[TREATMENT OF PATIENTS WITH CHRONIC RECURRENT HERPES VIRUS INFECTION OF GENITAL LOCALIZATION: A CLINICAL STUDY OF FORTEPREN PREPARATION].

AIM: Selection of optimal dosage regimen, length of treatment course (frequency of administration), safety, tolerance and clinical effectiveness evaluation of the medical preparation fortepren in patients with chronical recurrent herpes virus infection of genital localization. MATERIALS AND METHODS: The medical product of antiviral and immune modulating effect--fortepren (sodium polyprenyl phosphate) as a 4 mg/ml solution for injections combined with the base course of acyclic nucleoside acyclovir, 400 mg tablets, held studies. 40 male and female patients participated in the study. After a 10-day acyclovir course (400 mg x 3 times a day) for removing the acute phase, 4 groups of 10 individuals were formed: 1--5 ml (20 mg) of fortepren i/m once at day 13 ± 2 after the start of the study after the completion of the treatment of the acute phase of the disease; 2--5 ml (20 mg) fortepren i/m 3 times at an interval of 21 days; 3--2 ml (8 mg) fortepren i/m 3 times at an interval of 21 days; 4 (control)--5 ml of placebo i/m at remission stage 3 times at an interval of 21 days. Increase of the duration of inter-recurrence period, decrease of the severity of the recurrences, state of skin and mucous damage elements, improvements of immunologic parameters were considered during effectiveness evaluation. RESULTS: Significant differences in the frequency of recurrences of genital herpes were shown for 3 months of observation in experimental and control groups. A significant reduction of genital herpes recurrence frequency from 3.52 ± 0.09 (before treatment) to 2.89 ± 0.08 (after treatment) was noted in patients of group 3 (p < 0.001). The frequency of recurrences in the control group was 3.84 ± 0.10, that was higher than the parameters in all the experimental groups. A significant reduction of the rash area was noted in group 3, moreover, a redution of frequency of detection of clinical manifestations of genital herpes in the form of vesicle elements after treatment in groups 2 (p = 0.02) and 3 (p = 0.005) was found. Evaluation of local symptoms has established that burning have caused minimal discomfort for patients of groups 3 and 4 and itch and soreness--of groups 1 and 3. The least pronounced exacerbations were noted in patients of group 3. Intramuscular administration of fortepren preparation was established to result in the increase of titers of leukocyte virus-induced interferon for the whole duration of treatment. CONCLUSION: An intramuscular dose of 2 ml (8 mg) at recurrence stage 3 times at an interval of 21 days after the completion of the 10-day base course of treatment of the acute phase of chronical recurrent herpes virus infection of genital localization using acyclovir was accepted as an optimal dosage regimen. Analysis of the obtained results has shown an acceptable safety profile and a good level of tolerance for fortepren preparation.

[Antiviral activity and possible mechanisms of action of moraprenil phosphates during experimental infection caused by herpes simplex type 1 virus].

AIM: Study of antiviral activity of moraprenil phosphates (MPP) against herpes simplex type 1 virus (HSV1) in vitro and during experimental infection caused by HSV1 in mice. MATERIALS AND METHODS: Activity of MPP in vitro was tested by the ability to suppress formation of symplasts in VERO cells infected with HSV1, strain VR-3. A series of MPP that suppress virus-induced symplast-formation by 30 times was selected for in vivo experiments. Anti-viral activity of MPP in vivo was studied in HSV-1 infected mice after administration of either prophylaxis or therapy regimens. RESULTS: MPP at the dose of 20 microg/mice during s/c administration exhibited a pronounced prophylactic-therapeutic effect. Effectiveness of MPP during clinically evident herpes against the background of developing neurologic symptoms was demonstrated for the first time. Visual observation of the mice, that had received MPP as the first clinical symptoms of the disease appeared, has shown that against the background of preparation injection the clinical signs have ceased after 2 - 3 days and did not registered at least for the whole duration of the observation period (14 days). CONCLUSION: Active herpes infection is accompanied by the increase of FoxP3 expression in-thymus was shown. Possible mechanisms of anti-viral effect of MPP are discussed.

