pressure on 150 W exercise indicated persistence of mild left-ventricular failure.

Antibodies, Bacterial↗
PubMed1992

Dichloro-[1-(hydroxyphenyl)-2-phenylethylenediamine]platinum(II) complexes: testing on the human ovarian cancer cell lines NIH: OVCAR3 and SK OV 3.

The diastereoisomeric dichloro-[1-(2-, 3- and 4-hydroxyphenyl)-2-phenylethylenediamine]platinum(II) complexes were tested on two human ovarian cancer cell lines NIH: OVCAR-3 and SK-OV-3, both resistant against cisplatin. Dichloro-[threo-1-(3-hydroxyphenyl)-2-phenylethylenediamine]platinum(II) (threo-5-PtCl2) proved to be the most active representative of the new series, producing cytocidal effects at a concentration range of 2.5 to 5.0 microM on the NIH: OVCAR-3 cell line. On the more resistant SK-OV-3 cell line, threo-5-PtCl2 was only moderately active, while in combination with BSO, a GSH level lowering compound, threo-5-PtCl2 showed a strong synergistic effect.

Adenocarcinoma↗
PubMed1992

Stereoisomeric [1,2-bis(3-hydroxyphenyl)ethylenediamine]platinum(II) complexes, Part III: Evaluation of the mammary tumor inhibiting properties.

Stereoisomeric [1,2-bis(3-hydroxyphenyl)ethylenediamine]platinum(II) complexes produce a strong configuration-dependent inhibition of the hormone sensitive MXT-mammary carcinoma of the mouse. Besides an interference in the DNA synthesis in analogy to cisplatin an estrogen level lowering effect is supposed to be the mode of action. The new complexes show also a significant activity on the hormone-independent MXT-mammary carcinoma of the mouse.

Animals↗
PubMed1992

[1,2-Bis(2-hydroxyphenyl)ethylenediamine]dichloroplatinum(II), a new compound for the therapy of ovarian cancer. II. Synthesis and preliminary testing of the enantiomeric complexes.

The enantiomeric [1,2-bis(2-hydroxyphenyl)-ethylenediamine]dichloroplatinum(II) complexes were synthesized and their configuration assessed. A preliminary test in the cisplatin-resistant human NIH:OVCAR-3 ovarian cancer cell line, which was previously characterized by its sensitivity against several therapeutically used drugs, showed that both enantiomers produce cytocidal effects in a concentration of 2.5 microM. A difference between the enantiomers became evident from the faster onset of cytocidal activity of the S,S-configurated compound.

Adenocarcinoma↗
PubMed1992

[1,2-Bis(2-hydroxyphenyl)ethylenediamine]dichloroplatinum(II), a new compound for the therapy of ovarian cancer. III. Detailed evaluation of the antitumor activity of the enantiomeric complexes on the human NIH:OVCAR-3 ovarian cancer cell line.

The stereoisomeric [1,2-bis(2-hydroxyphenyl)ethylenediamine]dichloroplatinum(II) complexes were thoroughly tested on the cisplatin-resistant human NIH:OVCAR-3 ovarian cancer cell line. The racemate and its enantiomers produced cytocidal effects at a concentration of 2.5 microM (incubation time 256 h). The meso form, however, was merely cytostatically active. Differences between the enantiomers became evident after a short drug incubation time (1 h) followed by an incubation in drug-free medium (243 h). The S,S-configurated enantiomer (-)-3-PtCl2 proved to be the most active compound. To achieve cytocidal effects concentrations of 2.5-5.0 microM and incubation times of about 3 h were necessary for (-)-3-PtCl2. This compound is also sufficiently stable under test conditions as shown by the preincubation in cell-free medium for 3 h. These results and the augmentation of its antitumor activity by buthionine sulfoximine recommend the further preclinical development of (-)-3-PtCl2 for clinical use.

Antineoplastic Agents↗
PubMed1990

[Fibrin glue and tetracycline pleurodesis in recurrent malignant pleural effusions. A randomized comparative study].

In a prospective randomized study the effect of pleurodesis using fibrin-glue was compared with pleurodesis using tetracycline in the management of malignant pleural effusions. Intrapleural therapy with fibrin-glue was significantly more effective concerning long-term results as relapse of pleural effusion and improvement of lung function just as time of draining pleural effusion and pain during the application of fibrin glue/tetracycline. Thus, intracavitary therapy with fibrin glue may be recommended in the control of malignant pleural effusions.

Female↗
PubMed1990

Tumor inhibiting [1,2-bis(fluorophenyl)ethylenediamine]platinum(II) complexes. Part II: Biological evaluation-in vitro studies on the P 388 D1 leukemia cell line.

Experiments on the P 388 D1 cell line (48 h exposure) demonstrate that [1,2-bis-(fluorophenyl)ethylenediamine]platinum(II) complexes are comparably active on the cell number and 3H-thymidine incorporation, irrespective of the position of the fluorine atom (ortho, meta, or para) and the nature of the "leaving group" (Cl- or H2O). However, the compounds of the R,R/S,S series are more active than those of the R,S series and comparable to cisplatin. In the "tumor colony forming assay" the R,R/S,S configurated compounds are about ten times as active as cisplatin. The R,R/S,S configurated diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) salts reach their half maximum effect more readily (t1/2 approximately equal to 1.6 h) than their R,S configurated analogues (t1/2 approximately equal to 20 h). A time limited contact of the cells with R,R/S,S configurated diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) salts (-1h) leads to a similar inhibition like a permanent drug exposure indicating a fast uptake of the complex by the tumor cell. In experiments on the Ehrlich ascites tumor of the mouse and on the L 1210 leukemia cell line R,R/S,S-[1,2-bis(4-fluorophenyl)ethylenediamine]dichloroplatinum(II) turns out to be equipotent with cisplatin.

Animals↗