Stimulating effect of prodigiozan on nonspecific reactivity in typhoid fever, dysentery and staphylococcal infection]

A number of factors of nonspecific reactivity, i.e. complement, lysozyme, properdin, blood serum bactericidal activity, leucocyte phagocytal activity, phagocytal index and completed phagocytosis were studied on 160 guinea pigs with experimental typhoid fever, dysentery and staphylococcal infections. The data of the study showed that with the use of prodigiozan the non-specific reactivity of the host increased even within a short period of time. At the same time the pathological changes in the internal organs in their histochemical investigation decreased.     

Effect of prodigiozan and pyrimidine derivatives on the effectiveness of the antibiotic therapy of experimental infections]

The effect of prodigiozan and pyrimidine derivatives, such as methyluracyl, oxymetacyl and 2-methyl-4-amino-6-hydroxypyrimidine on the efficiency of antibiotic therapy of experimental infections caused by Staph. aures and E. Coli under conditions of immune depression due to levomycetin, prednisolone, 6-mercaptopurine and ionizing radiation was studied. The effect of prodigiozan on the efficiency of the antibiotic treatment of staphylococcal infection in the presence of the immune depression due to 6-mercatopurine, levomycetin and prednisolone was higher than that of pyrimidines. The combined use of prodigiozan and pyrimidines usually was not more effective than the use of every drug alone. The efficiency of the drugs in radiation disease was the same. After prednisolone administration prodigiozan increased the host resistance to the infection without the antibiotic use.     

Antibiotic therapy of acute dysentery in children with immunologic deficiency conditions

One hundred children with acute Sonnei and flexneri dysentery were followed up with respect to the infection process and main immunity indices. In 32 children the immunity indices were physiological (group 1) and in 68 children secondary immune deficiency was observed (group 2). The children were treated with aminoglycoside antibiotics and prodigiozan and it was stated that the time of recovery in the children with immune deficiency was longer by 5.2 days as compared to that in the children without immune deficiency. In the children with immune deficiency the combined use of one of the aminoglycosides, prodigiozan and lysozyme, led to a reduction of the host immunological reactivity and recovery within the same periods as those recorded for children with the physiological immunity status. It is recommended to use the antibiotic combination with prodigiozan and lysozyme in the treatment of all the forms of dysentery in children with secondary immune deficiency.     

Interferonogenic properties of prodigiozan and its effectiveness in treating acute respiratory diseases in children

The capacity of prodigiozan to stimulate interferon production in the cell culture of the human palatine tonsil lymphocytes was studied. The interferonogenic properties of prodigiozan administered in the form of aerosols to children were also investigated. The efficacy of the prodigiozan aerosols in treatment of children with viral respiratory diseases was estimated. It was shown that prodigiozan stimulated interferon production in the cell culture of the tonsil lymphocytes (the titers of 1 : 2--1 : 8) and induced formation of endogenic interferon in the host (in the tonsils and blood serum) 24 hours after the aerosol administration. 100 micrograms of prodigiozan administered in the form of aerosols in a single dose or in 2 doses at an interval of 1--2 days had a pronounced therapeutic effect 1--2 days after the administration. The use of prodigiozan in treatment of children with acute viral respiratory infections promoted a decrease in the frequency of complications, such as pneumonia and otitis. The data are indicative of the validity of prodigiozan in treatment of children with acute respiratory infections.     

Effect of gentamycin in combination with prodigiozan on the immunological reactivity of the body

The effect of gentamicin sulphate and its combination will prodigiozan on antibody formation in experiments and the levels of the immunobiologic reactivity of patients with purulent inflammatory processes was studied with a purpose of developing rational schemes of antibiotic therapy of infectious diseases. A decrease in the titers of the antibodies to Aeromonas and the number of antibody-forming cells in the spleen was noted on repeated administration of gentamicin to albino mice in a dose of 20 mg/kg. This was prevented by the use of prodigiozan in a dose of 500 micrograms/kg once every 4 days. The use of gentamicin in patients with purulent inflammatory diseases in doses of 40 or 80 mg twice a day for 7--10 days had no significant effect on the titers of IgA, IgG, IgM, lysozyme blood serum levels, serum bactericidal activity and absorption activity of the peripheral blood neutrophils. Still, it induced a marked suppression of the neutrophil digestive capacity as compared to the initial levels, especially on administration of gentamicin in a dose of 40 mg twice a day. An increase in the level of IgM and no suppression of the neutrophil digestive capacity were noted after completion of the therapy in the patients treated with gentamicin administered in a dose of 40 mg twice a day and prodigiozan administered in a dose of 50 micrograms once every 4 days. It is recommended to use prodigiozan in combinaed therapy with gentamicin for correction of the changes in the specific and nonspecific protective forces of the host.     

