Dielectric properties of poly[bis(trifluoroethoxy)phosphazene] and poly[bis(m-methylphenoxy)phosphazene]

Dielectric properties of poly[bis(trifluoroethoxy)phosphazene] (PFEP) and poly[bis(m-methylphenoxy)phosphazene] (PmMPP) were studied in a temperature range from ?195 to 120°C and at several frequencies between 0,1 and 100 kHz. In PFEP, two relaxations, an α relaxation above the glass transition temperature (T_g) and a β relaxation below T_g, which are related to a glass-rubber transition and a local molecular motion of short segments, respectively, were observed. However, PmMPP shows no β relaxation. From the above dielectric results, it was concluded that side groups play an important role in molecular motion of the polyphosphazenes. In PmMPP a γ′ relaxation was found below T_g by immersing the polymers into water. The γ′ relaxation is related to the molecular motin of absorbed water.     

Leukocyte(s) degranulation: therapeutic targets in [NTP]O and [NDP]O mediated leukocyte(s) degranulation

Extracellular nucleotide-induced stimulation and activation of peripheral blood leukocyte(s) and subsequent degranulation plays a critical role in immediate type hypersensitivity reaction and other inflammatory diseases. The extracellular nucleotides [NTP]O stimulate a P2Y receptor(s) on human PMN with the pharmacological profile similar to that of the P2Y2 receptor. Whereas, [NTP]O and [NDP]O, bind to P2Y2 and P2Y1 receptors on mononuclear leukocytes. Based on a recent proposal on the molecular mechanism of [NTP]O- and [NDP]O-induced leukocyte(s) degranulation, a scheme indicating the therapeutic targets with potential avenues for attenuating leukocyte(s) degranulation is suggested.     

Hyperbranched Poly[bis(alkylene)pyridinium]s

3,5‐Bis(bromomethyl)pyridine hydrobromide and 3,5‐bis(bromobutyl)pyridine hydrobromide were synthesized from commercially available 3,5‐lutidine. The poly(N‐alkylation) of these monomers readily yielded new hyperbranched polyelectrolytes. The progress of reaction was followed by ¹H NMR. A second‐order kinetic scheme fits the experimental data. Rate constants and activation parameters were determined, showing the higher reactivity of 3,5‐bis(bromomethyl)pyridine hydrobromide. This was explained by the electron‐attractive effect of pyridinium groups on the ? CH₂Br end groups. The structures of the hyperbranched poly[3,5‐bis(alkylene)pyridinium]s were investigated by ¹H and ¹³C NMR spectroscopy and a preliminary study of their properties is reported.

     

Polymorphism of poly[bis(p-methoxyphenoxy)phosphazene]

Well characterized poly[bis(p-methoxyphenoxy)phosphazene] (PB(4-MeO)PP) has been investigated employing X-ray diffraction and differential scanning calorimetry (DSC). The DSC heating scan of the original PB(4-MeO)PP specimen exhibits one exotherm at 110°C and two endotherms at 106°C and 126°C, respectively. Only a single endotherm at 131°C appears on the second heating. X-ray diffraction measurements at elevated temperature reveal that PB(4-MeO)PP crystal is monoclinic (β-form) with unit cell dimensions a = 2,47 nm, b = 1,98 nm, c = 0,983 nm and y = 102° in the range of 106–126°C. Initially PB(4-MeO)PP specimens are observed to be orthorhombic (α-form) with a = 2,39 nm, b = 1,79 nm and c = 0,983 nm. The crystal transforms at 106°C and then changes into the β-form at 110°C according to DSC measurements. At 126°C the β-form crystal changes into a mesophase with an intermolecular distance of 1,44 nm at 150°C. The 3-dimensional orthorhombic γ-form with a = 2,21 nm, b = 2,01 nm and c = 0,963 nm is found at room temperature after specimens are cooled through T(1) = 126°C from the mesophase.     

