[The application of low-frequency ultrasound for the comprehensive treatment and rehabilitation of the patients presenting with chronic endometritis]. / Primenenie nizkochastotnogo ul'trazvuka v kompleksnoi terapii i reabilitatsii patsientok s khronicheskim éndometritom.

The incidence of chronic endometritis remains rather high despite considerable progress in reproductive medicine including the advent of the new methods for assisted reproduction; the pregnancy rate after the treatment of this condition is still unacceptably low. It implies the necessity of the careful preparation of endometrium for the implantation of the embryo especially in women with a history of unsuccessful outcomes of the IVF treatment. It calls for the development of the efficient therapeutic modalities for the management of chronic endometritis and restoration of the normal reproductive function; their introduction into the therapeutic algorithm remains equally relevant. The characteristic features of chronic endometritis include blood circulatory disorders in the vessels of the uterus and in the pelvic vascular basin, changes of local immunity in the endometrium concomitant with the activation of cellular and humoral responses of inflammation in the form of enhanced leukocyte infiltration and increased production of cytokines. The long duration of such a process results in the development of fibrosis that, in its turn, leads to chronic tissue hypoxia, potentiation of inflammation, and disruption of decidualization that hampers successful implantation. The article shows the possibility of using low-intensity ultrasound for the treatment and rehabilitation of the patients presenting with chronic endometritis. The data concerning the primary biophysical processes developing in the tissues under the influence of ultrasound are discussed. The therapeutic effects and their underlying mechanisms and described. The physiotherapeutic treatment considerably improved vascular hemodynamics in the pelvic basin and produced trophotropic, defibrosing, and anti-inflammatory effects. The clinical data giving evidence of the high effectiveness of the application of intrauterine ultrasound cavitation provide a basis for the recommendation to include this physical factor in the existing algorithms for the pre-gravid preparation of the women presenting with disorders of the reproductive function and chronic endometritis.

[Recurrent herpetic corneal erosion: diagnosis and treatment].

Recurrent corneal erosion (CE) is a common anterior eye disease, which usually occurs after injury, substantially limits a patient's ability to work, and is intractable. The authors single out an individual form of CE herpetic CE (HCE) on the basis of immunofluorescence assay of a conjunctival scrape, which shows the high concentration of herpes simplex virus antigen in 53% of CE cases. Confocal microscopy revealed epithelocyte polymorphism and basement membrane defects. The treatment of patients with HCE involved 2 steps: 1) relief of acute signs of the disease via drug therapy, rapid local autocyte cinotherapy (RLACCT), or phototherapeutic keratectomy (PTK) and 2) prevention of recurrences. For this the authors developed a method based on the systemic use of a new composition of the intradermal herpes vaccine Vitaherpavac in combination with the subcutaneous interferon inducer Poludan. RLACCT was found to be the most effective medical treatment for CE and PTK was the most effective surgical one. Vaccination with the concurrent subcutaneous injection of Poludan is an effective method in preventing recurrent HCE. During a follow-up of 2 years or more, 81% of the patients achieved clinical resolution; there was a decrease in recurrence rates and severity in 15.1% and no effect in 3.8%.

[Intraocular correction of aphakia in patients after kidney transplantation]. / Intraokuliarnaia korrektsiia afakii u bol'nykh, perenesshikh transplantatsiiu pochki.

It was for the first time in the ophthalmologic practice that a possibility was demonstrated to ensure relatively high and stable functional results, in a significant number of patients with transplanted kidney (TK), related with different-type cataract extraction and with implantation of a variety of PMMA IOLs, i.e. model of B.A. Alexeev, "Storz" company models made from domestic and foreign-made PMMA and domestic-silicone models (P = 70). It was established that IOL implantation in patients with TK is possible in all cases provided the kidney transplant is compensated for and there are no foci of acute or chronic inflammation in the body. A minimal trauma caused by surgery and the suggested scheme of postoperative management (intramuscular injections of antibiotics and supplementary administration of solutions of poludan, naclof, catachrom and actovegin-gel made alongside with routine instillations) cuts the risk of infectious-and-inflammatory as well as of degenerative-and-dystrophic complications in patients with TK receiving the suppressor therapy. Clinical examinations denoted that the intraocular aphakia correction in patients with TK is a method of choice accelerating the medical and social rehabilitation in the discussed patients' category provided the therapeutic-and-diagnostic as well as preventive measures, as required by their status, are being taken.

