Clinical and interferon-modulating efficacy of a combination of rectal and topical dosage forms of interferon-α2b in acute respiratory infections.

AIM: The aim of the study was to evaluate the clinical and interferon-modulating efficacy of a combination of rectal and topical dosage forms of IFN-α2b with antioxidants in the treatment of acute respiratory infections (ARIs) in comparison with other variants of antiviral therapy. MATERIALS AND METHODS: A total of 90 servicemen aged 19.2±0.9 years with uncomplicated forms of ARI were hospitalized not later than 48 hours after the onset of the disease. Patients were randomized into 3 groups of 30 people each. In the first group, patients received rectal suppositories containing IFN-α2b (1 million IU) and antioxidants (alpha-tocopherol acetate and ascorbic acid) twice a day for 5 days. In the second group, patients received intranasally a gel formulation containing IFN-α2b (36 000 IU/1 g) and antioxidants 3 times a day in addition to the above suppositories. In the third group, patients were prescribed umifenovir (reference drug) at dose of 200 mg 4 times a day for 5 days. The dynamics of regression of clinical manifestations of ARI in different groups, changes in concentrations of IFN-α and IFN-γ in blood plasma, as well as spontaneous and induced production of these cytokines by blood cells ex vivo were evaluated. After that, the patients were observed for another 3 months to register repeated cases of hospitalization for ARI. RESULTS: Marked tendency to accelerate the regression of symptoms of intoxication and fever was observed when intranasal dosage form of IFN-α2b was administered to patients receiving the rectal form of this cytokine. The combination of rectal and topical dosage forms of IFN-α2b with antioxidants was more effective than monotherapy with the rectal suppositories in preventing repeated hospitalization for ARI. The above combination caused the most complete correction of induced production of IFN-α by blood cells ex vivo at its initial deviation from the norm. CONCLUSION: The obtained data indicate the expediency of using the combination of rectal and topical dosage forms of IFN-α2b with antioxidants for treatment of ARI.

[Lymphocyte subpopulations, levels of interferon, and expression of their receptors in patients with chronic hepatitis B and C: Correlation with the species of viruses and the degree of liver fibrosis]. / Subpopuliatsii limfotsitov, uroven' interferonov i ékspressiia ikh retseptorov u bol'nykh khronicheskimi gepatitami V i S: zavisimost' ot vida virusov i stepeni fibroza pecheni.

AIM: To determine whether there is a correlation of the composition of circulating lymphocyte subpopulations, the serum concentrations of interferon (IFN)-α, IFN-γ, and IFN-λ3, and the lymphocyte expression of types I and II IFN receptors with the species of a disease pathogen and the degree of liver fibrosis (LF) in patients with chronic hepatitis B (CHB) and in those with chronic hepatitis C (CHC). SUBJECTS AND METHODS: The investigation enrolled 44 patients with CHC, 9 patients with CHB, and 13 clinically healthy donors. The degree of LF in the patients was determined using transient elastography. The composition of peripheral blood lymphocyte subpopulations was examined; the concentrations of IFN-α, IFN-γ, and IL-28B were estimated. RESULTS: Lymphocyte counts were higher in patients with CHC and in those with CHB than those in healthy donors; and the number of neutrophils was lower. There were no differences between the groups in the composition of lymphocyte subpopulations with the exception of the number of CD3+CD4+ cells, which in patients with CHC was larger than in those with CHB. In CHC and CHB patients, the counts of CD118+ lymphocytes were higher than those in healthy donors. Patients with CHB and those with CHC did not differ between themselves and from healthy donors in the expression of CD119 on the lymphocytes. In CHC patients, the relative CD119+ cell counts were higher between CD4+ lymphocytes than those in healthy donors. The serum levels of IFN-α and IFN-γ in CHC and CHB patients were similar, but higher in healthy donors. The concentration of IL-28B genotype in patients with CHC was twice as high as in those with CHB, but the differences were statistically insignificant. The number of lymphocytes increased with the progression of fibrosis; that of neutrophils decreased. There was an inverse relationship between platelet counts and LF severity. Multiple comparisons of the clusters of patients with different degrees of LF revealed no differences in the number of major lymphocyte subpopulations. However, the number of CD3+CD16+CD56+ natural killer-like T (NKT) cells correlated with fibrosis severity. Patients with different degrees of LF showed no differences in the proportion of CD118- and CD119 cells between lymphocytes and in the serum levels of IFN-α, IFN-γ, and IL-28B levels. Patients with grade IV LF displayed a higher proportion of CD4+CD119+ lymphocytes between CD45+ cells than did those with grade III LF. CONCLUSION: Several new clinical and laboratory trends were identified and the nature and extent of previously described hematological and immunological changes were clarified in CHC or CHB patients with various degrees of LF. Some indicators may be used as additional criteria for the prognosis of the above forms of hepatitis, and a number of newly described facts suggest that it is necessary to revise the protective/phlogogenic value of types I, II, and III IFNs in chronic viral hepatitis C and B.

