Development of Prodrug-Payloads for Targeted Therapeutic Applications of Platinum-Acridine Anticancer Agents.

A synthetic platform has been developed that provides access to platinum(IV) prodrugs of highly cytotoxic platinum-acridine anticancer agents and allows them to be incorporated into conjugation-ready prodrug-payloads (PPLs). The PPLs can be conveniently assembled in highly efficient microscale reactions utilizing strain-promoted azide-alkyne cycloaddition chemistry. Model reactions were performed to study the stability of the PPLs in buffers and media and to assess their compatibility with cysteine-maleimide Michael addition chemistry. Amide coupling was a successful strategy to generate a conjugate containing integrin-targeted cyclo[RGDfK] peptide. Reactions with ascorbate were performed to mimic the reductive activation of the PPLs and the latter conjugate, and a cyanine (Cy5) fluorophore-labeled PPL was used to probe the reduction of platinum(IV) in cancer cells by confocal microscopy. The PPL concept introduced here should be evaluated for treating solid tumors with PAs using cancer-targeting vehicles, such as antibody-drug conjugates.

Novel Cyclopentaquinoline and Acridine Analogs as Multifunctional, Potent Drug Candidates in Alzheimer's Disease.

A series of new cyclopentaquinoline derivatives with 9-acridinecarboxylic acid and a different alkyl chain length were synthesized, and their ability to inhibit cholinesterases was evaluated. All designed compounds, except derivative 3f, exhibited a selectivity for butyrylcholinesterase (BuChE) with IC50 values ranging from 103 to 539 nM. The 3b derivative revealed the highest inhibitory activity towards BuChE (IC50 = 103.73 nM) and a suitable activity against AChE (IC50 = 272.33 nM). The 3f derivative was the most active compound to AChE (IC50 = 113.34 nM) with satisfactory activity towards BuChE (IC50 = 203.52 nM). The potential hepatotoxic effect was evaluated for both 3b and 3f compounds. The 3b and 3f potential antioxidant activity was measured using the ORAC-FL method. The 3b and 3f derivatives revealed a significantly higher antioxidant potency, respectively 35 and 25 higher than tacrine. Theoretical, physicochemical, and pharmacokinetic properties were calculated using ACD Labs Percepta software. Molecular modeling and kinetic study were used to reveal the mechanism of cholinesterase inhibition in the most potent compounds: 3b and 3f.

Arborinine, a potential LSD1 inhibitor, inhibits epithelial-mesenchymal transition of SGC-7901 cells and adriamycin-resistant gastric cancer SGC-7901/ADR cells.

Arborinine is a natural product isolated from G. parva leaf extracts, which displays potentially antiproliferative activity against human cervical cancer cells. In contrast, its anticancer effects against gastric cancer cells and drug-resistant gastric cancer cells remain unknown. In this work, arborinine was evaluated as a broad-spectrum antiproliferative agent, and it exhibited potently inhibitory activity against NCI-N87 (IC50 = 5.67 µM), BGC-823 (IC50 = 7.26 µM), MGC803 (IC50 = 4.75 µM), SGC-7901 (IC50 = 1.96 µM), HGC-27 (IC50 = 5.70 µM), SGC-7901/ADR (IC50 = 0.24 µM), SGC-7901/VCR (IC50 = 1.09 µM), and MGC803/PTX (IC50 = 1.32 µM) cell lines. Subsequent target verification experiments demonstrated that arborinine selectively and reversibly inhibited LSD1 in a time-dependent manner. Furthermore, it was found that arborinine suppressed the epithelial-mesenchymal transition of gastric cancer cell line SGC-7901 and adriamycin-resistant gastric cancer cell line SGC-7901/ADR in a dose-dependent manner. The in vivo antitumor study further indicated that arborinine can significantly reduce the growth of tumors both in SGC-7901 and SGC-7901/ADR xenograft mouse models. Overall, we demonstrated the potential of arborinine as an effective treatment for gastric cancer and adriamycin-resistant gastric cancer.

[Cycloferon efficacy in treatment of upper respiratory tract infections: systematic review and meta-analysis]. / Klinicheskaia éffektivnost' tsikloferona pri infektsiiakh verkhnikh dykhatel'nykh putei. Sistematicheskii obzor i metaanaliz.

