The role of the tuftsin and Selank peptides in the regulation of primary and plasma homeostasis

Experimental data on the effect of the natural immunopeptide tuftsin and its synthetic counterpart on hemostasis parameters in vitro and in vivo when administered intranasally to animals (white laboratory rats) are given. It has been shown that in vitro both preparations induced a fibrin-depolymerization effect on fibrin that is not stabilized by factor XIIIa. For each preparation, it was noted that, when administered to rats, simultaneous antiplatelet, anticoagulant, and fibrin-depolymerization effects were observed in the blood plasma, with Selank having a more pronounced effect.     

The effect of prostaglandins F2 alpha and E2 on the adrenergic activity of the uterus of laying hens (Gallus domesticus) in vitro

The effect of PGF2 alpha and PGE2 before or after administration of isoproterenol or norepinephrine was studied on uterine strips of White Leghorn laying hens. Prostaglandins (0.2 ng/ml of bath solution) always produced an increase in tension and area under the tracing, the effect of PGF2 alpha being significantly marked especially when administered after norepinephrine. Norepinephrine and isoproterenol (0.1 microgram/ml of bath solution) produced a marked decrease in area under the tracing, the effect of isoproterenol being more potent especially when administered before prostaglandins.     

Antagonism in the action of kinetin and actinomycin D on the cytogenetic effect of radiation

A study was made of the effect of kinetin when administered separately or in combination with actinomycin D on the chromosomal aberrations in Crepis capillaris L. irradiated by X-rays. Dry seeds were treated after irradiation or seeds soaked, prior to irradiation. Significant decrease in the frequency of chromosomal aberrations was shown when actinomycin D was administered separately and prior to kinetin. The latter used separately and prior to actinomycin D slightly increased the level of the aberrations, as compared with the control. Noticeable radioprotective effect was observed after treatment of seeds with kinetin, prior to irradiation.     

Mechanisms underlying the prolactin-lowering effect of metergoline in the rat

Metergoline (MCE), an ergoline derivative with anti-serotoninergic activity was used in rats to determine its effect on the release of prolactin (PRL) and, possibly, the mechanism(s) of this neuroendocrine effect. MCE given by oral, intraperitoneal or subcutaneous route to reserpinized male and female rats proved to be an effective and long-lasting anti-prolactin agent. MCE lowered PRL in hypophysectomized (hypox) rats bearing an ectopic anterior pituitary (AP) when administered parenterally but was completely ineffective when administered orally. In rats with CNS-AP disconnection, blockade of pituitary dopamine (DA) receptors by pimozide completely prevented the PRL-lowering effect of parenterally administered MCE, whereas treatment with 5-hydroxytryptophan (5- HTP) did not impair the effect of MCE on PRL release. In intact male rats, oral administration of MCE completely antagonized the PRL-releasing effect of quipazine and 5-HTP, stimuli which activate the serotoninergic system. MCE slightly inhibited PRL release from AP fragments $\text{in}$$\text{vitro}$.     

Effect of rubomycin and carminomycin on antibody formation during the immunization of mice with various antigens

The maximum immunodepressive effect of rubomycin and carminomycin was observed when the antibiotics were administered intravenously 24 hours after the immunization. The immune response induced by the sheep erythrocytes or the lipopolysaccharide was equally inhibited by rubomycin. Carminomycin in a dose of 0.5 mg/kg (0.1 of the LD50) to a larger extent inhibited the immune response stimulated by the lipopolysaccharide. Dependence of the immunodepressive effect of the antibiotics on their dose was found when the drugs were administered intravenously or orally.     

Effect of ovariectomy and replacement therapy on the tissue lipid pattern in rats.