[The influence of gel-like recombinant interferon α-2b on the clinical course of acute respiratory infection and the state of mucosal immunity in the pregnant women].

The objective of the present study was to evaluate the state of local immunity of the mucous membrane in the nose of the pregnant women presenting with acute respiratory infection (ARI). A total of 55 women with this condition were examined at the outpatient basis starting from week 14 of the gestation period. Viferon gel was administered intranasally to 34 such patients. The clinical and immunological effectiveness of the application of the topical form of this recombinant interferon α-2b preparation in these patients was evaluated. It is concluded that the inclusion of Viferon in the combined treatment of ARI in the pregnant women significantly decreases the frequency of bacterial complications. Simultaneously, this preparation reduces the IL-8 level in the nasal secretion in comparison with its initial value.

[The effect of viral infections on the cytokine profile in pregnant women with obstetric complications and immunotherapy with human alpha2b interferon].

The goal of this work was to examine the effects of infections caused by HSV1/2, CMV, and HPV on the cytokine profile in pregnant women with obstetric complications (OC) and to evaluate the efficacy of the therapy with recombinant human alpha2b interferon. Direct markers of the viruses were identified using PCR and rapid culture method in 85 pregnant women divided into 3 groups: group 1 (n = 21), women with visual HPV-related clinical manifestations; group 2 (n = 48), with detectable markers of viral infections and no clinical manifestations, and group 3 consisting of pregnant women with OC without markers and clinical manifestations of viral infections (n = 16). The rate of HPV DNA detection in pregnant women was higher than that of herpesviruses (HV) CMV and/ or HSV: 37.6% vs. 11.8%. The frequency of mixed HV/HPV infection in group 1 was 2.3-fold higher than in group 2. The cytokine levels of IFNalpha, IFNgamma, IL-4, IL-6, IL-8, and TNFalpha in blood plasma and vaginal washings were studied. Statistically significant differences in infected women (groups 1 and 2) in comparison with uninfected women (group 3) were detected: a) blood plasma concentration of IFNgamma increased in clinically manifested HPV infection; b) blood plasma IL-8 concentration increased in clinically manifested HPV and in mixed HV+HPV infections without clinical symptoms of HPV infection; c) blood plasma concentration of TNFalpha increased in women with asymptomatic HPV-infection; d) IL-6 concentration in vaginal washings increased in mixed infection in group 1. The effect of IFN-alpha2b was assessed by analyzing cytokine levels in women on basic therapy with and without Viferon. In infected women, Viferon caused a 2-3-fold decrease in the concentrations of IFNgamma and IL-8 in blood plasma, thus bringing them near those of uninfected women with OC. The analysis of the state of newborns health has shown that for women with OC the risk of giving birth to a child in critical condition is 4.3-fold higher when CMV is detected in the third trimester of pregnancy.

[Impact of herpesvirus infections on the level of proinflammatory cytokines in premature neonatal infants].

