[Open population comparative randomized clinical trial of lavomax efficacy and safety in combined treatment of non-gonococcal urethritis].

A total of 40 patients with non-gonococcal urethritis (NGU) were divided into two groups. Twenty patients of group 1 received standard antibacterial treatment while 20 patients of group 2 received the same treatment plus an immunotropic drug based on tiloron (lavomax) in a course dose 1.25 g. Patients of group 2 had no recurrences while in group 1 recurrences were seen in 25% patients. Addition of lavomax resulted in clinical and etiological cure and activation of local (secretory IgA) and systemic (interferons alpha and gamma in blood serum) factors in anti-infection defense in NGU patients.

[Interferon status of patients with non-specific ulcerous colitis and its correction with interferon inducers]. / Interferonovyi status bol'nykh nespetsificheskim iazvennym kolitom i ego korrektsiia induktorami interferona.

AIM: To examine validity of using interferon inductors (amixin and cycloferon) in combined treatment of patients with non-specific ulcerous colitis (NUC). MATERIAL AND METHODS: 113 NUC patients received basic antiinflammatory therapy (glucocorticoids and preparations of 5-aminosalycylic acid). Patients of groups 1 and 2 received interferon inductors (amixin and cycloferon in tables), respectively. Patients of groups 1a and 2a received placebo. All the patients were examined clinically with evaluation of interferon status and cellular immunity before and after the treatment. Colon mucosa biopsies obtained endoscopically were studied histologically. RESULTS: Alpha- and gamma-interferon production by leukocytes was substantially suppressed in all the examinees against normal levels of serum and spontaneous interferon. The interferon inductors stimulated relief of clinical symptoms and eliminated endoscopic signs of the disease. Amixin and cycloferon normalized interferon status in 36.3 and 33.3% of the treated patients, respectively. No response was registered in 9.1 and 8.4%, respectively. Improvement was seen in 54.6 and 58.3%, respectively. CONCLUSION: Cycloferon and amixin, interferon inductors, are effective in the treatment of NUC.

[Evaluation of amixine reactivity and efficacy for prophylaxis of acute respiratory tract infections]. / Otsenka reactogennykh svoistv amikcina i ego c'ffektivnosti pri profilaktike ostrykh infektsii respiratornogo trakta.

Amixine reactivity and tolerability were evaluated in controlled trial at the risk group of medical personal at the period of flu and respiratory viral infection season. Drugs safety was estimated according to anamnesis, direct observation and hemogram. High efficacy of the drug for the infections prophylaxis and treatment was demonstrated. The drug was well tolerated and had no side effects. Amixine unreactivity was proved.

Drug-induced lysosomal storage of sulphated glycosaminoglycans.

1. Certain compounds (e.g., the immunomodulator tilorone and congeners) are able to induce lysosomal storage of sulphated glycosaminoglycans (GAG), thus, producing cytological and biochemical alterations reminiscent of the inherited mucopolysaccharidoses. The drug-induced GAG storage has been studied in cultured fibroblasts of several species and in rats, and it is likely to occur also in humans. 2. The cytological hallmarks of GAG storage are enlarged lysosomes congested with material that is intensely stained by cationic dyes. With respect to fixation techniques, one has to keep in mind that the GAGs are highly water-soluble and are leached during conventional fixation and tissue processing. Biochemically, the elevation of GAG contents in tissues and cultured fibroblasts is due to storage of dermatan sulphate, predominantly. 3. The molecular structure of the potent inducers of GAG storage is characterized by a planar tricyclic aromatic ring system that is symmetrically substituted with two side chains of 4-5 sigma bond length, each carrying a protonizable nitrogen atom. The lysosomal storage of GAG is accompanied by lysosomal accumulation of the inducing drug, with the molar ratio of drug to GAG-disaccharide unit amounting to > 1:1. The reversibility of GAG storage is rather slow. 4. The pathogenic mechanisms underlying the drug side effects are discussed and the following hypothesis is put forward: The compounds in question are lysosomotropic weak bases. They get trapped in the acidic lysosomes and accumulate highly there. Physicochemical data suggest that the drugs form complexes with the sulphated GAGs, particularly with dermatan sulphate: The positively charged nitrogen atoms of the drug side chains interact with the negative charges of sulphate and carboxy groups of the GAGs, thereby crosslinking at least two GAG helices. Moreover, the interlinking drug molecules form parallel stacks resulting from interaction of the aromatic pi-electrons of the planar ring systems. This further stabilizes the complexes. The GAGs within the complexes are thought to be resistant to the degrading lysosomal enzymes. 5. Drug-induced GAG storage has not been directly demonstrated in man. Yet, clinical reports on keratopathy and basophilic cytoplasmic inclusions in blood lymphocytes of tilorone-treated patients suggest that this drug side effect may also occur in man.

The tilorone-induced mucopolysaccharidosis in rats. Biochemical investigations.

The tissues of rats chronically treated with tilorone exhibited a significant accumulation of acid glycosaminoglycans (GAGs): In the liver, the GAG concentration was found to be elevated by a factor of 38, in the spleen by a factor 15 and in the kidneys by a factor of 5. Furthermore, the renal excretion of GAGs was increased 32-fold as compared to control animals. Dermatan sulphate was predominant among the GAGs stored in the three organs; chondroitin sulphate and heparan sulphate were found in smaller amounts. GAG storage was accompanied by accumulation of the drug within the tissues: the molar ratio of tilorone per disaccharide unit of GAG was calculated to be one to two in each tissue. According to previous reports, tilorone-induced mucopolysacchariodosis is due to impaired lysosomal degradation of GAGs. The present results give support to the hypothesis that an interaction between the polyanionic GAGs and the dicationic drug may lead to GAG-drug complexes which cannot be digested by lysosomal enzymes.