[Antiviral and immunomodulating activity of polyprenyl phosphates in viral infections].

Expressed antiviral activity of Fortepren (FP) and Gamapren (GP), polyprenyl phosphate (PPP)-contaning agents, was demonstrated in experiments on mice infected with the human herpes simplex virus, type 1 (HSV1) or the vernal encephalitis virus (VEV). Since both the viral infections are of great social significance, the PPP-containing agents should be considered prospective for the medical practice. The experimental data suggested that both the drugs considerably inhibited the VEV infectiousness in the susceptible cell culture. The quantity of protein E, the main immunogen of VEV, in the culture fluid of the VEV infected cells was shown to be markedly lowered under the effect of FP and GP. It was demonstrated for the first time that FP and GP significantly inhibited evolution of the VEV protein E in the cell culture J-96. The experiments with the infectious rhinotracheitis virus (IRTV) of the corned cattle revealed that FP and GP greatly retarded the HSV1 development in the susceptible cell culture. One of the mechanisms of the antiviral action of the PPP-containing agents was likely the effect on the evolution of the virus proteins in the cells. The impact of FP on production of some key cytokines (CT) was studied on mice with experimental vernal encephalitis (IFN-gamma, IL-4 and IL-12). The content of the above mentioned CT in blood of the mice was determined by the IFA test. Under the normal conditions and in the mice infected with VEV, production of IL-12 and IFN-gamma was shown to be stimulated during the first 3-5 days after the FP administration, whereas in the animals not exposed to FP there was observed stimulation of the IL-4 production during the first 3 days after the contamination, followed by increased production of IL-12 and IFN-gamma.

Evaluation of antibiotic sensitivity of Chlamydia trachomatis using RT-PCR.

The sensitivity of 11 clinical strains of Chlamydia trachomatis to azithromycin, ofloxacin, doxycycline, and erythromycin was evaluated. The minimum inhibiting concentrations of all antibiotics for 90% strains, determined by PCR with reverse transcription of omp3B gene RNA (GenBank U68443) corresponded to, and those with reverse transcription of 16S rRNA gene RNA (GenBank X54451) far surpassed the minimum bactericidal concentrations for 90% strains determined by direct immunofluorescence with monoclonal antibodies to the major outer membrane protein.

Induced expression of melittin, an antimicrobial peptide, inhibits infection by Chlamydia trachomatis and Mycoplasma hominis in a HeLa cell line.

As the number of pathogenic microbial strains resistant to different antibiotics increases, amphipathic peptides with antimicrobial activity are promising agents for the therapy of infectious diseases. This work deals with the effect of an amphipathic antimicrobial peptide, melittin, expressed within recombinant plasmid vectors, on infection with urogenital pathogens Chlamydia trachomatis and Mycoplasma hominis in HeLa cell culture. Recombinant plasmid constructs with the melittin gene under the control of the tetracycline-responsive promoter of human cytomegalovirus were obtained. We showed inhibition of C. trachomatis and M. hominis infection after the introduction of recombinant plasmid vectors expressing the melittin gene into the infected cell culture.

[Detection of markers of the human T-cell leukemia virus in patients with T-cell lymphoma and Kaposi's sarcoma]. / Obnaruzhenie markerov virusa T-kletochnogo leikoza cheloveka u bol'nykh T-kletochnoi limfomoi i sarkomoi kaposhi.

Nine patients with Kaposi's sarcoma and five suffering from T-cell lymphoma have been examined. Antibodies to HTLV-1 were not found in these patients. The primary cellular cultures were isolated from blood and lymph nodes of the patients. Viral particles (type C) were found in the culture obtained from the patient with lymphoma of T-cell origin. DNAs from the primary cellular cultures from patients with lymphoma or sarcoma contained the sequences homologous to gag-gene of HTLV-1. The data suppose the patients with T-cell lymphoma and Kaposi's sarcoma to carry HTLV-1 virus.