The aim of this study was to estimate the frequency of HSV and/or CMV among the pathogens causing intrauterine infections (IUI) and to investigate their impact on the level of proinflammatory cytokines in premature neonatal infants. Examinations were performed in 3 neonatal groups: 1) premature neonates with clinical manifestations of IUI; 2) those without IUI; 3) full-term newborns. In group 1, viral (HSV and/or CMV) and bacterial infections were detectable with the same frequency. Quantitative analysis of plasma IL-6 and IL-8 levels and the induced production of these cytokines by blood cells in vitro showed that in Group 1 neonates, IL-6 and IL-8 concentrations were substantially higher and the induced production of these cytokines was lowerthan those in Group 3. The detection of HSV and/or CMV markers in premature newborn infants was attended by a statistically significant rise in plasma IL-6 levels; the identification of the opportunistic bacterial microflora correlated with the higher concentration of IL-8. In Group 1, wiferon produced an immunomodulatory effect, by lowering IL-8 concentrations to the level observed in Group 3.

[Evaluation of the efficacy of wiferon and arbidol in adult influenza].

The therapeutic efficacy of wiferon (recombinant alpha2beta-interferon) versus arbidol was studied in a double-blind controlled study in patients with laboratorily verified influenza. Within the first 24-36 hours after the onset of the disease, wiferon and arbidol reduced the duration of fever, intoxication, and the catarrhal symptoms of the disease as a whole. The agents were shown to have an immunomodulating effect.

[Effect of tumor necrosis factor DNA on immune response to DNA immunization against herpes simplex virus]. / Vliianie DNK faktora nekroza opukholi na immunnyi otvet pri DNK-immunizatsii protiv virusa prostogo gerpesa.

A study was made of the adjuvant effect of the mouse tumor necrosis factor alpha (mTNF alpha) on DNA immunization against the herpes simplex virus type 1 (HSV1). The HSV1 gD gene (pDNAgD) served as an immunogen; mTNF alpha or its gene cloned in an eukaryotic expression vector (pDNAmTNF) were used to modulate the immune response. Double immunization with pDNAgD led to a sixfold increase in the in vitro T-cell response, a high (1:2000) titer of anti-HSV1 antibodies (including virus-neutralizing antibodies), an increase in IgG2a/IgG1 (suggesting a shift of the immune response to the Th1 type), and no change in CD4/CD8 T-cell ratio. A single injection of mTNF alpha along with inactivated HSV1 allowed a twice higher antibody titer and a fourfold higher T-cell response as compared with immunization with HSV1 alone. Double immunization with both pDNAgD and pDNAmTNF increased the titer of anti-HSV1 antibodies and the T-cell response by factors of 8 and 1.5, respectively, as compared with immunization with pDNAgD alone. However, the protective effect was significantly lower with the two plasmids than with pDNAgD (73 vs. 100%). Thus, DNA immunization with pDNAgD induced both B- and T-cell responses and completely protected mice from a lethal doze of HSV1. The adjuvant properties of mTNF alpha and pDNAmTNF need further investigation.

Volatile metabolites of higher plant crops as a photosynthesizing life support system component under temperature stress at different light intensities.

The effect of elevated temperatures of 35 and 45 degrees C (at the intensities of photosynthetically active radiation 322, 690 and 1104 micromoles m-2 s-1) on the photosynthesis, respiration, and qualitative and quantitative composition of the volatiles emitted by wheat (Triticum aestuvi L., cultivar 232) crops was investigated in growth chambers. Identification and quantification of more than 20 volatile compounds (terpenoids--alpha-pinene, delta 3 carene, limonene, benzene, alpha- and trans-caryophyllene, alpha- and gamma-terpinene, their derivatives, aromatic hydrocarbons, etc.) were conducted by gas chromatograph/mass spectrometry. Under light intensity of 1104 micromoles m-2 s-1 heat resistance of photosynthesis and respiration increased at 35 degrees C and decreased at 45 degrees C. The action of elevated temperatures brought about variations in the rate and direction of the synthesis of volatile metabolites. The emission of volatile compounds was the greatest under a reduced irradiation of 322 micromoles m-2 s-1 and the smallest under 1104 micromoles m-2 s-1 at 35 degrees C. During the repair period, the contents and proportions of volatile compounds were different from their initial values, too. The degree of disruption and the following recovery of the functional state depended on the light intensity during the exposure to elevated temperatures. The investigation of the atmosphere of the growth chamber without plants has revealed the substances that were definitely technogenic in origin: tetramethylurea, dimethylsulfide, dibutylsulfide, dibutylphthalate, and a number of components of furan and silane nature.

