We have studied the pharmacokinetics of idarubicin and daunorubicin in a total of 16 leukemic patients treated with one of these drugs associated with aracytine. The AUCs obtained for unchanged drugs were proportional to the dose, and the dose-independent pharmacokinetic parameters were very similar for the two drugs: total plasma clearance (39.0 L/h/m2 for idarubicin versus 38.6 for daunorubicin), total volume of distribution (1756 versus 1725 L/m2) and elimination half-life (42.7 versus 47.4 h). The only metabolites detected were the 13-dihydroderivative of each drug, idarubicinol or daunorubicinol. The elimination half-life of idarubicinol was two times higher than that of daunorubicinol (80.7 versus 37.3 h) which provided an AUC ratio metabolite/parent drug higher for idarubicin than for daunorubicin. In view of the fact that idarubicinol is a much more active metabolite than daunorubicinol, this protracted half-life metabolite can account for the reported higher activity of idarubicin as compared to daunorubicin.

Daunorubicin↗

PubMedDate not supplied

Malakoplakia of the colon associated with villous adenoma: report of a case.

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Adenoma↗

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In vivo distribution of ferric-ATP complex.

At physiological pH, ferric-ATP complex presents ionic characteristics unlike those of ferric lactate. Its rapid diffusion into the tissues, and its reactivity which is not impaired by polymerization seem responsible for its toxicity. In comparison with ferric lactate, after parenteral administration there is a much higher spleen, lung, kidney and bone accumulation. After oral administration, on the other hand, the values are lower. ATP hydrolysis by the stomach's pH, and the subsequent iron insolubilization as phosphate could be the reason for this behaviour.

Adenosine Triphosphate↗

PubMedDate not supplied

Hepatic metabolism of doxorubicin in mice and rats.

We have studied the metabolism of doxorubicin in rat and mouse liver, heart and hepatocytes. Doxorubicinol was present in all cases at very low levels and 7-deoxyaglycones were present only in extraphysiological conditions: no aglycones were found either in fresh livers or in hearts of animals treated with the drug, but they were produced in large amounts when the organs were left at room temperature after the death of the animal. Hepatocytes grown in primary cultures or hepatoma cells grown in continuous lines produced no 7-deoxyaglycones. Freshly isolated hepatocytes synthesized small amounts of 7-deoxyaglycones; however, when these hepatocytes were homogenized prior to incubation, high levels of 7-deoxyaglycones were produced. We conclude that 7-deoxyaglycone formation is possible only in injured tissue and is not, therefore, a normal pathway for doxorubicin.

Animals↗

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In vivo behaviour of low molecular weight iron complexes.

The in vivo distribution in mice of ferric citrate, ferric beta-glycerophosphate and ferric lactate complexes has been studied. There is a relationship between the 59Fe uptake by various tissues and the physicochemical characteristics of the complexes. Ferric lactate seems a useful preparation for iron deficiency therapy.

Animals↗

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Ontogeny of CTX expression in xenopus.

In Xenopus, the type I transmembrane protein, CTX (cortical thymocyte-specific antigen of Xenopus), is hypothesized to play a role in thymocyte differentiation and/or thymic selection. The present studies were undertaken to gather additional evidence in support of a postulated association of CTX with a differentiation step of a cell population that corresponds to the murine immature double positive (CD4+CD8+TCR+) thymocyte subset. During ontogeny, cell surface expression of CTX on thymocytes can first be detected by immunocytochemistry and flow cytometry at 8 days post-fertilization, about 1 day after CD8+ cells first appear. By 12 days post-fertilization, T-cells in the entire cortex except for the outer most layer of cells, are intensely CTX positive, whereas those in the medulla are negative. This pattern persists throughout larval and postmetamorphic life.

Animals↗

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New anti-inflammatory N-pyridinyl(alkyl)phthalimides acting as tumour necrosis factor-alpha production inhibitors.

This paper describes the synthesis of N-pyridinyl(alkyl)phthalimides related to N-phenyl-4,5,6,7-tetrafluorophthalimides known to be inhibitors of tumour necrosis factor-alpha (TNFalpha) production. Pharmacomodulation at the phthalimidic nitrogen led to the selection of two pharmacophoric fragments (2,4-lutidinyl and beta-picolyl), allowing significant inhibition of TNFalpha production (compounds 12 and 17). Variation of the substituents linked to the homocycle of their phthalimide scaffold indicated that high (TNFalpha production) inhibitory potency could be achieved, notably by 5-fluoro, 4- or 5-nitro, 5-amino and especially tetrafluoro substitution. The most active compound, N-(pyridin-3-ylmethyl)-4,5,6,7-tetrafluorophthalimide (32) (84% inhibition at 10 microM), also produced an anti-oedematous effect in the PMA-induced mouse-ear swelling test. Although less active than dexamethasone, it exerted a marked reduction in ear thickness after oral administration (63% vs. 85% for dexamethasone at 0.2 mMkg(-1)) and remained efficient after topical application (46% vs. 96% for the dexamethasone). It also induced potent inhibition in the rat carrageenan foot oedema test with an ID(50) (0.14 microMkg(-1)) comparable with that of N-(2,6-diisopropylphenyl)phthalimide (4) (0.15 microMkg(-1)).

Animals↗

PubMedDate not supplied

[Spectroscopy of phosphorus in nuclear magnetic resonance. General review of clinical applications to the study of human skeletal muscle].

