[Effect of paraaminobenzoic acid on interleukine-6 production in patients with herpetic keratitis].

The purpose of the study was to compare the effect of para-aminobenzoic acid (PABA) (actipol) on tear interleukin-6 (IL-6) levels in patients with herpetic keratitis and in peripheral blood cells of volunteers in vitro. Enzyme immunoassay was used to measure lacrimal fluid IL-6 levels in the actipol and acyclovir groups before and 1, 2, 3, 4, and 7-8 days after therapy and after clinical recovery in 30 patients with herpetic keratitis. A control group comprised apparently healthy volunteers (n=13, 26 eyes) who used actipol instillations into the conjunctival sac 4-5 times a day. The spontaneous production of cytokines and their production in response to the induction with different PABA concentrations (0.001, 0.01, 0.1, and 10 microkg/ml) were studied on peripheral blood cells taken from 9 volunteers. In the patients with herpetic, actipol was found to reduce and normalize tear IL-6 levels while acyclovir failed to produce this effect. In the healthy individuals, actipol did not affect IL-6 production in the anterior segment of the eye. All study PABA concentrations exerted a modulating effect on the production of IL-6 in the peripheral blood cells in vitro.

[Individual changes of gene expression in the interferon system in human blood cells due to amixin and cycloferon].

The action of amixin and cycloferon on the expression of genes in the systems of interferon (IF) and cell apoptosis (CA) was studied by semi-quantitative RT-PCR in human blood microsamples before and after the administration of the drugs. Individual changes were determined in the transcription activity of genes of IF (alpha, beta, gamma), enzymes 2',5' oligoadenylatesynthetase (OAS), RNSase L, dsRNA-dependent proteinkinase (dsPK) and of CA effectors (FasAg, bcl-2, gamma-actin) registered dynamically in 24 h and 48 h. The activity parameters of IF genes were compared with the results of biological titration of IF activity in blood samples in vivo and in vitro. A pronounced ability of cycloferon to stimulate selectively the activity of genes of human IF, type I (beta IF--by 100 times and alpha IF--by 10 times), without affecting essentially the activity of other genes in blood cells, was detected. Amixin was found to inhibit the titration of genes with high activity levels. (alpha-, beta-IF, RNAases L, bcl-2 and gamma-actin). The antiviral and IF-induced properties of the drug are explained to a great extent by the apoptotic effect (activation of genes Fas, gamma-IF, OAS and affected transcription of gene bcl-2). A positive correlation was observed between the processes of activation of IF-genes transcription and the production of the total circulating IF. Antagonistic relations between type I and II IFs in human blood cells were shown.

[Time course of interferon status of patients with herpetic keratitis during treatment with actipol, a new inteferon inducer]. / Dinamika interferonogo statusa u bol'nykh s gerpeticheskimi keratitami pri lechenii novym induktorom interferona aktipolom.

Interferon (IFN) status was evaluated in 20 patients with various forms of herpetic keratitis over the course of treatment with actipol (0.07% para-aminobenzoic acid). Actipol was injected subconjunctivally parabulbarly in combination with instillations into the conjunctival sac or only instilled, depending on the disease severity. The following parameters were evaluated: 1) total content of various IFN types in circulating blood and 2) leukocyte capacity to produce IFN in vitro in patient's whole blood cells. IFN-alpha was induced with Newcastle disease virus and IFN-beta with staphylococcal enterotoxin. Before treatment IFN-producing capacity of blood cells in vitro was decreased in 60% patients and was normal or increased in 40%. Plasma concentrations of IFN were moderately increased in 45% patients. All IFN parameters in patients with initially disordered IFN status normalized during actipol therapy and after clinical cure and did not change in the patients with initially normal IFN values. Hence, local actipol therapy in patients with various forms of ophthalmic herpes modifies IFN status.

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.

[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.

[Para-aminobenzoic acid--an interferon inducer]. / Paraaminobenzoinaia kislota--induktor interferona.

Para-aminobenzoic acid (PABA) was shown to be an early type interferon inductor. PABA (10 micrograms/ml) induced interferon production in vitro in the cells of human peripheral blood and in vivo in albino mice (10 mg/kg). The results of the study suggested that PABA was able to induce production of interferon-alpha/beta in various immunocyte populations. By its interferonogenic activity PABA was comparable with the known interferon inductors. One of the mechanisms of the previously described in vivo antiherpes action of PABA can be attributed to its interferon inducing activity.

