The antinociceptive properties of dalargin as an agent of anesthesiologic protection

The antinociceptive properties of dalargin (D) under nembutal anesthesia and artificial ventilation were studied in hemodynamic response to mechanical algesic stimulation in rats. D was introduced i/v (20 micrograms/kg) against a background of myoplegia with Arduan (0.1 mg/kg) and without it. The naloxon (100 micrograms/kg) prevented the protective effects of D. It is considered that injection of D (20 micrograms/kg) on the background of total myoplegia and artificial ventilation prevented hemodynamic response on algesic stimulus. Subsequent dose increase of opium peptide up to 3500 micrograms/kg does not cause amplification of protective properties.     

Anti-stress effect of dalargin in immobilization stress in rats

The function of the isolated perfused rat hearts was studied in four groups of experiments. Group 1--included the hearts of intact animals ("absolute control"), group 2--the hearts of rats subjected to 24 hour immobilization in supine position against the background of triple intramuscular injections of placebo (control), group 3 included the hearts of rats, which during 24 hour immobilization stress were thrice injected a synthetic analogue of endogenous opioids Dalargin in a dose of 3 g/kg, and group 4 included the hearts of animals, which during immobilization were administered Dalargin in a dose of 10 g/kg of body mass. Ulcer index as indicator of stress injury of gastric mucosa was also determined. In the control group of experiments (group 2) 24 hour immobilization stress resulted in complete depression of cardiac performance as compared with group 1, and ulcer index approximated 1. In group 3 the indices of cardiac performance even exceeded those in group 1 (intact animals). As compared with group 2, ulcer index in group 3 decreased by 9 times. In application of Dalargin in a dose of 10 g/kg complete preservation of heart function indices and complete prevention of stress injury of gastric mucosa were also observed. Thus, Dalargin possesses cardioprotective and anti-ulcerogenic effect in immobilization stress in rats. Most probably, this phenomenon can be attributed to its ability to inhibit the activity of sympathoadrenal system, which gets enhanced during stress.     

Molecular mechanisms of antioxidant action of dalargin on the liver in experimental cholestasis]

Changes of antioxidant activity of dalargin in the liver after naloxone (100 micrograms/kg) administration were examined in experiment on 144 rats with cholestasis. It was found that dalargin inhibited the activity of xanthine oxidase by 32-37% in different time periods after the injection. Dalargin and naloxone, when used in combination, had no effect on the enzyme activity. Glutathione-S-transferase activity rose by 38.0% and 21.8% on hour 1 and 3 after the injection, respectively, while simultaneous injection of dalargin and naloxone induced no changes in the enzyme activity after 1 hour, though decreased it by 36.8% and 26.4% on hour 3 and 5, respectively. Dalargin inhibited lipid peroxidation by 29-35%, simultaneous injection of dalargin and naloxone raised lipid peroxidation by 109.2%, 80.7% and 25.7% after 1, 3 and 5 hours, respectively. Dalargin injection elucidated a marked tendency to lowering of blood release of the liver-specific enzymes histidase and urokaninase in line with enhancement of their activity in the liver. A combined injection of dalargin and naloxone promoted high release of histidase and urokaninase in blood and did not change histidase activity in the liver in all cases. Urokanidase activity elevated in 5 hours. It was noticed that dalargin raised leu-enkephalin levels in the liver 3.5-fold 1 h after the injection. The reduced dalargin antioxidant effect coupled with naloxone pretreatment demonstrated indirect action of the neuropeptide on the liver via neuron receptors of the liver.     

Effect of dalargin on blood and lymph microcirculation

Dalargin (a synthetic analog of leu-enkephalin), when applied to the microvessel surface or administered intramuscularly at doses 0.004-40.0 micrograms/kg increased the permeability of the rat mesenteric microvascular wall and activated the lymph flow due to enhanced contraction of lymphatic microvascular wall and valves. Moreover, Dalargin evoked leukocyte migration from venules and activated the intestinal muscular contractions.     

Effects of dalargin on hemodynamics of anesthesized rats during truncal vagotomy

I/v dalargin injection (20-25 g/kg) to narcotized rats in case of total myoplegia effectively protect hemodynamic changes under nociceptive stimulation. Bilateral truncal vagotomy partially decrease the protective effect of dalargin. Protective effect of the medicine results in activation of central and peripheral opioid receptors.     

Effect of gamma irradiation on brain enkephalin hydrolase activity in the rat

A study was made of the effect of different radiation doses on the brain enzymes degrading enkephalins. Enkephalin aminopeptidase activity decreased during the first 60 min following irradiation with a dose of 774 X 10(-4) C/kg and increased after a dose of 3096 X X 10(-4) C/kg; enkephalinase A exhibited opposite changes. 48 hr after irradiation, enkephalin aminopeptidase activity exceeded the normal level, and no significant changes occurred in encephaliase A activity irrespective of the radiation dose.     