Phosphorus nuclear magnetic resonance spectroscopy enables the energy metabolism of skeletal muscles to be studied non-invasively in vivo. Relative concentrations of phosphocreatine (PCr), inorganic phosphate (iP), monophosphoric sugars (mP) and ATP, as well as intracellular pH values, are directly accessible through the spectra. The striated muscle is continuously studied at rest, during exercise and during recovery. Exercise-induced changes in pH and mP provide indirect information on glycogenolysis and glycolysis. The speed of PCr resynthesis during post-exercise recovery and the PCr/iP ratio values at rest excellently reflect mitochondrial oxidative phosphorylations. Phosphorus NMR spectroscopy therefore is of interest not only to study the impact, through hypoxia, on muscle energy metabolism of such pathologies as cardiac or respiratory failure, or to study various acquired metabolic muscular diseases, but also and above all, to detect and locate muscular enzyme deficiencies involving glycogenolysis, glycolysis or mitochondrial metabolism, thereby pointing to the diagnosis of congenital, and mainly metabolic, myopathies.

Energy Metabolism↗

PubMedDate not supplied

[Gallium 67 fixation in nodular muscular sarcoidosis].

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Adult↗

PubMedDate not supplied

Acute ethanol treatment decreases intracellular calcium-ion transients in mouse single skeletal muscle fibres in vitro.

Alcohol misuse frequently leads to muscle weakness, which may also occur in the setting of acute and chronic alcoholic myopathies. At the cellular level, ethanol has been found to interfere with signalling mechanisms in cardiac myocytes, skeletal myotubes, and smooth muscle cells. In this study, we focused on the effects of ethanol on the intracellular calcium ([Ca(2+)](i)) transients responsible for excitation-contraction (EC) coupling in isolated mouse skeletal fibres loaded with the fluorescent Ca(2+) indicator fura-2. Following electrical stimulation, ethanol caused a significant reversible dose-dependent reduction in [Ca(2+)](i) transient amplitude, already significant at 100 mM ethanol (P = 0.03), without modifying resting [Ca(2+)](i). Evaluating the potential loci for the effects of ethanol, we indirectly measured sarcolemmal Ca(2+) entry by monitoring Mn(2+)-quenching of intracellular fura-2 via the nitrendipine-sensitive Ca(2+) channels during electrical pacing. Ethanol at doses of 20 mM and greater caused a dose-dependent reduction in the rate of fura-2 quenching (all at P<0.05). Moreover, the intracellular pool of Ca(2+) releasable by caffeine was found to be reduced at a minimum of 300 mM ethanol (P = 0.05). We conclude that ethanol reduces the [Ca(2+)](i) transients underlying EC coupling in single mouse skeletal muscle fibres. This acute effect of ethanol was primarily due to an inhibitory effect of ethanol on sarcolemmal Ca(2+) influx via voltage-operated Ca(2+)-channels and, to a lesser extent, to a reduction in the Ca(2+) sarcoplasmic reticulum loading state. This inhibitory effect of ethanol may be implicated in the development of muscle weakness with alcohol consumption.

Animals↗

PubMedDate not supplied

Preliminary technical, experimental and clinical results of the use of the HPLR 27 system for the treatment of deep-seated tumours by hyperthermia.

Based on the theoretical deep penetration of radio frequencies, we have developed several 27.12 MHz ridged wave guides, with large apertures, and filled with circulating deionized water. Different low impedance matching networks have been tested and a 0-800 W power generator has been designed for this particular clinical use. This can be driven easily by a microcomputer which is used to regulate the temperature at depth by varying the sequencing time and/or by adjusting the RF power. The complete system, known as HPRL 27, is manufactured by Sairem Ets. Studies of the spatial power density distributions show a relatively homogeneous RF field for an aperture greater than 30 X 14 cm. Preliminary heating patterns studied in phantoms indicate the possibility of treating volumes greater than 2000 cm3 within the 50 per cent isotherm. Maximum heating is observed between 2 and 5 cm deep with passive cooling, and between 3 and 6 cm deep with active cooling, in which case the 50 per cent isotherm is situated between 2 and 10 cm deep. Preliminary phase I clinical results on 20 patients with pelvic or thoracic carcinomas show the possibility of heating deep-seated tumours to above 42 degrees C with a good patient tolerance. Temperature is controlled by implantable catheters or in the case of pelvic heating, by inserting catheters into the vagina, the rectum and the bladder. This new device is well adapted for the treatment of pelvic tumours.

Aged↗

PubMedDate not supplied

Hyperthermia and cytotoxic drugs. Possible use of lanthanum as a potentiator of hyperthermia.

Recent studies indicate that differences in membrane fluidity may account for differences of thermal sensitivity. This possibility was studied by using lanthanum, a trivalent cation which is known to displace calcium in a number of biological systems, to modify the structural framework of cell membranes and consequently their biological properties. With Ehrlich ascites cells trypan blue exclusion uptake of 86Rb, 42K and 45Ca, indicate an increase of plasma cell permeability by La3+. The reduction of 86Rb and 42K uptake by tumour cells with La3+ appears to be independent of temperature. The increase of 45Ca2+ influx in the presence of lanthanum plus hyperthermia seems related to an important loss of cell viability. The enhancement of hyperthermia lethality by concentrations of lanthanum over 0.5 mM after 2 h at 44 degrees C has been demonstrated using HeLa S3 cells using a standard cloning technique. In vivo experiments have been performed on C3H mice bearing rhabdomyosarcoma using ultrasound heating at 44-46 degrees C. The results show a remarkable inhibition of tumour growth and a significant increase of the survival time after only one hyperthermia session of 30 min combined with one intratumoural injection of 1 mM lanthanum chloride.

Animals↗