Uterine metastases from primary breast-cancer - report of 2 cases.

The authors report on 2 cases of uterine dissemination from primary breast carcinoma. Special emphasis is made on this atypical site of metastases and on the necessity of a gynecological work-up in patients previously treated for breast cancer.

Antioxidant status and dietary lipid unsaturation modulate oxidative DNA damage.

High performance liquid chromatography with electrochemical detection (HPLC-EC) was used to measure 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker for oxidative DNA damage, in mammary gland isolated from tumor-bearing and tumor-free rats fed diets of varied fatty acid composition and vitamin E and selenium content. A method for tissue preparation and analysis is reported and a significant positive correlation shown between degree of unsaturation of dietary fatty acids and 8-OHdG concentration, regardless of antioxidant status. The increase in 8-OHdG concentration with greater fatty acid unsaturation was more pronounced in the absence of adequate dietary vitamin E and selenium.

Determination of an acetylcholinesterase inhibitor, MDL 73745, in dog plasma and urine by combined gas chromatography/negative ion chemical ionization mass spectrometry.

A highly sensitive and specific assay has been developed for the determination of MDL 73745 [2,2,2-trifluoro-1-(3-trimethylsilyl-phenyl) ethanone] (I) and the internal standard (MDL 74398) at the nanomolar level in dog plasma and urine by gas chromatography/mass spectrometry. After a single-step extraction process, an aliquot was directly injected onto the gas chromatograph column. The mass spectrometer was run in the negative ion chemical ionization mode with ammonia as reagent gas, and was set to monitor the abundant M-.

Pharmacokinetics of and monoamine oxidase B inhibition by (E)-4-fluoro-beta-fluoromethylene benzene butanamine in man.

MDL 72974A ((E)-4-fluoro-beta-fluoromethylene benzene butanamine HCl salt, CAS 120635-25-8) is a new irreversible inhibitor of the B form of monoamine oxidase (MAO-B). MDL 72974A's pharmacokinetic parameters were evaluated after administration of a single oral dose and after multiple oral doses. The concentration of parent drug was determined in plasma using a solid-liquid extraction method and gas chromatographic-mass spectrometric analysis.

MDL 72,974A: a selective MAO-B inhibitor with potential for treatment of Parkinson's disease.

MDL 72,974A [(E)-2-(4-fluorophenethyl)-3-fluoroallylamine, hydrochloride] was designed to be a selective, mechanism-based irreversible inhibitor of monoamine oxidase type B (MAO-B). The compound is a potent, selective MAO-B inhibitor in vitro and in vivo. In vitro studies revealed an IC50 value (MAO-B) of 3.

Validation of a gas chromatographic/mass spectrometric method for the determination of (E)-beta-fluoromethylene-m-tyrosine and its active metabolite in human plasma and urine.

(E)-beta-Fluoromethylene-m-tyrosine (FMMT, MDL 72394) represents a prodrug approach to site-selective, irreversible inhibition of monoamine oxidase. A sensitive and specific method for the quantification of FMMT and its active metabolite (MDL 72392) in human plasma and urine has been developed for future pharmacokinetic studies. The procedure consists of a liquid-liquid extraction of plasma and urine samples, esterification with HCl/butanol and, subsequently, N-acylation with pentafluoropropionic anhydride.

Utility of an oral diffusion sink (ODS) device for quantification of saliva corticosteroids in human subjects.

Measurement of cortisol by assay of single blood or saliva samples is inherently imprecise due to the episodic secretion of cortisol. In addition, assay of blood usually quantifies total cortisol, rather than separating free hormone, which is proportionately the much smaller fraction. Furthermore, the free fraction may be disproportionately higher in hypercortisolism.

Assessment of the biotransformation of the cardiotonic agent piroximone by high-performance liquid chromatography and gas chromatography-mass spectrometry.

14C-labelled piroximone was administered to rats at a dose of 10 mg/kg body weight. Of the total radioactivity administered, 74.9 +/- 7.

Lactational transfer of 3,3',4,4'-tetrachloro- and 2,2',4,4',5,5'-hexachlorobiphenyl induces cytochrome P450IVA1 in neonates. Evidence for a potential synergistic mechanism.

