Metabolism of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)-ethane and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane in the mouse

The metabolites of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane (DDD) found in the urine of female Swiss mice are reported. The metabolites of DDT are DDD, 1-chloro-2,2-bis(p-chlorophenyl)ethene (DDMU), 1,1-dichloro-2-bis(p-chlorophenyl)ethene (DDE), 2,2-bis(p-chlorophenyl)acetic acid (DDA), 2-hydroxy-2,2-bis(p-chlorophenyl)acetic acid (alpha OH-DDA) and 2,2-bis(p-chlorophenyl)ethanol (DDOH), while DDD afforded DDMU, DDE, DDA, alpha OH-DDA and DDOH. The relative excreted levels of DDA and DDOH and the absence of 2,2-bis(p-chlorophenyl)acetaldehyde (DDCHO) are not consistent with the generally accepted pathway for DDA formation, which involves sequential metabolism of DDT and DDD via DDOH to afford DDA. The quantitative results are interpreted to mean that DDA is formed by hydroxylation at the chlorinated sp3-side chain carbon of DDD to give 2,2-bis(p-chlorophenyl)acetyl chloride (DDA-Cl), which in turn is hydrolyzed to DDA. The excretion of alpha OH-DDA from both DDT- and DDD-treated mice has never been previously observed. It is suggested that this metabolite arises from the initial epoxidation of DDMU, a metabolite of DDT and DDD, to yield 1,2-epoxy-1-chloro-2,2-bis(p-chlorophenyl)ethane (DDMU-epoxide). This chloroepoxide is then hydrolyzed and oxidized to produce the alpha OH-DDA.     

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).     

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.     

Comparative in vitro activities of trovafloxacin (CP-99,219) against 221 aerobic and 217 anaerobic bacteria isolated from patients with intra-abdominal infections

Four hundred thirty-eight bacteria cultured from specimens of patients with serious intra-abdominal infections were tested by agar dilution against trovafloxacin and other quinolones and antimicrobial agents. Trovafloxacin inhibited 435 strains (99.3%) at < or =2 microg/ml. All the quinolones had similar activities against Enterobacteriaceae and Pseudomonas sp., but trovafloxacin showed superior activities against streptococci, enterococci, and anaerobic organisms. Because of its excellent in vitro activities against diverse bacteria, trovafloxacin has potential use as a single agent for polymicrobial infections.     

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.     

Blood cultures. Comparative study with 7 known and 2 new nutrient media for the detection of aerobic and anaerobic microorganisms (author's transl)

The growth promoting properties of seven commercially manufactured and two recently developed culture media are compared according to a standardized method. The study is carried out alternately without and with the addition of 10% fresh human blood to the culture media. The carefully selected test strains include 20 species of bacteria and 2 species of yeasts which represent obligatory aerobic, facultative anaerobic and obligatory anaerobic microorganisms with quite different nutritional and atmospherical requirements. The 9 tested media are good enough for the purpose of culturing nonfastidious bacteria. However, most of the commercially prepared media failed to detect small inocula of very fastidious microbial agents, especially when no blood is added. Collectively, thiol broth is the most noneffective medium. The last but one is thioglycollate medium. Three culture media based on brain heart infusion formula prove to be effective. Those are the commercial brain heart dextrose and the two media recently developed by the authors, namely brain heart dipeptone (BHD) and brain heart dipeptone cysteine (BHDC). BHD is the most suitable medium for the detection of obligatory aerobic and facultative anaerobic fastidious microorganisms. BHDC detects anaerobic fastidious bacteria quite effectively. The other media, namely Columbia, trypticase soy, trypticase soy sucrose, and Rosenow are of limited value with regard to the detection of small inocula of fastidious microorganisms. The causes of the unsatisfactory results with different commercial media are discussed in detail. The authors point out to the possible use of hypertonic media in special cases. Properties that should be fulfilled by blood culture media are proposed.