Metabolism of [1,3-(13)C]glycerol-1,2,3-tris(methylsuccinate) and glycerol-1,2,3-tris(methyl[2,3-(13)C]succinate) in hepatocytes from Goto-Kakizaki rats

The metabolism of [1,3-(13)C]glycerol-1,2,3-tris(methylsuccinate) and glycerol-1,2,3-tris(methyl[2,3-(13)C] succinate) was examined in hepatocytes prepared from hereditarily diabetic Goto-Kakizaki rats. Over 120 min incubation in the presence of one of the two (13)C-labelled esters (2.5 mM), the output of (13)C-enriched glucose averaged 57.1 +/- 18.5 and 54.1 +/- 22.7 nmol per 10(6) cells, when expressed as [1,3-(13)C]glycerol and [2,3-(13)C] succinate equivalent, respectively. In the case of [1,3-(13)C]glycerol-1,2,3-tris(methyl-succinate), the molecules of glucose were symmetrically labelled. In the case of glycerol-1,2,3-tris(methyl[2,3-(13)C] succinate), however, both the single-labelled and double-labelled isotopomers of glucose contained more (13)C atoms in their C(6)-C(5)-C(4) than C(1)-C(2)-C(3) moiety. These findings indicate that glycerol-1,2,3-tris(methylsuccinate), recently proposed as a novel insulinotropic tool for the treatment of non-insulin-dependent diabetes mellitus, is efficiently metabolized in hepatocytes from diabetic rats, the high rate of gluconeogenesis coinciding with channelling of D-glyceraldehyde-3-phosphate between glyceraldehyde-3-phosphate dehydrogenase and phosphofructoaldolase.     

Antiallergic activity of 6-(2-cyclohexylethyl)-[1,3,4]thiadiazolo- [3,2-a]-1,2,3-triazolo-[4,5-d]pyrimidin-9(3H)-one (DS-4574) in rats.

The antiallergic activity of DS-4574 was evaluated in several commonly used rat models for allergic diseases. In passive cutaneous anaphylaxis, DS-4574 given intravenously and orally induced dose-dependent inhibition with ID50 values of 0.55 and 2.8 mg/kg, respectively. In contrast, this compound had no antagonistic activity against the histamine- and serotonin-induced cutaneous vascular permeability. In lung anaphylaxis, DS-4574 inhibited pulmonary function changes induced by the antigen in a dose-dependent manner when it was given intravenously and orally, the ID50 values being 0.04 and 0.89 mg/kg, respectively. DS-4574 also inhibited antigen-induced histamine and leukotriene release in passive peritoneal anaphylaxis following oral administration. In addition, this compound prevented antigen-induced histamine release in passively sensitized mast cells in vitro. These potent activities of DS-4574 in in vivo and in vitro models of immediate-type hypersensitivity reactions suggest that this compound could be useful in the treatment of allergic diseases including asthma.     

Metabolism of D-[1-(13)C]fructose, D-[2-(13)C]fructose, and D-[6-(13)C]fructose in rat hepatocytes incubated in the presence of H(2)O or D(2)O

Isolated hepatocytes from fed rats were exposed for 120 min to D-[1-(13)C]fructose, D-[2-(13)C]fructose, or D-[6-(13)C]fructose in the presence of H(2)O or D(2)O. The identification and quantification of (13)C-enriched metabolites (D-glucose, L-lactate) in the incubation medium and the measurement of their deuterated isotopomers indicated that the ketohexose was phosphorylated predominantly at the intervention of fructokinase and that the majority of the D-glyceraldehyde molecules generated from d-fructose 1-phosphate were further metabolized, e.g., after phosphorylation to D-glyceraldehyde 3-phosphate. It is proposed that the present procedure may help to further characterize the regulation of D-fructose metabolism in both hepatocytes and other cell types.     

Crystallization kinetics of poly[imino(1-oxooctamethylene)] (nylon 8)

Dilatometry and differential scanning calorimetry have been used to study the crystallization kinetics of poly[imino(1-oxooctamethylene)] (Nylon 8) over the temperature range of 182–190°C. The influence of molecular weight and nucleating agents on the kinetic parameters was investigated. Experimental data, analyzed by the AVRAMI equation: Θ = exp(-Ktⁿ), gave values of n = 5 and 6. A mechanism of crystal growth according to a sheaf-like structure, accounted for by the theory for such values of n, has been supported by microscopic observations.     

Antiviral effect of 3-[bis-(2-hydroxyethyl)-amino]-acetophenone-[4,5-diphenyl-oxyazolyl-(2)]hydrazone (IMET 98/69) in mice.