On the first day of lactation, material rats were treated with a single low dose of 5 mg/kg body weight of 3,3',4,4'-tetrachlorobiphenyl (TCB) or 2,2',4,4',5,5'-hexachlorobiphenyl (HCB) or with a combination of both congeners. Lactational transfer of these polychlorinated biphenyls (PCBs) was found in neonates and significant increases in microsomal cytochrome P450, cytochrome b5 and in glutathione-S-transferase activity were observed. Treatment with HCB did not increase neonatal ethoxyresorufin-O-de-ethylation (EROD) activities whereas a more than 26-fold increase in EROD activity was noted in response to exposure to TCB.

Effects of a standardized meal on the pharmacokinetics of the new cardiotonic agent piroximone.

The influence of food on the pharmacokinetics of piroximone (MDL 19.205, CAS 84490-12-0) was evaluated in two groups of 6 healthy male volunteers receiving either 25 or 50 mg of the drug. Single doses were administered intravenously and orally under fasting conditions or orally with a standard breakfast on 3 different days with a washout period of at least 3 days in-between doses, according to an open, 3-way crossover, randomized design.

Determination of an irreversible inhibitor of monoamine oxidase B (MDL 72974A) in human plasma and urine by gas chromatography-positive-ion chemical ionization mass spectrometry.

A sensitive and specific assay has been developed for the quantitative measurement in human plasma and urine of the irreversible inhibitor of monoamine oxidase B [(E)-4-fluoro-beta-fluoromethylenebenzene-butanamine HCl salt] (MDL 72974A) (I). This assay is based on gas chromatography-mass spectrometry with ammonia as the chemical ionization reagent gas. After addition of 1-fluoro-2-(4-chlorobenzene)-ethanamine HCl salt (MDL 71946A) as the internal standard, plasma (1 ml) and urine (100 microliter) samples were extracted using an automated solid-liquid extraction procedure on CN columns.

Cardioselectivity of alpha-tocopherol analogues, with free radical scavenger activity, in the rat.

MDL74270 (6-acetyloxy-3,4-dihydro-N,N,N,2,5,7, 8-heptamethyl-2H-1-benzopyran-2-ethanaminium, 4-methylbenzenesulfonate) is a quaternary amine analogue of alpha-tocopherol with free radical scavenger properties. Rats were injected iv with [14C]MDL74270 (0.91 mg/kg), and whole blood and heart tissue were sampled.

Time-integrated measurement of corticosteroids in saliva by oral diffusion sink technology.

Saliva, as a medium for assessing adrenocortical function in humans, has many advantages and a few distinct disadvantages. Interpretation of measurements of saliva cortisol is complicated by the contamination of saliva by steroid-binding proteins from blood plasma, enzyme activity in the salivary gland that converts cortisol to cortisone, and the amplification in saliva of the episodic fluctuations in systemic cortisol concentrations. We describe a new measurement technology that rejects artifacts from contamination of saliva by plasma protein, provides for measurement of both cortisol and cortisone, and integrates episodic fluctuations in concentration over a period of hours.

A single-dose-finding study of the antiemetic effect and associated plasma levels of MDL 72222 in patients receiving cisplatin.

A total of 25 patients (5 groups of 5) were given single i.v. doses of 5, 10, 20, 40 and 60 mg MDL 72,222 (a 5-HT3 receptor antagonist) at 15 minutes before the commencement of a 24-h cisplatin infusion (total dose, 120-200 mg) to determine the efficacy and safety of the former in the prevention of nausea and vomiting associated with such chemotherapy.

A cardioselective, hydrophilic N,N,N-trimethylethanaminium alpha-tocopherol analogue that reduces myocardial infarct size.

The alpha-tocopherol analogue 3,4-dihydro-6-hydroxy-N,N,N,2,5,7,8- heptamethyl-2H-1-benzopyran-2-ethanaminium 4-methylbenzenesulfonate (1a, MDL 73404) and its O-acetate 1b (MDL 74270) were synthesized. Compound 1a was found to be hydrophilic (log P = -0.60) and to prevent lipid autoxidation in rat brain homogenate with an IC50 of 1.

