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Effects of acid proteinase inhibitors on human neutrophil chemotaxis and lysosomal enzyme release. II. Bromphenacyl bromide and 1,2-epoxy-3-(p-nitrophenoxy)propane.

Two active site inhibitors of acid proteinases were tested for their effects on human neutrophil chemotaxis and lysosomal enzyme release. Both bromphenacyl bromide (BPAB) and epoxy-p-nitrophenoxypropane (EPNP) inhibited chemotaxis and chemotaxin-induced enzyme release elicited by pepstatin and formylmethionyl peptides, which share membrane receptors, and also by zymosan-activated serum, the major active component of which (C5a) occupies a different receptor. In contrast to the previously tested acid protease inhibitor diazoacetylnorleucine methyl ester, neither BPAB nor EPNP blocked binding of [3H]fMLP to neutrophils. Thus BPAB and EPNP inhibit chemotaxin-mediated neutrophil functions, but not by interaction with the chemotaxin receptor.

Acetophenones↗

Reinforcement of polymers of 2,2 bis-4(2-hydroxy-3-methacryloyloxy propoxy) phenyl propane by ultra-high modulus polyethylene fibres.

A study has been made of the reinforcement of 2,2 bis-4(2 hydroxy-3-methacryloyloxy propoxy) phenyl propane/tetra-hydrofurfuryl methacrylate copolymers with ultra-high modulus polyethylene fibres. The fibres were orientated longitudinally, in loadings up to 50% w/w, and both untreated and surface treated fibres were studied. Modulii up to approximately 35 GPa were achieved in the axial direction, and the specimens could not be broken in the simple flexure test employed. Electron microscopy of fractured specimens showed extremely good contact between resin and fibre. No deterioration in properties was observed over 6 months in water.

Biocompatible Materials↗

Evaluation of skin carcinogenicity of technical 2,2-bis-(p-glycidyloxyphenyl)-propane in CF1 mice.

The carcinogenic potential of a technical-grade epoxy resin, Araldite GY 250, of which the diglycidyl ether of bisphenol A (DGEBPA) is the main component, was investigated in CF1 mice. Groups of 50 male and 50 female mice were treated for 2 yr by repeated epidermal application of a 1 or 10% (v/v) solution in acetone. The controls, 50 mice of each sex, were treated with acetone alone. The treatment had no effect on survival and no excess incidence of skin tumours occurred. A positive control group of 50 male and 50 female CF1 mice was treated by epidermal application of 2% (v/v) beta-propiolactone in acetone. In this group there was a high incidence of malignant skin tumours at the site of application and, consequently, increased mortality. Treatment with neither DGEBPA technical nor beta-propiolactone induced systemic neoplasia.

Acetone↗

Polymorphism of pindolol, 1-(1H-indol-4-yloxyl)-3-isopropylamino-propan-2-ol.

Crystallization of pindolol from the melt was studied by differential scanning calorimetry (DSC) and polarized light thermomicroscopy (PLTM) in order to discriminate the polymorphic forms obtained by this method. The crystallization process originates one exothermic signal localized in two different well-defined temperature ranges. Fusion gives rise to overlapped curves, which were analysed by peak-fitting. The polymorphs were identified as the clusters formed with the values obtained for T(peak) of the component curves. Three polymorphic forms were exhibited by pindolol crystallized from the melt. Commercial pindolol presents only two of these forms.

Calorimetry, Differential Scanning↗

The Mt. Diwata study on the Philippines 2000-treatment of mercury intoxicated inhabitants of a gold mining area with DMPS (2,3-dimercapto-1-propane-sulfonic acid, Dimaval).

Ninty-five inhabitants of the gold mining area of Mt. Diwata (on Mindanao, Philippines), who were diagnosed to be mercury (Hg) intoxicated, were orally treated with 2 x 200 mg of the chelating agent DMPS (Dimaval, Co. Heyl, Germany) for 14 days in the course of a UNIDO project focusing on mercury pollution abatement. Blood and urine samples before and after treatment, urine after the first application of DMPS and a hair sample were collected and analyzed for Hg. Before and after treatment extensive anamnestic data were collected, medical and neurological investigations and some neuro-psychological tests were performed. In spite of the short time of treatment most of the patients reported a marked improvement of the complaints which were stated by them before the therapy and which are characteristic for a chronic Hg intoxication, for example tremor, loss of memory, sleeplessness, metallic taste, etc. But even in some of the objective neurological parameters like hypo-mimia, Romberg test and tests for tremor/ataxia a statistical significant improvement could be found. Significant improvements could also be found in two neuro-psychological tests (pencil tapping and Frostig). In some cases an extreme high urinary Hg excretion was found under the chelating therapy with DMPS, and by this a distinct reduction of the Hg body burden. Nevertheless, in most cases Hg in blood and urine was not markedly decreased by the treatment. This shows that the duration of the treatment (14 days) was not sufficient for a permanent decrease in Hg. As DMPS excretes Hg mainly through the kidney, it can be concluded that in most cases even after 14 days of treatment there was an ongoing redistribution of Hg from other tissues to the kidney. In conclusion, this study proves that a chelating therapy with DMPS is highly effective even in the case of a mixed chronic and acute intoxication with an unknown combination of Hg vapor, inorganic Hg and organic Hg=methylmercury (MeHg), as characteristic for gold mining areas in the third world. Adverse side effects were rarely reported. Only in one case the medication had to be terminated after the first application due to an allergic skin reaction.

