A Review Of Mri Appearances Of Lipiodol In Conventional Tace (Ctace) Treated Hepatocellular Carcinomas.

Background: The global burden of patients affected by chronic liver disease (CLD) has shown a steady rise over the last few decades and is now considered the 11th most frequent cause of death globally. In addition, as the world population is facing increased obesity rates coupled with alcohol consumption, these rates are predicted to continue to rise. The Objective was to assess the appearance of Lipiodol retention upon different MRI sequences with a special focus on non-contrast sequences. Lipiodol Trans-arterial chemoembolization (TACE) has become the standard treatment for unresectable hepatocellular carcinoma (HCC) without vascular invasion. However, data regarding Lipiodol TACE imaging via MRI is limited and results are not familiar to radiologists for regular assessment of treatment response. Methods: After IRB and EC approval, we included all those patients who underwent TACE treatment with Lipiodol and chemotherapeutic agent; having both 4-6-week post-treatment CT and MRI imaging. This criterion was fulfilled by a total of 25 patients. Only lipiodol-containing areas within the lesion were noted for signal intensities on all MRI sequences and labelled as hyperintense, isointense, hypointense and mixed intensity. Data was entered and analyzed by SPSS v27. Frequencies and percentages were calculated for qualitative data. Results: The most sensitive sequence in detecting Lipiodol retention was Fat suppressed T1 imaging sequence, with low signal intensity seen on T1 weighted fat-suppressed sequences in up to 76% of lesions. While on non-fat suppressed T1 weighted images, 60% of Lipiodol retention areas appeared hyperintense. 52% of lesions showed a hypointense appearance on the T2 weighted sequence. A much more variable appearance was seen in Diffusion-weighted imaging sequences demanding cautious interpretation. MR patterns were clearer in patients having more than 50% lipiodol retention on CT and lesion size more than 2 cm. . Conclusion: While MRI is deemed as a reliable and most useful imaging modality for assessing HCC's following lipiodol TACE it requires cautious interpretation with knowledge of variable signal appearance seen on different imaging sequences.

Large-scale prediction and testing of drug activity on side-effect targets.

Discovering the unintended 'off-targets' that predict adverse drug reactions is daunting by empirical methods alone. Drugs can act on several protein targets, some of which can be unrelated by conventional molecular metrics, and hundreds of proteins have been implicated in side effects. Here we use a computational strategy to predict the activity of 656 marketed drugs on 73 unintended 'side-effect' targets. Approximately half of the predictions were confirmed, either from proprietary databases unknown to the method or by new experimental assays. Affinities for these new off-targets ranged from 1 nM to 30 µM. To explore relevance, we developed an association metric to prioritize those new off-targets that explained side effects better than any known target of a given drug, creating a drug-target-adverse drug reaction network. Among these new associations was the prediction that the abdominal pain side effect of the synthetic oestrogen chlorotrianisene was mediated through its newly discovered inhibition of the enzyme cyclooxygenase-1. The clinical relevance of this inhibition was borne out in whole human blood platelet aggregation assays. This approach may have wide application to de-risking toxicological liabilities in drug discovery.

[Prevention of bone loss by chlorotrianisene in oophorectomized rats].

OBJECTIVE: To determine the influence of chlorotrianisene on bone metabolism in oophorectomized rats. METHODS: Forty-eight Wistar female rats, 70 days of age, were randomly divided into four groups: SV group (sham operation + vehicle), OV group (oophorectomy + vehicle), SE group (sham (operation + chlorotrianisene) and OE group (oophorectomy + chlorotrianisene). Chlorotrianisene or vehicle 4 ml/kg was given i.p. daily for 45 days from day 7 of being ovariectomized or sham operated. At the time of death, uterine weight was measured, and the thoracic vetebra 12, left tibia were collected and made into decalcified bone specimens for histomorphometry. RESULTS: There were significant difference in the uterine weight among each group. Significant different appearance by bone histomorphometry was seen between OV and the other three groups, but not shown between SV and SE, OE groups. CONCLUSION: These results suggest chlorotrianisene could inhibit bone loss and delay the atrophy of uterus induced by ovariectomy in Wistar female rats. It has protective effects on bone like other estrogen preparations.