Medical scientific sources about randomized clinical trials of Cycloferon were studied as a single plot of 531 articles. AIM was to get the generalized cycloferon efficacy's assessment in comparison with basic therapies curing the otorhinolaryngologic diseases. Groups heterogeneity and responding parameters' variability were estimated also. Comparison groups were symmetric enough to annihilate end-point variabilities, so the results' interpretations were clear enough and vector of clinical effects was detectable. Comparison groups were integrated to increase statistical power of metaanalysis. In result, cycloferon additional administration in treatment of otorhinolaryngologic diseases added 25% to absolute and relative usefulness of medical intervention. Also cycloferon increased 3,5 times the chances of recovery and absence of recurrent exacerbation.

Amustaline (S-303) treatment inactivates high levels of Chikungunya virus in red-blood-cell components.

BACKGROUND AND OBJECTIVES: Chikungunya virus (CHIKV) infections have been reported in all continents, and the potential risk for CHIKV transfusion-transmitted infections (TTIs) was demonstrated by the detection of CHIKV RNA-positive donations in several countries. TTIs can be reduced by pathogen inactivation (PI) of blood products. In this study, we evaluated the efficacy of amustaline and glutathione (S-303/GSH) to inactivate CHIKV in red-blood-cell concentrates (RBCs). MATERIAL AND METHODS: Red-blood-cells were spiked with high level of CHIKV. Infectious titres and RNA loads were measured before and after PI treatment. Residual CHIKV infectivity was also assessed after five successive cell culture passages. RESULTS: The mean CHIKV titres in RBCs before inactivation was 5·81 ± 0·18 log10 50% tissue culture infectious dose (TCID50 )/mL, and the mean viral RNA load was 10·49 ± 0·15 log10 genome equivalent (GEq)/mL. No CHIKV TCID was detected after S-303 treatment nor was replicative CHIKV particles and viral RNA present after five cell culture passages of samples obtained immediately after S-303 treatment. CONCLUSION: Chikungunya virus was previously shown to be inactivated by the PI technology using amotosalen and ultraviolet A light for the treatment of plasma and platelets. This new study demonstrates that S-303/GSH can inactivate high titres of CHIKV in RBCs.

[CLINICAL EFFICIENCY OF CYCLOFERON IN CHILDREN AND ADULTS WITH HIV AND/ OR HERPES INFECTION: SYSTEMATIC REVIEW AND META-ANALYSIS].

Aim was to estimate and compare clinical efficiency of cycloferon use against basic therapy in treatment of HIV and/ or herpes infection. There were comparisons of treatment results with patient (n=1274) groups' heterogeneity taken into account. 9 randomized clinical trials with cycloferon efficacy data were mobilized, in all studies there were protocols of injections, tablets or liniments cycloferon administration. Homogeneous and symmetric groups combination during meta-analysis increased statistic power of comparisons and led to integrative efficiency assessment, proved its' stability in statistic models. Cycloferon use in children and adults with HIV and/ or herpes infection was more the 3 times more effective to provide stable remission and exacerbation frequency diminish against basic therapy.

Acridin-3,6-dialkyldithiourea hydrochlorides as new photosensitizers for photodynamic therapy of mouse leukemia cells.

Acridin-3,6-dialkyldithiourea hydrochlorides (AcrDTUs) have been evaluated as a new group of photosensitizers (PSs) for photodynamic antitumor therapy (PDT). Mouse leukemia cells L1210 were used for testing of AcrDTUs as the new PSs. The irradiation (UV-A light (365 nm), 1.05 J/cm(2)) increased cytotoxicity of all derivatives against L1210 cells more than ten times. The highest photocytotoxicity was found for propyl-AcrDTU with IC50=0.48±0.03 µM after 48 h incubation. A generation of the superoxide radical anion upon UV-A irradiation of propyl-AcrDTU was confirmed by in situ photochemical EPR experiments. To explain a mechanism of photocytotoxic action of AcrDTUs, an intracellular distribution of propyl-AcrDTU has been studied. It was found that AcrDTU in non-irradiated cells was not present in their nucleus but in the lysosomes and partly in the mitochondria, and sequestration of propyl-AcrDTU was dependent on pH in lysosomes. After irradiation, the cell death was induced by oxidative damage of lysosomal and mitochondrial membranes. Concerning the cell cycle, flow cytometry after PDT with propyl-AcrDTU showed a significant increase of the cells in the subG0 phase. Observed signs of necrosis, apoptosis, and autophagy indicate that PDT/AcrDTU leads to multiple cell death types (caspase independent apoptosis, necrosis, and autophagy).

Pyrrolidine-Acridine hybrid in Artemisinin-based combination: a pharmacodynamic study.

