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At least 19 recordsLinked to original sources

PubMed1992

Immunomodulation and drug acetylation: influence of the immunomodulator tilorone on hepatic, renal and blood N-acetyltransferase activity and on hepatic cytosolic acetyl coenzyme A content.

The biochemical alteration responsible for immunomodulator enhancement of drug acetylation in vivo was probed ex vivo and in vitro in the rat. Rat liver or kidney cytosol, obtained by differential centrifugation, or whole blood served as the source of N-acetyltransferase (NAT). Addition of tilorone (0.5-8.0 mM) to incubation mixtures containing procainamide (PA, 0.6 mM) and acetyl coenzyme A (AcCoA, 0.42 mM) resulted in the inhibition of N-acetylprocainamide formation, while lower concentrations of tilorone had no effect. Pretreatment of rats with tilorone (50 mg/kg) administered orally 48 hr prior to sacrifice did not alter hepatic apparent Km and Vmax for NAT toward PA compared to control animals. Utilization of an AcCoA regenerating system in the incubation mixtures also resulted in no significant differences in the apparent Michaelis-Menten parameters obtained. Acetylation activity in kidney and whole blood also was not altered by immunomodulator pretreatment. Hepatic cytosolic AcCoA content was reduced significantly 48 hr after tilorone pretreatment (5.10 +/- 2.1 vs 11.97 +/- 2.2 nmol/mg protein) (P less than 0.05). These data indicate that an increase in NAT content or activity is not the biochemical alteration responsible for immunomodulator enhancement of drug acetylation, and that the required cofactor, cytosolic AcCoA, is decreased by immunomodulator pretreatment.

Acetyl Coenzyme A↗

PubMed1991

Therapeutic effectiveness against MOPC-315 plasmacytoma of low or high doses of the synthetic thymic hormone THF-gamma 2 in combination with an "immunomodulating" or a "non-immunomodulating" drug.

We reported previously that treatment of mice bearing MOPC-315 plasmacytoma with the drugs L-PAM (phenylalanine mustard) or 5-FU (5-fluorouracil), in combination with low doses of THF-gamma 2, was more effective in increasing their survival time than treatment with the drug alone. We show here that in the combined treatment using a single injection of 5-FU followed by multiple (8-15) injections of THF-gamma 2, the megadoses were more effective than the low doses in increasing the survival time of MOPC-315 tumor-bearing mice. On the other hand, in combination with L-PAM, both low and high doses of THF-gamma 2 were equally effective. The need for high doses of THF-gamma 2, when used in combination with 5-FU, could be due to the fact that 5-FU acts as a "non-immunomodulating" drug and has to be used at a high, immunosuppressive dose.

Animals↗

PubMed1991

[Synthesis of heterocyclic immunomodulators. 1. Alkyl derivatives of 1,2,4-dithiazolidin-3,5-diyliden-bis(o-benzoquinone-meth ide): synthesis and testing of immunomodulating action].

Reactions of 1,2,4-dithiazolidine-3,5-diylidene-bis(o-benzoquinone-met hid) 3 with alkyl and substituted benzyl or phenacyl halides yield 1,2,4-dithiazol-3-ylidene-quinone-methides 4a-4i. Mass spectral fragmentations of 4a, 4c, and 4f are discussed. Tests for immunomodulating properties of 4a-c, 4e, and 4g are described. Some of these compounds show immuno-stimulatory activity.

Adjuvants, Immunologic↗

PubMed1988

E. coli infections of the lower urinary tract and their treatment by immunomodulation or combined immunomodulation and antigen therapy.

A model of infection by E. coli 022 of the lower urinary tract in the rat is described. The infection is characterized by the presence in the urine of a large number of E. coli (10(5)-10(7) bacteria per ml). There is pus formation in the urine. A few infected rats also exhibited prostate hypertrophy and the presence of ACB could be detected in some of the latter group. Treatment of the infected rats by the C. granulosum-derived immunomodulator P40, injected intravenously either as a single dose of 1 mg per rat 1 day after infection or as 2 fractionated doses of 0.5 mg 1 day and 3 days after infection resulted in sterilization of a significant number of urines. The interest of fractionating the dose of P40 is to reduce the incidence of prostate hypertrophy formation. Comparable results were obtained when P40 was given preventively to the rats either as a single dose 7 days before infection or as 2 fractionated doses 7 days and 1 day before infection. The association of a single preventive dose of 1 mg of P40 given 7 days before infection by administering a suspension of heat-killed E. coli 022, as a specific antigen, 1 day after infection permitted the sterilization of urines in all infected rats and prostate hypertrophy formation did not occur.