Keratopathy in rats after treatment with tilorone.

According to clinical reports, the antitumor drug tilorone induces corneal opacities in patients. The present communication shows that keratopathy can be experimentally reproduced in rats and describes the cellular alterations underlying the corneal opacities. Tilorone was applied either orally (60-90 mg/kg) for several weeks or topically (2%) for a few days. Biomicroscopic examination performed after treatment for 6 weeks or longer revealed fine punctate opacities throughout the corneal stroma. Ultrastructurally, the keratocytes were swollen due to large, optically empty vacuoles in the cytoplasm. Similar, albeit smaller, vacuoles were also numerous in the endothelium and less frequent in the epithelium. Histochemical experiments showed that the cellular alterations represented lysosomal storage of polyanionic substances, most probably sulfated glycosaminoglycans, thus mimicking the cytological picture of mucopolysaccharidosis. Upon discontinuation of drug treatment, the alterations tended not to recede. This keratopathy in rats is part of a generalized mucopolysaccharidosis-like disorder induced by tilorone.

Retinopathy after tilorone hydrochloride.

Two patients, a 34-year-old woman and a 50-year-old woman, received tilorone HCl, an experimental antitumor drug. After taking the drug orally (total dose, 152 g), the first patient developed corneal subepithelial infiltrates and toxic retinopathy characterized by fine pigment mottling of the peripheral fundus and macula with mild arteriolar narrowing. Although visual acuity was 6/6 (20/20) throughout treatment, Goldmann perimetry showed marked peripheral constriction of the visual fields and results of an electroretinogram and an electro-oculogram were abnormal. After taking the drug orally (total dose, 189 g), the second patient developed corneal subepithelial infiltrates, severe bilateral arteriolar narrowing, and mild pigment mottling of the macula. ERG and EOG were moderately attenuated. Visual fields by Goldman perimetry were within normal limits. Tilorone HCl, like chloroquine, may be an antioxidant that affects the free radical scavenging mechanism of the retinal pigment epithelium. Extensive testing should be done on all patients taking tilorone HCl in order to detect the initial manifestations of retinopathy.

Keratopathy after oral administration of tilorone hydrochloride.

Two patients given tilorone HCl orally for varying periods of time had clinical and histopathologic ocular changes. Retrospective study of 14 cancer patients who were taking tilorone HCl orally revealed that three patients had similar ophthalmic findings accompanied by the appearance of blue halos around pinpoint light sources. Examination revealed a diffuse clouding of the epithelium sometimes associated with subepithelial infiltrates. Abnormalities seen histologically included cloudy swelling of the epithelium and cytoplasmic inclusions. By electron microscopy these were found to be myelinoid bodies. Gas chromatography and mass spectrophotometry showed that tilorone HCl was present in the cornea and conjuctiva. Visual acuity was not affected and these changes were slowly reversible with the cessation of therapy. Biomicroscopic and conjunctival cytologic examination may serve to indicate the drug's storage and potential damage in the body.

Therapeutic trial of tilorone in ALS: lack of benefit in a double-blind, placebo-controlled study.

Sixteen patients with amyotrophic lateral sclerosis (ALS) participated in a double-blind, placebo-controlled study using tilorone hydrochloride, a drug active against a variety of DNA and RNA viruses in animals. On the basis of neurologic examination, pulmonary function studies, quantitative muscle examination, speech recording, and periodic filming of functional muscle strength, it was concluded that at a dose of 1 gm per week, tilorone did not alter the course of ALS.

Induction of morphological transformation in mouse C3H/10T1/2 clone 8 cells and chromosomal damage in hamster A(T1)C1-3 cells by cancer chemotherapeutic agents.

Various cancer chemotherapeutic agents including alkylating agents, antimetabolites, and antibiotics or natural products were studied for their ability to produce morphological transformation in the C3H/10T1/2 clone 8 mouse cell line and chromosomal damage in the A(T1)C1-3 hamster cell line following a 24-hr exposure of each agent at different concentrations. Those drugs that were known to be carcinogenic in vivo also produced morphological transformation and chromosomal damage, whereas those agents that have not been shown to be carcinogenic in vivo produced neither transformation nor chromosomal lesions. The concentrations used for these studies were in general similar to those actually reached in the plasma of patients treated with these same drugs for malignant, as well as certain nonmalignant, conditions.

Necrotic myelopathy (myelomalacia) in rats with allergic encephalomyelitis treated with tilorone.

Necrosis of the spinal cord was produced by administering tilorone to rats before or during the incubation period of experimental allergic encephalomyelitis (EAE). Under slected conditions of dose and timing, the drug delayed onset of clinical signs but did not prevent progression to paralysis. The lymphocytic component of the inflammatory lesions was reduced, but this was accompanied by a dramatic increase of monocytes in the spinal cord, followed by softening (myelomalacia). This new variant of EAE simulates necrotic myelopathy in man. The similarity provides support for an autoimmune etiology of the latter. Furthermore, the inverse relation between lymphocytic cuffs around vessels and massive monocytic infiltration of the cord adds to the growing evidence that lymphocytic cuffs protect the neural parenchyma by "vascular blockade."