The potential in vivo antiviral activity of 3-[bis-(2-hydroxyethyl)-amino]-acetophenone-[4,5-diphenyl-oxazolyl-(2)]-hydrazone (IMET 98/69) was evaluated on model infections in mice. Animals treated subcutaneously (s.c.) with 1 mmole of the drug per kg body weight once daily for five days were significantly protected against a lethal infection with cardioviruses, Semliki forest virus and vaccinia virus. In influenza A and B virus models no antiviral activity was observed either after s.c. or oral treatment.     

Ion-aggregation in poly[ethylene-co-(2-(4-carboxyphenoxy)ethyl methacrylate)] and poly[ethylene-co-(2-(3-carboxypyridin-6-yloxy)ethyl methacrylate)] based ionomers

Two new ethylene ionomers were synthesized, poly[ethylene-co-(5.4-mol-% 2-(4-carboxyphenoxy)ethyl methacrylate)] partially neutralized with Zn(II) (EMAA-BZnX), and poly[ethylene-co-(5.4 mol-% 2-(3-carboxypyridin-6-yloxy)ethyl methacrylate)] (EMAA-N) and its hydrochloride (EMAA-NHCl). Differential scanning calorimetric (DSC), X-ray diffraction, and dielectric and dynamic mechanical relaxation studies were made for the two ionomers to investigate the formation and structure of ionic aggregates. In EMAA-BZnX, DSC, dielectric and dynamic mechanical data suggest the formation of ionic aggregates in the neutralization range above 40%; X-ray diffraction data, however, did not show any ionic peak, while the ionic groups were not aggregated at all in EMAA-NHCl. From these results, the ion-aggregation in ionomers is discussed with respect to chemical structure and the nature of ionic groups.     

Immunopharmacologic Properties of 1,6-Bis[2-(Diethylamino) Ethoxylxanthen-9-One Dihydrochloride (Wy-15297)

When tested in a series of immunopharmacologic assays, the inter-feron inducer, WY-15297, was shown to lack activity in early vascular and humoral phases of the inflammatory response, while it was quite effective against the immunologic phase. The profile of activity of Wy-15927 was, however, unlike those previously described for reference antiinflamatory and immunosuppressive drugs and this may represent one of a new class of immunopharmacologic agents capable of selectively modulating the lymphoreticular system.     

Pancreatic uptake of [2-(14)C]alloxan

The uptake of [2-(14)C]alloxan by the pancreatic gland was investigated in control and streptozotocin-induced diabetic (STZ) rats, using both in vitro and in vivo techniques. Whether after 10 to 60 min incubation of pieces of pancreas in the presence of [2-(14)C]alloxan or 60 min to 24 h after intravenous injection of [2-(14)C]alloxan to control and insulin-treated STZ rats, the radioactive content of the pancreas (dpm/mg wet weight) only represented, in the STZ rats, about two thirds of the reference value found in control animals. These findings indicate that insulin-producing islet B-cells participate to a sizeable extent to the overall uptake of [2-(14)C]- alloxan by the whole pancreatic gland, despite the fact that they account for no more than about one percent of the total pancreas mass. Hence, it should be possible to preferentially label the endocrine moiety of the pancreas, in the perspective of its imaging and quantification by a non-invasive procedure, by use of a suitable radiolabelled molecule selectively taken up by islet, as distinct from acinar, pancreatic cells.     

Cationic degradation of poly(thio-1,1-dimethylethylene) [poly(isobutylene sulfide)]

High molecular weight poly(thio-1,1-dimethylethylene) [poly(isobutylene sulfide)] obtained by anionic polymerization of 2,2-dimethylthiirane (isobutylene sulfide) was degraded to a mixture of low molecular weight compounds when treated with a catalytic amount of methyl trifluoromethanesulfonate. The following degradation products were found: 2,2,5,5-tetramethyl-1,4-dithiane (3) , 2,2,6,6-tetramethyl-1,4-dithiane (4) , 2-isopropyl-4,4-dimethyl-1,3-dithiolane (2) , and an equimolar mixture of 3,3,6,6-tetramethyl-1,2,5-trithiepane (5) and 2-methylpropene (isobutylene). The formation of dithiolane 2 is explained by a hydride transfer to a transient carbenium ion.     