Adjuvants, Immunologic↗

PubMed1985

[Effect of different immunomodulators on the subpopulations of immunocompetent cells. The immunomodulating therapy of respiratory diseases].

Subpopulation analysis of immunocompetent cells of peripheral blood was performed in 286 patients with bronchopulmonary diseases (acute and protracted pneumonia, chronic obstructive and non-obstructive bronchitis). All the examined manifested the presence of secondary immune deficiency of different nature. The authors describe the results of immunomodulatory therapy with levamisole, diuciphon, zixorin, catergen and prodigiosan. Discuss in detail possible causes of the development of immune deficiencies and the mechanisms of action of the immunomodulators.

Adjuvants, Immunologic↗

PubMed1979

Histamine 2 receptor-mediated immunomodulation in the mouse. I. Immunomodulation by the H2 agonist tolazoline.

Tolazoline, a drug used in the treatment of hypertension, has been described as a typical H2 agonist. In this study possible immunomodulating properties of tolazoline were investigated. A single injection of tolazoline 1 day before immunization caused an effect on delayed hypersensitivity that depended on the antigen dose. The response to 10(5) and 10(6) sheep red blood cells (SRBC) was decreased, whereas the response to 10(9) SRBC was enhanced. Administration of tolazoline 4 days after immunization predominantly affected the humoral response. The IgM response was inhibited in favour of the IgG response. Low doses of tolazoline, given to animals simultaneously with the elicitation for delayed hypersensitivity, lead to a more severe inflammation. The possible involvement of suppressor cells and vessels in tolazoline action is discussed. The application of tolazoline in the immunotherapy of human cancer is suggested.

Animals↗

PubMed1990

Chemically induced immunomodulation in domestic food animals.

There is extensive research underway on development of chemical immunomodulators for use in humans. This research is primarily driven by the need for therapeutic immunomodulators for use in patients with cancer or AIDS. Currently, there are no chemicals approved as immunomodulators by the Food and Drug Administration for use in domestic food animals. There is considerable potential for applying the rapid advances in immunomodulation research to benefit domestic animals. In domestic food animals, immunomodulators have the greatest potential for prevention and perhaps therapy in early stages of infectious diseases associated with immunosuppression. There are many different causes for immunosuppression and many different molecular mechanisms responsible for defective function of immune cells. It is unlikely that any one immunomodulator will be capable of preventing or reversing all of these various causes of immunosuppression. Therefore, research is needed to understand the mechanisms of immunosuppression and the mechanism of action of immunomodulators so that rational approaches can be developed for their prophylactic and therapeutic use. Without this information and information on effective dosages and duration of action, attempts to use immunomodulators clinically are likely to produce discouraging results.

Adjuvants, Immunologic↗

PubMed1989

Immunomodulators and feeding regulation: a humoral link between the immune and nervous systems.

Cells of the nervous and immune systems have specific receptors for humoral substances that originate in both systems. These elements establish a bidirectional information exchange network between the nervous and immune systems. In particular, neuroregulators (neurotransmitters and neuromodulators) can modulate specific immune system function(s) and immunoregulators (immunomodulators) can modulate specific nervous system function(s). Modulation of immune functions by neuroregulators has been receiving considerable attention; however, modulation of nervous system functions by immunomodulators has been little studied. The presence of immunomodulators in the brain and cerebrospinal fluid may represent local synthesis by astrocytes, microglia, endothelial cells, intrinsic macrophages and blood-derived lymphocytes which cross the blood-brain barrier, or the concentration of substances derived from the peripheral blood. Acute and chronic inflammatory processes, malignancy, and immunological reactions stimulate the synthesis and release of immunomodulators in various cell systems. These immunomodulators have pivotal roles in the coordination of the host defense mechanisms and repair and induce a series of endocrine, metabolic, and neurologic responses. This paper focuses on the effects of immunomodulators (interleukins, tumor necrosis factor, tuftsin, platelet activating factor, and others) on the central nervous system (CNS), in particular, on feeding regulation. It is proposed that an immunomodulatory system regulates food intake by a direct action in the CNS through a specific neuro-immuno interaction. This regulatory system may be operative during acute and chronic disease.

