Effect of lipoic acid on cyclophosphamide-induced diabetes and insulitis in non-obese diabetic mice.

In an animal model of type I diabetes, the non-obese diabetic (NOD) mouse, the influence of the antioxidant lipoic acid (LA) on the development of diabetes was investigated. Acceleration of diabetes development with cyclophosphamide (CY) resulted in 60% diabetic animals with severely infiltrated islets within 1-3 weeks. Daily administration of lipoic acid for 20 or 30 days around cyclophosphamide treatment suppressed the incidence of diabetes to 30% (P < 0.05) and 33%, respectively. Semiquantitative analysis of islet infiltration showed a reduction of severe intraislet infiltration and an increase in the percentage of islets with mild per-insular and periductular infiltrates (from 8.4 to 29.6 and 25.9%, respectively, P < 0.01) after lipoic acid treatment. These results show that the protective effect of lipoic acid on diabetes development correlates with partial suppression of islet inflammation. The anti-inflammatory action of lipoic acid may be due to its ability to scavenge oxygen radicals and to suppress nitric oxide production.

[New central analgesic-acting triaminopyridines]. / Neue zentralanalgetisch wirksame Triaminopyridine.

New Triaminopyridines with a Central Analgesic Activity 2-Amino-3-((prop-1-en-3-yl)oxycarbonylamino)-6-(4-fluorobenzyla mino) pyridine hydrochloride (D-19050) is a centrally and peripherally acting analgesic with rapid onset, long duration of action and a good therapeutic range. D-19050 can be obtained in a 5-step-synthesis starting from 2,6-dichloropyridine.

Azelastine, a new antiallergic/antiasthmatic agent, inhibits PAF-acether-induced platelet aggregation, paw edema and bronchoconstriction.

Azelastine is a phthalazinone derivative with a wide spectrum of pharmacologically relevant activities. Since PAF-acether has been considered to be a potent mediator of asthma, azelastine was assayed for its ability to counteract PAF-acether-induced platelet aggregation, paw edema development and bronchoconstriction. Azelastine exerted a concentration-dependent inhibition of PAF-acether-induced platelet aggregation in human platelet rich plasma with an IC50 of 87 mumol/l and was as effective as ketotifen. PAF-acether-induced paw edema was reduced by intraperitoneal administration of azelastine resulting in an ID50 of 14.4 mg/kg after 2 h. By contrast, ketotifen was not able to inhibit edema development up to a dose of 32 mg/kg i.p. Azelastine and ketotifen, administered intravenously, dose-dependently inhibited PAF-acether-induced bronchoconstriction, starting from the dose of 0.01 mg/kg and resulting in ID50s of 0.03 and 0.02 mg/kg, respectively. These results show that azelastine is endowed with a peculiar anti-PAF-acether action, which may be advantageous in its therapeutic use, in the treatment of asthma.

Effects of mellitic acid (MA) and sodium fluoride (NaF) on the histological appearance of murine fetal tibiae cultured in vitro.

The aim of this study was to develop a standardized image analysis method for localization and quantitative measurement of calcified structures of murine fetal tibiae cultured in vitro as a completion and verification of previous biochemical studies. The calcified structures of bone stained by von Kossa silver technique and the epiphyseal cartilages showing intensive metachromasia with toluidine-blue staining were converted with grey-value window programs and afterwards the areas of the selected structures were measured. The histomorphological investigations showed that the murine tibiae, incubated for a period of 6 days in a medium with addition of 5 mmol mellitic acid, showed both a significant reduction of calcium deposits and an increase of epiphyseal intercellular cartilage matrix. The tibiae incubated in a medium with addition of 0.5 mmol sodium fluoride significantly showed an increase of calcium deposits in the thickened lamellae of the compacta. These histomorphological results confirm previous biochemical studies.

A method for induction of cold, indomethacin and restraint ulcers in rats.

A new method has been developed for producing gastric ulcers in rats. The rapid induction of gastric lesions was achieved by a combination of the administration of indomethacin in addition to cold and restraint stressors. Ulcer indices were easily reproducible and remained constant. In addition, atropine, cimetidine and an antacid were tested for their antiulcerogenic effects with the same model. All three drugs inhibited ulcer development in a dose-dependent manner.