Aiming to develop new artemisinin-based combination therapy (ACT) for malaria, antimalarial effect of a new series of pyrrolidine-acridine hybrid in combination with artemisinin derivatives was investigated. Synthesis, antimalarial and cytotoxic evaluation of a series of hybrid of 2-(3-(substitutedbenzyl)pyrrolidin-1-yl)alkanamines and acridine were performed and mode of action of the lead compound was investigated. In vivo pharmacodynamic properties (parasite clearance time, parasite reduction ratio, dose and regimen determination) against multidrug resistant (MDR) rodent malaria parasite and toxicological parameters (median lethal dose, liver function test, kidney function test) were also investigated. 6-Chloro-N-(4-(3-(3,4-dimethoxybenzyl)pyrrolidin-1-yl)butyl)-2-methoxyacridin-9-amine (15c) has shown a dose dependent haem bio-mineralization inhibition and was found to be the most effective and safe compound against MDR malaria parasite in Swiss mice model. It displayed best antimalarial potential with artemether (AM) in vitro as well as in vivo. The combination also showed favourable pharmacodynamic properties and therapeutic response in mice with established MDR malaria infection and all mice were cured at the determined doses. The combination did not show toxicity at the doses administered to the Swiss mice. Taken together, our findings suggest that compound 15c is a potential partner with AM for the ACT and could be explored for further development.

[HUMAN CYTOMEGALOVIRUS INFECTION AND SPONTANEOUS ABORTION IN PREGNANT WOMEN OF I AND II TRIMESTER].

The goal of this work was the evaluation of the frequency of human CMV infection among the women, whose pregnancy ended in miscarriage, detection of active forms of infection and treatment before pregnancy. Virological and sero-immunological techniques were used. A total of 116 women who had miscarriages before the 28 week of pregnancy were submitted to the CMV test. 109 women (94.0%) demonstrated positive results. 49 women (42.2%) had active form of the cytomegalovirus infection. 13 women (26.5%) had the recurrent form and 36 patients (73.5%) had the persistent form of CMV infection (stage of productive replication). All the women with active CMVI were treated before the next pregnancy. Immunomodulatory therapy for the treatment was used.

Pathways of apoptosis regulation in hepatocytes induced by first-line antitubercular drugs.

We studied pathways of apoptosis regulation during experimental hepatopathy caused by treatment with antitubercular drugs and involvement of some hepatoprotectors and immunomodulators in the regulation of hepatocyte apoptosis induced by antitubercular drugs. The intensity of apoptosis and expression of apoptosis-associated molecules were evaluated. It was shown that antitubercular drugs induce apoptosis in hepatocytes by triggering external signaling pathway and p53-dependent signaling pathway and simultaneously reducing the level of anti-apoptotic Bcl-2 protein. Runihol, remaxol, and cycloferon reduced degenerative effects in the liver, though the level of apoptosis remained high. Ademetionine in tablets and reamberin improved the microstructure of the liver by inhibiting both apoptotic pathways induced by the antitubercular drugs; in other words, they have distinct hepatoprotective and apoptosis-protective effects, which is especially important at the late stages of ontogeny.

[Immunomodulator Intensification of Etioropic Therapy in Patients with Advanced Pulmonary Tuberculosis].

The study was aimed at possible increase of the therapy efficacy in patients with advanced tuberculosis by including immunomodulators to the treatment schemes. The data concerning 6034 patients with advanced tuberculosis, mainly fibrocavernous tuberculosis of the lungs, were analysed. Four groups of the patients were randomized. In group 1 the management of the patients included etiotropic therapy and some treatment and rehabilitation measures with the use of Cycloferon. The group 2 patients in addition to the etiotropic therapy and some treatment and rehabilitation measures were given Omega-3. In group 3 the management included the etiotropic therapy and some treatment and rehabilitation measures. In group 4 the etioropic therapy was used alone. The analysis showed that 3419 patients had primary pulmonary tuberculosis, 340 patients had relapsing tuberculosis and 2275 patients had long-term process. The etiotropic therapy efficacy was estimated after an intensive phase of not more than 3 months. In the cases with Mycobacterium tuberculosis drug resistance and some other unfavourable factors it was estimated after a 5-month intensive phase. The results confirmed that inclusion of immunomodulators to the treatment schemes allowed to increase the therapy efficacy and the patients' adherence to the treatment, as well as to shorten the period of the bacteria carriage. Thus, the use of Cycloferon in the schemes of the treatment of the patients with fibrocavernous pulmonary tuberculosis allowed to shorten the period of the pathogen carriage (as well as the drug resistant forms) in 94.1 ± 3.33% of the patients in spite of concomitant diseases. The effect of Cycloferon in such cases was likely due to both its direct immunoprotective action and the improvement of the general state of the patients and their higher adherence to the treatment.