Ovariectomy increases the percentage of total lipids in liver, kidney and uterus of intact cyclic rats. Estrogen and progesterone, when administered individually to ovariectomized rats, caused a decrease in the total lipid content of all tissues. Th effect of progesterone in estrogen-primed rats is not significant. Triglyceride and cholesterol content increases after ovariectomy; treatment with estrogen in ovariectomized rats led to a decrease in the concentration of these lipids. Progesterone has no significant effect on these lipids but showed an antagonistic action when given in estrogen-primed ovariectomized rats. The proportions of ethanolamine, choline and inositol phospholipids decreased after spaying and increased when estrogen was given to spayed rats. Progesterone alone had effect only on the uterus whereas progesterone administered to estrogen-primed rats showed an antagonistic effect in all tissues.     

Extracorporeal excretion of the mercury from organs by sulfur-bridged complex

The extracorporeal excretion of mercury from the organs by [Mo3S4(Hnta)3]2- (referred to as the NTA complex) solution was investigated using mice exposed to metallic mercury vapor. A decrease in mercury levels was seen in the organs of mice that were administered NTA complex solution when compared to organs in mice receiving L-cysteine or water. Moreover, in mice that were administered NTA complex solution, mercury level in the kidneys decreased at the third and fifth days following mercury exposure. These results suggest that NTA complex solution has the effect of releasing mercury in the living-body as seen when mercury levels are compared with those in the organs of mice that were administered L-cysteine or water.     

Protective Effect of Dietary Xylitol on Influenza A Virus Infection

Xylitol has been used as a substitute for sugar to prevent cavity-causing bacteria, and most studies have focused on its benefits in dental care. Meanwhile, the constituents of red ginseng (RG) are known to be effective in ameliorating the symptoms of influenza virus infection when they are administered orally for 14 days. In this study, we investigated the effect of dietary xylitol on influenza A virus infection (H1N1). We designed regimens containing various fractions of RG (RGs: whole extract, water soluble fraction, saponin and polysaccharide) and xylitol, and combination of xylitol with the RG fractions. Mice received the various combinations orally for 5 days prior to lethal influenza A virus infection. Almost all the mice died post challenge when xylitol or RGs were administered separately. Survival was markedly enhanced when xylitol was administered along with RGs, pointing to a synergistic effect. The effect of xylitol plus RG fractions increased with increasing dose of xylitol. Moreover, dietary xylitol along with the RG water soluble fraction significantly reduced lung virus titers after infection. Therefore, we suggest that dietary xylitol is effective in ameliorating influenza-induced symptoms when it is administered with RG fractions, and this protective effect of xylitol should be considered in relation to other diseases.     

Biological activity of a new Soviet natural inducer, double-stranded RNA

Antiviral activity of a two-spiral RNA (ts RNA), a new natural interferon inductor was studied. It was shown that ts RNA extracted from a phage infected E. coli culture was an active inductor of interferon and resistance to infection with the forestspring encephalitis virus experimental animals. In experiments on 10-12 g mice ts RNA administered in a dose of 50 micrograms/mouse 6 hours after the infection induced up to 1280 units/ml of the serum interferon. When the inductor was administered repeatedly, the experimental animals developed hyporeactivity resulting in a marked decrease in interferon production after the 3rd subsequent injection. The most pronounced effect with respect to the forest-spring encephalitis virus was observed when the inductor was administered intraperitoneally in a dose of 20 micrograms/mouse 4 hours before the infection. The protective effect was less pronounced when the inductor was administered 24 and 48 hours before the infection. A two-fold administration of the inductor did not increase the antiviral effect. When the inductor was administered in a dose of 100 micrograms 14 days before the infection, the animals showed an increase in the nonspecific resistance to the infection resulting in a marked antiviral effect.     