[The isolation and characteristics of long-term continuous lymphoid cell lines (IK-10 and IK-12) from patients with mycosis fungoides]. / Poluchenie i kharakteristika dlitel'no perevivaemykh limfoidnykh kletochnykh linii (IK-10 i IK-12) ot bol'nykh gribovidnym mikozom.

Examinations of 26 cell cultures have detected in two cases continuous IK-10 and IK-12 cell lines from patients with mycosis fungoides. Studies of these cell ultrastructure, carried out by transmission electron microscopy, have shown organoids of all types, that are characteristic of both minor and medium lymphocytes and of lymphoblasts. Markers of T-, B-cells and mononuclears are also detectable in these cell lines. The cells express surface immunoglobulins and interleukin-2 receptors. Noteworthy that association of these cells in a population may be in vitro cultivated for more than 2 years.

[A clinico-experimental study of patients with mycosis fungoides and Kaposi's sarcoma]. / Kliniko-éksperimental'noe izuchenie bol'nykh gibovidnym mikozom i sarkomoi Kaposhi.

Twenty-six cultures were prepared by the cultivation method. Continuous cells lines (IK-10 and IK-12) were obtained in two cases, in the rest short-lived cell cultures were prepared. All the isolated cell cultures were studied by transmission electron microscopy. Abnormal lymphoblasts were detected in some cell cultures isolated from the blood and lymph nodes of mycosis fungoides (IJ-137, IK-140, IK-142, IK-143) and Kaposi's sarcoma patients (IK-145). Cell population consisted of small, medium, and large lymphocytes. Electron microscopic examination has revealed retroviruses in IK-143 culture, isolated from the lymph node of a patient with mycosis fungoides. Morphologically these particles were typical of type C oncoviruses, 120-140 nm in diameter, with a spherical core in the center of the virion.

[The determination of receptor proteins in patients with mycosis fungoides]. / Opredelenie retseptornykh belkov u bol'nykh gribovidnym mikozom.

Measurements of the blood serum R-protein levels in patients with mycosis fungoides have revealed their elevation by 2-10 times as against healthy donors. Referon therapy combined with prospidine and indomethacin resulted in improvement of the clinical course of the process and was accompanied by a reduction of R-protein level. These data suggest that measurements of R-protein levels may help monitor the treatment efficacy.

[The interferon status of patients with lymphoproliferative diseases of the skin and Kaposi's sarcoma]. / Interferonovyi status bol'nykh limfoproliferativnymi zabolevaniiami kozhi i sarkomoi Kaposhi.

Differences in the interferon status of various nature were revealed in patients with lymphoproliferative diseases of the skin and with Kaposi's sarcoma, whose interferon system was examined in respect of its three major parameters. Such data are a sufficient basis for the correction of the detected changes by interferon preparations combined with other chemical drugs. Two parameters of the interferon system may serve as criteria of interferon therapy efficacy: increased alpha-interferon level and, more so, normalization of the gamma component of interferon production, tested by the gamma parameter.

Antiviral activity of lambda-, beta-, and gamma-interferons in the presence of theophylline: involvement of 2',5'-oligo(A) synthetase.

Theophylline, an inhibitor of cAMP phosphodiesterase, induces in human ovary carcinoma cells (CaOv) a 2-2.5-fold elevation of intracellular cAMP. This rise in the cAMP level is followed by an increase of the activity of 2',5'-oligo(A) synthetase in CaOv cells -insignificant (1.5-fold) after 16 hr incubation, and substantial (3.7-fold) after 30 hr incubation, as well as the development of antiviral resistance. Once CaOv cells have been incubated with the mixtures containing theophylline (2 mM) and lambda-, beta-, and gamma-interferon preparations (0.5-13 IU/ml), the total antiviral effect of the mixtures exceeds that generated by interferon or theophylline separately; the action of the above agents being additive. These data agree with the previously obtained results and support the suggestion that cAMP phosphodiesterase inhibitors partially mimic the antiviral action of interferon.