[Local express auto-cytokine therapy (a complex of cytokines) in the treatment of viral and nonviral eye lesions]. / Lokal'naia ékspress-autotsitokinoterapiia (kompleks tsitokinov) v lechenii virusnykh i nevirusnykh porazhenii glaz.

The method of local express-autocytocinetherapy (LEACCT) consists in using an experimentally tested autologous complex of cytokines (alpha- beta- gamma-interferons, interleukins 2.8, tumor necrosis factor gamma etc.), which is produced by joining the autoblood of patients with immune-modulator poludan (complex poly A:poly U). The external LEACCT and the intrachamber LEACCT are distinguished. The former presupposes the administration (subconjunctivally and in installations) of the autoblood-poludan mixture. This method is used in herpes- and adenovirus keratoconjunctivitis, slow re-epithelization after laser keratectomy and in eye burns (178 patients). The latter comprises, apart from the external LEACCT procedures, a 1-4-time introduction of the mentioned mixture into patient's anterior chamber. It was used in endothelial herpetic keratoiridocyclitis, initial bullous keratopathy, severe keratoconus and in injuries of the anterior lens capsule (117 patients). The clinical-study results (main group--295 patients) show that the designed method based on poludan has pronounced anti-inflammatory and regenerative effects in different viral and virus-free lesions of the eye tissues; it is simple and can be applied in clinical settings. An increased visual acuity ranging from 0.05 to 1.0 was registered in 85% of cases. The action of the complex of cytokines is as close as possible to the physiological mechanism, which provides for avoiding the side-effects and for applying the treatment scheme in situations when the administration of other drugs is limited or their efficiency is not sufficient.

[Modern aspects in the treatment of ophthalmic herpes]. / Sovremennye aspekty lecheniia oftal'mogerpesa.

The author report about study results conducted in Russia during the recent 30 years and dedicated to the treatment of ocular pathologies caused by the virus of herpes simplex. Three high-efficiency directions took shape during the mentioned period: 1. Non-specific antiviral therapy based on the local and systemic administration of interferon inductors (poludan--complexes of poly A, poly U etc.) possessing an extensive spectrum of the antiviral and immune-modeling actions; 2. Antirecurrent therapy, including the application of herpetic vaccine against the virus of herpes simplex, types I and II, combined with immune-modeling agents. A focal allergic test with herpetic vaccine was offered, it made it possible, for the first time, a non-invasive diagnostics of intraocular herpes. 3. A system of sparing microsurgical methods adapted to the treatment of an active herpetic keratitis and its outcomes. A synergistic effect of interferon inductors and acyclovir was proven both experimentally and clinically; a method of local autocytokinotherapy (based on poludan), which turned out to be most effective in the treatment of severe lesions at the cornea and of intraocular herpes, was worked out. The authors believe that the methods and means offered for the treatment of ophthalmoherpes contribute, to a great extent, to handling with the ocular herpes viral infection.

[Epidemiologic effectivness of poludane in preventing influenza and other acute respiratory diseases in troops]. / Epidemiologicheskaia éffektivnost' poludana v profilaktike grippa i drugikh ostrykh respiratornykh zabolevani v voiskakh.