Predictability of Painful Stimulation Modulates the Somatosensory-Evoked Potential in the Rat

Somatosensory-evoked potentials (SEPs) are used in humans and animals to increase knowledge about nociception and pain. Since the SEP in humans increases when noxious stimuli are administered unpredictably, predictability potentially influences the SEP in animals as well. To assess the effect of predictability on the SEP in animals, classical fear conditioning was applied to compare SEPs between rats receiving SEP-evoking electrical stimuli either predictably or unpredictably. As in humans, the rat’s SEP increased when SEP-evoking stimuli were administered unpredictably. These data support the hypothesis that the predictability of noxious stimuli plays a distinctive role in the processing of these stimuli in animals. The influence of predictability should be considered when studying nociception and pain in animals. Additionally, this finding suggests that animals confronted with (un)predictable noxious stimuli can be used to investigate the mechanisms underlying the influence of predictability on central processing of noxious stimuli.     

Effect of superoxide dismutase,allopurinol and glucocorticoids on liver and lung metallothionein induction by endotoxin in the rat

Liver and lung metallothionein (MT) levels were increased by endotoxin. The administration of superoxide dismutase (SOD) or allopurinol (ALLO) before (30–60 min) or after (24–32 h) the endotoxin treatment either increased or did not affect the effect of endotoxin on MT levels, depending on the particular treatment and tissue. SOD and ALLO also increased liver and lung MT levels in control rats. In contrast, liver MT levels tended to be decreased by the glucocorticoid prednisolone (PRED) when administered before the endotoxin and were significantly decreased when it was administered after endotoxin. The effect of PRED on lung MT levels was completely different, since it decreased the effect of endotoxin when injected before the lipopolysaccharide, but increased it when injected after the endotoxin. Liver lipid peroxidation, as measured by thiobarbituric acid reactants (TBARs), increased after endotoxin in the liver but not in the lung, an effect even potentiated in some cases by the antioxidants studied. As expected, tissue MT and TBARs could not be correlated.     

The prophylactic administration of interleukin-2 increases the survival of mice with an acute intra-abdominal infection caused by Staphylococcus aureus]

The effect of RIL-2 on the survival of mice with acute Staphylococcus aureus strain 5/2 intra-abdominal [correction of intraperitoneal] infection was studied. RIL-2 was ineffective when administered simultaneously with the LD100 dose of bacteria. Antibiotics (gentamycin or combination of penicillin and streptomycin) administered in the same fashion cured 100% of animals. However, RIL-2 proved to be effective when administered simultaneously with LD70 dose of bacteria. The prophylactic course of RIL-2 consisting of repeated injections on days 3, 2 and 1 before the challenge with LD100 dose of bacteria also resulted in the marked increase of the survival of mice. The hypothetical mechanisms of action and the prospects of RIL-2 application are discussed.     

Facilitation of receptive behavior in estrogen-primed female rats by the anti-progestin, RU 486

The progestin receptor antagonist RU 38486 (henceforth referred to as RU 486) was tested for facilitative effects on female receptive behavior in ovariectomized Long-Evans rats primed with 2 micrograms estradiol benzoate (EB). RU 486 (0, 0.5, 1.6, or 5.0 mg) was administered 48 hr after estrogen priming. The lordosis quotient (LQ) and lordosis score (LS) were assessed 4 hr after RU 486 administration in a standardized test consisting of a 10-mount test by a stimulus male. A significant dose effect was found by both LQ and LS, with those subjects receiving 5 mg of RU 486 being significantly more receptive than vehicle control animals. Thus RU 486 acted as a weak progestin agonist under testing conditions typical for assessment of progestin facilitation of female sexual behavior in rats. Low levels of proceptive behavior (hops and darts) were seen in a minority of the tests, and did not vary systematically as a function of the dose of RU 486 administered. We also examined the effects of RU 486 given before progesterone (P) on receptivity in a blocking paradigm and confirmed previous reports that the antagonist significantly attenuates facilitation of sexual behavior when given in combination with P. A progestin receptor assay of the cytosols of the hypothalamus-preoptic area in estrogen-primed female rats treated with 5 mg RU 486 revealed a significantly greater depletion of available cytosolic P receptors than when rats were treated with a similarly facilitating dose of P (100 micrograms). The results suggest a possible dual mode of action for RU 486--a weak, receptor-mediated agonistic effect on sexual behavior when given alone to estrogen-primed rats, and a competitive blocking effect on receptivity when administered with P.     