Effects of diclofenac-sodium and salicylate, carticaine, lidocaine and procaine in the cadmium- and heat-induced hemolysis.

In the present study we examined the utility, sensitivity and specificity of the cadmium- and heat-induced hemolysis, investigating the effects of diclofenac, salicylate and lidocaine, carticaine and procaine on the rabbit erythrocyte membrane. In the cadmium-induced hemolysis, which has not been reported, as far as we know, as a test model for local anesthetics, the studied local anesthetics have, to a large extent, protective effects on the erythrocyte membranes, probably based on an osmotic action at drug concentrations of 10(-4) to 10(-2) M. On the other hand, these local anesthetics amplify the heat-induced hemolysis to a variable extent. The studied antirheumatic drugs showed in the cadmium-induced hemolysis that they cannot have the same binding sites as the local anesthetics investigated. In the cadmium-induced hemolysis, the reaction products of the antirheumatic drugs with the membrane protein presumably cannot cause an increase in surface area/volume ratio of the erythrocytes, which is generally regarded as a cause for stabilization. This interpretation could be an explanation for the increase of the cadmium-induced hemolysis by the antirheumatic drugs studied. On the other hand, the antirheumatic drugs inhibited to a variable extent the heat-induced hemolysis.

Effects of NiCl2 and NiO in Wistar rats after oral uptake and inhalation exposure respectively.

The effects of NiCl2 and NiO after oral uptake and after inhalation exposure respectively were investigated in three experiments, using clinical and clinico-chemical methods. I. Oral application of NiCl2 in male rats over a period of 28 days. The NiCl2 concentrations were 2.5; 5.0 and 10.0 microgram/ml in drinking water. II. Inhalation exposure of male rats with NiO-aerosols (0.2; 0.4 and 0.8 mg/m3) over a period of 28 days. III. Inhalation exposure of non-pregnant and pregnant rats with NiO-aerosols (0.8; 1.6 and 3.2 mg/m3) over a period of 21 days. After oral application of NiCl2 and inhalation exposure of NiO in male rats a significant dose-dependent hyperglycaemia occurred. In contrast of these findings the serum glucose content in non-pregnant rats exposed to Ni-concentrations of 0.8 and 1.6 mg/m3 were content in non-pregnant rats exposed to Ni-concentrations of 0.8 and 1.6 mg/m3 were significantly reduced. After NiO inhalation (1.6 and 3.2 mg/m3), exposure signs of a marked macrocytosis occurred in pregnant and non-pregnant rats. The oral application of NiCl2 in drinking water in male rats induced a significant decrease of urea in serum and a significant increase of urea in urine. The activity of alkaline phosphatase in serum was inhibited in male rats exposed to 0.4 and 0.8 mg/m3 NiO-aerosols. No significant difference in serum protein pattern and no 'nickeloplasmin' was detected by serumelectrophoresis and tandem-crossed immunoelectrophoresis after oral inhalation exposure in male rats. Fetuses of exposed dams showed in the groups receiving 1.6 and 3.2 mg/m3 significantly reduced body weights.

[Study on histological and histochemical appearance of fetal mouse tibiae cultured in vitro in comparison with freshly excised tibiae (author's transl)]. / Vergleichende Untersuchungen zum histologischen und histochemischen Bild in vitro kultivierter und frisch exzidierter fetaler Mäuse-Tibiae.

The histological and histochemical appearance of murine fetal tibiae was studied in order to furnish the morphological background for biochemical investigations on in vitro cultures of these organs, used as an experimental model for the study of drug influences on metabolic processes of mesenchymal tissues. Freshly excised tibiae until the 14th day of gestation showed solely cartilagenous structures; first signs of calcification were found after 15 days of gestation and ossification of the diaphysis proceeds until the 17th day. A comparison of tibiae explants excised on the 17th day of gestation and cultured for 6 days in vitro with freshly excised tibiae of the same age (17 days) indicates a continuous growth of the explants in vitro without any signs of degenerative processes which could be due to the culture conditions.

[Effects of zinc-aerosols on the inhalation toxicity of cadmium (author's transl)]. / Der Einfluss von Zink-Aerosolen auf die Inhalationstoxizität von Cadmium.