Chemotherapeutic effect of 3-(5-nitrofuryl)-7-(5-nitrofurfurylidene)-3,3a,4,5,6,7-hexahydro-2H-indazole in experimental staphylococcal infection]

Chemotherapeutic activity of 3-(5-nitrofuryl)-7-(5-nitrofurfuryliden)-3, 3a, 4, 5, 6, 7-hexahydro-2H-indazol (compound 26) was studied on albino mice with experimental staphylococcal infection. The animals were contaminated intraperitoneally. The results of culture of the specimens of the organs of the mice killed within various terms and the values of the spleen bacterial index served as the criteria of the effectiveness. Compound 26 was administered in doses of 20, 10 and 5 mg/kg once a day for 3 days. The treatment was started simultaneously with or 24 hours after the contamination. The results showed that compound 26 in a dose 20 mg/kg (0.4 mg/mouse) possessed high chemotherapeutic activity in experimental staphylococcal infection of albino mice and could be recommended for a thorough study as a potential agent for chemotherapy of staphylococcal infection.     

Combined use of prodigiozan and methyluracil with immunosuppressive drugs in adjuvant arthritis in rats

The effect of the combined use of prodigiozan (0.5 mg/kg bw) prodigiozan with immunosuppressants on the development of adjuvant arthritis was studied on rats. The drugs were given during the prearthritis period from the 1st to the 16th day after injection of complete Freund's adjuvant. It was shown that the combined use of prodigiozan and cyclophosphamide (5 mg/kg) induced significant inhibition of the arthritis development and extraarticular signs of the disease. The efficacy of the combination was higher than that of cyclophosphamide alone. Azathioprine (4 mg/kg/bw) produced no immunosuppressant effect and did not influence the inhibitory effect of prodigiozan on the development of the adjuvant disease. Prednisolone (1.6 mg/kg) either did not inhibit the arthritis development. However, it eliminated the prodigiozan effect. Methyluracil did not change the effect of the immunosuppressants on the articular syndrome. Still, it increased the number of nodular affections in the animals treated with cyclophosphamide and prednisolone. The data obtained show the possibility of prodigiozan combination with certain immunosuppressants in autoimmune affections and confirm the suggestion that the inhibitory effect of this drug is mediated through macrophages.     

Effects of alpha-interferon on the level of adenosine metabolism enzymes and bactericidal activity of macrophages in staphylococcal infection]

In staphylococcal infection the changes in functional ability of macrophages occur: their oxygen-depending bactericidity and adenosine-desaminase activity are depressed 5-nucleotidase ability increases. Introduction of homologous alpha-IFN in the dose of 1 x 10(3) u/mouse leads to enhancing macrophage bactericidity of the animals infected, inhibits their 5-nucleotidase activity and enhances adenosine desaminase one. Influence of alpha-IFN on the activity of adenosine metabolism enzymes in macrophages can be considered one of the most important mechanisms of its modulating effect in bacterial infections.     