[Bone metabolism in postmenopausal women and after estrogen treatment].

Changes of bone metabolism in 11 premenopausal women and 109 postmenopausal women were studied. 50 postmenopausal women were randomly divided into 4 groups: 20, 10 and 6 cases were given nylestriol, diethyl stilbestrol and chlorotrianisen respectively, and 14 cases served as control. It was shown that bone mineral content (BMC), and, blood estrogen level in postmenopausal women were significantly lower than those of premenopausal women. Close correlation existed between E1, E2, and BMC. Serum alkaline phosphatase (ALP), bone GLA protein (BGP), urine Ca/Cr and Hpr/Cr were markedly increased in postmenopausal women and declined after 3 months of treatment with nylestriol, diethylstilbestrol or chlorotrianisen. The radial BMC increased by 0.8% with (P > 0.05) nylestriol treatment for one year and decreased by 1.1% (P < 0.05) in the control cases. The present study indicated that postmenopausal estrogen deficiency accelerated bone loss, which was prevented by small substitution doses of estrogen such as nylestriol.

Small cell carcinoma of prostate: effectiveness of hormonal versus chemotherapy.

Small cell carcinoma of the prostate is rare and associated with a rapidly fatal course. Since 1977, 47 cases have been reported in the world literature with data from 3 additional cases presented herein. The purpose of our review was to determine the effectiveness of hormonal versus chemotherapy. Thirty-four of the 50 cases have known clinical histories. Four patients were not treated, and all were dead of their disease within an average of 2.75 months. Six patients were eliminated from our review because small cell carcinoma was discovered at autopsy. Another 5 cases were omitted because hormonal +/- chemotherapy had already been given for a previous diagnosis of adenocarcinoma, but no specific therapy was given once the small cell carcinoma developed. Of the remaining 19 cases, only 2 have survived. One is still alive forty-three months after hormonal treatment, and another is alive with disease six months after the initiation of hormonal therapy and chemotherapy. Five patients were given hormonal therapy only, and none of them responded. In 4 patients chemotherapy was given after hormonal therapy had failed, and they too died of their disease within a short period of time. However, an additional 8 patients were treated with immediate chemotherapy +/- hormonal therapy and had substantially longer clinical remissions. Therefore, although small cell carcinoma is a uniformly fatal disease, immediate chemotherapy should be considered to promote better clinical remissions.

Role of P-450c in the formation of a reactive intermediate of chlorotrianisene (TACE) by hepatic microsomes from methylcholanthrene-treated rats.

A previous study has shown that chlorotrianisene is metabolized by hepatic microsomal cytochrome P-450 monooxygenase(s) to a reactive intermediate that binds covalently to microsomal proteins [Juedes, Bulger, and Kupfer: Drug Metab. Dispos. 15, 786 (1987)]. Covalent binding of chlorotrianisene in hepatic microsomes is dramatically stimulated by treatment of rats with methylcholanthrene (MC), which is known to induce two major P-450 isozymes, P-450c (IA1) and P-450d (IA2). To determine whether P-450c and/or P-450d are involved in catalysis of covalent binding of chlorotrianisene, antibodies to P-450c and P-450d were used. Incubations of chlorotrianisene were conducted with liver microsomes from MC-treated rats (MC microsomes) and a monoclonal antibody (mAb) raised to the major MC-induced isozyme P450c, mAb 1-7-1, or a polyclonal monospecific antibody (pAb) to P-450d, pAb anti-d (-c). At a 5:1 ratio of antibody to microsomal protein, mAb 1-7-1 inhibited covalent binding by 67%, whereas pAb anti d (-c) showed a 10% inhibition. Maximal inhibition by mAb 1-7-1 was 89% at a 100:1 ratio of antibody to microsomal protein. From these findings it was concluded that P-450c is the major isozyme responsible for the metabolism of chlorotrianisene to the covalently binding reactive intermediate in MC microsomes. Additionally, it was observed that potentiation of covalent binding occurred with the noninhibitory mAbs used in these incubations. Substituting bovine serum albumin (BSA) for antibodies showed that this increase in binding is probably due to an increase in acceptor sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Inactivation of the uterine estrogen receptor binding of estradiol during P-450 catalyzed metabolism of chlorotrianisene (TACE). Speculation that TACE antiestrogenic activity involves covalent binding to the estrogen receptor.