Protection from radiation-induced apoptosis by the radioprotector amifostine (WR-2721) is radiation dose dependent

The radioprotective agent amifostine is a free radical scavenger that can protect cells from the damaging effects of ionising radiation when administered prior to radiation exposure. However, amifostine has also been shown to protect cells from chromosomal mutations when administered after radiation exposure. As apoptosis is a common mechanism by which cells with mutations are removed from the cell population, we investigated whether amifostine stimulates apoptosis when administered after radiation exposure. We chose to study a relatively low dose which is the maximum radiation dose for radiation emergency workers (0.25 Gy) and a high dose relevant to radiotherapy exposures (6 Gy). Mice were administered 400 mg/kg amifostine 30 min before, or 3 h after, whole-body irradiation with 0.25 or 6 Gy X-rays and apoptosis was analysed 3 or 7 h later in spleen and bone marrow. We observed a significant increase in radiation-induced apoptosis in the spleen of mice when amifostine was administered before or after 0.25 Gy X-rays. In contrast, when a high dose of radiation was used (6 Gy), amifostine caused a reduction in radiation-induced apoptosis 3 h post-irradiation in spleen and bone marrow similar to previously published studies. This is the first study to investigate the effect of amifostine on radiation-induced apoptosis at a relatively low radiation dose and the first to demonstrate that while amifostine can reduce apoptosis from high doses of radiation, it does not mediate the same effect in response to low-dose exposures. These results suggest that there may be a dose threshold at which amifostine protects from radiation-induced apoptosis and highlight the importance of examining a range of radiation doses and timepoints.     

Modulation of morphine induced antinociception by intracerebroventricularly administered captopril

Captopril when administered intracerebroventricularly (icv) in doses of 100, 300, 500 and 1000 micrograms induced a dose dependent antinociceptive effect in rats. Naloxone pretreatment (10 mg/kg, ip) completely antagonised antinociceptive effect of captopril, suggesting thereby the involvement of brain enkephalinergic system. Captopril 300 micrograms, icv potentiated the antinociceptive effect of morphine in intact animals. The bilateral adrenalectomy did not have any effect on this potentiation as against the reported blockade of potentiation in adrenalectomized animals when captopril was administered by systemic route. Thus potentiation of morphine induced antinociception by icv captopril is unlikely to be exerted through an effect on adrenal function and is most likely due to increased brain enkephalin levels.     

The effect of collagen degradation products (CDP) on the central dopaminergic system

The effect of collagen degradation products (CDP I--molecular weight circa 3000 D and CDP II--molecular weight circa 1200 D) on the central dopaminergic system was studied. Differences in the action of both these fractions in the apomorphine stereotypy test were noted; CDP I administered to rats in a dose of 5 micrograms just before application of the drug inducing the stereotypy enhanced the stereotypic behaviour of the animals whereas a dose of 40 micrograms significantly inhibited such behaviour. CDP II, on the other hand, had no effect on this type of stereotypy. Both fractions given in doses of 15 and 40 micrograms enhanced the stereotypy induced by amphetamine. CDP I and CDP II (15 and 40 micrograms) administered 30 min before observation of the animals intensified the cataleptic action of haloperidol, whereas both fractions (CDP I and CDP II) when administered 45 min before observation reduced the catalepsy.     

Potentiation of the Antihypertensive Activity of Orally Administered Ovokinin,a Vasorelaxing Peptide Derived from Ovalbumin,by Emulsification in Egg Phosphatidylcholine

Ovokinin, a vasorelaxing octapeptide derived from ovalbumin, significantly lowered the systolic blood pressure of spontaneously hypertensive rats (SHR) when orally administered as an emulsion in 30% egg yolk at a dose of 25 mg/kg, this effect being larger than that of the peptide administered as a solution at a dose of 100 mg/kg. Egg phospholipid, especially phosphatidylcholine, showed essentially the same effect as egg yolk. However, egg neutral lipid was ineffective. Soybean phospholipid was less effective than egg phospholipid in potentiating the antihypertensive activity of ovokinin.     