Animals↗

PubMed1991

[Comparative multifactorial analysis of combined administration of injection and peroral forms of an antibiotic with a microbial immunomodulator in experimental anthrax].

Comparative efficacy of the use of injection and oral dosage forms of rifampicin in the subtherapeutic doses in combination with peptidoglycan , an immunomodulator of microbial origin, was studied in respect to experimental anthracic infection with application of multifactorial analysis. It was shown that the antibiotic and immunomodulator had a pronounced synergistic effect. Polynomial statistic models were developed and nomograms or equal level curves defining the survival rate and average life-span (ALS) of the experimental animals within a wide range of the antibiotic and immunomodulator doses and the peptidoglycan dosing time were plotted. The combined use of the injection rifampicin in the subtherapeutic doses and the immunomodulator provided a significant increase in the survival rate and ALS, whereas the use of the oral antibiotic in combination with the immunomodulator increased only the ALS and not the survival rate. Multifactorial analysis proved to be an optimal methodical approach to comparative study of various antibiotic dosage forms used in combination with immunomodulators under experimental conditions.

Adjuvants, Immunologic↗

PubMed1991

[Optimal combined use of rifampicin and immunomodulator of microbial origin in experimental Q-Rickettsia infection].

Multifactorial analysis of the combined use of rifampicin and an immunomodulator of the microbial origin, such as peptidoglycan, was performed on a model of experimental Q fever in albino mice. On the basis of the experimental results, statistic polynomial models describing the weight of the murine spleens and the titers of the complement-binding antibodies were designed. It was shown that the action of the immunomodulator and antibiotic was highly synergistic with respect to the chemotherapeutic activity and antibody titers. The preventive use of the immunomodulator yielded a 30-fold decrease in a rifampicin therapeutic dose. The use of the immunomodulator also provided a pronounced immunomodulating effect with respect to humoral immunity. Nomographs for optimizing the dose-time parameters of the antibacterial and immunomodulating therapy were plotted.

Adjuvants, Immunologic↗

PubMed1986

Immunomodulators and the complement system.

The possible role of immunomodulators in the host-defense mechanism against neoplasm is discussed from the standpoint of the complement system. Serum complement is activated by the majority of immunomodulators in vitro via either the classical or the alternative pathway, and this activation is sometimes observed following systemic administration of immunomodulators. Besides activating the complement, systemic administration of immunomodulators elevates serum complement levels, and in some cases binds complements to tumor cells. Activated serum complement by an immunomodulator induced an accumulation of PMNs in ascites with tumor cell destruction when intraperitoneally injected, indicating that complement-derived chemotactic factors C3a and C5a generated by an immunomodulator had an antitumor effect. This evidence strongly supports the concept that complement system plays an important role in the host-defense mechanism against neoplasm.

Adjuvants, Immunologic↗

PubMed1992

Determination of the antiinfectious activity of RU 41740 (Biostim) as an example of an immunomodulator.