[Interferon inducers: new generation of immunomodulators]. / Induktory interferona - novoe pokolenie immunomoduliatorov.

Interferon (IFN) inducers are the agents having a wide range of antiviral activity. They have not only etiotropic, but marked immunomodulating effects. INF inducers different in its nature cause IFN synthesis in different immunocytic populations. The kinetics of the production of IFN and their antigenic composition depend on the chemical structure of an inducer and on their stimulated target cell populations. Their capacity of stimulating the synthesis of IFN in these or those organs determines the spectrum of application of an inducer and the time course of serum IFN accumulation--the strategy of its use. IFN inducers have a number of advantages over exogenous IFN. They stimulate the synthesis of the body's own IFN, which has no antigenicity unlike the most widely used recombinant IFN. IFN inducers cause IFN circulation at the therapeutical levels, at the same time to achieve such an effect requires multiple administration of large-dose exogenous agents. Some IFN inducers includes IFN synthesis in particular cell populations and organs, which has certain advantages over the polyclonal stimulation of IFN immunocytes. IFN inducers are well combined with IFN and other antiviral agents. The combination of these properties leads to the conclusion that IFN inducers are a highly promising group of agents having both etiotropic and immunomodulating effects.

[Study of interferon-inducing activity of para-aminobenzoic acid injected subconjunctivally in rabbits]. / Izuchenie interferonindutsiruiushchei aktivnosti paraaminobenzoinoi kisloty v glazakh krolikov pri subkon''iunktival'nom vvedenii.

Para-aminobenzoic acid (PABA) is an early interferon inductor. The present study assesses the interferon-inducing activity of PABA (0.007 and 0.06% solutions) and poludan (Poly A:U) injected subconjunctivally to rabbits. Interferon (If) titer in the conjunctival washings and anterior chamber humor was assessed 4-48 h after injection of If inductors. After the first injection of 0.007% PABA, If titer in the conjunctival washings was constantly increasing and reached the maximum after 48 h (64-128 U/ml). Repeated injection of PABA after 5 days still more stimulated the production of If, with the peak after 24 h (128 U/ml); after 48 h the titer of If was still high. If titers induced by 0.007% PABA and poludan were compatible after both injections in the conjunctiva but not in the anterior chamber humor. With poludan, the maximum If titer (16 U/ml) was observed 6 h postinjection, after which it was no longer detected, while after PABA the maximum If titer (64 U/ml) was observed during the 4th and 12th hours postinjection and then decreased, remaining rather high after 24 h. After 0.06% PABA, If titers were 2-4 times lower in all experiments than after 0.007% PABA. The detected interferon-inducing activity of PABA suggests its therapeutic efficacy in ocular diseases involving disorders in If production.

[The radioprotective and interferonogenic properties of influenza vaccine]. / Radioprotektivnye i interferonogennye svoistva grippoznoi vaktsiny.

Different methods of prophylactic treatment with influenza virus vaccine increase survival of irradiated mice and hamsters by 25-55% as compared to unprotected ones. Higher radioresistance occurs in the same time intervals as a rise of interferon in the blood after immunization with influenza virus vaccine.

[Immunopharmacological analysis of secondary postradiation immunodeficiency]. / Immunofarmakologicheskii analiz vtorichnogo postluchevogo immunodefitsita.

A model for secondary postradiation immunodeficiency of mice has been used to compare immunocorrective activities of some new immunomodulators (arbidol, cagocel, myelopid, proleukinferon and fragmine) administered at late times (2-3 months) after exposure to a nonlethal radiation dose (4.0 Gy). The highest immunocorrective effect has been shown with fragmine and proleukinferon.

[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.

[Combined experimental use of vaccine against acute human encephalomyelitis and immunomodulators]. / Kombinirovannoe primenenie v éksperimente vaktsiny protiv ostrogo éntsefalomielita cheloveka s immunomoduliatorami.

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.

[Interferon-inducing activity of hydroxybenzylamine derivative]. / Interferonindutsiruiushchaia aktivnost' proizvodnogo oksibenzilamina.

