Effects of paracetamol and propacetamol on gastric mucosal damage and gastric lipid peroxidation caused by acetylsalicylic acid (ASA) in rats.

We have studied the effect of paracetamol and its pro-drug propacetamol on gastric mucosal damage induced by acetylsalicylic acid (ASA) and its possible relation to changes in gastric lipid peroxidation status in rats. Paracetamol or propacetamol were administered intragastrically 1h before ASA (300 mg kg(-1)) in the following equivalent doses: 62.5, 125.0 and 250.0 mg kg(-1) or 125.0, 250.0 and 500.0 mg kg(-1), respectively. The effects of the tested agents were compared to that of prostaglandin E2 (PGE2) 15, 30 and 60 mg kg(-1). Gastric ulcer formation was estimated morphometrically 4h after ASA administration. Malondialdehyde (MDA), glutathione (reduced, GSH, and oxidized, GSSG) and uric acid (UA) were determined in gastric mucosa and blood plasma and used as biochemical markers of the oxidative status. The results showed that paracetamol (250, 125, 62.5 mg kg(-1)) and propacetamol (500, 250, 125 mg kg(-1)) diminished the area of ASA-induced gastric lesions. The effect of propacetamol was more pronounced than that of paracetamol and similar to that of PGE2. Gastric MDA increased 3-fold in the ASA-group. The tested agents reduced it by a range of 30-70%. In all pretreated groups gastric glutathione and UA levels were found higher than that of control group and lower than that of ASA-group. Paracetamol and propacetamol, as well as PGE2, diminished the lipid peroxidation in plasma to a lesser extent than in gastric mucosa, but maintained elevated levels of the selective plasma antioxidant UA. These results show that the ASA-induced gastric mucosal damage is accompanied by the development of oxidative stress, evidenced by the accumulation of MDA, and concomitant initial activation of cell antioxidant defences. As paracetamol and propacetamol tend to decrease gastric lesions caused by ASA and alter gastric mucosal MDA, glutathione and UA values in a favorable manner, it could be suggested that their effects on the gastric mucosa could be related to interference with oxidative stress development.

A post-ischaemic single administration of galanthamine, a cholinesterase inhibitor, improves learning ability in rats.

Transient forebrain ischaemia is widely observed in clinical practice. We have examined the effect of a single administration of the cholinesterase inhibitor galanthamine (2mg kg(-1) i.p.) 25 min after reperfusion in male Sprague-Dawley rats (180 +/- 20 g) after a 20-min common carotid artery occlusion. Twenty-four-hours post-ischaemia there was no difference in motor co-ordination or muscle tonus of the rats treated with or without galanthamine as assessed by the rota-rod test. Learning ability was examined using the shuttle-box test, evaluating the latency time and the number of errors for six days in succession. The performance of the ischaemic saline-injected rats was significantly impaired on days 4, 5, 6 (latency time) compared with the non-ischaemic rats and with the ischaemic animals administered galanthamine (P < 0.05). Similar results were obtained when counting the number of errors (failure to cross the cage during conditioned or unconditioned stimulus). The monitoring of body temperature during the first 12-h post-ischaemia did not show any significant difference between the groups. The data showed a beneficial effect of galanthamine on the recovery of learning ability when administered once only post-ischaemia. This suggests a direct effect on the early pathologic mechanisms of CNS damage. Cholinesterase inhibitors may prove useful in the early clinical treatment of ischaemic conditions.

Effect of the acetylcholinesterase inhibitor galanthamine on learning and memory in prolonged alcohol intake rat model of acetylcholine deficit.

Different cholinomimetics are used in conditions of CNS acetylcholine (ACh) deficit. In this study, we examined the effect of the acetylcholinesterase inhibitor galanthamine in a prolonged alcohol intake model of ACh deficit in male Wistar rats. After 16 weeks of alcohol intake and a 2-week pause, rats administered galanthamine (2.5 mg/kg/day i.p.) showed an improved speed of learning and short-term memory in the shuttle box test as compared to the saline-injected alcoholic group (p < 0.05). Four weeks later, significant improvement in the passive avoidance memory of alcoholic galanthamine-treated rats was noted in the eight-arm radial maze (14 day test duration) as compared to the saline-injected alcoholic group (p < 0.05). During the first week in the shuttle box test, the nonalcoholic galanthamine-treated animals exhibited significantly impaired performance as compared to the untreated nonalcoholic control, while four weeks later, in the eight-arm radial maze, both groups did not differ. Our results show that galanthamine improves the speed of learning, short-term memory and spatial orientation of rats in conditions of prolonged alcohol intake.