Administration of monoclonal anti-IFN-gamma antibodies in vivo abrogates natural resistance of C3H/HeN mice to infection with Leishmania major

C3H/HeN mice that are naturally resistant to cutaneous disease and systemic infections with the protozoan parasite, Leishmania major, were treated at the time of infection, and weekly thereafter, with mouse anti-rat IFN-gamma mAb or an irrelevant antibody of similar isotype. Anti-IFN-gamma-treated mice developed cutaneous lesions; parasites spread to the regional lymph nodes and then metastasized to spleens and livers. The course of disease in these animals was similar to that of genetically susceptible BALB/c mice. Two exceptions in the pathology of L. major infections were noted between BALB/c and anti-IFN-gamma-treated C3H/HeN mice: 1) BALB/c mice died of systemic complications, whereas C3H/HeN mice did not, and 2) multinucleated giant cells were observed in lymph nodes and spleens of infected BALB/c mice, whereas these cells were not observed in infected C3H/HeN mice. Control mice, those treated with either saline or irrelevant antibody of the same isotype as the anti-IFN-gamma monoclonal, showed no evidence of cutaneous disease (development of footpad lesions) or systemic infection (by histopathology). Total abrogation of the natural resistance of C3H/HeN mice could be achieved by treatment with as little as 0.5 mg/mouse/wk of anti-IFN-gamma antibody, or by a single dose of 1 mg/mouse anti-IFN-gamma antibody administered at the time of parasite inoculation. If antibody treatment was delayed for as little as 1 wk after parasite inoculation, the infections in treated animals resembled that of untreated or control antibody-treated mice: no cutaneous lesions (by footpad swelling or viable counts of leishmania in footpad tissue) or systemic disease (by microscopic analysis of touch preparations of internal organs, and histopathology of same). The production of IFN-gamma during the initial interaction of the parasite and host cells appears to be a major component of genetic control of natural resistance to infection with L. major in C3H/HeN mice.     

Nematode infections are risk factors for staphylococcal infection in children

Nematode infection may be a risk factor for pyogenic liver abscess in children and we hypothesized that the immunomodulation induced by those parasites would be a risk factor for any staphylococcal infection in children. The present study was designed to compare, within the same hospital, the frequency of intestinal nematodes and Toxocara infection in children with and without staphylococcal infections. From October 1997 to February 1998, 80 children with staphylococcal infection and 110 children with other diseases were submitted to fecal examination, serology for Toxocara sp., evaluation of plasma immunoglobulin levels, and eosinophil counts. Mean age, gender distribution, birthplace, and socioeconomic conditions did not differ significantly between the two groups. Frequency of intestinal nematodes and positive serology for Toxocara, were remarkably higher in children with staphylococcal infections than in the non-staphylococcal group. There was a significant correlation between intestinal nematodes or Toxocara infection and staphylococcal infection in children, reinforced by higher eosinophil counts and higher IgE levels in these children than in the control group. One possible explanation for this association would be the enhancement of bacterial infection by the immunomodulation induced by helminth infections, due to strong activation of the Th2 subset of lymphocytes by antigens from larvae and adult worms.     

Chemotherapeutic effectiveness of a new derivative of 5-alkyl-3N-furanones in experimental staphylococcal infection

High chemotherapeutic efficacy of the compound 1929, a new derivative of 5-alkyl-3H-furanones was shown in albino mice with experimental staphylococcal infection caused by intraperitoneal administration to the animals. The efficacy was found to be higher than that of furagin used for comparison. The average therapeutic dose (AD50) of the compound for intraperitoneal administration amounted to 40 mg/kg while the average lethal dose (LD50) was 3000 mg/kg.     

Experimental effect of lysozyme on macrophage metabolism and resistance to infection

The peritoneal macrophages of mice treated with lysozyme were studied by cytochemical assay. In single and repeated doses of 0.5-5 mg/kg lysozyme induced an increase in macrophage metabolism. This was evident from an increased activity of succinate dehydrogenase, NADP X N-DH and the enzymes catalyzing glycolysis typical of these cells (lactate dehydrogenase and alpha-glycerophosphate). The changes in the activity of the enzymatic systems were most pronounced in minute and less mature macrophages after repeated administrations of the drugs. In a dose of 50 mg/kg lysozyme somewhat decreased the activity of a number of the enzymes. In the doses optimal for the macrophage activity lysozyme had a low effect on the infection resistance and slightly increased the cephotaxim efficiency in experimental staphylococcal infection. This may be mainly due to the immunomodulating effect of lysozyme and its low effect on the large macrophages having the bactericidal effect.     