Interferon-inducing activity of the interferon inductor savrats, an oxybenzylamine derivative of was studied. It was shown on experimental animals that along with its low toxicity, savrats had a high interferon inducing capacity. There were early and late peaks of interferon production (4-8 and 48-96 hours later, respectively) depending on the route of the inductor administration. It was noted that for optimization of the schemes for using interferon inductors, careful choosing of the drug pairs participating in the induction and employment of various routes for administration of the same drug are required.

[Pharmacokinetics of the interferon inducer PHL-6 and interferon synthesis in target organs under various methods of drug administration]. / Farmakokinetika induktora interferona PKhL-6 i sintez interferona v organakh-misheniiakh pri razlichnykh sposobakh ego vvedeniia.

The pharmacokinetics of PHL-6 and interferon synthesis dynamic in the target organs (tissues) of mice were studied during its and intraperitoneal administration. In the experimental setting, there was a direct correlation between the interferon production in the murine organs with single PHL-6 and distribution of 14C PHL-6. The highest radioactivity with its oral administration was detected in the liver and intestine. Interferon was actively synthesized in the intestine, liver and serum, showing the levels of 20000, 1024-2048 and 512-1024 IU/ml, respectively. The prolonged action of the drug was in good agreement with the low PHL-6 excretion from the body. It was also shown that almost the whole radiation dose 1 (greater than 98%) was excreted with feces and urine after single and chronic administrations of uniformly labeled PHL-6 which proved important clinical drug use.

[The role of immunocytes in the production of interferon in response to its induction by aromatic hydrocarbons]. / Uchastie immunotsitov v produktsii interferona v otvet na induktsiiu aromaticheskimi uglevodorodami.

Interferon (IF) was synthesized in animals by diverse populations of immunocytes in response to induction by various low molecular weight aromatic hydrocarbons. The level of the involvement of either population of the immunocytes in IF production is determined by the chosen inductor. IF induction by acridanone L-1 was mainly observed in macrophages and B-lymphocytes. T-Cells actively participated in IF synthesis induced by amyxin, a representative of the fluorenone group. IF synthesized by lymphocytes of human peripheral blood in response to L-1 was completely neutralized by antiserum to alpha-IF while IF induced by amyxin in the same culture was a mixture of alpha- and beta-IFs at a ratio of 3:1.

[The comparative characteristics of the interferon-inducing capacity of 2 preparations related to aromatic hydrocarbons]. / Sravnitel'naia kharakteristika interferonindutsiruiushchei sposobnosti dvukh prparatov, otnosiashchikhsia k aromaticheskim uglevodorodam.

Aromatic hydrocarbons are rightly considered to belong to most active synthetic interferon inducers among low molecular compounds. A comparative evaluation of L-1 (acridanon) and amixin (fluorenon) showed L-1 to have more marked interferon-inducing properties. Both compounds differed not only in the dynamics and levels of interferon synthesis in different organs which suggests the possibility of their employment in different diseases, but also in the efficacy of the modes of application. L-1 induced IF synthesis most actively after subcutaneous inoculation, amixin after oral administration.

[Role of macrophages in interferon production]. / Rol' makrofagov v produktsii interferonov.

The role of macrophages in production of interferons (IF) is manysided. They are able to synthesize IFs after any induction. However, the function of macrophages as producers of IFs is not, probably, basic. The levels of IFs produced by them are mainly low. When they are stimulated by inducers of "early" IF the synthesis is performed by intact macrophages whereas with the use of inducers of "late" IF there is always observed joint activity of macrophages and other immunocompetent cells. The main role of macrophages in production of IFs is in regulation of synthesis of these proteins in the host. In addition, they are able to serve as stimulating cells in inducing IF production by the majority of drugs by transmitting information on IF synthesis to lymphocytes. This function of macrophages is not species-specific.

[Clinical research on the tolerance for and the interferon-inducing activity of amiksin]. / Klinicheskie issledovaniia perenosimosti i interferonindutsiruiushchei aktivnosti amiksina.

Tolerance and interferon-inducing activity of amixine, an interferon inducer, was studied by the double-blind method clinically in healthy volunteers given tableted amixine orally in doses of 0.125-0.25 g by different schedules. According to clinical laboratory examinations and studies of indirect parameters of labor capacity amixine was found to be tolerable for man. The amount of interferon in the blood serum depended on the schedule of administration of the inducer, the optimal being 1-2 amixine tablets at least 2 days apart.