[Volatile metabolites and external CO2 exchange of wheat cenoses under optimal conditions and thermal stress]. / Letuchie metabolity i vneshnii gazoobmen CO2 tsenozov pshenitsy pri optimal'nykh usloviiakh i temperaturnom stresse.

The effects of elevated temperature (35 and 45 degrees C) on photosynthesis, respiration, and both the qualitative and quantitative compositions of volatile emissions (VE) of wheat (Triticum aestuvum L. cultivar 232) cenoses at light intensities of 70, 150, or 240 W/m2 of photosynthetically available radiation (PAR) were studied. At a PAR of 240 W/m2, the thermal stabilities of photosynthesis and respiration increased at 35 degrees C and decreased at 45 degrees C. Elevated temperatures nonuniformly changed the rates and direction of VE syntheses. In this process, the highest increase in VE evolution was observed at 70 W/m2; the lowest, at 240 W/m2 and 35 degrees C. In addition, the concentrations and composition of VE during the repair period differed from the initial values.

Russian experience in screening, analysis, and clinical application of novel interferon inducers.

This review describes a long-standing experience of screening for interferon (IFN) inducers in Russia. IFN inducers represent a special group of potential antiviral compounds. The main requirements for them are (1) high IFN-inducing activity, (2) absence of side effects, (3) wide spectrum of antimicrobial activity, (4) broad therapeutic security and, (5) good solubility in water and biologic liquids. IFN inducers stimulate IFN production in different cells and organs, and that determines the strategy for their application. Amixin (OOO "Lancepharm," Moscow, Russia) induces IFN-alpha/beta production mostly in T cells. Cycloferon (NTFF "Polysan," St. Petersburg, Russia) stimulates B cells and macrophages to produce almost pure IFN-alpha. Double-stranded RNA (dsRNA) and polyphenols of natural origin stimulate IFN production in different populations of immunocytes. Only polymers, such as Larifan (Riga, Latvia), Kagocel ("NIARnedicplus," Moscow, Russia), and Ragosin (N.F. Gamaleya Institute, Moscow, Russia), induce IFN synthesis in muscles, so they may be effective against rabies. Cycloferon, Larifan, and Kagocel, which induce IFN formation in lungs, may be effective against influenza and rhinoviral infections. Cycloferon and Larifan stimulate IFN production in liver and spleen and may be effective against hepatitis B. Oral compounds (Amixin, Kagocel) that stimulate IFN production in intestines may be effective against hepatitis A and enteroviral infections. Low molecular weight inducers (Amixin, Cycloferon, Kagocel) that penetrate the blood-brain barrier may be active against viral encephalitis. At present, clinical trials of IFN inducers are limited, but in the near future, IFN inducers may be used against very different infections and conditions.

[Production of cytokines from blood donor leukocytes]. / Produktsiia tsitokinov leikotsitami krovi donorov.

Cytokine production by donor blood leukocytes was investigated in vitro. LPS stimulation led to the production of IL-1 beta, IL-6, and TNF-alpha, if their spontaneous production was below the threshold sensitivity of the test method, and to a statistically negligible increase of production if spontaneous production was pronounced. The concentrations of cytokines produced depended on the nature of inductors and their doses. The inductor modulating effect can be used for stimulation and inhibition of cytokine production.

[Effect of actipol on interferon level in tears (clinico-laboratory study)]. / Vliianie aktipola na uroven' interferona v sleznoi zhidkosti (kliniko-laboratornye issledovaniia).

High interferon-inducing activity of a new antiviral drug actipol (0.007% para-aminobenzoic acid) instilled into the eye was demonstrated in animal experiments. In the present study the effect of actipol on interferon production in ocular tissues was investigated clinically. Interferon (IFN) content was measured in washings from the conjunctiva in 20 patients with herpetic keratitis, treated by actipol. Actipol was instilled frequently or injected subconjunctivally parabulbarly. The reference group consisted of 7 patients with herpetic keratitis treated with acyclovir locally. IFN titer was the last dilution of the sample ensuring 50% cell protection in comparison with complete cell destruction in the virus control. The samples were collected before, on days 1, 2, 3, 7 of treatment, and after clinical cure. Time course of IFN concentrations was wave-like in all the patients. The peak of IFN content surpassed the initial level 2-4-fold in all patients (26.13 +/- 5.9 vs. 58.9 +/- 4.4 U/ml, p < 0.01), which seems to be due to actipol induction of IFN production in the surface structures of the eyeball. In the reference group IFN content did not increase in comparison with the control during treatment. Hence, actipol induces the production of IFN in the surface eyeball structures in patients with various forms of herpetic keratitis.