Oxidative and phagocytic functions of macrophages during infections induced in mice by Mycobacterium intracellulare and Listeria monocytogenes

The oxidative metabolism (chemiluminescence and H2O2 release) and phagocytic activity of mouse peritoneal macrophages during chronic infections induced by Mycobacterium intracellulare and more acute infections due to Listeria monocytogenes were studied. In M. intracellulare infections, macrophage chemiluminescence in response to phorbol myristate acetate (PMA) was greatest at around 2 weeks, with a 1 week lag phase after infection, while the PMA-triggered H2O2 release was markedly enhanced even 1 d after challenge, and remained high thereafter for up to 10 weeks. The pattern of changes in the phagocytic activity of host macrophages in response to latex beads during this infection resembled the pattern seen with macrophage H2O2 release. In the L. monocytogenes infections, the PMA-triggered chemiluminescence of the host macrophages increased 4 d (in a sublethal infection) and 2 d (in a lethal infection) after bacterial challenge, whereas the PMA-triggered H2O2 release was markedly enhanced as early as 1 d after infection and the elevated level persisted until either the bacteria were eliminated or the animals died. The patterns of changes in phagocytic activity of the host macrophages during L. monocytogenes infection at sublethal and lethal doses differed. In the former, phagocytosis was most active in the early phase of infection, with a peak around day 2, followed by a rapid decrease; in the latter, the phagocytic ability increased more slowly, and remained elevated until the animals died. The results suggest that the macrophages induced by M. intracellulare are in a more activated state than are those induced by L. monocytogenes.     

Side effects of antibiotics in patients with thermal burns]

The possibilities of antibacterial therapy in the clinics of burn diseases has at present decreased because of increasing microflora resistance to antibiotics. This phenomenon is one of the most often causes of antibacterial drug side effects in burn patients. For control of infections complications in burn patients which are most often lethal it is necessary to use biologically active subtance, such as prodigiozan and lysozime in addition to the directed antibiotic therapy. The use of specific antitoxic antistaphylococcal drugs, such as antistaphylococcal plasma and antistaphylococcal gamma-globulin in combination with the antibiotics of the direct action provided effective control of infectious complications and sepsis of staphylococcal genesis in burn patients. Decamine proved to be effective along with the usual use of nystatin in cases with dysbacteriosis as a result of the antibiotic side effects. In the patients treated with decamine the sings of candidosis disappeared by the 5th--7th day. Therefore, for decreasing the side effects of antibiotics in the clinics of burn patients it is expedient to use antibiotics in combination with the biologically active and immune preparations which increases the efficacy of antibiotic therapy, impfoves the treatment results and decreases the antibiotic side effects.     

Effect of Diet and Strain Difference on the Virulence of Staphylococcus aureus for Mice

Years of intensive investigations in our laboratories on staphylococcal infections in mice have indicated a gradual decrease in the virulence of Staphylococcus aureus for this animal, particularly the strain we were using, the random-bred BT mouse. The present investigations, based on changes in diet and strain differences in mice, were undertaken in an attempt to improve susceptibility of our stock strain, on the one hand, and to determine whether susceptibility was influenced by genetic strain differences, on the other. In the first series of experiments, littermate mice of the BT strain were placed on different diets: one group received a commercial diet; the other, a basic diet previously established in our laboratories as adequate for growth requirements of the animals. An increase in the susceptibility of the animals to staphylococcal infection was noted in the mice receiving the basic diet. In the second series of investigations, three other strains of mice (the Swiss albino, the C3H/HeJ, and the C57B1) previously not used by our laboratories in staphylococcal experiments were studied for staphylococcal susceptibility. These experiments revealed that all of these strains of mice were highly susceptible to the infection, even though they were maintained on a commercial diet.     

Effect of gentamycin, decamethoxin and prodigiozan on the course and outcome of experimental pyocyanic infection in white mice]

The therapeutic and prophylactic effectiveness of gentamicin, decamethoxin and prodigiozan was determined on albino mice infected with two-fold lethal doses of the antibiotic-resistant strain of Ps. aeruginosa. Correlation between the effectiveness of the drug and the dose and time of its administration was found. Pronounced prophylactic and therapeutic effect of gentamicin in combination with decamethoxin was noted. Prodigiozan, a bacterial polysaccharide had no significant effect on the experimental pyocyanic infection of albino mice.     