Administration, Oral↗

Alkoxy propane prodrugs of foscarnet: effect of alkyl chain length on in vitro antiviral activity in cells infected with HIV-1, HSV-1 and HCMV.

The identification of more effective and less toxic foscarnet (PFA) analogs for antiviral therapy would be useful. We recently synthesized 1-O-octadecyl-sn-glycero-3-phosphonoformic acid (ODG-PFA) and noted a 93-fold increase in its anti-HCMV activity relative to PFA. In addition, the antiviral activity of ODG-PFA in herpes simplex virus type-1 (HSV-1) and human immunodeficiency virus type-1 (HIV-1) infected cells was increased 40-fold relative to PFA (Hostetler et al., 1996. Antiviral Res. 31, 59). To evaluate structure-activity relationships further, we synthesized alkoxypropyl esters of foscarnet with varying alkyl chain lengths and degrees of saturation. These compounds were tested in vitro for activity and selectivity in comparison with PFA and ODG-PFA in cells infected with HCMV, HSV-1 or HIV-1. Antiviral activity was strongly dependent on chain length with alkyl ethers 14-18 carbon atoms long exhibiting the greatest antiviral activity against HCMV and HSV-1. In HIV-infected HT4-6C cells, optimal activity was observed at 18-22 carbon chain lengths. The antiviral activities of 1-octadecyloxypropane-3-PFA and 1-docosyloxypropane-3-PFA were 135- and 338-fold greater than that of PFA in HT4-6C cells infected with HIV-1. This also represents a 2.6-6-fold improvement in antiviral activity over ODG-PFA, the previously reported analog.

Antiviral Agents↗

Syntheses and characterization of titanium(IV) and titanium(III) complexes with (2-dimethylphosphino)ethane-1-thiolate and (3-dimethylphosphino)propane-1-thiolate as ligands.

Reactions of Cp(2)TiCl(2) (Cp = eta(5)-cyclopentadienide) with 2 or 1 equiv of hybrid P-S ligands (L), (CH(3))(2)P(CH(2))(n)()S(-) (n = 2, dmpet; n = 3, dmppt), produced new dicyclopentadienyltitanium(IV) complexes with L, Cp(2)Ti(L-kappaS)(2) (1, L = dmpet; 2, L = dmppt) and [Cp(2)Ti(L-kappa(2)S,P)]BPh(4) (3, L = dmpet; 4, L = dmppt). The Ti(III) complexes, Cp(2)Ti(L-kappa(2)S,P) (5, L = dmpet; 6, L = dmppt), were prepared by the reaction of Cp(2)Ti(eta(3)-C(3)H(5)) with 1 equiv of L. The structures of complexes 1-6 were confirmed by X-ray diffraction analyses. It was found that complexes 3 and 5 were isostructural around Ti(IV) and Ti(III) centers: the Ti(IV)-S bond length in 3 (2.3498(9) A) is shorter by 0.14 A than Ti(III)-S in 5 (2.4877(7) A), while Ti(IV)-P (2.534(1) A) was merely 0.05 A shorter than Ti(III)-P (2.5844(7) A). The redox potential between 3 and 5 in acetonitrile was -1.14 V vs the ferricinium/ferrocene couple. A heterobimetallic complex that has the frame of complex 1, [Cp(2)Ti(dmpet)(2)Cu]PF(6) (7), was also isolated and structurally characterized: the Ti-Cu distance (2.95(1) A) was shorter than that in [Cp(2)Ti(SC(2)H(4)PPh(2))(2)Cu]BF(4), previously reported by White and Stephan. Structural characterization was also carried out for CpTi(dmpet-kappaS)(2)(dmpet-kappa(2)S,P) (8) and CpTiCl(2)(dmppt-kappa(2)S,P) (9), which were obtained by the reactions of Cp(or Cp)TiCl(3) (Cp = eta(5)-C(5)Me(5)(-)) with n equiv (n = 1-3) of L. The mutual site-exchange reaction between phosphorus atoms on a coordinated dmpet in the kappa(2)S,P mode and on two other coordinated dmpet's in the kappaS mode within complex 8 was analyzed by the variable-temperature (31)P[(1)H] dynamic NMR method. The kinetic parameters for this process, k(ex)(298) = 1.9 x 10(5) s(-)(1), DeltaH = 48 kJ mol(-)(1), and DeltaS = 17 J mol(-)(1) K(-)(1), as well as the rather long Ti(IV)-P distance (2.652(1) A), indicate the fluxional nature of the coordination geometry in complex 8.

Journal Article↗