[The proarrhythmogenic activity of non-anti-arrhythmia drugs. Is treatment with antihistamines and cisapride safe?]. / Proaritmogenna aktivnost na neantiaritmichni medikamenti. Bezopasno li e lechenieto s antikhistamini i s tsizaprid?

The non-antiarrhythmic drugs, which possess antiarrhythmic properties could induce dangerous, potentially fatal arrhythmias--extrasystoles, ventricular tachycardia, sudden cardiac arrest. The arrhythmogenic properties are due to block of the potassium channels of the cells and are realized by prolongation of the QT interval on ECG. Accelerating mechanisms are the bradycardia and the hypokalemia. Such drugs are the H1 blockers--astemisol (hismanal) and terfenadine, the prokinetic cisaprid (prepulsid, propulsid, coordinax) and the macrolides. These preparations should be carefully prescribed and not combined with each other, as well as, with antiarrhythmics and blockers of the cytochrome oxidase system (antifungal antibiotics, metronidazole, cyprofloxacin, antidepressants). During their use the patients have to be followed up for changes in QT, bradycardia, arrhythmia, hypokalemia.

Effect of roxatidine bismuth citrate (MX1) against acetylsalicylic acid- and indomethacin-induced gastric mucosal damage in rats.

We have studied the effect of the newly synthesized agent, roxatidine bismuth citrate (N-[3-(3-(1-piperidinyl-methyl)phenoxy)propyl]-hydroxyacetamide-2- hydroxypropane-1,2,3-tricarboxylate-bismuth(3+) complex), code name MX1, against acetylsalicylic acid (ASA)- and indomethacin-induced gastric mucosal damage in rats. Effects of MX1 (12.5, 50, 125, 184, 250 mg/kg) were compared to the effects of equimolar doses of roxatidine and bismuth subcitrate. Effect of MX1 (10(-6) M) on mucin biosynthesis measured by [3H] glucosamine incorporation in rat gastric corpus has been determined. MX1-pretreatment dose-dependently decreased the mean ulcer number and length in all doses used in an extent similar to that of roxatidine and more pronounced in comparison with bismuth subcitrate. The morphometrical results have been confirmed histomorphologically. The biosynthesis of mucin was found to be significantly enhanced after MX1 addition. The results of the present study suggest that MX1 has a gastroprotective effect against ASA- and indomethacin-induced ulcers which might be due both to its H2-blocking and mucus-stimulating activity.

Effects of dexamethasone in rat neonatal model of axotomy-induced motoneuronal cell death.

In this study the effect of dexamethasone on the motoneuronal cell death and the nuclear and somatic morphology changes occurring after peripheral nerve transection in the neonatal rats has been determined. The study was performed on 3 day old Wistar rats. Animals were divided into 3 groups--control, axotomised, and axotomised and dexamethasone-treated. The nerve transection was performed bilaterally. A dose of 0.5 mg/kg/24h dexamethasone, administered i.p., was used. On day 7 after the operation the animals were sacrificed and the motoneurons in segments L4 and L5 in the spinal cord were counted and their morphology was analysed. 25. 88% cell loss was found in the axotomised group (p<0.001 vs. control) versus 43.33% cell loss in the dexamethasone-treated and axotomised animals (p<0.01 vs. control). Dexamethasone significantly decreased the number of the surviving motoneurons (p<0.05 vs. axotomised). The axotomised group showed enlargement of the somatic area and the maximal and minimal diameters of the cell while the dexamethasone-treated and axotomised group showed soma shrinkage and decrease in the minimal cell diameter. Our results propose a possible hazard towards the application of dexamethasone in the treatment of new-borns with concomitant nerve injuries.

Gastroprotective effect of MX1 (a novel salt of the active metabolite of roxatidine with a complex of bismuth and citric acid) against stress ulcers in rats.

We have studied the effect of the newly synthesized agent MX1, a salt of the active metabolite of the H2-blocker roxatidine with a complex of bismuth and citric acid (N-[3-(3-(1-piperidinylmethyl)phenoxy)propyl]-hydroxyacetamide+ ++ -2-hydroxypropane-1,2,3-tricarboxilate-bismuth(3+) complex), against restraint stress ulcers in rats (24 h immobilization). The effects of MX1 (12.5, 50, 125, 184 and 250 mg kg-1) were compared with the effects of equimolar doses of roxatidine (6.5, 25, 70, 100 and 140 mg kg-1) and bismuth subcitrate (6.5, 25, 70, 100 and 140 mg kg-1). The results show that MX1-pre-treatment, at all the doses used, significantly reduces the mean number and size of ulcers. Even at the lowest dose the number of ulcers was reduced by 64.3% and the size of the ulcer by 55.9%. Roxatidine (25, 70, 100 and 140 mg kg-1) dose-dependently reduces ulcer size and number by 24.6, 55.6, 85.3 and 89.0% and by (+7.2), 14.3, 57.1 and 67.9%, respectively. Bismuth subcitrate significantly reduces ulcer size and number only at the highest dose employed (-28.5 and -44.8%, respectively). The morphometric results have been confirmed histomorphologically. The results suggest that MX1 has a gastroprotective effect against stress-induced ulcers which is similar to that of the parent compound and more pronounced than that of bismuth subcitrate.