The efficacy of some newer broad spectrum anthelmintics against third-stage larvae of Ancylostoma caninum in the mouse

The efficacy of eight anthelmintics against Ancylostoma caninum larvae in the skeletal muscles of mice was evaluated. Levamisole (5 X 40 mg/kg), thiabendazole (5 X 400 mg/kg), oxfendazole (5 X 100 mg/kg), albendazole (5 X 100 mg/kg), flubendazole (5 X 200 mg/kg), benacil (5 X 200 mg/kg) and phenacizole (5 X 200 mg/kg) showed marked larvicidal activity (98 to 99%). Sch 18099 did not show larvicidal activity even at 5 X 400 mg/kg.     

Bioavailability of dalargin and its metabolism during intranasal administration to rats

Bioavailability and metabolism of a peptide drug Dalargin with a chemical structure Tyr-D-Ala-Gly-Phe-Leu-Arg have been examined. Dalargin is applied for the treatment of gastric and duodenal ulcers. Bioavailability was estimated following intramuscular (i/m) and intranasal (i/n) routes of administration of 3H-dalargin in anesthetized dogs. The highest dalargin concentration was achieved about 10 min after i/m and i/n administration. Absolute dalargin bioavailability was 15% and 8%, while its elimination half-life was 23.2 min and 21.3 min, respectively. Tyrosine, N-terminated tetra- and pentapeptides were the main metabolites detected in the blood. The intranasal route of dalargin administration is concluded to be possible in the clinical practice.     

Solid phase catalytic hydrogen isotope exchange in dalargin

A [3H]Dalargin preparation with a molar radioactivity of 52 Ci/mmol was obtained by the high temperature solid-state catalytic isotope exchange (HSCIE) of tritium for hydrogen at 150 degrees C. This tritium-labeled peptide was shown to completely retain its biological activity in the test of binding to opioid receptors from rat brain. The dissociation constant of the Dalargin-opioid receptor complex was found to be 4.3 nM. The dependencies of the chemical yield and the molar radioactivity on the reaction time and temperature of HSCIE were determined. The activation energy of the HSCIE reaction for the peptide was calculated to be 32 kcal/mol. The amino acid analysis showed that tritium is distributed between all the amino acid residues of [3H]Dalargin at the HSCIE reaction, with the temperature growth significantly increasing the total tritium incorporation and, especially, enhancing the radioactivity incorporation into aromatic residues.     

An evaluation of the efficacy of monensin against Fasciola hepatica in the albino rat

The in vivo efficacy of monensin against Fasciola hepatica was determined in the albino rat. The results were variable, with monensin generally showing greater activity against juvenile (two-week-old) than adult (12-week-old) flukes. Significant (p less than 0.005) reductions in worm burdens were obtained only following treatment of adult flukes with 2 X 10 mg/kg monensin (52.9% efficacy), and of juvenile flukes with 1 X 10 mg/kg (42.4% efficacy) and 2 X 10 mg/kg (56.23% efficacy). Monensin administered in the diet (200 ppm) had a negligible effect on juvenile and adult fluke burdens. Prophylactic treatment of rats with monensin (100 ppm) produced a 45.5% efficacy, but this was not statistically significant. At doses of 1 X 5 mg/kg and 2 X 2.5 mg/kg, monensin had little effect on egg output by F. hepatica. No clear relationship was established between egg output and worm burden, and so faecal egg counting was not a reliable indicator of fluke burdens in the rat.     

The solid-state catalytic isotope exchange of hydrogen in dalargin

A [³H]Dalargin preparation with a molar radioactivity of 52 Ci/mmol was obtained by the high temperature solid-state catalytic isotope exchange (HSCIE) of tritium for hydrogen at 150°C. This tritium-labeled peptide was shown to completely retain its biological activity in the test of binding to opioid receptors from rat brain. The dissociation constant of the Dalargin-opioid receptor complex was found to be 4.3 nM. The dependences of the chemical yield and the molar radioactivity on the reaction time and temperature of HSCIE were determined. The activation energy of the HSCIE reaction for the peptide was calculated to be 32 kcal/mol. The amino acid analysis showed that tritium is distributed between all the amino acid residues of [³H]Dalargin at the HSCIE reaction, with the temperature growth significantly increasing the total tritium incorporation and, especially, enhancing the radioactivity incorporation into aromatic residues.     

The effect of dalargin on stress-induced changes in the 5'-nucleotidase activity of the macrophages and in the level of endogenous blood cortisol in mice]

The action of dalargin, synthetic analogue of leuenkephaline, on stress-induced changes in 5'-nucleotidase activity and endogenous hydrocortisone levels was investigated in mice. It was found that there is a direct relation between the activity of 5'-nucleotidase and the level of hydrocortisone in CBA mice. For C57Bl/6 mice the relation was inverse. Dalargin is able to change the dependence from direct to opposite in CBA mice.     