Evaluation of the anti-infectious activity of an immunomodulator performed either in vitro or in vivo in animals as in humans must answer three questions: what are the targets? what models should be used to study the mechanism of action? what methodology should be selected for the assessment of therapeutic benefit? In the case of RU 41470 (Biostim), an immunomodulator with a known structure and of biological origin affects immunocompetent cells and two essential mediators: II1 and CSF. Because of multiple interactions between anti-infectious, anti-inflammatory and anti-allergic responses, as well as the pleiotropism of mediators, there exists no absolute predictive index of activity in vivo and, independently of models of immune deficiency, experimental infections are a particularly useful pharmacological model for study of the anti-infectious activity of any immunomodulator. In this model, RU 41470 tested by oral, intraperitoneal and aerosol administration, proved to be active regardless of the type of infectious agent for extracellular bacteria, intracellular bacteria, viruses or yeasts. Because of special local features of anti-infectious defences (pulmonary, cutaneous), the target organ must be identified when studying mechanism of action. RU 41740 stimulates the metabolic activities of alveolar macrophage and the target organ is the respiratory tract. From a clinical pharmacology standpoint, stimulation of different immune components has been investigated with RU 41470 at different dosages, using double-blind versus placebo designs. Target pathology, regardless of severity, includes a risk of infection and the existence of an immunological deficiency. Chronic bronchitis is a reference pathology since patients are subject to episodes of infection, resulting in acute decompensation and contributing to worsening of the ventilatory obstructive disorder. Clinical efficacy in terms of anti-infectious prophylaxis must be evaluated by a strict methodological approach: randomized double-blind placebo-controlled trials with prolonged follow-up. RU 41470 is effective in prophylaxis of respiratory infections in chronic bronchitis (reduction in the number of respiratory infections, their duration and in antibiotic consumption) and in prophylaxis of respiratory tract infections in children over one year old. Clinicians faced with the perplexity of the mechanism of action of immunomodulators and their number are preoccupied above all by the response which such an anti-infectious immunomodulator can offer in a context of clinical reality.(ABSTRACT TRUNCATED AT 400 WORDS)

Adjuvants, Immunologic↗

PubMed1990

Model systems to study immunomodulation in domestic food animals.

Development of immunomodulators for use in food producing animals is an active area of research. This research has generally incorporated aspects of immunosuppression in model systems. This methodology is appropriate because most of the research has been aimed at developing immunomodulators for certain economically significant diseases in which immunosuppression is believed to be an important component of their pathogenesis. The primary focus has been on stress-associated diseases (especially bovine respiratory disease), infectious diseases in young animals, and mastitis. The model systems used have limitations, but they have demonstrated that immunomodulators are capable of significantly increasing resistance to these important infectious disease syndromes. As our understanding of molecular immunology increases and as more potential immunomodulators become available, the use of relevant model systems should greatly aid advancement in the field of immunomodulation.

Animals↗

PubMed1992

[Combined experimental use of vaccine against acute human encephalomyelitis and immunomodulators].

Combined use of vaccine and immunomodulators such as ridostin, inosiplex and polyribonate against acute encephalomyelitis of humans (AEMHs) was studied. It was shown that low immunogenic doses of the vaccine did not provide a protective action against the virus of AEMHs while after administration of the vaccine in combination with the immunomodulators there was protection in all the groups of the animals exposed to the low immunogenic doses of the vaccine during the first immunization. It was noted in regard to all the combinations of the immunomodulators and vaccine used in the low immunogenic doses that the level of the increase in the titer of the virus-specific antibodies, the proliferative activity to the specific antigen and mitogens and of interferon induction depended on the immunomodulator type. At the same time, it was found that the marked production of interferon within the first 24 hours observed after the use of the combination of inosiplex, ridostin and the vaccine resulted in increased activity of natural killer cells and lower proliferative activity of cells and production of virus-specific antibodies. This was indicative of the necessity of choosing the immunomodulators, their doses and time of the administration in relation to the immunization.

Acute Disease↗

PubMed1992

Evaluation of assay procedures measuring macrophage stimulation by immunomodulators in vitro.

Several assay procedures for measuring the stimulatory effect on macrophages (møs) of bacterial-derived immunomodulators (OM-85, OM-89, OM-163, Laboratoires OM, Meyrin/Geneva, Switzerland) were evaluated with regard to their complexity, speed, and general convenience. To this effect, bone marrow-derived or peritoneal exudate macrophages were exposed to the immunomodulators in vitro, then tested for metabolic stimulation (glucose oxidation through the hexosemonophosphate shunt pathway, synthesis of type E prostaglandins, release of superoxide, and production of L-arginine-derived nitrogen oxidation products), as well as for enhancement of functional activities (production of tumor necrosis factor-alpha, extracellular cytolysis of P815 target cells, and intracellular parasite destruction). All these tests were found to provide adequate measurements of the mø response to the immunomodulators, with significant effects detectable using the compounds in the ng/ml to microgram/ml range. Concomitant incubation with crude macrophage activating factor or with recombinant murine interferon-gamma (IFN-gamma) dramatically increased the sensitivity of møs to the immunomodulators, and was an absolute requirement for induction of mø cytotoxic activities by the bacterial extracts. The measurement of nitrite production by møs exposed to the immunomodulators with or without treatment with 10 U/ml of IFN-gamma was found to be a highly convenient procedure, which correlated well with functional assays.

