An in vivo model for the experimental selection of drugs able to prevent immune complex glomerulonephritis.

Polyclonal activation of lymphocytes and immune complex-mediated glomerular lesions were induced in C57Bl/6 mice by injecting bacterial lipopolysaccharide (LPS) twice a week for 2 weeks. The usefulness of such a model for in vivo evaluation of immunomodulatory and therapeutic effects of drugs, was investigated by treating mice with DIAM4, a cyclophosphazenic compound known to modulate polyclonal activation of lymphocytes and to prevent mouse lupus nephritis. Prevention of LPS-triggered lymphocyte polyclonal activation and glomerular lesions was observed in the DIAM4-treated mice. Such a model can be used conveniently to select compounds effective in the treatment of immune glomerulonephritis.

The antitumoral action of polyamine linked cyclophosphazenes on human malignant glioma heterografts in nu/nu mice.

Since the polyamine metabolism system is very active in proliferative glioma cells, polyamine linked drugs are to be considered as potential antineoplastic agents against malignant gliomas. This study reports the trial of a new compound lineage, the Polyamine Linked Cyclophosphazenes, on human glioblastoma heterografts in nu-nu mice. Two agents are tested: DIAM 3 and DIAM 4. Both show an important antineoplastic action either on a chronic treatment schedule or as single dose. Systemic tolerance is satisfactory.

Treatment of end stage MRL-1pr/lpr mouse lupus disease by a cyclophosphazene derived drug and by cyclosporin A.

MRL-lpr/lpr mice develop T cell lymphadenopathy, polyclonal activation of B lymphocytes, autoantibodies and lupus nephritis. B and T cell populations, the dysfunctions of which play a role in the pathophysiology of the mouse disease, represent potential targets for lupus treatment. MRL-lpr/lpr mice are treated from the age of 19 weeks, i.e. after the onset of renal disease and lymphoproliferation, with Cyclosporin A which acts at the T cell level, or with DIAM4 which can down modulate polyclonal activation of B lymphocytes. DIAM4 induces the disappearance of the lymphoproliferation, the increase in C3 levels and the decrease in anti-DNA antibody, immunoglobulin and urea levels, and proteinuria. Cyclosporin A reduces lymph node hyperplasia, but has no effect on other parameters of the disease.

Modulation of polyclonal activation of lymphocytes by cyclophosphazenic compounds bearing ethylene-imino groups and vectorized by polyamines.

Cyclophosphazenic compounds bearing ethylene-imino groups are cytocydal chemicals which can modulate polyclonal activation of lymphocytes (PAL) and prevent the development of murine lupus. The effects on PAL of the different parts of these chemicals and of vectorization by polyamines have been investigated by treating lipopolysaccharide injected C57Bl/6 mice with various cyclophosphazenic compounds and thiotepa. The immune effects of the cyclophosphazenic substances have been found to be mediated by ethylene-imino groups and to be modulated by polyamine vectorization. These compounds might represent a new class of drugs for treatment of immune mediated diseases of the lupus type.

In vivo modulation of polyclonal activation of lymphocytes by SOAz, a cyclophosphazene derived drug. Prevention of murine glomerulonephritis induced by chronic injections of lipopolysaccharide.

The effects of a cyclophosphazene derived drug (SOAz), on the polyclonal activation of B lymphocytes induced by bacterial lipopolysaccharide (LPS) have been studied in C57B1/6 mice. It has been found that this drug is able to inhibit the polyclonal stimulation of lymphocytes and a dose-dependent effect has been observed. The therapeutic effects of SOAz injected five times a week at 40 mg/kg/day have been investigated in mice chronically injected with LPS (twice a week, 2.5 mg/kg/day) which developed an immune complex type of glomerulonephritis. A marked prevention of glomerular lesions and of deposits of IgM and IgG, and of the third complement component has been found in mice treated with SOAz as compared to not treated mice.

Alteration of delta psi-dependent amino acid transports in Streptococcus pneumoniae by the antitumoral drug SOAz.

Interactions of the antitumoral drug SOAz with natural and model membranes are described. Biological studies were carried out with the bacterium Streptococcus pneumoniae taken as a model system. They reveal that SOAz is able to reduce delta psi and the delta psi-dependent amino acid transports without being cytotoxic for the bacteria. With respect to model membranes, leakage studies carried out with Na+ and K+ loaded lipid vesicles demonstrated that SOAz exhibits no ionophore activity. In contrast, the drug is shown to decrease the surface potential of monolayers of acidic phospholipids but without penetrating within the film. The possibility that SOAz might alter the delta psi part of the proton motive force by decreasing the outside surface potential of the bacterial membrane is discussed.