The epidemiological effectiveness of interferon inductor "Poludanum" produced by "LENS Pharm" (Russia) for prevention of acute respiratory viral infections was tested. The drug was administered among the students of Military Medical Academy (101 students) according to scheme 1: in a nose, 3 drops in each nasal passage two times per week during 4 weeks, with 2 week interruption then the scheme was repeated. The scheme 2 included 3 drops in each nasal passage once a week during 10 weeks (95 students). The placebo group (96 students) received the distilled water. In the students receiving "Poludanum" according to scheme 1 the incidence of acute respiratory diseases (ARD) was significantly lower than in the control group (p = 0.058). The coefficient of effectiveness was 50%, i.e. the incidence has decreased in two times. The use of poludanum according to scheme 2 caused no decrease in ARD incidence.

[The use of cycloferon in the therapy of experimental herpetic keratitis]. / Ispol'zovanie tsikloferona v terapii éksperimental'nogo gerpeticheskogo keratita.

The cycloferon efficacy was investigated in the treatment of experimental herpesvirus kerato-conjunctivitis in rabbits. The model was demonstrated to reflect the main aspects of herpesvirus eye lesions in humans. Cycloferon application similarly to that of known interferon inducer poludan has been shown to enhance processes of inflammation and subsequent regeneration of eye tissues as well as to decrease mortality of animals due to the generalization of infection.

[Development of a suppository form of the interferon inducer poludan and potentiation of its action by hyaluronic acid]. / Razrobotka svechevoi formy induktora interferona poludan i potentsirovanie ego deistviia gialuronovoi kislotoi.

A promising dosage form of interferon inductor poludan has been developed for the treatment of patients with genital herpes and ophthalmic herpes: suppositoria. High interferon-producing and antiviral activity of poludan in suppositoria is potentiated by hyaluronic acid and antioxidants.

Stimulating re-epithelialization after photorefractive keratectomy.

BACKGROUND: Re-epithelialization is usually complete in eyes 3 to 4 days following photorefractive keratectomy (PRK). However, this process is delayed in 0.5% of these eyes, leading to early development of haze. The authors investigated a method to stimulate re-epithelialization following PRK. METHODS: PRK was performed with the Nidek EC-5000 excimer laser. Following surgery, express-cytokinotherapy was applied. This method consisted of a single subconjunctival injection of 2.5 to 3.0 ml of ex juvanticus mixture of autoblood and immunomodulator Poludan. This mixture was then applied topically 4 times a day until re-epithelialization was complete. Poludan is an interferon inducer (complex polyA: polyU), stimulates expressed production of interferon and interleukin-2, and increases natural cytotoxicity. RESULTS: Thirty eyes of 30 patients with delayed re-epithelialization were treated with the described method. The average time to re-epithelialization was 7.00 + 0.64 days. Total epithelialization was complete on day 3 + 0.38 after beginning the cytokinotherapy (P < .05). Early haze developed in only 2 patients from this group. Occurrence of early haze in the control group of patients who had persistent epithelial defects 8 to 16 days postoperatively and were given traditional therapy--including corticosteroid and non-steroidal drugs--was reliably higher: 8 to 10 days (P < .01). CONCLUSION: Local express-cytokinotherapy appears to be an effective method to promote quick and complete epithelialization in eyes following PRK that experience delayed re-epithelialization. This treatment may be an important part of the prevention of early haze development and achievement of better visual acuity.

[The clinical characteristics and immunotherapy of complicated forms of adenovirus keratoconjunctivitis]. / Klinicheskie osobenoosti i immunoterapiia oslozhnennykh form adenovirusnogo keratokon''iunktivita.

Analysis of case histories and clinical and direct immunofluorescent examinations of 72 patients enabled the authors to single out 3 forms of complicated adenovirus keratoconjunctivitis (AVKC): 1) acute grave; 2) with toxic allergic reaction to previous treatment; and 3) steroid-complicated. Recommendations on the treatment of these forms are offered. A common remedy is interferon inductor poludan and chigain obtained from human colostrum and containing secretory IgA. Poludan was administered by instillations (4-6 times a day) and periocular injections in a dose of 100 U every 1-2 days, 5-6 injections per course, chigain was administered by instillations (2-4 daily). This combined treatment was highly effective and well tolerated. Periocular injection of poludan ensured much more intensive local and even systemic interferon production than instillations alone. Mean terms of treating complicated AVKC were compatible with those in uncomplicated forms: 14.3 +/- 2.1 vs. 13.2 +/- 1.2 days, respectively. Signs of herpesvirus infection were detected in one-third of patients with steroid-complicated AVKC. For eliminating corneal opacities in AVKC patients, enzyme phonophoresis, phototherapeutic keratectomy, and (in grave cases) lamellar keratoplasty are recommended.