Esterolytic action of poly[p-vinyl(thiophenol)-co-acrylic acid]

Hydrolyses of p-nitrophenyl acetate (PNPA) and 3-acetoxy-N,N,N-trimethylanilinium iodide (ANTI) catalyzed by poly[p-vinyl(thiophenol)-co-acrylic acid] (PSH) were studied in the pH range of 8 – 9,5. The reaction of PNPA followed pseudo-first-order kinetics and was found to be catalyzed by the thiophenolate ions on the polymer backbone. In the case of positively charged ANTI, the rate of catalysis showed substrate saturation phenomena and could be described by a Michaelis-Menten kinetics. This indicates that this reaction proceeds via a complex formed by electrostatic interaction between the substrate and the negatively charged polymer catalyst. When ionic strength was increased to 0,12 mol/l the reaction did not further follow the Michaelis-Menten kinetics, suggesting that the complexation constant or the reaction rate of the complex might vary with the amount of the substrate incorporated in the polymer domain. Positively charged N,N,N-trimethylanilinium iodide competively inhibited the PSH-catalyzed hydrolysis of ANTI.     

Effect of 3-[bis-(2-hydroxyethyl)-amino]-acetophenone-[4.5-diphenyl-oxazolyl-(2)]-hydrazone (IMET 98/69) on lethal mengo virus encephalitis.

3-[Bis-(2-hydroxyethyl)-amino]-acetophenone-[4.5-diphenyl-oxazolyl-(2)]-hydrazone (IMET 98/69) was found to afford maximum "rates of protection" in intraperitoneally (i.p.) or intranasally (i.n.) induced Mengo virus encephalitis in mice when administered once daily at doses of 1 mmole/kg (456.5 mg/kg) subcutaneously (s.c.) or 4 mmoles/kg (1 826 mg/kg) perorally (p.o.). Three days of treatment were sufficient if started on the day before or at the time of virus inoculation. Initiation of treatment 6 hours after inoculation was no longer effective. In a remarkable number of brains from infected and treated mice no virus was detectable, while in the remaining brains the appearance of virus was strongly delayed, and its amount significantly reduced.     

Immobilization of alpha-[di-(beta-chloroethyl)-amide]-N-(m-nitrobenzoyl)-D,L-asparagic acid on xanthan

The paper studies the coupling reaction, through ester-type covalent bonds, of an oxazolone derived from the N-(m-nitrobenzoyl)-L-asparagic acid, the cycle of which is opened with an N-mustard derivative, on xanthan (a polysaccharide of microbian synthesis), in conditions of activation with dicyclohexyl carbodiimide. The coupling product has been characterized through elemental analysis and IR spectroscopy. For the establishment of the capacity of the active principle's controlled release by the polymer-active principle system thus obtained, active principle's release kinetics from the polysaccharide support, in conditions of basic hydrolysis, is studied. In vivo tests realized on mice proved the antitumoral activity of the compounds resulted by chemical bonding of the N-mustard derivative on xanthan.     

Study on antithrombogenicity of poly[beta-(acetylsalicylyloxy)ethyl methacrylate] relative to poly(hydroxyethyl methacrylate)

The antithrombogenicity of a polymer made of aspirin bound to hydroxyethyl methacrylate (HEMA), abbreviated as ASA-polymer, was compared with that of poly(hydroxyethyl methacrylate) (PHEMA). Platelet from platelet rich plasma (PRP) incubated with ASA-polymer surface exhibited noticeable decreases in adhesion and aggregation as compared to platelets incubated with PHEMA. Low molecular weight components other than aspirin, which may be released from ASA-polymer during the incubation with PRP, or contact with ASA-polymer causing denaturation of platelets without morphological changes could be responsible for the decrease of adhesion and aggregation. Both PRP and PPP exposed to ASA-polymer-coated surfaces exhibited a much smaller partial thromboplastin time (PTT) than if exposed to PHEMA-coated surfaces; the PTT of ASA-polymer was similar to that of glass exposed plasma. With respect to the in vivo antithrombogenicity, the ASA-polymer surface led to thrombus formation. This may be due to the partial hydrolysis of the acetyl groups resulting in the formation of a negatively charged surface which in turn accelerates the coagulation cascade despite its inhibitory effects on platelet adhesion and aggregation. On the other hand, neointima formed around a thrombus layer on PHEMA-coated sutures after 14 days.