[The participation of nitric oxide in the functions of the central nervous system and the cardiovascular system]. / Uchastie na azotniia oksid vuv funktsiite na tsentralnata nervna sistema i surdechno-sudovata sistema.

Nitric oxide (NO) exerts its vasodilatator effect in smooth muscle by activation of guanylyl cyclase. This in turn leads to decreases in intracellular calcium and dephosphorylation of myosin light chains and relaxation. NO is synthesised from L-arginine by a family of enzymes called Nitric oxide synthase (NOS). In the vascular system two isoenzymes of NOS are largely expressed: the constitutive NOS and the inducible NOS. The constitutive NOS identified in the endothelium generates NO continuously providing the vasodilatator tone and modulating platelet function. NOS type 1 is expressed in preoptic and infundibular nucleus of hypothalamus. NO acts as presynaptic agonist of glutamatergic NMDA-receptor mediation in the motor nucleus of nervus vagus. NO decreases the frequency of the spontaneous discharges in the carotid bodies. NO is involved in the processes of synaptic plasticity in the hippocampus.

[The microcomputer study and processing of the values of the blood pressure and intersystolic interval in laboratory animals]. / Mikrokompiuturno proslediavane i obrabotvane na stoinostite na arterialnoto naliagane i mezhdusistolniia interval na laboratorni zhivotni.

A system is created for study of the agents, affecting the arterial pressure and baroreflectory sensitivity, which comprises:transducer for arterial pressure Statham P23 ID, connected to a polygraph Biomedica O.T.E.; eight-bite analogous-numerical transformer; microcomputer, compatible to Apple 2+; two diskette devices and printer. The arterial pressure of the lab animals (rats, rabbits, cats) is directly measured in a. carotis communis by means of the transducer and is recorded on the polygraph. For the system a computer program is designed which allows archivation of the primary experimental data; automatic and precise determination of the momentary values of the systolic and diastolic arterial pressure and intersystolic interval; determination of the baroreflectory sensitivity by means of linear regressive analyses; printing of the results under the form of diagrams and tables. By means of this system much time is spared, related to the accounting and handling of the experimental data.

[Study of the effect of analgeton on the release of beta-endorphin and its effect on chronic hyperalgesia]. / Prouchvane na efekta na analgeton vurkhu osvobozhdavaneto na beta-endorfin i povliiavaneto na khronichna khiperalgeziia.

The effect of the combined preparation analgeton and its components--analgin (metamizol, noramidopyrindimethansulfonate) and aminton (2-amino-4-methyl-pyridinphosphate) was studied on the release of beta-endorphin and its influence on chronic hyperalgesia. Experiments were carried out in vivo and in vitro on white rats and it was established that analgin, aminton and analgeton stimulated the release of beta-endorphin, affecting various regulatory levels. Analgeton in contrast to analgin showed longer analgetic effect in animals with chronic hyperalgesia (adjuvant arthritis of white rats). Possibilities for pharmacological control of chronic pain by influencing the levels of endogenous opioids are discussed.

[Antiexudative effect of naringin in experimental pulmonary edema and peritonitis]. / Antieksudativen efekt na naringina pri eksperimentalen belodroben otok i peritonit.

The authors examined antiexudative activity of bioflavonoids naringin and rutin in comparative aspect in two models of acute inflammation. The experiments were carried out on 180 male white rats and 24 guinea pigs. The two flavonoids manifested marked antiexudative effect in rats with experiments peritonitis, induced by the model of U. M. Teotino et al. ED50 of naringin was 200 mg per kg after oral administration, but of rutin-260 mg per kg. In the same model ED50 of naringin was 67 mg per kg of body weight after intramuscular administration. In rats and guinea pigs with experimental lung oedema naringin, used in a dose of 200 mg per kg intraperitoneally two hours before injection of edemogenous substance (a water solution of ammonium chloride), reduced lethality with 57,4% in rats and with 37% in guinea pigs, but rutin-with 50% and 25% respectively. The examined substances were used in doses, presenting 10% of DL50. There was no statistically significant difference in respect to their antiexudative activity.