[Biological actions and therapeutic perspectives of double stranded polyribonucleotides: a reappraisal]. / Actions biologiques et perspectives thérapeutiques des polyribonucléotides double-brins: une réévaluation.

Double-stranded polynucleotides, which are composed of two complementary homopolyribonucleotides containing no genetic information, are synthetic molecules capable of mimicking the action of natural double-stranded RNA or viral RNA on cells. Double-stranded polyribonucleotides act as an alarm system alerting the cell to the presence of an external aggression, e.g. a viral attack. In addition, polyribonucleotides have a more active function in that they trigger cell defense processes through activation of a family of genes, of which some encode cytokines, activation of cytoplasmic enzymes involved in antiviral mechanisms or signal transduction, and activation of nonspecific immune responses. Double-stranded polyribonucleotides containing one mismatched base pair per helix have been found to be especially interesting. The best known example is poly(I).poly(C12U), also called ampligen. Poly(I).poly(C12U) is capable, in experimental models, of limiting the development of viruses (including HIV), reducing tumor growth, eliminating metastases, and, according to one report, preventing steady declines in T-cell counts in HIV-positive patients. Therapeutic doses used in the USA as an experimental drug induced little toxicity. In vitro, poly(I).poly(C12U) acts synergistically with interferon, interleukin 2 or AZT, suggesting that these latter drugs may be effective in lower, less toxic doses when used in combination with poly(I).poly(C12U). The therapeutic activity of poly(I).poly(C12U) holds promise. More extensive prospective studies of this agent are warranted.

[Inhibition of alfa interferon and ampligen of human immunodeficiency virus (HIV) replication in monocyte-macrophage subpopulations]. / Inibizione da interferon alfa e ampligen della replicazione del virus dell'immunodeficienza umana (HIV) in sottopopolazioni di monocito-macrofagi.

Levels of replication of HIV in two different populations of monocyte/macrophages (M/M) at different stages of maturation were evaluated, as well as the antiviral activity of alpha-interferon (alpha-IFN) and Ampligen (an inductor of endogenous production of alpha-IFN). HIV replication was found to be 5-10 times greater in mature than in young M/M. Furthermore, alpha-IFN and Ampligen showed a substantial anti-HIV activity in young M/M, while little effect was achieved in mature M/M. Finally, HIV replication in chronically-infected M/M was not affected by alpha-IFN. These results suggest that alpha-IFN might be useful in combination with other anti-HIV drugs in the therapy of HIV-related disease.

Growth of astrocytomas in the human tumor clonogenic assay and sensitivity to mismatched dsRNA and interferons.

Nine astrocytoma specimens were received from seven patients and processed for testing in the human tumor clonogenic assay (HTCA). Cells derived from these specimens were challenged with human natural alpha-interferon (alpha-IFN) and beta interferon (beta-IFN), recombinant beta interferon (beta ser-IFN), and mismatched double-stranded (ds) RNA (Ampligen). Six of the astrocytoma specimens formed adequate colonies for drug sensitivity testing (greater than or equal to 30 colonies/plate), and all were high-grade (III-IV) tumors. Sensitivity was defined as a greater than or equal to 50% decrease in tumor colony formation following drug exposure and was observed with alpha-IFN (2/4), beta-IFN (3/4), and mismatched dsRNA (4/5) exposure. No decrease in colony growth was observed after recombinant beta ser-IFN exposure, and in 2 of 3 cases, colony formation was stimulated. The sensitivity of 75 non-CNS solid tumors to mismatched dsRNA was compared to the high-grade astrocytomas in the HTCA. Of the 10 additional histologic tumor types studied, carcinoid and renal cell carcinomas exhibited the greatest sensitivity to mismatched dsRNA: 63% and 52%, respectively. However, in comparison, 80% of the high-grade astrocytomas were sensitive, demonstrating that these gliomas are among the most sensitive of human tumors to mismatched dsRNA in vitro. Clinical trials of interferons and mismatched dsRNA, coupled with in vitro sensitivity studies, should further define their therapeutic potential.