In vitro metabolism of [14C]4-chlorobiphenyl and [14C]2,2',5,5'-tetrachlorobiphenyl by hepatic microsomes from rats and pigeons. Evidence against an obligatory arene oxide in aromatic hydroxylation reactions.

1. The catalytic activities of cytochromes P-450IA1 and P-450IIB1 in control and Aroclor 1254 treated rats and pigeons (1 mmol/kg) were assessed using [14C]4-chloro- and [14C]2,2',5,5'-tetrachlorobiphenyl as substrates. Treatment of rats resulted in increases of the total amount of chloroform-extractable metabolites of [14C]4-chlorobiphenyl from 37.

Effect of long-term vigabatrin therapy on selected neurotransmitter concentrations in cerebrospinal fluid.

Ten patients, suffering from drug-resistant complex partial seizures were treated for a period of up to 3 years with vigabatrin (Sabril). Vigabatrin is a novel antiepileptic agent, whose action is based on the inhibition of gamma-aminobutyric acid (GABA) aminotransferase, the enzyme responsible for the catabolism of the neurotransmitter GABA. Samples of lumbar cerebrospinal fluid were obtained from the patients prior to commencing vigabatrin therapy, and thereafter at 6 months, 1 year, 2 years, and up to 3 years following the initiation of vigabatrin treatment.

Progress in the assessment of lymphatic spread in rectal cancer. Rectal endoscopic lymphoscintigraphy.

Rectal endoscopic lymphoscintigraphy was performed in 10 control subjects and in a series of 85 patients with adenocarcinoma of the rectum as a prospective study to evaluate lymphatic drainage of the rectum and lymphatic spread in rectal cancer. Complete cranial drainage was demonstrated in all control subjects, and internal iliac nodes were also visible in 50 percent of cases. Results were correlated with histologic node examination in all patients operated upon for rectal cancer.

[Fasciitis in granulomatous myositis--an atypical manifestation of sarcoidosis?].

We report about two female patients with a histopathological proven granulomatous myositis associated with a fasciitis. One patient showed noncaseating granulomas in the muscle fascia. She suffered from symmetrical contractures of the digital flexors and ankles.

[Progress in the evaluation of lymphatic involvement in cancer of the rectum: endoscopic rectal lymphoscintigraphy].

The preoperative evaluation of lymphatic spread in rectal cancer constitutes a considerable problem. A prospective study including 45 patients operated for rectal cancer, was carried out in order to assess the diagnostic value of a new technique: endoscopic rectal lymphoscintigraphy. The results of the preoperative assessment were compared with histological data according to Dukes' classification (Dukes A/B: 22 cases, Dukes C: 23 cases).

Randomized phase II study of a combination of cisplatin (DDP), 5-fluorouracil (5-FU), and allopurinol (HPP) versus 5-FU in advanced colorectal carcinoma. An EORTC Gastrointestinal Tract Cancer Cooperative Group study.

In order to improve the therapeutic index of fluorouracil (5-FU), it has been combined with cisplatin (DDP) as synergistic agent and with allopurinol (HPP) as toxicity modulator. Patients with measurable colorectal carcinoma, previously untreated by chemotherapy, were randomized to receive either 5-FU alone 500 mg/m2 push iv days 1-5 or HPP 3 x 300 mg po, days 1-5, 5-FU 800 mg/m2 push iv, days 3-5 and DDP 50 mg/m2 d6. Treatment was repeated every 4 weeks.

Review: Normal and abnormal central nervous system GABA metabolism in childhood.

The metabolism and function of central nervous system GABA is briefly reviewed. Hereditary disorders of the GABA metabolism presenting in childhood are discussed with particular emphasis on the recently identified succinic semialdehyde dehydrogenase deficiency and GABA-transaminase deficiency, and on diseases associated with low CSF GABA which await further unravelling. Low CSF GABA concentrations are not always associated with convulsions.

[African trypanosomiasis in children treated with eflornithine. A case].

We report the case of a 14-year old African girl presenting with late-stage African T. gambiense trypanosomiasis. She was treated with eflornithine, an ornithine decarboxylase inhibitor which is a key enzyme in the biosynthesis of polyamine.