Chlorotrianisene (TACE) exhibits in vitro little or no binding to the uterine estrogen receptor (ER) but demonstrates potent estrogenic activity in vivo, indicating that TACE is a proestrogen/proantiestrogen. Our earlier studies demonstrated that the incubation of TACE with rat liver microsomes and NADPH generates a reactive intermediate (T*) which binds covalently to proteins. The current study examined the possibility that T* may inactivate the uterine ER. The incubation of TACE with rat liver microsomes and NADPH in the presence of rat uteri, under conditions which generate T*, markedly decreased the binding capacity of the ER for [3H]estradiol (E2). The evidence indicates that ER inactivation was probably due to irreversible (covalent) binding of T* to the E2 binding site. The possibility that the antiestrogenic action of TACE and of other triphenylethylenes involves such a novel mechanism is discussed.

Differential responses of pituitary kallikrein and prolactin to tamoxifen and chlorotrianisene.

Glandular kallikrein, a trypsin-like serine protease, and prolactin (PRL) are both estrogen-induced proteins in rat anterior pituitary lactotrophs. The estrogen agonist and antagonist effects of tamoxifen (TAM, a triphenylethylene antiestrogen) and chlorotrianisene (TACE, a triphenylethylene estrogen) on anterior pituitary glandular kallikrein and PRL were examined to see if TAM and TACE differentially affect these estrogen response of lactotrophs after in vivo dosing of rats. TAM and TACE acted as partial agonists on PRL and uterine weight induction. In contrast, on glandular kallikrein induction TAM acted as a pure estrogen antagonist and TACE acted as an almost pure antagonist. The results document that both TAM and TACE exhibit protein-specific estrogen agonist and antagonist efficacies in lactotrophs, with the estrogen induction of glandular kallikrein being particularly sensitive to antagonism by TAM in vivo. The marked antiestrogen character of TACE was surprising since TACE has been classified and clinically used as an estrogen.

Monooxygenase-mediated activation of chlorotrianisene (TACE) in covalent binding to rat hepatic microsomal proteins.

Chlorotrianisene is a therapeutic estrogen and contaminant of the pesticide methoxychlor. Incubation of [3H]chlorotrianisene with rat liver microsomes, supplemented with NADPH, yielded covalent binding of radiolabeled metabolite(s) to microsomal components. This binding was dramatically stimulated when microsomes from methylcholanthrene-treated rats were used. However, microsomes from phenobarbital-treated animals did not enhance binding. Analysis of solubilized microsomes by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed radiolabeled bands in the 45- to 66-kDa range. Furthermore, these bands were sensitive to protease degradation, indicating that the recipient macromolecules were proteins and possibly cytochrome P-450(s). Selective inhibition of binding to microsomes prepared from control, phenobarbital-, and methylcholanthrene-treated rats by inhibitors of monooxygenase activity [beta-diethylaminoethyl diphenylpropylacetate (SKF-525A) and metyrapone], by alternate substrates (ethylmorphine and benzo[a]pyrene), and by oxygen exclusion indicated that the binding was dependent upon monooxygenase activity and that a specific P-450 may be involved. Compounds containing free sulfhydryls markedly inhibited covalent binding, suggesting that the reactive intermediate is an epoxide or a free radical. The epoxide hydratase inhibitor (1,1,1-trichloropropane oxide) failed to enhance covalent binding, suggesting that an epoxide of chlorotrianisene was not the reactive intermediate. By contrast, free radical scavengers (propyl gallate, N,N'-diphenylenediamine, and ascorbic acid) markedly inhibited covalent binding, indicating that binding was mediated via a free radical. Since both methylcholanthrene and phenobarbital did not enhance demethylation of chlorotrianisene and methylcholanthrene increased covalent binding, it appears that demethylation products are not involved in covalent binding or that demethylation is not the rate-limiting step. A possible pathway for the metabolism and covalent binding of chlorotrianisene is presented.