Protective efficacy of combined administration of the multicomponent vaccine and the immunomodulator myelopid in experimental infections in mice

The influence of myelopid (MP) on the protective activity of polycomponent vaccine VP-4 prepared from the antigens of opportunistic bacteria was studied on experimental infections of mice, caused by Klebsiella pneumoniae, Salmonella typhimurium and Staphylococcus aureus. In staphylococcal and Klebsiella infections the joint administration of vaccine VP-4 and MP produced more pronounced protective effect than each of these preparations, introduced alone. The protective action of vaccine VP-4 was specially enforced by MP in cases of local staphylococcal infection. Recommendations on the joint use of two or more immunomodulating agents are possible only on the basis of the experimental substantiation of their effect in definite infections.     

Prophylactic Effects of γ-Aminobutyrylhistidine (Homocarnosine) on Experimental Staphylococcal Infections in Mice

Prophylactic administration of the dipeptide homocarnosine induced a high degree of resistance to staphylococcal infections in Swiss albino mice. It expressed its antistaphylococcal properties 1 hr after administration, and this protection lasted for at least 1 month. Although 5 mg per animal (approximately 200 to 250 mg/kg) was routinely used in our studies, experiments showed that comparable results could be obtained with 1.5 mg per animal. Rechallenge experiments indicated that an active infection by itself may confer immunity up to 4 weeks, but an infection after treatment with homocarnosine gave complete immunity to reinfection for at least 2 months. Studies in vitro showed that homocarnosine had no effect on the growth or certain other characteristics (ability to ferment mannitol, liquefy gelatin, and to produce coagulase, deoxyribonuclease, and pigment) of S. aureus. It appears that resistance induced by this peptide is an indirect effect mediated by some nonimmunological host reaction. The possible involvement of homocarnosine, among other compounds, in the protective action of deproteinized beef extract against staphylococcal infections is suggested.     

Breaking the species barrier: use of SCID mouse-human chimeras for the study of human infectious diseases

Mouse-human chimeras have become a novel way to model the interactions between microbial pathogens and human cells, tissues or organs. Diseases studied with human xenografts in severe combined immunodeficient (SCID) mice include Pseudomonas aeruginosa infection in cystic fibrosis, group A streptococci and impetigo, bacillary and amoebic dysentery, and AIDS. In many cases, disease in the human xenograft appears to accurately reproduce the disease in humans, providing a powerful model for identifying virulence factors, host responses to infection and the effects of specific interventions on disease. In this review, we summarize recent studies that have used mouse-human chimeras to understand the pathophysiology of specific bacterial and protozoan infections.     

Experimental protective action of kanamycin, ampicillin and their combination with methyluracil and pyrogenal]

Efficacy of kanamycin, ampicillin and their combinations with methyluracyl and pyrogenal in experimental Coli infections was studied. The antibiotics were administered an hour after the infection. Methyluracyl and pyrogenal were used according to 2 schemes. Scheme No. I: the drug is used daily for 7 days in increasing doses, the last dose is administered 24 hours before the infection. Scheme No. 2: the drug is used once at the moment of the infection. The methyluracyl doses were: 0.5, 1.0, 2.5 mg and 5 mg and 5 mg per a mouse during the following 4 days. The pyrrogenal doses were: 5, 10, 15, 25, 30 and 35 minimum pyrogenic doses. 5 mg of methyluracyl and 35 minimum pyrogenic doses of pyrogenal were used according to scheme No. 2. The most pronounced increase in the efficacy of kanamycin, ampicillin and their combination was observed in the animals treated simultaneously with methyluracyl and pyrogenal according to scheme No. 1. The efficacy of kanamycin and ampicillin increased 3 and 2.68 times respectively. ED50 of kanamycin and ampicillin used in combination in the animals treated with methyluracyl and pyrogenal was lowered 4 and 2.9 times respectively as compared to that in the animal groups treated only with the antibiotic combination and 21 and 15.2 times respectively when the antibiotics were used alone. Sanation of the animal organs was also rather successful. A single administration of methyluracyl and pyrogenal simultaneously with the infection (scheme No. 2) had a lower effect on the efficacy.