[Kinetics of Virus Load HCV-RNA in Blood Serum and Peripheral Mononuclear Cells in a Patient with Hepatocirrhosis and Chronic Virus Hepatitis C Termination Treated According to Noninterferon Treatment Scheme (Cycloferon + Ribavirin)].

A clinical case of hepatocirrhosis with chronic hepatitis C termination (1b genotype) is described. Taking into account the cirrhotic stage of the disease, the extrahepatic HCV replication in the peripheral mononuclears, unfavourable HCV genotype, infavourable IL-28B gene polymorphism, inefficiency of the previous two courses of the standard antiviral therapy (PegIFN + ribavirin) and secondary immune deficiency, noninterferon antiviral therapy for 24 weeks was used in the treatment of the patient: interferon-inductive therapy with cycloferon in combination with ribavirin. There was observed by the 12th week of the treatment biochemical remission and a significant decrease of the virus load from 1 x 10(7) IU/ml to 7 x 10(5) IU/ml in the blood serum and from 1.35 x 10(7) IU/ml to 8 x 10(5) IU/m in the peripheral mononuclears. Investigation of the molecular biological markers of the viremia (PCR HCV-RNA) in the cells of peripheral mononuclears is an obligatory diagnostic technology in cases with suspected extrahepatic HCV infection. The kinetics of the virus load and the positive dynamics of the immunological indices in the patient at the cirrhotic stage of chronic virus hepatitis C are indicative of the efficient etiopathogenic approach with the use of the noninterferon treatment scheme (cycloferon + ribavirin), when recombinant interferons are contraindicated.

Acridone acetic acid, sodium salt, as an agent to stop vitiligo progression: a pilot study.

Vitiligo progression is attributed to immune system malfunctioning, thus immunomodulating compounds might be beneficial in stopping vitiligo progression which is a prerequisite for successful repigmentation. The goal of this study was to assess efficacy of acridone acetic acid, sodium salt (Na-AAA), an immunomodulating compound with favorable safety profile, in stabilizing active vitiligo, and to reveal prognostic factors of treatment outcome. Sixty consecutive patients with progressing nonsegmental vitiligo were treated with 10 i.m. injections of Na-AAA every other day. Disease stability was assessed in 1, 3, 6, and 12 months post-treatment. Statistical analysis was applied to correlate treatment outcome and available clinical parameters. Of the 60 patients treated, vitiligo stopped progression in 44 patients (73.3%). Older age (p = 0.0219), age of 35 and older (p = 0.0189, odds ratio (OR) = 5.2, 95% confidence interval (CI) 1.30-20.84) or age of 40 and older (p = 0.0039, OR = 6.48, 95% CI 1.86-22.61), longer disease duration (p = 0.0234), pre-treatment interleukin-6 level over 2 pg/mL (p = 0.0005, OR = 13.7, 95% CI 2.97-63), and over the reference threshold value 5.9 pg/mL (p = 0.0009, OR = 25.8, 95% CI 2.8-239) as well as presence of other autoimmune diseases (p = 0.038, OR = 7.0, 95% CI 1.14-42.97) were negative prognostic factors of treatment success. In conclusion, acridone acetic acid, sodium salt, emerges as an efficient option for stopping vitiligo progression.

[Pharmacological prophylaxis and treatment of recidivating respiratory disorders in children].

Interferon is the most important mediator of natural immunity, which suggests the use of interferon inducers as therapeutic and preventive agents in the treatment of acute respiratory diseases (ARDs) in children classified into a group of sickly and repeated-ARD patients. The article describes cycloferon--a drug belonging to the group of endogenous interferon inductor--and its mechanism of action, shows its prophylactic and therapeutic efficacy in children with recurrent ARDs. The clinical and pharmacological effectiveness of cycloferon has been confirmed by studying the proteomic profiles of blood plasma in sickly children.

[Using cycloferon in the complex treatment of herpetic infection in patients with atopic dermatitis].

Clinical efficacy of including cycloferon liniment in combined treatment of herpetic infection in a group of 40 patients with atopic dermatitis has been analyzed. It is concluded that the administration of cycloferon favors dynamic disappearance of general infectious syndrome, reduces timeline of rash as well as length of local inflammation, accelerates epithelization of erosions (on the average 1.2 - 1.4 times, p < 0.05), decreases frequency of recurrent infections, and reduces the level of pro-inflammatory cytokines in the blood of patients.

[Application of immunomodulators in the treatment of mandibular fractures in elderly patients with incomplete secondary adentia].