Clinical, immunological, and virological effects of ampligen, a mismatched double-stranded RNA, in patients with AIDS or AIDS-related complex.

10 patients with the acquired immunodeficiency syndrome (AIDS), AIDS-related complex (ARC), or lymphadenopathy syndrome (LAS) were given 200-250 mg ampligen, a mismatched double-stranded (ds) RNA with in-vitro antiviral activity against human immunodeficiency virus (HIV), twice a week for up to 18 weeks, without side-effects or toxicity. In all 9 patients who were positive for HIV RNA in peripheral blood mononuclear cells before therapy, levels became undetectable between days 10 and 40 of the start of therapy. 6 of the 7 patients with ARC or LAS also showed a progressive reduction in HIV load as measured by co-culture assays. All 10 patients had augmentation of delayed-type hypersensitivity skin reactions. Other changes noted during ampligen therapy included an increase in or maintenance of numbers of helper-inducer T lymphocytes, improvements in HIV-related symptoms, rises in titre of neutralising antibodies against HIV, and restoration of proper functioning of the natural lymphocyte antiviral dsRNA-dependent (2'-5'-oligoadenylate/RNA-ase L) pathway. Thus, in the short term, ampligen seems to have the dual ability to restore immunological function and to control HIV replication.

Potential role of polyribonucleotides in human neoplastic diseases.

In experimental models polyribonucleotides, either alone or in combination with various polycations, are potent immunomodulators, inducers of interferons, and antitumor compounds. However, emerging clinical and preclinical results suggest they may have useful therapeutic roles of types not yet described with interferons. Thus, further Phase I and Phase II clinical trials are warranted to define their potential usefulness in humans.

Clinical studies with ampligen (mismatched double-stranded RNA).

Results of an ongoing clinical study of a mismatched double-stranded (ds) RNA, termed Ampligen, in patients with metastatic cancer are described. In a pilot study of Ampligen (lot 1) involving mostly hematologic malignancies, patients received cumulative doses up to approximately 450 mg without untoward effects. Evidence of biologic/antitumor effects was observed (3/5 patients) by monitoring tumor-specific markers or tumor cell morphology. In patients with solid tumors receiving lot 2, Ampligen cumulative doses over 4 g were well tolerated. The drug was given by intravenous infusion (10-80 mg/infusion, twice weekly), in some instances for more than 1 year, without clinically significant side effects. Specifically, no evidence of hematologic, liver, or renal toxicity, which was previously noted with other dsRNAs, was observed. Side effects consisted of occasional mild fatigue or flu-like symptoms. Fever, when encountered, was transient and low grade (less than 100.5 degrees F). Importantly, an analysis of patient sera for dsRNA antibodies revealed that no patient had evidence of specific antibodies directed against Ampligen. Other dsRNAs cause up to a 60% incidence of antibody formation. Additionally, a novel method was developed to monitor Ampligen blood levels. In a survey of seven patients, Ampligen had a mean plasma half-life of 23 min. Ampligen administration can also result in activation of both natural killer (NK) cells and a lymphocyte, interferon-associated, intracellular enzyme. Dose-dependent antitumor effects were seen in several solid tumors; in doses of 10-40 mg, 3/9 patients showed stable disease for up to 1 year. At the 80-mg dose level, 2/5 patients showed tumor regressions (mixed and partial responses).(ABSTRACT TRUNCATED AT 250 WORDS)