Female rats were continuously exposed for 3 months to an aerosol containing 50 micrograms/m3 Cadmium-Oxyd and 1.25 mg/m3 Zinc-Oxyd. Our results were compared with those of Prigge (1977), who studied the CdO-toxicity under equal conditions. Inour investigations we studied with clinical and clinico-chemical methods a possible protective effect of ZnO on the Cd-toxicity, given simultanously. A protective effect of ZnO on the Cd-toxicity was evident in out investigations in form of a reduced deposition of Cd in lungs, in livers and kidneys. A reduction of the cadmium-induced hyperplasia of lungs was a remarkable sign for a protective action of Zn. There are some criterions, that Zn, given simultaneously in the studied concentrations, can inhibit the Cd-induced disorder of function in kidneys.

Effects of flufenamic acid, dexamethasone, and SP 54 (a pentosanpolysulphate) on the histological appearance of murine embryonic tibia explants cultured in vitro.

The histological investigation of cultured, embryonic tibia explants of NMRI-mice showed, after a six day period, that incubation concentrations of Flufenamic acid, SP54 (a Pentosanopolysulphate), and Dexamethasone (9alpha-Fluor-16-beta-Methyl-Prednisolone) predominantly induced resorptive and degenerative processes, in different degrees, affecting cartilage and bone matrix. In the experiments with Flufenamic acid and Dexamethasone, the degenerative processes were found to be accompanied by the inhibition of the synthesis of cartilage matrix. The investigations with SP54, on the other hand, showed a medium increase of cartilage matrix.

[Experimental studies on the possibility of influencing mast cells in experimental carrageenin-induced rat paw edema. Histological study on the effects of some non-steroidal anti-inflammatory agents (author's transl)]. / Quantitative Untersuchungen zur Beeinflussbarkeit der Mastzellen bei der experimentell durch Carrageenin hervorgerufenen Entzündung an der Rattenpfote. Histologische Untersuchungen zur Wirkung einiger nichtsteroider Antiphlogistika

The protective effect on mast cells of some non-steroid antiphlogistics in the carrageenin-induced edema of the rat hind paw was studied with histological methods. The number of the mast cells was counted in the inflamed connective tissue of unpretreated animals and also such pretreated with acetylsalicylacid, phenylbutazone and indometacin and the results of the test periods were compared with one another. The number of mast cells in the inflamed connective tissue of unpretreated animals was reduced in comparison to the controls during the first 5-35 min after inflammation. Six hours after inflammation the number of mast cells increased. Our investigations demonstrated that the used antiphlogistics produced a significant reduction of mast cell degeneration during the first 5-70 min after inflammation. The results are discussed.

[Histochemical aspects in carrageenan induced inflammation]. / Einige histochemische Aspekte bei der carrageenininduzierten Entzündung

Some changes of groundsubstance and cell proliferation are histochemically demonstrated in the carrageenin induced edema, in the connective tissue of the rat hund paw. We observed, that the leucocytic infiltration (beginning 5 minutes after inflammation) and the desintegration of these cells, induced by liberated lysosomal enzymes, can be assumed to be connected with mastcell degeneration. Fibroblasts and mastcells are correlating in the phase of woundhealing. Iron, which is found in the phagocytes of the connective tissue, in the acute stage of inflammation may not only be a consequence of the desintegration of erythrocytes, its appearance could be interpreted as support of the hypothesis of its antitoxic function.

[Histochemical studies of acid phosphomonoesterase activity in experimental inflammation of the rat's paw caused by carrageenin]. / Histochemische Untersuchungen auf Aktivität der sauren Phosphomonoesterase bei der experimentell durch Carrageenin hervorgerufenen Entzündung an der Rattenpfote)

During the primary phase of inflammation of connective tissue of the paw there was an increase in enzyme activity among the resident connective tissue cells, probably as a result of catabolic processes (lytic processes, phagocytosis). As early as two days after the start of inflammation it was possible to recognize a close relationship between regeneration of the altered tissue (anabolic processes) and the increase of phosphomonoesterase activity in resident cells of the inflamed tissue. The role of the enzyme during inflammation was discussed.