Structural and functional changes in photosynthetic apparatus of wheat under exposure to sulfur dioxide fumes.

Changes in photosynthesis of wheat (pigment content and chlorophyll fluorescence) have been measured to study effect of gaseous sulfur dioxide on wheat cenosis. Several biochemical and biophysical techniques have been estimated to evaluate their ability for early detection of destructive effect of SO2. A mathematical model of toxic gas absorption in a closed system with plants has been proposed.

[Effects of interferon inducers on chemically-induced mutagenesis and carcinogenesis]. / Vliianie induktorov interferona na khimicheski indutsirovannyi mutagenez i kantserogenez.

The murine bone marrow cellular chromosomal aberration technique was used to reveal anticlastogenic effects of the natural interferon inductors ridostin and larifan, as well as the synthetic ones polyguacil and amyxin. The action of the interferon inductors was timed to the maximum production of interferon in the body. Anticarcinogenic, antitumor, and antimetastatic properties of the above interferon inductors were found by using classical experimental models of carcinogenesis. Some mechanisms of antimutagenic and coupled anticarcinogenic action of interferon inductors were considered. The natural interferon inductor larifan was found to have an antipromoter activity. The treatment regimen by using interferon inductors in combination with the immunomodulator thymosin, a thymic hormone, was under discussion.

[Effect of kagocel on the postradiation recovery of the hematopoiesis and immune status in mice exposed to ionizing radiation in sublethal dosage]. / Vliianie kagotsela na postradiatsionnoe vosstanovlenie krovetvoreniia i immunnogo statusa u myshei pri deistvii ioniziruiushchei radiatsii v subletal'noi doze.

The efficiency of interferon inductor, kagocel, in hemopoiesis and immunity disturbances caused by sublethal doses of ionizing radiation was investigated. The experiments showed that irradiation of mice with a dose of 0.9 Gy causes short-term drop of a number of cells in the bone marrow and lymphoid organs, reducing of CFUs and CFU-GM levels, decrease in a number of antibody-formation cells in spleen and falling of reaction of blast-transformation of lymphocytes. The injection of kagocel 1 and 5 days after irradiation enhanced post-irradiation recovery of bone marrow hematopoiesis, stimulated compensatory potential of hematopoietic system and increase in antiviral resistance of irradiated animals.

[The effect of the interferon inducer ridostin on photrin-induced mutagenesis in bone marrow cells in mice]. / Vliianie induktora interferona ridostina na indutsirovannyi fotrinom mutagenez v kletkakh kostnogo mozga myshei.

The number of aberrant metaphases was used to assess the influence of a highly active interferon inducer--ridostin, a two-spiral RNA, on spontaneous mutagenesis and that induced by an antitumor drug photrin. A new property of ridostin, viz. the antimutagenic effect, was established. The effect may be important for protection of cells from potent mutagens such as cytotoxic drugs used for cancer treatment.

[A study of the effect of thymotropin on immunologic indicators and excretion of virus in women with chronic cytomegalovirus infection]. / Izuchenie vliianiia timotropina na immunologicheskie pokazateli i ékskretsiiu virusa u zhenshchin s khronicheskoi tsitomegalovirusnoi infektsiei.

Thymotropic hormone was given subcutaneously in a dose of 100 mg twice a week for 3 months to 10 women with verified chronic cytomegalovirus infection. After termination of the treatment, in 8 women the virus excretion was decreased and this was accompanied with some improvement in immunological parameters: increased activity of natural killers, enhanced interferon-producing activity of lymphocytes, higher theophylline-resistant lymphocytes, and lower theophylline-sensitive T-cells. The above results confirm the association between the activity of cytomegalovirus infection and the state of immunity and allow thymotropic hormone to be recommended for treatment of other groups of patients with cytomegalovirus infection.