Spectroscopic studies of conformational transitions in double stranded DNAs in the presence of carcinogenic nickel compounds and an antitumoral drug (SOAZ).

The influence of an antitumoral drug, the pentaziridinocyclodiphosphatiazene (SOAZ), on the right----left-handed helix conformational transition of Poly (dG-dC). Poly (dG-dC) induced by carcinogenic or mutagenic Nickel compounds has been studied by ultraviolet absorbance and circular dichroïsm measurements. The B----Z transition of the polynucleotide is induced in two steps, in a similar way whatever the origin of the Nickel ions (NiCl2, NiSO4, Ni3S2, NiCO3). The midpoint of the second step (right----left-transition) is located around 0.4 mM Ni2+. The addition of SOAZ to the Poly (dG-dC). Poly (dG-dC) modifies this transition which is shifted to 2 mM Ni2+ for a 1 SOAZ/10 DNA phosphates ratio. The right-handed helix is stabilized and for a 1.5 SOAZ/phosphate ratio no B----Z transition is observed even for a tenfold amount of added Nickel (4 mM Ni2+). The addition of SOAZ to the DNA initially converted to a Z conformation by the presence of Nickel inhibits the return to the B form.

Z-form induction in DNA by carcinogenic nickel compounds: an optical spectroscopy study.

The B----Z conformational transition of double-stranded poly(dG-dC) induced by various nickel salts (chloride, sulfate, subsulfide, carbonate) has been studied by ultraviolet absorption and circular dichroism. The spectra of the nickel compounds, both free and complexed with DNA, have been obtained in the visible and near infrared regions. In all cases the nickel adopts the hexacoordinated ionic form [Ni(H2O6]2+ and induces the B----Z transition of the nucleic acid at submillimolar concentrations (typically 0.4 mM). The addition to the poly(dG-dC)-poly(dG-dC) of an antitumoral drug, pentaziridinocyclodiphosphathiazene (SOAz), inhibits the B----Z transition even at a ten-fold higher nickel concentration (4 mM). Possible implications for carcinogenesis are discussed.

The antineoplastic activity of hexaziridinocyclotriphosphazene (Myko 63) in murine tumors.

The antineoplastic activity of hexaziridinocyclotriphosphazene (Myko 63) has been investigated in a panel of murine ascitic and solid tumors. Myko 63 was found to significantly retard primary and secondary tumor growth and to prolong the survival rates in each of the nine models employed. These included the L1210 and P388 leukemias, P815 mastocytoma, the 3LL and Madison 109 carcinomas, M5076 reticulum cell sarcoma, the line 26 colon and line 16 mammary carcinomas, and an intracranially implanted ependymoblastoma. The possible modes of action of this compound and the potentials of cyclophosphazenes, a chemical class largely unexplored as antitumor agents are discussed.

Mass spectrometry as a technique for testing the purity of drugs for biological use: the case of new antitumor cyclophosphazenes.

Mass spectrometry has been used for testing the chemical purity of some new antitumor cyclophosphazene compounds. the spectrum of N3P3Az6 (code name MYKO 63)--which exhibits noticeable activity on murine P 388, L 1210 and B 16 tumors--appeared to be remarkably simple, as most of the fragmentations arose from successive losses of the aziridino radicals. Traces of the pentaziridinomonochloro impurity formed by an incomplete substitution of N3P3Cl6 chlorine atoms under aziridinolysis could be detected in an impure and toxic sample by spectral subtraction. Quantification of this impurity was performed by selected ion monitoring in the direct inlet mode of sample introduction. The mass spectra of other derivatives of this class of compounds are slightly more complex, since the decomposition pathways showed more intense H-transfers associated with the loss of substituents.

[Broncho-pulmonary manifestations and gastroesophageal reflux]. / Manifestations broncho-pulmonaires et reflux gastro-oesophagien.

In 196 cases of gastro-oesophageal reflux, simple or connected to a hiatal hernia or to a cardio-tuberous misplacement, the respiratory signs that are found in 1 patient out of 4, are analyzed. The nocturnal fits of coughing (39 cases, 20% of the reflux) is the most frequent sign of laryngo-tracheal aspiration of stomach content. This symptom of great diagnostic value, though neglected, should be looked for systematically. Other troubles are less frequent: bouts of recurring broncho-pulmonary infections, asthma attack, Mendelson's syndrome, pulmonary fibrosis. In absence of a patent cause, the symptoms should lead to suspect a reflux of stomach content in the airways. Similarly to oesophagitis, respiratory signs represent a complication sometimes serious, of gastro-oesophageal reflux, needing more frequently a surgical treatment of hiatal herniae or of the cardiac inefficiency.