Responses of baboons to traditionally pyrogenic agents

It is not clear whether baboons develop fever in response to endotoxin or other pyrogens. We injected various pyrogens intravenously in 12 unrestrained baboons (Papio ursinus) and measured their body temperature using intra-abdominal radiotelemeters. Serum iron concentration was also measured. The baboons developed fever after injection of killed Staphylococcus aureus (5 X 10(7) organisms/kg). No significant fever was measured after injection of lipopolysaccharide (Salmonella typhosa) (0.1, 8, 40, and 100 micrograms/kg), bovine serum albumin (4 mg/kg), killed Salmonella minnesota (5 X 10(7) organisms/kg), and killed Salmonella typhi (5 X 10(7) organisms/kg). A significant decrease in serum iron concentration was found only after injection of S. aureus and lipopolysaccharide, 100 micrograms/kg. The phagocytic synthesis of interleukin-1 following pyrogen stimulation in baboons and some other primates appears to differ from that in man and in nonprimates.     

Long-term gentamicin ototoxicity in the rat: research on retro-cochlear involvement by study of evoked auditory potentials of the brain stem

Four groups of rats treated with single (50 mg/kg and 200 mg/kg) or multiple (3 X 200 mg/kg and 5 X 200 mg/kg) doses of gentamycin were studied over a 6-month period and compared with a control group. At 50 mg/kg no significant changes were observed. Significant signs of intoxication were observed at 200 mg/kg doses and at multiple doses. A significant lengthening of the latencies with changes in amplitude and a transitional increase in the auditory threshold were observed as early as the end of treatment. This was followed by a phase of amplitude decrease, a rise in auditory threshold and a decrease in latencies which remains unexplained.     

Effect of dalargin on the processes of memory and learning in the rat

In experiments on rats, the influence was studied of dalargin on the elaboration and preservation of various homogeneous and heterogeneous conditioned reflexes (CRs) elaborated in single and multiple pairings. The effect of dalargin on the processes of learning and memory was compared with the action of the peptide on the activity of hypothalamic neurones. Administration of dalargin delayed the elaboration of maze defensive CRs and practically did not affect the elaboration of two-way avoidance. The preservation of CR also deteriorated under the influence of dalargin. Administration of dalargin 10 min before the CRs testing did not prevent their reproduction. When using CRs elaborated in a single pairing, dalargin disturbed the preservation of the drinking CR and improved that of passive avoidance CR. Dalargin in this dose affected the emotional state of animals in the open field and did not significantly affect their motor activity. Dalargin suppressed impulse activity in 17 out of 22 tested neurones of the lateral hypothalamus, with maximum effect in 20-50 min after its administration. The obtained data show that the character of dalargin action on the elaboration of CR and mainly on its consolidation, depends on the character of the elaborated CR and is probably due to great extent to the effect of the peptide on the brain emotional mechanisms.     

Different isotonic density gradients in separation of renin granules from rat kidney cortex

Crude renin granule preparations isolated from the rat renal cortex were further purified in isotonic conditions (300 mOsm/kg) using various density gradient materials. It was not possible to separate renin granules from other subcellular organelles using dextran, 40,000-sucrose or metrizamide-sucrose gradients at about 300 mOsm/kg. When osmolality of dextran-sucrose gradients was increased, some separation was found but both renin granules and mitochondria gained density. During a short centrifugation (4640 X g, 30 min) renin granules remained intact and appeared in two populations in Percoll-sucrose gradients. The apparently heavier (larger) particles (at 1.12-1.13 kg/l) were greatly purified from mitochondria (80 X purification vs. the whole homogenate), protein (120 X) and lysosomes (24 X). Electron micrographs demonstrated many dense core granules. The fraction containing apparently lighter (small) granules (at 1.08-1.09 kg/l) was heavily contaminated with mitochondria and lysosomes. During longer centrifugation (4640 X g, 60 min), only one major peak showing renin activity was observed at 1.12-1.13 kg/l, and other cell organelles were lighter. Hence the two renin populations evidently do not differ in density but rather in size. In the animals kept on a low-sodium diet, both types of renin granules were increased.     