Subcutaneous or oral administration of rhIL-11 modulated the contact hypersensitivity response

Recombinant human interleukin 11 (rhIL-11) is a multifunctional cytokine with immunomodulatory activity on both T cells and macrophages. The effects of rhIL-11 in a murine model of contact hypersensitivity (CHS) response have been studied. The CHS response is a T cell-mediated response directed against chemically modified self-proteins following epidermal exposure to haptens. CHS is generated in two phases. The sensitization phase involves dermal dendritic cell recognition of haptenized proteins and antigen presentation. The effector phase involves T cell recognition and activation. In mice sensitized with oxazolone, CHS was induced by secondary challenge to the right ear and measured by ear swelling 24 h later. rhIL-11 significantly suppressed CHS as measured by ear swelling and tissue myeloperoxidase activity when injected subcutaneously for 5 days from the day of sensitization or when administered only on the day before and the day of challenge, but was not effective when administered prior to or on the day of sensitization. These results indicate that subcutaneously administered rhIL-11 may modulate the effector phase of CHS. Administration of rhIL-11 as an oral gavage prior to sensitization also reduced CHS. However oral administration of rhIL-11 after sensitization had no effect. These results suggest that orally and subcutaneously administered rhIL-11 may act through different mechanisms to affect CHS.     

A theory of drug tolerance and dependence II: the mathematical model

The preceding paper presented a model of drug tolerance and dependence. The model assumes the development of tolerance to a repeatedly administered drug to be the result of a regulated adaptive process. The oral detection and analysis of exogenous substances is proposed to be the primary stimulus for the mechanism of drug tolerance. Anticipation and environmental cues are in the model considered secondary stimuli, becoming primary in dependence and addiction or when the drug administration bypasses the natural-oral-route, as is the case when drugs are administered intravenously. The model considers adaptation to the effect of a drug and adaptation to the interval between drug taking autonomous tolerance processes. Simulations with the mathematical model demonstrate the model's behaviour to be consistent with important characteristics of the development of tolerance to repeatedly administered drugs: the gradual decrease in drug effect when tolerance develops, the high sensitivity to small changes in drug dose, the rebound phenomenon and the large reactions following withdrawal in dependence. The present paper discusses the mathematical model in terms of its design. The model is a nonlinear, learning feedback system, fully satisfying control theoretical principles. It accepts any form of the stimulus-the drug intake-and describes how the physiological processes involved affect the distribution of the drug through the body and the stability of the regulation loop. The mathematical model verifies the proposed theory and provides a basis for the implementation of mathematical models of specific physiological processes.     

Combined action of doxycycline and mytilan on the immune response to tularemia antigen]

Combined action of doxycycline and mytilan, a natural polysaccharide, on the primary immune response to the antigen of the tularemia vaccinal strain in CBA mice was studied. The polysaccharide was used to compensate the immunosuppressive effect of doxycycline high doses on the humoral immune response. The maximum stimulation of the antibody titers as compared to the controls (more than 250 per cent) was observed when mytilan was administered simultaneously with or prophylactically 3 days prior to the antibiotic in doses of 2.5 and 25 mg/kg. The use of mytilan in combination with doxycycline high doses made it possible to compensate the antibiotic-induced decrease of DTH and even to stimulate it as compared to the controls. The highest levels of DTH (150 per cent against the control) were observed when mytilan was administered prophylactically in doses of 2.5 and 11.25 mg/kg 3 days prior to immunization. Mytilan had the highest stimulating effect on antibody production. The combined use of doxycycline and mytilan was characterized by significant stimulation of antibody production and DTH when the dose/time regimens were rational.