The aim of the work was to study the experience of using complex pharmacotherapy in the treatment of mandibular fractures in elderly patients with incomplete secondary periodontitis, which were divided into two groups. In the first group, patients (n = 46; average age 69.0 ± 3.6) were treated using the authors' original device combined with application of antimicrobial MetrogilDenta gel onto gums two times a day during ten days. Patients in the second group (n = 52; average age 61.0 ± 3.1) were treated with the same device combined with (i) application of MetrogilDenta antimicrobial gel onto gums two times a day during ten days, (ii) application of 1.5 ml of Cycloferon 5% liniment by cotton pellet for 20 min during the same 10 days (30 minutes after the antimicrobial gel), and (iii) intramuscular injections of 6 mg of synthetic immunomodulator Polyoxidonium once a day for 3 days, then once every two days (for a total of 17 days). It is established that the use of the combination of interferon inducers of immunomodulator group--Cycloferon in the form of liniment and synthetic immunomodulator Polyoksidonium together with MetrogilDenta antimicrobial gel--led to the most pronounced regression of inflammatory and destructive processes in periodontal tissues (in 7.1%, d = 0.05), optimized the state of local immunity of the oral cavity, and normalized microflora in periodontal pockets in elderly patients with incomplete secondary adentia.

[The therapeutic efficacy of cycloferon and the pharmacological activity of interferon inducers].

The review describes endogenous interferon inductors that belong to antiviral drugs and contain different chemical compounds. Among the groups identified by the authors, there are promising and most effective medicines inducing different types of interferon in the body, as well as their mechanism of action. The paper shows the synthesis of endogenous interferon and the level of its accumulation in the organs and tissues. The clinical effects of methylglucamine acridonacetate (cycloferon) are depicted in patients with major viral (influenza, acute respiratory viral and arboviral infections, and viral hepatitis) and bacterial (brucellosis, tuberculosis) infections, or endometrial hyperplastic processes. Cycloferon is shown to be used as an etiotropic and antipathogenic drug.

[Pulmonary vasculitis as a clinical mask of HCV infection: efficiency of interferon-free antiviral therapy].

The paper describes a clinical case of pulmonary vasculitis caused by hepatitis C virus (HCV). Its diagnosis was established on the basis of in-depth laboratory testing and an investigation of the molecular biological markers of viremia (polymerase chain reaction--PCR--HCV RNA) in peripheral blood mononuclear cells. By taking into account of extrahepatic HCV replication and contraindications to interferon therapy, the female patient was given an interferon-free antiviral therapy cycle using an interferonogenic inductor in combination with ribavirin. Pathogenic therapy (methylpred and ursodeoxycholic acid) was additionally performed. An interferon-free regimen of cycloferon + ribavirin led to sustained remission of HCV infection running with its systemic manifestations. The therapy could improve the function of not only the liver, but also the lung. In suspected extrahepatic HCV infections, an investigation of molecular biological markers for viremia (HCV RNA PCR) in the peripheral blood mononuclear cells is an essential diagnostic technique. Interferonogenic inductors, cycloferon in particular, should be used in combination with ribavirin when a chronic hepatitis C patient with the extrahepatic manifestations of HCV infection has contraindications to conventional therapy with recombinant interferon-α.

[Cycloferon and management of herpes virus infection].

The treatment of patients with various forms of herpes requires a complex approach with using chemo- and immunotropic drugs. The use of Cycloferon, an interferon inductor (12.5% injection solution, 150 mg tablets or 5% liniment) was shown efficient. It had antiviral and immunotropic action in the mono- and combination therapy of herpes simplex of the skin and mucosa, genital herpes, ophthalmoherpes, herpes zoster, infectious mononucleosis. Cycloferon lowered the level and period of the disease clinical signs, prolonged the remission, corrected the immunity shifts, prevented the complications. The results of the study presented a conclusive proof for recommending such a use of Cycloferon in wide medical practice.

[Meglumine acridonacetate and complex therapy of patients with newly identified advanced pulmonary tuberculosis].

Clinical and immunological efficacy of meglumine acridonacetate (cycloferon) tablets was evaluated in complex treatment of patients with newly diagnosed advanced pulmonary tuberculosis. It was shown that the use of cycloferon according to our scheme increased the efficacy of the therapy (earlier disappearance of the disease symptoms and bacteria isolation, shorter-terms of cavern healing, more pronounced positive radiographic dynamics vs. the patients under the etiotropic therapy). The use of cycloferon normalized the number of gamma interferon receptors, increased the gamma interferon serum levels, reduced the incidence of the side effects (liver damage) due to the use of TB drugs. Such a use of cycloferon was cost effective. The use of sycloferon is possible in the complex treatment of outpatients with advanced pulmonary tuberculosis.