Mesenteric venous thrombosis associated with estrogen therapy for treatment of prostatic carcinoma.

We report 2 cases of mesenteric venous thrombosis in men taking estrogen for carcinoma of the prostate. The possible relationship between the estrogen therapy and mesenteric venous thromboses is stressed, as well as the potential danger of resumption of estrogen therapy without anticoagulation postoperatively.

[Steroid hormone receptors and cellular proliferative activity following the short-term use of tamoxifen and chlorotrianisene in breast cancer]. / Retseptory steroidnykh gormonov i proliferativnaia aktivnost' kletok posle kratkovremennogo primeneniia tamoksifena i khlortrianezena pri rake molochnoi zhelezy.

The content of estrogen receptors (ER), progesterone receptors (PR), the proliferative pool level in the tumour tissue were investigated in 6 patients with the disseminated breast tumour before and after 9-day treatment with tamoxifen and chlorotrianisene for intensification of the effect of cytostatic preparations. A significant increase of the DNA synthesis intensity and proliferative pool value is observed in ER+ tumours of 2 patients. An increase of the PR level in tumour biopsies was registered in 2 patients. A decrease of the ER+ level was detected in ER+ tumours in all three patients.

The effects of chlorotrianisene (Tace) of kinetics of 3H-testosterone metabolism in patients with carcinoma of the prostate.

Alterations in the metabolism of testosterone and plasma levels of testosterone, luteinising hormone (LH), follicle stimulating hormone (FSH), prolactin and oestradiol were studied in 6 patients with newly diagnosed prostatic carcinoma before and during treatment with chlorotrianisene at a daily dosage of 48 mg for 14 days. Parameters of plasma kinetics were determined according to the single injection technique and the 2-compartment model, and the plasma hormones by radioimmunoassay. Chlorotrianisene altered neither plasma levels of testosterone, gonadotrophins, prolactin and oestradiol, nor metabolic clearance rate, production rate and other kinetic parameters of testosterone. Thus the beneficial effects which have been reported previously cannot be explained by suppression of peripheral testosterone metabolism.

The effect of chlorotrianisene as postpartum lactation suppression on blood coagulation factors.

Coagulation changes and increased risk of thromboembolic disease may occur in association with estrogen administration. The puerperium is also a high-risk period for thromboembolism, and estrogen administration at this time may increase this risk. Patients with congenital deficiency of antithrombin III have recurrent venous thromboembolic disease, suggesting that low levels of this factor may be associated with "hypercoagulability" states. We studied 50 postpartum patients who received chlorotrianisene (Tace) or placebo for lactation suppression in a prospective, double-blind, randomized fashion. Antithrombin III values were significantly lower on the third day post partum in the treated group compared to the placebo group (p less than 0.05). In addition, our clinical data from a total of 99 patients support the previous evidence that estrogens delay rather than prevent breast engorgement. Thus, with questionable benefit and a possible increased thromboembolic risk, it would appear prudent to discontinue the practice of estrogen administration for lactation suppression.

Rabbit hepatic microsomal O-demethylation of chlorotrianisene.

The in vitro hepatic O-demethylation of the nonsteroidal estrogen chlorotrianisene (CTA) has been studied. The rate of O-demethylation was maximal at 0.4 mM NADPH. Although NADH did not catalyze the reaction alone, it had a synergistic effect in the presence of equimolar amounts of NADPH. Carbon monoxide decreased the rate of O-demethylation. Nicotinamide was found to decrease the O-demethylation rate at a concentration of 40 mM, but had no apparent effect at concentrations of 20 mM or lower. Extracts from incubation mixtures contained one major (mono-O-demethylated) and a minor (bis-O-demethylated) metabolite. Extracts of mixtures containing soluble rather than microsomal enzymes or from mixtures in which microsomal protein had been denatured did not contain these metabolites.