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Adsorption of four 5-pyrazolone derivatives and two carboxylic acids from aqueous solutions was studied. Partition coefficients for the analyzed drugs were calculated. Good corelation between log(k1, k2) (Langmuir constants) and log (octanol-water partition coefficient) of the drugs were found. The higher log(k1k2) value the higher solubility of the non-narcotic and analgetic drugs.
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Lens-induced granulomatous uveitis was produced in brown Norway rats. To determine the role of the lipoxygenase and cyclo-oxygenase products of arachidonic acid in the modulation of granulomatous uveitis, one group of experimental animals was treated with nafazatrom, while another group was treated with nordihydroguaiaretic acid (lipoxygenase inhibitors). Both resulted in significant attenuation of granulomatous inflammation, with reduced giant-cell infiltration into the choroid. In contrast, indomethacin (a cyclo-oxygenase inhibitor) therapy resulted in increased giant-cell formation. These findings suggest that the lipoxygenase and cyclo-oxygenase products of arachidonic acid play a role in the development of granulomatous uveitis and that such inflammation can be selectively suppressed by lipoxygenase inhibitors.
Famprofazone (1) metabolites were studied in human urine after medication by 50 mg oral dose. The human urine was collected over 48 h from six volunteers at time intervals of 6, 12, 24 and 48 h. The amount of famprofazone metabolites were recovered from the urine samples by application of Extrelut extraction method. The resultant extracts were derivatized using N-methyl-N-trimethylsilytrifluoroacetamide (MSTFA) for trimethylsilylation followed by N-methyl-bis-trifluoroacetamide (MBTFA) for trifluoroacetylation. Methamphetamine (2) and 3-hydroxymethyl-propyphenazone (3), excreted in human urine, were identified as famprofazone metabolites by gas chromatography-mass spectrometry (GC-MS). The quantitative results revealed that the average amounts of 2 and 3, excreted in human urine were equal to 2.6 and 4 mg, respectively, through 48 h. However, 3 was analysed after enzymatic hydrolysis of the urine samples using beta-glucuronidase/arylsulphatase. The excreted methamphetamine enantiomers could be separated by application of indirect GC-technique using S-(-)-N-trifluoroacetylprolyl chloride (TPC) as a chiral derivatizing agent. The average amount of (-)-methamphetamine isomer excreted in the urine was found to be three fold those of the (+)-isomer.
Following administration of famprofazone to humans, the stereoselective metabolism from the drug to its known metabolites (+,-)-ephedrine, (+,-)-pseudoephedrine, (+,-)-norephedrine, (+,-)-norpseudoephedrine, (+,-)-p-hyroxyamphetamine, (+,-)-p-hydroxymethamphetamine, and (+,-)-p-hydroxynorephedrine was studied. The enantiomers of the metabolites were derivatized with alpha-methoxy-alpha -(trifluoromethyl)-phenylacetyl chloride (MPTA.Cl) as the chiral derivatizing agent for amino groups and N-methyl-N-trimethylsilyl trifluoroacetamide (MSTFA) or N-methyl-N-triethylsilyl trifluoroacetamide (MTESTFA) as protecting agents of the hydroxyl groups. The diastereomeric derivatives were well separated by capillary gas-liquid chromatography and determined by mass spectrometry with selected-ion monitoring (SIM). (-)-Methamphetamine, (-)-amphetamine, (-)-p-hydroxyamphetamine, and (-)-p-hydroxymethamphetamine were exerted in greater amounts than their enantiomers after administration of racemic famprofazone; and (-)-ephedrine, (-)-pseudoephedrine, (-)-norephedrine, and (-)-norpseudoephedrine were found in higher concentration than their enantiomers. Famprofazone was metabolized by product and substrate stereoselective N-dealkylation, beta-hydroxylation, and p-hydroxylation, metabolites of which may be predominantly responsible for the side effects of famprofazone.
Nafazatrom (Miles Laboratories, West Haven, CT) is a potent inhibitor of metastasis in several animal model systems. The compound is active whether cancer cells are injected intravenously or are allowed to spontaneously metastasize from established tumors. Before studying the antimetastatic effects of Nafazatrom in a long-term randomized clinical trial, the authors conducted a preliminary study to evaluate its toxicity as well as its effects on certain parameters hat have been associated with the biology of metastasis. Since the interaction of platelets, monocytes, and tumor cells may be important for metastasis formation, the authors serially evaluated plasma levels of factors secreted from activated platelets (beta-thrombo-globulin and platelet factor 4) that are inversely correlated with platelet survival. Products of arachidonate metabolism from monocytes were also measured since Nafazatrom is known to modulate prostaglandin production. Thirty-one patients received doses of Nafazatrom ranging from 75 to 1500 mg/m2 orally three times a day. The dose was escalated every 2 weeks. There was no toxicity at any dose level. No major antitumor responses were observed. There was no consistent change in levels of platelet factors either within individual patients or for the population as a whole. Although Nafazatrom (20 microM) decreased tritiated arachidonate incorporation into peripheral blood monocytes from normal subjects in vitro, this effect was not seen in patients treated with the drug. Release of 3PGE2 and 3HETE from cultured monocytes was also not altered by treatment with Nafazatrom. It was concluded that Nafazatrom is safe and well-tolerated up to total doses of 4500 mg/day. The data suggest that the antimetastatic activity of Nafazatrom in vivo is mediated by mechanisms other than by a decrease in platelet consumption or by modulation of arachidonate metabolism by monocytes.
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The cobalt(II), nickel(II) and copper(II) complexes of N1-isonicotinoyl-3-methyl-4-(p-hydroxybenzilidene)-2-pyrazolin+ ++-5-one (IMHBP) with different counter anions have been prepared and characterized. An octahedral geometry has been assigned to the cobalt(II) and nickel(II) complexes and a square-planar structure to the copper(II) complexes. IMHBP acts as a neutral bidentate ligand in all these complexes by coordinating through the oxygen atoms of the amide group and carbonyl at position-5. The other coordination sites are satisfied by anions alone or anions and water molecules. The ligand and the complexes were screened for their possible antitumour activity. The copper(II) complexes are appreciably active in reducing mice tumours.
The B-16 melanoma animal cell line and HEC-1A human endometrial cell line treated with Nafazatrom (NFZ) (5 mu/ml) and varying doses of ionizing radiation show a dose response curve of increased colony inhibition with increasing radiation dose. The B-16 line consistently demonstrated enhanced colony inhibition when NFZ was added prior to radiation. This colony inhibition by NFZ was not seen in the HEC-1A cell line. No adverse effect, i.e., increased tumor colony growth, was evident when NFZ and radiation were combined. This study suggests that ionizing radiation can be combined with NFZ without adverse effect on the cell killing effects of either modality.
Nafazatrom was tested against a variety of human malignancies with the human tumor stem cell assay at one or more of the following concentrations: 1, 10, 25, and 100 micrograms/ml X 1 h or 0.05, 0.5, or 5 micrograms/ml by continuous exposure. Major (greater than or equal to 70%) inhibition was noted in 7/52 adenocarcinomas, in 0/9 squamous carcinomas, and 1/17 other malignancies. Intermediate levels of inhibition (50 to 69%) were noted in 7/52, 4/9, and 6/17 of these respective subtypes. No clear trend toward superiority of any dose-schedule was noted. Since nafazatrom has proven non-toxic in our nearly completed Phase I study, and since this study suggests activity against several human cancers, Phase II level testing is warranted.