Adjuvants, Immunologic↗

PubMed1992

Immunomodulators: current and future development and application.

It has been amply demonstrated that immunomodulators have a place in the armamentarium with other therapeutic modalities for the treatment of various diseases. They presently are, and in the future will be, most effective in preventing diseases which cause, or are the result of, immunodeficiencies. For future development the biological agents that are potent immunomodulators can be more purified and their molecular structures defined and synthesized, such as muramyldipeptides are products of BCG, etc. The active moiety of Picibanil (OK 432), a very powerful immunostimulator should be defined. Further investigations in isolating and characterizing biological agents as immunomodulators should continue in view of the success that has been achieved with BCG in treating superficial transitional cell bladder carcinoma. This mode of treatment is much less toxic to the patient than treatment with the cytotoxic agents thiotepa, mitomycin C. Chemically defined immunomodulators have been used successfully when combined with other therapeutic modalities. Levamisole and its additive therapeutic effect when combined with 5-FU in the treatment of Stage C colorectal carcinoma establishes the potential usefulness of chemicals which specifically augment the immuno response. The explosive growth of cytokine research has led to many technical advances which were key to give cloning and the availability of recombinant cytokines which have extended and modified our concepts of cytokines. The capability of cloning to provide considerable quantities of pure cytokines, permitted studies of immunological, physiological, and therapeutic roles of cytokines. All three classes of immunomodulators: biologicals; chemical; and cytokines will continue to play a major role in advancing and improving the quality of treatment of several of human as well as animal diseases.

Adjuvants, Immunologic↗

PubMed1989

[Immunomodulating properties of interferon inducers].

Data on the immunomodulating activity of interferon inductors are presented. It was revealed that the inductors increased the animal vaccinal response. Schemes for combined use of the interferon inductors and immunomodulators were developed. The immunomodulators were shown to increase the host interferon response evident from synergistic increasing of the interferon titers or prolongation of interferon circulation in blood of the animals. The efficiency of the schemes for combined use of the interferon inductors and immunomodulators was obvious from stimulation of the antibody production. As a result the time of the antibody circulation in blood increased. The effect of the combined use of the immunomodulators and interferon inductors was studied. The combined use of the preparations significantly increased the average life-span of the animals and the rate of their survival.

Animals↗

PubMed1988

[Screening of immunomodulators by using the system of mononuclear phagocytes].

Immunomodulating effects of various agents can be mediated by the system of mononuclear phagocytes (SMP). Immunomodulators are able to interfere with the initial events in activation of mononuclear phagocytes (MP) on their membranes which inevitably has its impact on molecular manifestations of the MP activation: the oxidative outburst events. At the initial (tentative) stage of the screening potential immunomodulators it is expedient to use tests providing estimation of the oxidative outburst intensity by the activity of glucoso-6-phosphate dehydrogenase, the key enzyme of the hexose monophosphate shunt and by the level of superoxydanions production judged by reduction of nitroblue tetrasolium (NBTT). The use of transplantable macrophage-like lines J.744 and P 338D as the targets instead of murine peritoneal MP made it possible to increase reproducibility of the results in screening of immunomodulators. An experimental model of the mouse abdominal cavity clearance within the first hours after intraperitoneal administration of the test bacteria was used for estimating the effect of the potential immunomodulators on the barrier function of the SMP in the host. Experimentally modeled quantitative and functional defects in the SMP served as and adequate test system for study of immunostimulating agents.

Adjuvants, Immunologic↗