Effect of cyclosporin A and some derivatives in Litomosoides carinii-infected Mastomys natalensis

Litomosoides carinii-infected Mastomys natalensis were treated 85 days post infection with cyclosporin A (CyA) or 8 derivatives with different immunosuppressive capacities. CyA (oral doses of 5 X 25 mg/kg, 5 X 50 mg/kg, 5 X 80 mg/kg on consecutive days) reduced parasitaemia levels in a dose dependent way, beginning 3 weeks after first drug administration. Using 5 X 50 and 5 X 80 mg/kg animals were free from circulating microfilariae on the day of necropsy (day 56). Derivatives were administered in 5 daily oral doses of 50 mg/kg. Compounds B-5-49 and G-7-53 had similar effects as CyA. Compounds A-4-16 and E-6-44 caused mean microfilaraemia reductions of about 80% until day 56. Compounds C-5-34, D-6-45, F-7-62 and H-7-94 were only marginally effective (10-40%). None of the drugs affected the number or the motility of adult worms. However, in the case of efficacious compounds the number of intrauterine microfilariae was considerably reduced and most of the intrauterine stages were pathologically altered. The efficacy of the various derivatives was independent of their immunosuppressive activity in vivo and in vitro, their anti-inflammatory activity and their activity against Plasmodium berghei. Effects on intrauterine stages were first detectable 7 days after treatment with 5 X 80 mg CyA/kg when the number of intrauterine microfilariae had decreased and the proportion of pathologically altered stages had increased. Alterations increased with time after treatment. Additionally, the uteri contained relatively large amounts of highly active microfilariae which were still included in an ovoid sheath.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tissue-specific clastogenic effects of chromium and selenium salts in vivo

The clastogenic effects of inorganic compounds of chromium (K2Cr2O7) and selenium (Na2SeO3) on the chromosomes of rat lymphocytes and bone marrow have been investigated. In vitro exposure of rat lymphocytes to K2Cr2O7 gave highly significant and dose-related increases in abnormal metaphases at 6 concentrations from 7 X 10(-6) M to 3.2 X 10(-5) M. Similar in vitro exposure of lymphocytes to Na2SeO3 showed that it was clastogenic at concentrations of 7.5 X 10(-6) M, 1 X 10(-5) M and 2.5 X 10(-5) M. However, with in vivo exposures of K2Cr2O7 (i.p. and i.v.) it was only possible to demonstrate clastogenicity in lymphocytes at sublethal concentrations (36 mg/kg X 2 i.v.) and then only if the results were tested against all controls combined (1900 metaphases, 19 animals). On the other hand, very highly significant clastogenic effects were obtained in bone marrow cells exposed in vivo to K2Cr2O7 at 21 mg/kg i.p. and 12, 18, 24 and 36 mg/kg i.v. In vivo exposure to Na2SeO3, with concentrations up to 6 mg/kg X 2 i.v., caused no significant increase in abnormal metaphases in lymphocytes but 5 and 6 mg/kg X 2 i.v. caused a significant increase in abnormal metaphases in bone marrow. These results suggest that K2Cr2O7 and Na2SeO3 are acting as 'S' dependent chemicals. Although not directly comparable, they are compatible with the warnings given by other authors both on the detection of aberrations in lymphocytes after chronic exposure in man and on short-term testing of lymphocytes at low doses related to human exposure.     

Effect of the synthetic Leu enkephalin dalargin on the protein and nucleic acid content of the muscles in the rainbow trout

After dalargin treatment of fish eggs (at the stage of swollen egg envelopes) and on juveniles (at the stage of early meiotic oocyte appearance in gonads) DNA content is observed to raise up to 85% and 66%, respectively in yearlings and up to 20% and 23% respectively in second-year fish as compared to the control ones. Dalargin also influences the exchange of muscle RNA in yearlings and second-year rainbow-trout. Dalargin effect is higher when peptide influences at the very onset of organism differentiation.     

Agonistic activities of isoleucine8-angiotensin II in man

In order to clarify the importance of C-terminal phenylalanine in angiotensin II (ANG II) molecule, agonistic activities of a C-terminal substituted peptide, isoleucine8-angiotensin II (Ile8-ANG II), were studied in comparison with those of sarcosine1-, isoleucine8-angiotensin II (Sar1-, Ile8-ANG II) and isoleucine5-angiotensin II (Ile5-ANG II) in 5 normal men. When infused iv at a rate of 600 pmol/kg X min for 30 min, Ile8-ANG II and Sar1-, Ile8-ANG II raised the blood pressure to the same extent (15/15 mmHg on the average), while the average blood pressure increase was 21/21 mmHg after an iv infusion of Ile5-ANG II at a rate of 5 pmol/kg X min for 30 min. Duration of the pressor action after the cessation of each infusion was 50-90, 90-120 and 10-25 min, respectively. In each case plasma renin activity (PRA) decreased and plasma aldosterone (PA) increased. When infused iv at a rate of 10 pmol/kg X min (maximum non-pressor dose) for 120 min, both Ile8-ANG II and Sar1-, Ile8-ANG II lowered PRA and increased PA gradually, but 100 mg oral captopril given immediately before these infusions caused no significant increase in PRA or no significant decrease in PA but again a decrease in PRA and an increase in PA.(ABSTRACT TRUNCATED AT 250 WORDS)